PATENT IN THE UNITED STATES PATENT AND TRADEMARK OFFICE

In re United Patentee(s) Assignee Issue Date

States : Edward : Trustees

Patent

No.

5,344,932 Attn: Mail Stop Patent Ext.

C. Taylor of 6, Princeton 1994

University

: September
LETTER

OF TRANSMITTAL

OF APPLICAT;CON TJ.ZR&l

!

:::L‘ -:

FOR EXTENSION

OF PATENT

.iI ‘._ -, z- 4 : -.

Commissioner for Patents P.0, Box 1450 Alexandria, VA 22313-1450 Sir: Transmitted herewith for filing is an application for extension of term of U.S. Patent No. 5,344,932 and a duplicate thereof, certified as such. Please charge the filing fee of $1,120 to deposit account No. 05-0840 in the name of Eli Lilly and Company. An original and two copies of this paper are enclosed. The Commissioner is hereby authorized to charge any additional fees which may be required or credit any overpayment to account No. 05-0840. The application transmitted herewith has been executed by the undersigned agent of the owner of record of the subject patent., Therefore, the present application is complete and entitled to a filing date of March 19, 2004, as indicated by the Certificate of Mailing by "Express Mail". ELI By: LILLY
65-I

AND COMPANY

Eli Lilly and Company Patent Division P-0. Box 6288 Indianapolis, Indiana

.I' V Elizfabeth A. McGraw Attorney for Applicant Registration No. 44,646 317-277-7443 Phone:

46206-6288

PATENT IN TEE UNITED STATES PATENT AND TRAD=ARlf In re United Patentee(s) Assignee Attn Issue Date States : : : : Patent No. 5,344,932 Univer OFFICE

Edward C. Taylor Trustees of Princeton Mail Stop Patent Ext. September 6, 1994

REQUEST FOR IZXTENSION OF PATENT TERM UNDER 35 U.S.C. 156 Commissioner for Patents P.O. Box 1450 Alexandria, VA 22313-1450 Sir: Competition Pursuant to and Patent Section 201(a) of Term Restoration the Act Drug Price of 1984, 35 U.S.C.

156, Eli Lilly and Company, agent of the patent owner, by grant of an exclusive license to the patent, hereby requests an extension of the patent term of U.S. Patent No. 5,344,932 (hereinafter 5,344,932" variously or referred to either as "U.S. Patent No. "the '932 patent"). in accordance,with follows the The following 35 U.S.C. 156(d) numerical format set information and 37 C.F.R. forth in 37

is submitted 1.710 D- seq. and et C.F.R. I.740 (a): (1) product structure

A complete

identification chemical

of and generic

the

approved name, physical

as by appropriate or characteristics:

The approved product is pemetrexed, which has the chemical name, as assigned by Chemical Abstracts, L-Glutamic acid, ~-[4-[2-(2-amino-4,7-dihydro-4-oxo-l~-pyrrolo[2,3dlpyrimidin-5-yl)ethyl]benzoyl]-. Pemetrexed has the following structure:

in the product Alimta@ as Pemetrexed is the active ingredient can be seen from the Product Information sheet, e.g. lines 1216, which is attached as Exhibit I. Pemetrexed can exist in multiple tautomeric forms, see e.g. column 1, lines 48-55 of United States patent number 5,344,932. The aforereferenced nomenclature is in no way to be interpreted as limiting the protection of the drug product pemetrexed.
(2) A complete identification provision of the of Federal law under which

statute including the the regulatory review

applicable occurred:

The regulatory review occurred under Section 505 of the Federal Food, Drug and Cosmetic Act (FFDCA), 21 U.S.C. 301 Section 505 provides for the submission and approval et -- seq. of new drug applications (NDAs) for human drug products meeting the definition of "new drug" under Section 201(p) of the Act..
(3) product received provision review under the regulatory An identification permission for of the date the on which marketing applicable the or use

commercial

of law under which period occurred:

Pemetrexed was approved by the Food and Drug Administration (FDA) for commercial marketing pursuant to Section 505 of the FFDCA on February 4, 2004.
(4) In the case of a drug product, au

identification of each active ingredient in the product and as a statement that it has not been to each active ingredient, previously approved for ccxmercial marketing or.use under the Federal Food, Drug, and Cosmetic Act, the Public Health Service Act, or the Virus-Serum-Toxin Act, or a statement of 2

when the

active

ingredient (either the law under

was approved

for

commercial

marketing or use active ingredients), the provision of

alone or in co&&nation with other use for which it was approved, and which it was approved.

The active ingredient in the product Alimtae is Pemetrexed had not previously been approved for pemetrexed. commercial marketing or use under the Federal Food, Drug and Cosmetic Act, the Public Health Service Act, or the VirusApproval under the Federal Food, Drug and Serum-Toxin Act. Cosmetic Act was received on February 4, 2004 for the use of pemetrexed in combination with cisplatin for the indication of malignant pleural mesothelioma under Section 505 of the FFDCA.
(5) submitted pursuant last day
A

statement

that

the

application

is

being

within the to §1.720(f) on which the

sixty day period permitted and an identification of application could

for submission the date of the

be submitted:

The product was approved on February 4, 2004. The last day within the sixty day period permitted for submission of this application for extension of a patent is April 4, 2004. As this application is being hand-carried to the Office of Patent Legal Administration (Crystal Plaza 3, 3D09) on March 19, 2004, this application is timely filed within the permitted sixty day period.
(6) A complete identification of the patent for date

which an extension is being sought by the name of the the patent number, the date of issue, and the inventor,

of expiration: The patent for which extension 5,344,932 U.S. Patent No.: Edward C. Taylor Inventor: Issued: September 6, 1994 September 6, 2011 Expires:
(7)
A

is being

sought

is:

copy

of the patent
the entire

for

which

au extension (including

is

being sought, including claims) and drawings:

specification

3

V.L.

--u-e**

-.-

.

-,--

.

attached

A com plete copy of U.S. hereto as Exhibit II.
(8)
A copy

Patent

No. 5,344,932

is

of

any

disclaimer, fee in the

certificate payment, patent: or

of

correction, reexam ination

receipt

of

xnaintenance issued

certificate

A copy of the receipt of m aintenance fee paym ent certificate No disclaim er, attached hereto as Exhibit III. or reexam ination certificate has issued in correction, connection with the '932 patent.
(9) product,! or A statement of which the that using or lists mannex the patent each in claims the at or least the

is of

approved

a method

manufacturiug applicable which

approved patent one such of

and a showing product, claim and demonstrates patent using

claim reads on the approved OF manufacturing the approved

product product:

a method

Claims 1 and 7 The '932 patent contains 7 claims. claims 2-6 are independent claims; each one of rem aining depends directly from Claim 1. Claims 1, 2, 3 and 7 recite genus or species claims which read on the active ingredient contained in the approved product, pem etrexed. recites a For exam ple, Claim 1 of the '932 patent com pound as follows: Claim 1. A com pound of the form ula:
0 * II i-H&H-RklHCHCH,CH,C--OR2 I CH Ian $-OR’ A 0 0 II

piR 5/ C *N’ C y-

in which: R1 is -OH or -MHz;

R2 is hydrogen or a pharmaceutically acceptable cation; R3 is X,4-phenylene unsubstituted or substituted with chloro, fluoro, methoxy, or trifluoromethyl; methyl, R4 is hydrogen, or methyl; R5 is amino; and the configuration about the carbon atom designated * is S. Specifically, pemetrexed is read upon when R1 is OH, R2 is a pharmaceutically acceptable cation, R3 is Thus, Claim unsubstituted 1,4-phenylene, and R4 is hydrogen. 1, reads on pemetrexed. Claims 2, 3 and 7 each reads on the active ingredient contained in the approved product.

(10) relevant order to the agglicable

A statement

beginning

on a new page

of

the in or the

dates and information enable the Secretary of Agriculture, review regulatory

pursuant of Health period

to 35 U.S.C. 156(g) and Iiuman Semites to determine

Secrcstary

as appropriate, ae follows:

(i) For a patent claiming a human drug, antibiotic, or human biological product, the effective date of the investigational new drug (TM)) application and the IND number; the date on which Application a new drug (PLA) application on which the (MDA) or.a submitted, Product and the or NDA License was initially

or PLA number and the date the Product License issued;

NDA was apptOVed

(ii) For a patent claiming a new animal drug, the d date a major health or environmental effects test on the drug was initiated and any available substantiation of that date, or the date an exemption under subsection (j) of Section 512 of the Federal Food, Drug, and Cosmetic Act became effective for such animal drug; the date on which a new animal drug application (NADA) was initially submitted and the NADA number; and the date on which the NADA was approved; (iii) For a patent claiming a veterinary biological product,. the date the authority to prepare an experimental biological product under the Virus-Serum-Toxin Act became effective; the date an application for a license was submitted under the Virus-Serum-Toxin Act; and the date the license issued; (iv) For,.a patent claiming a food or color additive, the date a major health or environmental effects test on the additive was initiated and any available substantiation of that date; the date on which a petition for product approval under the Federal Food, Drug, and Cosmetic Act was initially submitted and the petition number; and the date on which the FDA published a Federal Register notice listing the additive for use; (v) For a patent claiming a medical device, the effective date of the investigational device exemption (IDE) and the IDE number, if applicable, or the date on which the 6

applicant began the first clinical if no IDE was submitted, device, substantiation of that date; the for product approval or notice of development protocol under section Drug, and Cosmetic Act was initially of the application; and the date approved or the protocol declared

investigation involving the and any available date' on which the application completion of a product 515 of the Federal Food, submitted and the number on which the application was to be completed:

--__---.

_-..--_.

--_-.___-

- ---.---..----

--

7

On July

8‘ 1992

Eli

Lilly

and Company, the

submitted to the FDA a "Notice of pemetrexed, Investigational Exemption for a New Drug" (IND) under Section 505(i) of the FFDCA to permit the interstate shipment of LY231514 disodium (now known as pemetrexed) for the purpose of conducting clinical studies to support the approval of a A copy of the letter subsequent NDA for pemetrexed. transmitting the IND to the FDA is attached hereto as Exhibit IV. The FDA acknowledged receipt of the IND, and assigned the IND number 40,061. On August 24, 1992, during a I teleconference, Eli Lilly and Company was notified by the FDA that clinical investigation of compound LY231514 disodium may be initiated simultaneously upon submission of certain information. A confirmation letter was received from the FDA in writing the FDA by Lilly on September 11, 1992, reiterating position in the teleconference of August 24th. A copy of the Liliy provided the letter is attached hereto as Exhibit VI. FDA with information requested on September 10, 1992, and administered the first human dose of LY231514 disodium on September 29, 1992. Copies of these letters are attached As the clinical hereto as Exhibits V and VI, respectively. investigation of pemetrexed was allowed to be initiated simultaneously upon submission of the information requested, which information was submitted on September 10, 1992. Therefore, review period" the,beginning of the "regulatory under 35 U.S.C. 156(g)(l) is September 10, 1992, the effective date of an exemption under Section 505(i). Eli Lilly and Company submitted an NDA for pemetrexed, NDA 21-462, as a "rolling" submission as per the Fast Track Designation for Alimta granted by the FDA on June was 10, 2002. The final stage, stage D, of the NDA submission Copies of the letters submitted on September 29, 2003. transmitting all four stages (A through D) of the NDA are Stage D of the NDA submission attached hereto as Exhibit VII. was received by the FDA on September 30, 2003 as indicated by Exhibit VIII. Thus, for the purpose of the "regulatory review period" under 35 U.S.C. 156(g)(l), September 29, 2003, is the 8

NDA owner of Claimed

- _.- -

-____.-_ -

.

-,

date the new drug application for pemetrexed was initially submitted under Section 505. The NDA described above was approved on February 4, 2004. Attached as Exhibit IX is a letter dated February 4, 2004, from the FDA to Eli Lilly and Company approving the NDA for pemetrexed. Thus, for the purpose of the."regulatory review period" under 35 U.S.C. 156(g)(l), February 4, 2004 is the date of approval of the NDA application for pemetrexed submitted on September 29, 2003.

(11) A brief description beginning on a new p%ge of the significant activities undertaken by the marketing applicant during the applicable regulatory review period with respect to the approved prodtaot and the significant dates applicable to such activities: During the applicable regulatory review period, Eli Lilly and Company was actively involved in obtaining NDA approval for pemetrexed. As discussed in Section (IO) above, the IND f:or pemetrexed was submitted on July 8, 1992, the NDA was a rolling submission which was finally submitted on September 29, 2003, and the NDA was approved on February 4, 2004. Eli Lilly and Company was in close consultation with the FDA during the clinical studies conducted under the IND. Similarly, subsequent to the submission of the NDA, Eli Lilly and Company had numerous contacts and meetings with the FDA with respect to the NDA approval. The description of significant activities undertaken by Eli Lilly and Company with respect to pemetrexed during the applicable regulatory review period as set forth in Exhibit X attached hereto is illustrative of the activities undertaken.

10

(12) the opinion of extension claimed,

A statement the applicant

beginning the patent

on a new page is eligible

that for

in. the

and a statement as to the length of including how the length of extension

extension was determined:

(a) Statement regarding eligibility of the '932 patent for extension under 35 U.S.C. 156(a): Section 156(a) provides, in relevant part, that the term of a patent which claims a product, a method of using a product, or a method of manufacturing a product shall be extended from the original expiration date of the patent if (1) the term of the patent has not expired before an application for extension is submitted, (2) the term of the patent has never been extended, (3) the application for * extension is submitted by the owner of record of the patent or its agent in accordance with 35 U.S.C. 156(d), (4) the product has been subject to a regulatory review period before its commercial marketing or use, and (5) the permission for the commercial marketing or use of the product after such regulatory review period is the first permitted commercial marketing or use of the product under the provision of law under which such regulatory review period occurred. As described below by corresponding number, each of these elements is satisfied in the present case: (1) The term of U.S. Patent No. 5,344,932 expires on September 6, 2011. This application for patent term extension has, therefore, been submitted before the expiration of the patent term. (2) The term of the '932 patent has never been extended. (3) This application is being submitted by the NDA owner of pemetrexed who is also the agent of the owner of record of the '932 patent, as is evidenced in Exhibit XI. The applicant is the exclusive licensee of patent '932 by agreement executed between Eli Lilly & Co. and the Trustees of Princeton University on December 19, 1985. The Trustees of Princeton University are the owner of patent '932 by an Assignment recorded in the United States Patent and Trademark 11

----

-- --__-

-.--

-,-

,

Office on January 12, 1990, in Reel No. 5274, Frame No. 0016. This application is submitted-in accordance with 35 U.S.C. 156(d) in that it is submitted by the agent of the patent owner in accordance with 37 CFR 1.730(c) within the sixty day period beginning on the date, February 4, 2004, the product received permission for marketing under the FFDCA and contains the information required under 35 U.S.C. 156(d). (4) As evidenced by the February 4, 2004, letter from the FDA (Exhibit IX), the product was subject to a regulatory review period under Section 505 of the *FFDCAbefore its comercial marketing or use. the permission for the commercial (5) Finally, marketing of pemetrexed after regulatory review under Section 505 is the first permitted commercial marketing of pemetrexed. This is confirmed by the absence of any approved new drug application for pemetrexed prior to February 4, 2004. Statement as to length of extension claimed, how the length of extension was determined: The term of U.S. Patent No. 5,344,932 should be This extension was extended by 1784 days to July 25, 2016. determined as follows and as outlined in Supplemental Exhibit B(Exhibit XII). As set forth in 35 U'.S.C. 156(g) (1) and 37 C.F.R. 1.775(c), the regulatory review period equals the length of time on and between the effective date of the initial IND (September 10, 1992) and the initial submission of the NDA (September 29, 2003), a period of 4,037 days, plus the length of time between the initial submission of the NDA (September 29, 2003) to NDA approval (February 4, 20041, a period of 129 days. These two periods added together equal 4,166 days. Pursuant to 35 U.S.C. 156(c) and 37 C.F.R. 1.775 for extension shall (dl (1) (ii), the term of the patent eligible be extended by the time equal to the regulatory review period In this which occurs after the date the patent was issued. case, this is a period running from the date of patent issue, September 6, 1994, to the date of NDA approval, February 4, 2004, a period of 3,439 days. 12 (b) including

----

--_-__-

-

As discussed in paragraph (11) above and as illustrated in Exhibit X, Eli Lilly and Company was continuously and diligently working toward securing NDA As Eli Lilly and Company acted with approval for pemetrexed. due diligence during the entire period of regulatory review, the 3,439 day period calculated above as the term of the patent eligible for extension should not be reduced for lack of diligence under 35 U.S.C. 156(c)(l) or 37 C.F.R. 1.775 (d) (l)(ii). Pursuant to 35 U.S.C. 156(c)(2) and 37 C.F.R. 1.775 (d) (1) {iii), this 3,439 day period is to be reduced by one-half of the time from the effective date of the initial IND, September 29, 1992, or the date of patent issue, September 6, 1994, whichever is later, to the date of initial submission of the NDA, September 29, 2003, a period of 3,310 The 3,310 day days. One half of this period is 1,655 days. period is reduced by 1,655 days, leaving a revised regulatory period o:f 1,784 days. Pursuant to 35 U.S.C. 156(c)(3), the term remaining on the '932 patent after the date of approval of pemetrexed, February 4, 2004, when added to the revised regulatory period may not exceed fourteen years. Fourteen years Epost approval The term remaining on the patent expires on February 4, 2018. added to the revised regulatory period is July 25, 2016, which does not exceed the fourteen year limit. The period of patent term extension as calculated above is also subject to the provisions of 35 U.S.C. 156(g)(4) and 37 C!.F.R. 1.775(d)(5-6). The patent to be extended issued after, and clinical evaluation of the approved product began, Since after the enactment of the statute, September 24, 1984. commercial marketing of the drug was approved after enactment of the statute, the five year maximum on extension as provided in 35 U.S.C. 156(g)(6)(B) and 37 C.F.R. 1.775(d) (6) is for applicable. Thus, the term of the '932 patent is eligible a 1,784 day extension until July 25, 2016.

13

(13) to the disclose Secretary to any of
of

A statement the Health information entitlement

that

applicant of Patents is the material extension

acknowledges
and Trademarks or the to Secretay the

a duty
and of

Commissioner which to

and Runmu Services

Agriculture determination si1.765):

sought

(See

Applicant acknowledges a duty to disclose to the Director of the United States Patent and Trademark Office and the Secretary of Health and Human Services or the Secretary of Agriculture any information that is material to the determination of entitlement to the extension sought herein.
(IQ) upou the The prescribed for fee for (See receiving 51.20(j)): and acting

application

extension

As indicated on the letter of transmittal submitted with this application, the Commissioner of Patents and Trademarks has been authorized to charge the filing fee of $1,120.00, and any additional fees which may be required by any overpayment, to this or any other related paper, or credit and Deposit Account No. 05-0840 in the name of Eli Lilly Company..
(15) person to application for The name, patent address, and tcilsphone are to number be directed: of the

whom inquiries

and correspondence
term extension

relating

to the

Please address all correspondence to Elizabeth A. Lilly McGraw, Eli Lilly and Company, Patent Division/lZAM, Please direct Corporate Center, Indianapolis, Indiana 46285. Please telephone calls to Elizabeth A. McGraw, 317-277-7443. direct facsimiles to 317-277-1917.
(16) submission application. of In accordance with 37 C.F.R. 1.740(b),

two additional copies of the present As requested by the Office of 'Legal two additioual copies have been included, Administration, a total of four copiest

for

In addition to the present application of the patent term of U.S. Patent No. 5,344,932,
14

for extension Applicant

also total

submits herewith three additional complete of four copies of the present application.
(17) Signature subnission Requiiremkts: of proof that In the

copies,

for

a

accordance present

with is

37

C.F.R.

1.,730,

apnliicat%on

for extexmion of the term of U.S. submitted on behalf of the patent practitioner owner: who is authorized to

Patent No. 5,344,932 owner by a registered act on behalf of the

patent

Eli Lilly and Company, the current NDA holder and exclusive licensee of United States patent 5,344,932, is acting as agent for the Trustees of Princeton University, owner of United States patent 5,344,932 by assignment recorded on January 12, 1990, in Reel No. 5274, Frame No. 0016, for which an extension of the term is sought in the present application. This application is submitted on behalf of Eli Lilly and Company by Elizabeth A. McGraw, Registration No. 44,646, authorized as an agent thereof with full power to transact all business in the United States Patent and Trademark Office in This is evidenced by the Power of connection therewith. Attorney submitted concurrently with this application. Respectfully submitted,

for

Registration 317-277-7443 Phone:

McGraw Applicant No. 44,646

Eli Lilly and Company Patent Division P.O. Box 6288 Indiana 46206-6288 Indianapolis,

15

U.S.

Patent

No.

5,344,932

EXHIBITS

I. II. III. IV. v.

PRODUCT INFORMATION U.S. PATENT NO.

SHEET

5,344,932

MAINTENANCE

FEE STATEMENT THE IND TO THE FDA

LETTER TRANSMITTING

ELI LILLY LETTER PROVIDING THE FDA WITH INFORMATION REQUESTED ON SEPTEMBER 10, 1992 CONFIRMATION LETTER RECEIVED LILLY ON SEPTEMBER 11, 1992 LETTERS TRANSMITTING D) OF THE NDA ALL FROM THE FDA BY ELI

VI.

VII.

FOUR STAGES (A THROUGH

VIII.

LETTER CONFIRMING STAGE D OF THE NDA WAS RECEIVED BY THE FDA ON SEPTEMBER 30, 2003 NDA APPROVAL LETTER DESCRIPTION OF SIGNIFICANT ACTIVITIES UNDERTAKEN BY ELI LILLY AND COMPANY WITH RESPECT TO PEMETREXED DISODIUM DURING THE APPLICABLE REGULATORY REVIEW PERIOD LETTER INDICATING THAT ELI LILLY IS THE AGENT OF THE OWNER OF RECORD OF THE '932 PATENT SUPPLEMENTAL EXHIBIT B

IX. X.

XI.

XII.

EXHIBIT I

1 PA 9301 FSAMP

1 2 3 4 ii 7 i 10 11

ALttVtTA’
pemetrexed for injection
DESCRlPTION ALIMTA@, pemetrexedfor injection, is an antifolate antineoplasticagent that exerts its action by disrupting folate-dependentmetabolic processes essentialfor cell replication. Pemetrexed disodium heptahydratehas the chemical name L-Clutamic acid, j%[4-[2-(2-amine-4,7-dihydro-4oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate.It is a white to almost-white solid with a molecular formula of C&Ir9N5Na~O6*7H@and a molecular weight of 597.49. The structural formula is as follows:

ALIMTA is supplied as a sterile lyophilized powder for intravenousinfusion available in single-dosevials. The product is a white to either light yellow or green-yellow lyophilized solid. Bach 500-mg vial of ALIMTA contains pemetrexeddisodium equivalent to 500 mg pemetrexed and 500 mg of mannitol. Hydrochloric acid and/or sodium hydroxide may have been addedto adjust pH. 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 CLINICAL PHARMACOLOGY Pharmacodynamics Pemetrexedis an antifolate containing the pyrrolopyrimidine-basednucleus that exerts its antineoplastic: activity by disrupting folate-dependent metabolic processesessentialfor cell replication. In vitro studies have shown that pemetrexedinhibits thymidylate synthase(TS), dihydrofolate reductase(DHFR), and glycinamide ribonucleotideformyltransferase(GARPT), all folate-dependent enzymesinvolved in the de novo biosynthesisof thymidine and purine nucleotides.E’ emetrexed transportedinto cells by both the reducedfolate carrier and is membranefolate binding protein transport systems.Once in the cell, pemetrexedis convertedto polyglutamate forms by the enzyme folyl polyglutamate synthase.The polyglutamate forms are retainedin cells and are inhibitors of TS and GARPT. Polyglutamation is a time- and concentration-dependent processthat occurs in tumor cells and, to a lesser extent, in normal tissues.Polyglutamatedmetabolites have an increasedintracellular half-life resulting in prolonged drug action in malignant cells. Preclinical studieshave shown that pemetrexedinhibits the in vitro growth of mesothelioma cell lines (MSTO-21lH, NCI-H2052). Studieswith the MSTO-211H mesotheliomacell line showedsynergistic effects when pemetrexedwas combined concurrently with cisplatin. Absolute neutrophil counts (ANC) following single-agentadministration of pemetrexedto patients not receiving fohc acid and vitamin Br2 supplementationwere characterizedusing population pharmacodynamicanalyses.Severity of hematologic toxicity, as measuredby the depth of the ANC nadir, is inversely proportional to the systemic exposure of ALIMTA. It was also observedthat lower ANC nadirs occurred in patientswith elevatedbaseline cystathionine or homocysteineconcentrations.The levels of thesesubstances be reduced by folic acid and can vitamin B12supplementation.There is no cumulative effect of pemetrexedexposureon ANC nadir over multiple treatment cycles.

2 42 43 44 45 46 i;: 49 50 :: 53 54 :z 57 58 59 60 61 62 63 z 66 67 ti 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 Time to A.NC nadir with pemetrexedsystemic exposure(AUC), varied between8 to 9.6 days over a range of exposures from 38.3 to 3 16.8 pg+tr/mL. Return to baselineANC occurred 4.2 to 7.5 days after the nadir over the samerangeof exposures. Pharmacokinetics The pharmacokineticsof pemetrexedadministeredas a single agentin dosesranging from 0.2 to 838 mg/‘ infused over a lo-minute period have been evaluatedin 426 cancerpatients m2 with a variety of solid tumors. Pemetrexed not metabolizedto an appreciableextent and is is primarily eliminated in the urine, with 70% to 90% of the dose recoveredunchangedwithin the first 24 hours following administration.The total systemic clearanceof pemetrexedis 91.8 mL/min and the elimination half-life of pemetrexedis 3.5 hours in patients with normal renal function (creatinineclearanceof 90 niL/min). The clearancedecreases, and exposure(AUC) increases, renal function decreases. as Pemetrexedtotal systemic exposure(AUC) and maximum plasmaconcentration(C&,& increaseproportionally with dose. The pharmacokineticsof pemetrexeddo not changeover multiple treatmentcycles. Pemetrexed has a steady-state volume of distribution of 16.1 liters. In vitro studiesindicate that pemetrexed is approximately 81% bound to plasmaproteins. Binding is not affectedby degreeof renal impairment. Drug Interactions Chemotherapeutic Agents - Cisplatin does not affect the pharmacokineticsof pemetrexedand the pharmacokineticsof total platinum are unalteredby pemetrexed. Vitamins - Coadministrationof oral folic acid or intramuscularvitamin Br2 doesnot affect the pharmacokineticsof pemetrexed. Drugs Metabolized by CytochromeP4SOEnzymes- Results from in vitro studieswith human liver microsomespredict that pemetrexedwould not causeclimcally significant inhibition of metabolic clearanceof drugs metabolizedby CYP3A, CYP2D6, CYP2C9, and CYPlA2. No studieswere conductedto determinethe cytochrome P450 isozyme induction potential of pemetrexed,because ALIMTA used as recommended(once every 21 days) would not be expectedto causeany significant enzyme induction. Aspirin - Aspirin, administeredin low to moderatedoses(325 mg every 6 hours), does not affect the pharmacokineticsof pemetrexed.The effect of greaterdosesof aspirin on pemetrexed pharmacokineticsis unknown. Ibuprofen Daily ibuprofen dosesof 400 mg qid reducepemetrexed’clearanceby about -s 20% (and increaseAUC by 20%) in patients with normal renal function. The effect of greater dosesof ibupmfen on pemetrexedpharmacokineticsis unknown (seeDrug Interactions under PRECAUTIONS). Special Populations The pharmacokineticsof pemetrexedin special populations were examinedin about 400 patients in controlled and single arm studies. Geriatric - No effect of age on the pharmacokineticsof pemetrexedwas observedover a range of 26 to 80 years. Pediatric -’ Pediatricpatients were not included in clinical trials. Gender- The pharmacokineticsof pemetrexedwere not different in male and female patients. and Race - The pharmacokineticsof pemetrexedwere similar in Caucasians patients of African descent.Insufficient data are available to comparepharmacokineticsfor other ethnic groups.

3 88 iii 91 92 93 94 Ei 97 ;; 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 Hepatic Insu$Eciency There was no effect of elevatedAST (SGOT), ALT (SGPT), or total bilirubin on the pharmacokineticsof pemetrexed, However, studiesof hepatically impaired patients have not beenconducted(see PRECAUTIONS). Renal Inst@ciency - Pharmacokineticanalysesof pemetrexedincluded 127 patients with reducedrenal function. Plasmaclearanceof pemetrexed the presenceof cisplatin decreases in as renal function decreases, with increasein systemicexposure.Patientswith creatinine clearances of 45,50, and 80 mL/min had 65%, 54%, and 13% increases, respectively in pemetrexedtotal systemic exposure(AUC) comparedto patientswith creatinineclearanceof 100 mL/mm (see WARNINGS and DOSAGE AND ADMINISTRATION). CLlNlCAL STUDIES Malignant Pleural Mesothelioma- The safety and efficacy of ALIMTA have been evaluated in chemonaivepatientswith malignant pleural mesothelioma(MPM) in combination with cisplatin. RandomizedTrial: A multi-center, randomized,single-blind study in 448 chemonaivepatients with MPM comparedsurvival in patientstreatedwith ALIMTA in combination with cisplatin to survival in patientsreceiving cisplatin alone. ALIMTA was administeredintravenously over 10 minutes at a doseof 500 mg/m2 and cisplatin was administeredintravenously over 2 hours at a dose of 75 n&m2 beginning approximately 30 minutes after the end of administration of ALLMTA. Both drugs were given on Day 1 of each21&y cycle. After 112 patients were treated,white Ceil and GI toxicity led to a changein protocol whereby all patients were given folk acid and vitamin Br2 supplementation. The primary analysis of this study was performedon the population of all patiems randomly assignedto treatmentwho received study drug (randomizedand treated).An analysis was also performed on patients who received folic acid and vitamin Br2 supplementationduring the entire course of study therapy (fully supplemented), supplementation recommended(see as is DOSAGE AND ADMINISTRATION). Resultsin all patients and those fully supplemented were similar. Patient demographicsare shown in Table 1. Table 1: Summary of Patient Characteristics Randomized and Treated Fully Supplemented Patients Patients ALIMTAkis Cisplatin ALIMTAkis Cisplatin (N=226) (N=222) (NFl63) (N=l68)

Patient characteristic

4

iI!: 118
119 120 121 122 123

confirmedby Independent ’ Only 67% of the patientshadthe histologic diagnosisof malignantmesothelioma review. b Kamofsky Performance Scale.

Table 2 summarizesthe survival results for all randomizedand treatedpatientsregardlessof vitamin supplementationstatusand those patients receiving vitamin supplementation from the time of enrollment in the trial. Table 2: Effkacy of ALIMTA~plus Cisplatin vs. Cisplatin

Efficacy Parameter

Hazard ratio 124 125 126 127 128 129 130 131 132
* p-valuerefersto comparison betweenarms.

Similar results were seenin the analysis of patients (N=303) with confumed histologic diagnosisof malignant pleural mesothelioma.Exploratory demographicanalysesshowedno apparentdifferencesin patients over or under 65. There were too few non-white patients to assess possible ethnic differences.The effect in women (median survival 15.7 months with the combination vs. 7.5 months on cisplatin alone), however, was larger than the effect in males (median survival 11 vs. 9.4 respectively). As’with any exploratory analysis,it is not clear whether this difference is real or is a chancefinding.

5 133
Mbdian Survival = 12.1 mos Hazard ratio Log rank p-value Percent censored 0.77 0.020 32

Median Survival = 9.3 mos

I 5

1 10

I 15

I

I

I

20

25

30

Survival Time (Months) - - - - - ALIMTA + Cisplatin (n=226) Cisplatin (n=222)

Figure 1: Kaplan-Meier Estimates of Survival Time for ALIMTA plus Cisplatin and Cisplatin Alone in all Randomized and Treated Patients. 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 Objective tumor responsefor malignant pleural mesotheliomais difficult to measureand responsecriteria are not universally agreedupon. However, basedupon prospectively defined criteria, the objective tumor responserate for ALIMTA plus cisplatin was greaterthan the objective tumor responserate for cisplatin alone. There was also improvement in lung function (forced vital capacity) in the ALIMTA plus cisplatin arm comparedto the control arm. Patientswho received full supplementationwith folic acid and vitamin Bi2 during study therapy receiveda median of 6 and 4 cycles in the ALIMTAkisplatin (N=l68) and cisplatin @ I=‘ arms, respectively. Patients who never received folic acid and vitamin Bi2 1 63) during study therapy received a median of 2 cycles in both treatmentarms (IV=32 and N=38 for the ALIMTAkisplatin and cisplatin arm, respectively). Patientsreceiving ALIMTA in the filly supplemented group received a relative dose intensity of 93% of the protocol specified ALIMTA dose intensity; patients treatedwith cisplatin in the samegroup received 94% of the projected dose intensity. Patientstreatedwith cisplatin alone had a doseintensity of 96%. INDICATIONS AND USAGE ALIMTA in combination with cisplatin is indicated for the treatmentof patients with malignant pleturalmesotheliomawhose diseaseis unresectable who are otherwise not or candidatesfor curative surgery. CONTRAINDICATIONS ALIMTA is contraindicatedin patients who have a history of severehypersensitivity reaction to pemetrexedor to any other ingredient used in the formulation. WARNINGS Decreased Renal Function ALIMTA is primarily eliminated unchangedby renal excretion.No dosageadjustmentis neededin patientswith creatinine clearance245 ml/mm. Insufficient numbers of patients have been studied with creatinine clearance~45 mL/min to give a dose recommendation.Therefore, ALIMTA should not be administeredto patients whose creatinineclearanceis ~45 mL/min (see Dose Reduction Recommendations under DOSAGE AND ADIMINISTRATION).

6 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 One patient with severerenal impairment (creatinine clearance19 mUmin) who did not receive folic acid and vitamin Br2 died of drug-relatedtoxicity following administration of ALIMTA alone. Bone Marr<zlwSuppression ALIMTA can suppress bone marrow function, manifestedby neutropenia,thrombocytopenia, and anemia (see ADVERSE REACTIONS); myelosuppression usually the dose-limiting is toxicity. Dose reductionsfor subsequent cycles are basedon nadir ANC, platelet count, and maximum nonhematologictoxicity seenin the previous cycle (seeDose Reduction Recommendations under DOSAGE AND ADMINISTRATION). Need for Folate and Vitamin 8%~Supplementation Patientstreatedwith ALIMTA must be instructed to take folic acid and vitamin Br2 as a prophylactic measureto reducetreatment-related hematologic and GI toxicity (seeDOSAGE AND ADMINISTRATION). In clinical studies,less overall toxicity and reductionsin Grade 3/4 hematologic and nonhematologictoxicities such as neutropenia,febrile neutropenia, and infection with Grade3/4 neutropeniawere reported when pretreatmentwith folic acid and vitamin Bi2 was administered. Pregnancy Category D ALIMTA may causefetal harm when administeredto a pregnantwoman. Pemetrexedwas fetotoxic and teratogenicin mice at i.v. dosesof 0.2 mg/kg (0.6 mg/m*) or 5 mg/kg (15 mg/m2) when given on gestationdays 6 through’ Pemetrexedcausedfetal malformations (incomplete 15. ossificatio? oEtalus and skull bone) at 0.2 mg/kg (about l/833 the recommended human dose i.v. on a mg/m basis), and cleft palate at 5 mgkg (about l/33 the recommended human dose on i.v. a mg/m basis). Embryotoxicity was characterizedby increasedembryo-fetal deathsand reduced litter sizes. There are no studiesof ALIMTA in pregnantwomen. Patientsshould be advisedto avoid becoming pregnant.If ALIMTA is used during pregnancy,or if the patient becomes pregnantwhile taking ALIMTA, the patient should be apprisedof the potential hazardto the fetus. , PRECAUTIONS General ALIMTA should be administeredunder the supervision of a qualified physician experiencedin the use of antineoplasticagents.Appropriate managementof comphcationsis possible only when adequatediagnosticand treatmentfacilities are readily available. Treatment-related adverseeventsof ALIMTA seenin clinical trials have been reversible.Skin rash has been reported more frequently in patients not pretreatedwith a corticosteroid in clinical trials. Pretreatment>withdexamethasone equivalent) reducesthe incidenceand severity of (or cutaneousreaction (seeDOSAGE AND ADMINISTRATION). The effect of third spacefluid, such as pleural effusion and ascites,on ALIMTA is unknown. In patients with clinically significant third spacefluid, considerationshould be given to draining the effusion prior to ALIMTA administration. Laboratory Tests Complete blood cell counts, including platelet counts and periodic chemistry tests, should be performed on all patients receiving ALIMTA, Patients should be monitored for nadir and recovery, which were tested in the clinical study before each doseand on days 8 and 15 of eqch cycle. Patients should not begin a new cycle of treatment unlessthe ANC is 21500 cells/mm , the platelet count is 2100,000 cells/mm , and creatinine clearanceis 245 n&/mm.

7 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 Drug Interactions ALIMTA is primarily eliminated unchangedrenally as a result of glomerular filtration and tubular secretion.Concomitant administration of nephrotoxicdrugs could result in delayed clearanceof ALIMTA. Concomitant administrationof substances are also tubularly secreted that (e.g., probenecid)could potentially result in delayedclearanceof ALIMTA. Although ibuprofen (400 mg qid) can be administeredwith ALIMTA in patients with normal renal function (creatinineclearance280 mL/min), caution should be used when administering. ibuprofen concurrentlywith ALIMTA to patientswith mild to moderaterenal insufficiency (creatinine clearancefrom 45 to 79 mL/min). Patientswith mild to moderaterenal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence dataregardingpotential interactionbetweenALIMTA and NSAIDs with of longer half-lives, all patients taking theseNSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration.If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinaltoxicity. Drug/Laboratory None known. Test Interactions

Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studieshave been conductedwith pemetrexed.Pemetrexedwas clastogenic in the in vivo micronucleusassayin mousebone marrow but was not mutagenic in multiple in vitro tests (Ames assay,CHO cell assay).Pemetrexed administeredat i.v. dosesof 0.1 mg&g/day or greaterto male mice (about l/l666 the recommended human dose on a mg/m’ basis) resulted in reducedfertility, hypospermia,and testicular atrophy. Pregnancy PregnancyCategoryD (seeWARNINGS). Nursing Mothers It is not known whether ALIMTA or its metabolitesare excretedin human milk. Because many drugs are excretedin human milk, and because the potential for serious adverse of reactionsin nursing infants from ALIMTA, it is recommended nursing be discontinued if the that mother is treatedwith ALIMTA. Pediatric Use The safety and effectivenessof ALIMTA in pediatric patientshave not been established. Geriatric Use Dose adjustmentsbasedon age other than thoserecommended all patients have not been for necessary(see Special Populations under CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Gender Dose adjustmentsbasedon genderother than thoserecommendedfor all patients have not been necessary(see Special Populations under CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Patients with Hepatic Impairment Patientswith bilirubin >1.5 times ‘ upper limit of normal were excluded from clinical trials the of ALIMTA. Patientswith transaminase >3.0 times the upper limit of normal were routinely excluded from clinical trials if they had no evidenceof hepatic metastases. Patients with

8 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 transaminase from 3 to 5 times the upper limit of normal were included in the clinical trial of ALIMTA if they had hepatic metastases. Dose adjustmentsbasedon hepaticimpairment experiencedduring treatmentwith ALIMTA are provided in Table 6 (seeSpecial Populations under CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Patients with Renal Impairment ALIMTA is known to be primarily excretedby the kidney. Decreasedrenal function will result in reducedclearanceand greaterexposure(AUC) to ALIMTA comparedwith patientswith normal renal function. Cisplatin coadministrationwith ALIMTA has not been studiedin patients with moderaterenal impairment (seeSpecial Populations under CLINICAL PHARMACOLOGY). ADVERSE REACTIONS In Table 3 adverseeventsoccurring in at least 5% of patients are shown along with important effects (renal failure, infection) occurring at lower rates. Adverse events equally or more common in the cisplatin group are not included. The adverseeffects more common in the ALIMTA group were primarily hematologiceffects, fever and infection, stomatitis/pharyngitis, and rastidesquamation.

9

269 Table 3: Adverse Events* in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in MPM CTC Grades (g/oincidence1 All Reported Adverse Events Regardlessof Causality
ALEMTAkiS I Cisplatin

* Refer to NC1 CTC Version 2.0.

271 272 273 274 275 276 277

Table 4 comparesthe incidence (percentage patients) of CTC Grade314toxicities in patients of who received vitamin supplementation with daily folic acid and vitamin Bi2 from the time of enrollment in the study (fully supplemented) with the incidence in patients who never received vitamin supplementation(never supplemented) during the study in the ALIMTA plus cisplatin arm. Table 4: Selected Gk-ade314Adverse Events Comparing Fully Supplemented versus Never Supplemented Patients in the ALIMTA plus Cisplatin arm (% incidence) Adverse Event

Infection with Grade 3/4 neutropenia Fatigue 278 279 280 281 282

1 17

1

6 25

a Refer to NC1 CTC criteria for lab and non-laboratory valuesfor eachgradeof toxicity (Version 2.0).

,

The following adverseeventswere greaterin the fully supplementedgroup comparedto the never supplementedgroup: hypertension(1 l%, 3%), chest pain (8%, 6%), and thrombosis/embolism(6%, 3%).

11

283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303
304

For fully supplemented patients treatedwith ALIMTA plus cisplatin, the incidence of CTC Grade 3/4 fatigue, leukopenia,neutropenia,and thrombocytopeniawere greater irrpatients 65 years or older as comparedto patients younger than 65. No relevant effect for ALIMTA safety due to genderor race was identified, except an increasedincidence of rash in men (24%) comparedto women (16%).
OVERDOSAGE

There have beenfew casesof ALIMTA overdose.Reportedtoxicities included neutropenia, anemia, thrombocytopenia,mucositis, and rash. Anticipated complications of overdose include bone marrow suppressionas manifestedby neutropenia,thrombocytopenia,and anemia. In addition, infection with or without fever, diarrhea,and mucositis may be seen.If an overdose occurs, generalsupportivemeasuresshould be instituted as deemednecessaryby the treating physician. In clinical trials, leucovorin was permitted for CTC Grade4 leukopeniti lasting 23 days, CTC Grade4 neutropenialasting 23 days, and immediately for CTC Grade4 thrombocytopenia, bleeding associatedwith Grade 3 thrombocytopenia,or Grade3 or 4 mucositis. The following intravenousdosesand schedulesof leucovorin were recommended intravenoususe: for 100 mg/m’ intravenouslyonce, followed by leucovorin, 50 mg/m*, intravenously every 6 hours , for 8 days. The ability of ALIMTA to be dialyzed is unknown.
DOSAGE AND ADMINISTRATION ALIMTA is for Intravenous Infusion Only Combination Use With Cisplatin

305 306 307 308 309 3 10 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330

dose of ALlMTA is 500 mg/m2 Malignant Pleural Mesothelioma- The recommended administeredas an intravenousinfusion over 10 minutes on Day 1 of each 2 1-day cycle. The recommendeddose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. Patientsshould receive hydration consistent with local practice prior to and/or after receiving cisplatin. Seecisplatin package insert for more information.
Premeditation Regimen

Corticosteroid - Skin rash has been reportedmore frequently in patients not pretreatedwith a corticosteroid. Pretreatmentwith dexamethasone equivalent)reducesthe incidence and (or severity of cutaneousreaction In clinical trials, dexamethasone mg was given by mouth 4 twice daily me day before, the day of, and the day after ALIMTA administration. Vitamin Supplementation To reduce toxicity, patients treatedwith ALIMTA must be instructed to t&e a low-dose oral folic acid preparationor multivitamin with folic acid on a daily basis. At least 5 daily dosesof folic acid must be taken during the 7&y period preceding the first dose of ALIMTA; and dosing should continue during the full course of therapy and for 2 1 days after the last dose of ALIMTA. Patientsmust also receive one (1) intramuscular injection of vitamin BQ,during the week preceding the first dose of ALIMTA and every 3 cycles thereafter.Subsequent vitamin Bt2 injections may be given the sameday as ALIMTA. In clinical trials, the dose of folic acid studied ranged from 350 to 1000 hg, and the dose of vitamin B12was 1000 pg. The most commonly used dose of oral folic acid in clinical trials was 400 fig (see WARNINGS).
Laboratory Monitoring and Dose Reduction Recommendations

Monitoring - Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is 21500 cells/mm3,the platelet count is

12 331 332 333 334 335 336 337 X00,000 cells/mm3,and creatinine clearanceis 245 mUmin. Periodic chemistry tests should be performed to evaluaterenal and hepatic function. cycle Dose Reduction Recommendations Dose adjustmentsat the start of a subsequent should be basedon nadir hematologic counts or maximum nonhematologictoxicity from the precedingcycle of therapy. Treatmentmay be delayedto allow sufficient time for recovery. Upon recovery, patients should be retreatedusing the guidelines in Tables 5-7. Table 5: Dose Reduction for ALIMTA and Cisplatin - Hematologic Toxicities 75% of previous dose (both drugs). 50% of previous dose (both drugs). 338 339 340 341 342 343 If patients develop nonhematologictoxicities (excluding neurotoxicity) 2Grade 3 (except Grade3 transaminaseelevations),ALIMTA should be withheld until resolution to less than or equal to the patient’ pre-therapyvalue. Treatmentshould be resumedaccordingto guidelines in s Table 6. Table 6: Dose Reduction - Nonhematologic ToxicitiesPyb 1 Dose ofALIMTA 1 Dose of Cisnlatin or 4 toxicities except mucositis requiring hospitalization
Toxicity Criteria (CTC). 3% ba’ NC1 Common:3transaminaseelevation. Excluding neurotoxicity. 346 Except Grade

75% of previous dose 75% of previous dose 50% of orevious dose

(msln2)

75% of previous dose 75% of previous dose 100% of nrevious dose

@w&4

1

347 348 349 350 351

In the event.of neurotoxicity, the recommendeddose adjustmentsfor ALIMTA and cisplatin are describedin Table 7. Patients should discontinuetherapy if Grade 3 or 4 neurotoxicity is experienced. Table 7: Dose Reduction for ALIMTA and CisDlatiin - Neurotoxicitv Dose of Cisplatin Dose of ALIMTA (mg/m2) (mg/m2) 100% of previous dose 100% of previous dose 50% of orevious dose 100% of nrevious dose

352 353 354 355 356 357 358 359 360 361 362

ALIMTA therapy should be discontinuedif a patient experiencesany hematologicor nonhematologicGrade 3 or 4 toxicity after 2 dose reductions (except Grade 3 transaminase elevations) or immediately if Grade3 or 4 neurotoxicity is observed. Elderly Patients - No dose reductions other than those recommendedfor all patientsare necessaryfor patients 265 years of age. Children -- ALIMTA is not recommended use in children, as safety and efficacy have not for been establishedin children. Renaliy Impaired Patients - In clinical studies,patients with creatinine clearance245 mL/min required no dose adjustmentsother than those recommendedfor all patients. Insufficient numbersof patients with creatinineclearancebelow 45 mL/min have beentreatedto make

13 363 364 365 366 dosagerecommendations this group of patients. Therefore,ALIMTA should not be for administeredto patientswhose creatinine clearanceis c45 mL/min using the standardCockcroft and Gault formula (below) or GFR measuredby Tc99m-DPTA serumclearancemethod: [ 140 - Age in years] x Actual Body Weight (kg) 72 x Serum Creatinine (mg/dL) Females: Estimatedcreatinine clearancefor males x 0.85 Males: 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 = mL/min

Caution should be exercisedwhen administering ALIMTA concurrently with NSAIDs to patients whose creatinineclearanceis ~80 mL/min (seeDrug Interactions under PRECAUTIONS). Hepafica@ Impaired Patients - ALIMTA is not extensivelymetabolizedby the liver. Dose adjustmentsbasedon hepatic impairment experiencedduring treatmentwith ALIMTA are provided in Table 6 (seePatients with Hepatic Impairment under PRECAUTIONS). Preparation and Administration Precautions As with other potentially toxic anticanceragents,care shouldbe exercisedin the handling and preparationof infusion solutions of ALIMTA. The use of gloves is recommended.If a solution of ALIMTA contactsthe skin, wash the skin immediately and thoroughly with soap and water. If ALIMTA contactsthe mucousmembranes,flush thoroughly with water. Severalpublished guidelinesfor handling and disposal of anticanceragentsare available.‘ There is no general -s agreementthat all of the proceduresrecommendedin the guidelinesare necessaryor appropriate. ALIMTA is not a vesicant. There is no specific antidote for extravasationof ALIMTA. To date, there have beenfew reportedcasesof ALIMTA extravasation,which were not assessed as seriousby the investigator.ALIMTA extravasationshouldbe managedwith local standard practice for extravasationas with other non-vesicants. Preparation for Intravenous Infusion Administration 1, Use aseptictechniqueduring the reconstitution and further dilution of ALIMTA for intravenousinfusion administration. 2. Calculatethe dose and the number of ALIMTA vials nee&d. Each vial contains 500 mg of ALIMTA. The vial contains an excessof ALIMTA to facilitate delivery of label amount. 3. Reconstitute500-mg vials with 20 mL of 0.9% Sodium Chloride Injection (preservative free) to give a solution containing 25 mg/mL ALIMTA. Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and rangesin color from colorlessto yellow or green-yellow without adverselyaffecting product quality. The pH of the reconstitutedALIMTA solution is between6.6 and 7.8. FURTHER DILUTION IS REQUIRED. 4. Parenteraldrug products should be inspectedvisually for particulate matter and discoloration prior to administration. If particulate matter is observed,do not administer. 5. The appropriatevolume of reconstitutedALIMTA solution should be further diluted to 100 mL with 0.9% Sodium Chloride Injection (preservativefree) and administered as an intravenousinfUsion over 10 minutes. 6. Chemical and physical stability of reconstitutedand infusion solutions of ALIMTA were demonstrated up to 24 hours following initial reconstitution,when stored at for refrigeratedor ambient room temperature[see USP Controlled Room Temperature]and lighting. When preparedas directed, reconstitution and infusion solutions of ALIMTA contain no antimicrobial preservatives.Discard any unusedportion. Reconstitution and further dilution prior to intravenousinfusion is only recommendedwith 0.9% Sodium Chloride Injection (preservativefree). ALIMTA is physically incompatible with

14 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 ii:. 443 444 445 446 447 448 449 450 451 452 453 454 455 456 diluents containing calcium, including LactatedRinger’ Injection, USP and Ringer’ s s
Iniection. USE’ thereforetheseshould not be used. Coadministrationof ALIMTA with other and

drugs and diluents has not been studied, and thereforeis not recommended. HOW SUPPLIED ALIMTA*, pemetrexedfor injection is available in sterile single-usevials containing 500 mg pemetrexed. NIX 0002-7623-01(VL7623): single-usevial with flip-off cap individually packagedin a carton. Storage ALIMTA, pemetrexedfor injection, should be stored at 25°C (77°F); excursionspermitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Chemical arid physical stability of reconstitutedand infusion solutions of ALIMTA were , demonstratedfor up to 24 hours following initial reconstitution, when stored refrigerated, 2-8°C (36-46”F), or at 25°C (77”F), excursionspermitted to 1S-30°C (59-86°F) [see USP Controlled Room Temperature],When preparedas directed, reconstitutedand infusion solutions of ALIMTA contain no antimicrobial preservatives.Discard unusedportion. ALIMTA is not light sensitive. REFERENCES 1. ONS Clinical Practice Committee. CancerChemotherapyGuidelines and Recommendations Practice. Pittsburgh, PA: Oncology Nursing Society; 1999:32-41. for 2. Recommendations the Safe Handling of Parentera Antineoplastic Drugs. for Washington,DC: Division of Safety, Clinical Center PharmacyDepartmentand Cancer Nursing Services,National Institutes of Health, 1992.US Dept of Health and Human Services,Public Health Service Publication NIH 92-2621. 3. AMA Council on Scientific Affairs. Guidelines for Handling ParenteralAntineoplastics. JAMX 1985;253:1590-1591. 4. National Study Commission on Cytotoxic Exposure-Recommendations Handling for Cytotoxic Agents. 1987. Available from Louis P. Jeffrey, ScD, Chairman,National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacyand Allied Health Sciences,179 Longwood Avenue, Boston, MA 02 115. 5. Clinical Gncological Society of Australia. Guidelines and Recommendations Safe for Handling of Antineoplastic Agents. Med J Australia. 1983;k426-428. 6. JonesRB, Frank R, Mass T. Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA -A Cancer Jfor Clin. 1983;33:258-263. 7. American Society of Hospital Pharmacists.ASHP Technical AssistanceBulletin on Handling Cytotoxic and HazardousDrugs. Am J Hosp Pharm. 1990;47:1033-1049. 8. Controlling OccupationalExposureto HazardousDrugs. (OSHA Work-Practice Guidelines).Am J Health-SystPharm. 1996;53:1669-1685.
Literature issued February 5, 2004

Manufactured by Lilly France S.A.S. F-67640 Fegersheim, France for Eli Lilly and Compan Indianapolis, IN 46285, U !zA www.ALIMTA.com
PA 9301 FSAMP Copyright 0 2004, Eli Lilly and Company. All rights reserved.

15 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 PA 9301 FSAMP

CNFORMATION FOR PATIENTS AND CAREGIVERS

ALIMTA@ (uh-LIM-tuh)
(pemetrexed for injecticm)
Read the Patient Information that comeswith ALIMTA before you start treatment and each time you get treatedwith ALIMTA. There may be new information, This leaflet doesnot take the place of talking to your doctor about your medical condition or treatment.Talk to your doctor if you have any questionsabout ALIMTA. What is ALIMTA? ALIMTA is a treatmentfor a type of cancercalled malignant pleural mesothelioma.This cancer affects the inside lining of the chest cavity. ALIMTA is given with cisplatin, anotheranti-cancer medicine (chemotherapy).To lower your chances of side effects @ fALIMTA, you must also take folic acid and vitamin B12prior to and during your treatment with ALIMTA. Your doctor will prescribea medicine called a “corticosteroid”’ take for 3 days during your to treatment with ALIMTA. Corticosteroidmedicineslower your chancesof getting skin reactions with ALIlvITA. ALIMTA has not been studiedin children. What should I tell my doctor before taking ALIMTA? Tell your doctor about all of your medical conditions, including if you:
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are pregnant or planning to become pregnant. ALIMTA may harm your unborn baby. are breastfeeding. It is not known if ALIMTA passesinto breastmilk. You should stop breastfeedingonce you start treatmentwith ALIMTA. * are taking other medicines, including prescription and nonprescriptionmedicines, vitamins, and herbal supplements.ALIMTA and other medicinesmay affect each other causingseriousside effects. Especially, tell your doctor if you are taking medicines called “nonsteroidal anti-inflammatory drugs”(NSAIDs) for pain or swelling. There are many NSAID medicines.If you are not sure, ask your doctor or pharmacist if any of your medicines are NSAIDs.

How is ALIMTA given? ALIMTA is slowly infused (injected) into a vein. The injection or infusion will last about 10 minutes. You will usually receive ALIMTA once every 2 1 days (3 weeks). Cisplatin is infused in your vein for about 2 hours starting about 30 minutes after your treatmentwith ALIMTA. Your doctor will prescriie a medicine called a “corticosteroid” to take for 3 days during your treatmentwith ALIMTA. Corticosteroidmedicines lower your chancesfor getting skin reactionswith ALIMTA. It is very important to take folic acid and vitamin B12during your treatment with ALIMTA to lower your chances of harmful side effects. You must start taking 350-l 000 micrograms of folic acid every day for at least 5 days out of the 7 days before
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16 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 5 13 5 14 515 5 16 5 17 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 your first doseof ALIMTA. You must keep taking folic acid every day during the time you are getting treatmentwith ALIMTA, and for 21 days after your last treatment. You can get folic acid vitamins over-the-counter. Folic acid is also found in many multivitamin pills. Ask your doctor or pharmacistfor help if you are not sure how to choosea folic acid product. Your doctor will give you vitamin 312injections while you are getting treatmentwith ALIMTA. You will get your first vitamin Br2 injection during the week before your first dose of ALIMTA, and then about every 9 weeks during treatment. You will have regular blood testsbefore and during your treatmentwith ALIMTA. Your doctor may adjust your dose of ALIMTA or delay treatmentbasedon the results of your blood tests and on your generalcondition.

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What should I avoid while taking ALIMTA? Women who can become pregnant should not become pregnant during treatment with ALIMTA. ALIMTA may harm the unborn baby. * Ask your doctor before taking medicines called NSAIDs. There are many NSAID medicines.If you are not sure, ask your doctor or pharmacistif any of your medicines are NSAIDs.
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What are the possible side effects of ALIMTA? Most patients taking ALIMTA will have side effects. Sometimesit is not always possible to tell whether ALIMTA, anothermedicine, or the canceritself is causingthese side effects. Call your doctor right away if you have a fever, chills, diarrhea, or mouth sores. Thesesymptoms could mean you have an infection. The most common side effects of ALIMTA when taken with cisplatin are:
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Stomach upset, including nausea, vomiting, and diarrhea. You can obtain medicines to help control some of these symptoms. Call your doctor if you get any of these symptoms. Low blood cell counts: Low red blood cells. Low red blood cells may make you feel tired, get tired easily, appearpale, and become short of breath. Low white blood cells. Low white blood cells may give you a greaterchancefor infection. If you have a fever (temperatureabove 100.4”F) or other signs of infection, call your doctor right away. Low platelets. Low platelets give you a greaterchancefor bleeding. Your doctor will do blood tests to check your blood counts before and during treatment with ALIMTA. ., Tiredness. You may feel tired or weak for a few days after your ALIMTA treatments.If you have severeweaknessor tiredness,call your doctor. Mouth, throat, or lip sores (stomatitis, pharyngitis). You may get rednessor soresin your mouth, throat, or on your lips. These symptoms may happena few days after ALIMTA treatment.Talk with your doctor about proper mouth and throat care. Loss of appetite. You may lose your appetite and lose weight during your treatment. Talk to your doctor if this is a problem for you.
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537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557
$58

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Rash, You may get a rash or itching during treatment.Theseusually appearbetween treatmentswith ALIMTA and usually go away before the next treatment. Call your doctor if you get a severerash or itching.

Talk with your doctor, nurse or pharmacistabout any side effect that bothers you or that doesn’ t go away. Theseare not a11 side effects of ALIMTA. For more information, ask your doctor, nurse or the pharmacist. General information about ALIMTA Medicines arc sometimesprescribedfor conditions other than those listed in patient information leaflets. ALIMTA was prescribedfor your medical condition. This leaflet summarizesthe most important information about ALIMTA. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about ALIMTA that is written for health professionals.You can also call 1-800-LILLY-RX (l-800-545-5979) or visit www.ALIMTA,com. Literature issued February 5,2004 Manufactured by Lilly France S.A.S. F-67640 Fegersheim, France for Eli Lilly and Company Indianapolis, IN 46285, USA www.ALIMTA.com PA 9301 FSAMP Copyright 0 2004, Eli Lilly and Company. All rights reserved.

N~YRR!fXO@,SD)PYRiMIDXN~ YLACYLMXJJTAMICACIDDERIVATfVES Inventor Edward CT. Taylor, Princeton, NJ.

Roferenceacitotl
U.S. PATENT DOCUMENTS
4,889,859 W1989 Taylor et aL ..m........-....... 5141258 4,996,206 21’ 1991 Taylor et al. -..........w...... 514/258 4,997,838 3/3991 AJcimao et al. . . . . . . . . .. 514/258

Assignee: Tt3lsteesof pntncetonuni.versitp, Priuceton, NJ. Appl. No.: 674,!%1 Filed: Mar.22,1991 R&ted U.S. Application Data
continuation of Ser. No. 448,742,Dec. 11.1989, abandoned, ant?Sm. No. 479,655,Feb. 8,1990, abandoned. lnt. cl.5 . . . .e...... . . . . . *. cB7D 487/w, A61K 3v505

FOREIGN PATENT DOCUMENTS
334636 9/1989 EumpeanPat.Olf. .

&bna@xa&~yBernhard

AttorneyApr. or l?Pm--Mathews, Woodbridge &
collills ABsrRAcr f57l N-(Acyllglntami~. acid derivatives in which the acyl ‘ group is substituted with 4-hydroxypyrrolo[2,3d]pyrbnidin-3-yl group are antineoplastic agents. A typical embodiment,is N-[4-(2-~4-hydroxy-6-aminopyr10lo[2,3-d]pvrjunidzn-3-yI~~y~~y~~~u~c acid 7Claims,NoDra~

us. CL ..........I..............................~......... 844/280 Fiekl of Search ..... .. ... ... .. .... .. 544/2% 514/258

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5344,932

proces%e the pl$pamt& of thesecompounds for and theirsalts,tochemWintennediatcsuseMiapreparat.GL~~CAcIDDERNATIyEs tiOllOfth~ compoands,toamethodofcombatfing neoplasticgrowthinamammaLandtophsrmaceutiad CRos-~mRHLAm 5 compositions containing these compounds their salts. or APPLICATIONS AWtgroupofusefid&emicalintenn~es,wbich This is a contimmtionof Ser. No. W448,742 @ed canbecunvezteddirectlytothedesiredfiaalcomDes. 11,1989 Ser.No. 07L479,655 Feb.8,199O pods of Formuh I through removal of protecting and filed groups are compounds the form& of both now abandoned. ‘ prese-imi I%6 inventionpertaimtoglutamicacid de&- lo atives havingthe fofmulaz 0 II pyIulmDYN-3-mw N4PYRROLOCZ,3-Dl

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I
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in whichz

R3isBsdefiaedabov~ R2’ hydrogenor a carboxyprotectinggroup; is in whicl& Re is hydrogen, methyl,ltydroxymethyl,or hydroxyRt is -0lH or --NH% methyl carry& a hydroxy protectinggroup; Rz is hydrogenor a pharmaceutkallyacceptable Rs’is hydrogen,aikyl, amino, or amino carqing a catiom R3is l&phenyleneor If-phenyleneunsubstituted 25 or P-g groaa;and R6 is hydrogenor alkanoyoxy, substituted with chbr0, fluoro, methyl, methoxy, at leastone of R2’ aad RS’ *R4’ , beinga carkoxy proor trifluoromqhyk thienediylor faranediyl escb unsu~tuted or substitutedwith cllloro, flnoro* techg group, a hydroxy protectinggroup,or an methyl, methoxyS trifluoromethy~ cyclobex- 3. or aminoPnrtectinggroup,respectinly. anediyl;or allcauediyk ThecompoundsofFormnlaIcanbeemployedinthe R* is hydrogea, methyl, or hydroxymethy~ form of the Free dicarboxylicacid, in which caseboth RS is hydrogen,al&y1of 1 to 6 carbon atoms, or R2 grool~ arehydrogen.Alternatively, the compounds amino;aud oftencanbe employed adv8ntageously the form of a in the co~tion aboutthe carbonatomdesignated is 35 pharmaceutically * acceptable in which caseone or salk 0 3. both R2tzrouus arc a oharmadcall~ acceotable catThe campouuds this invention hereindesaii of are ion. Suck S& forms,-incladiaghydrkes tlkreo& are as embodyingthe pyrrolo@J-dlpyrimidiaeheterocy- often c3lysahe and advantageous forming solu* for clic ring syslsem which ring systemis numbered folas tions or Formulatingphsrmaceatscllrcompositions. IOWS: acceptable salrs with basesinclude 40 Pharmacentically thoseformedfkomthe&lkalimeta&alkalkearthmetal% non-toxic met& aumioni~and~o-,di-and trisuw aminessuch as for examplethe sodim potassiuIu,lithium, c%dchuqmagneai~ ahlmina 45 ziac, ammonimn,trim$hyhtmmoxliuIq -lammOnmm, pyrim and sabstitated pyridinium salts. The monoanddisodkm salts,particnlarlythe disodium It will be appreciated the py~olo[2,3-dJpyrimi- sal&areadvantageons. that ThegronpRJisa~~~tgrouphavingatIeasttwo dines as deyplcted Foxmula I are the tautomexic by equivalentof the corroding 5-H-6-oxoor J-H4 H) carbonatomsbetweenthecarbonatomscarqingthe free valence bonds. R3 for example be a l,dphenycan iminostru&mSunlessotherwiseindi~forsimplicity’ sakethe compounds depictedherein and lene or l,f-pheuylene rixg which is unsub&tutedor s are optionally substitated v&h chloro, fluo~~,methyL menamedusingthe 6-hydroxyand6-amino convention, it beingmderstoodthe S-H4oxo andS-H-~&I&Ostrac- thoxy, or tfifluorometbyL ture5are fully equivalent. 55 Alternatively, Rs can be a thienediyl or faranediyl group, that is, a thiophene fkane ring from which or The compou.uds Formula I have an inhiiry of two hydrogenatomshavebeenremovedfrom two kg effw on oneor moreenzymes which utilixe folio acid, carbonatoms,asforexampiethe~~~~y~~~~ andinpardcularmetabolic derivatives aFfolic acid, asa 3,%iiyl$thiene-&4difi andtbiene-3,4-d@ systems ring substrata The compounds appearto be partkularly active as idfibitors of thymidylatesyntbetase, which 60 and the the furane-2J-diyL furane-3,5-diyl, iimne-2,4 riag catalyses methylfdion deoxyuxidylic to deox- diyl, and farane-3,4-d&l systems,which ring systhe of acid gor4ii ad utilizing lG~~“-met$ylidenetetrahy- tC33lSCanbtlll?SUbSti~OrsabstitntedWithChlO~, fhoro, methy&methoxy,or triflttoromethyL It will be ofmxymaThemmpoundsthuscanbe appreciated whereas the abstmctthe thiene-3,Sthat in us&aloneorincombinati~toinhiithRgrowthof thoseneoplasmswbichothenvisedependuponthe65 diyl systemis the equivalentof the thiene-2&l&l system,thetwotermsan:ut&edhereintodendethetwo ilabikdenzyme. TheinveMionalsopertakstothep~ isomesicforms resulting fiwm the orieutationof the thiopheaerimg within the remainderof the molecuk acoeptableaaltsofthe compowdsofForm~I,to

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3
q.thesmmturei.uwhichthedepicted~ygroup

4

WsthrespecttoR~,~anaminogroupcanbeprotec@ adjacent to R3 is in the 2qositi0xmf the thi0&lne ring asanaddellti&hgan~lgroupwhichissel~ely andthat in which the depictedcarboxygroupadjacent rexmable undermild conditions,eqcially finmy& a toR!isio~~3-positionofthethiopheaering.~same lower tioyl gronpwhich is branched to the cara 5 bonyl gronp,particulsrly tertky alkanoylsuch as piconventionas apply to the furanering, Alternatively, R3 cambe a cyclobexanedQl group, valoyS, a lower alkanoylgroupwhich is sub&Ned or namelya divalentcycloalka~e groupof6 carbonatoms in the positiona to the carbonylgroup*as for example suchas cyclobexane-l$diyl and cyclobexane-l&diyl. tlif3-L Alternatively, R3 can be a akmediyl, aamely a Preferred compolmdsofFoImulaIarethosewherein straightor branched divalentaliphaticgroupof fkom2 10 Rsis aminoor hydrogen.Witbin this class,Rlpref&rato 4 carbonatomssuch as etham#t.i+met.hy~en~ tetra- bly is hydroxy,R3is l&ph~yleae, andR4is hydrogen metbylene, propan+l&diyl, propane&3diyl, butane- or hydlmymeayl. Alsa preferred within this classare 2,3diyl, butane-l&diyl, and butane-2,4-diyl. again thecompoundsin It which RQs hydroxy,R3isthkediyl, willbeappre&tedtbatwhereasintlteabstmctpropane-l&diyl is the edphleut of propsne-2J+& qd 15 andR”is hydrogenor hydroxym&hyL The compunds of this invention can be prepared. butane-1,3diiyl equivalentof butane-2,4diyl,the the according a first pr~~~~~,througb to catalytic hydrogetwotermsareutilizedhereiutodenotethetwo~ nationof a compound ofthe formula: forms resultingfkom the orieatationoffm unQma&& calaBauediyIchsinwitbr~totheremaiade-rofthe 2n molecule. The protecztiag groupsdesignated R2’R4’ R5’ by , a@ and ntiliqedhereindenotegroupswhich genera& are not foundin the final thempeutic compounds which but 8reintentionallyintroduced a stageof the syatll&s in at orderto protectgroupswhich othe&se might reactin 25 the coursed chemicalmanip~ons. the being removedat a later stageof the syathesis.SincecominWhich: poundsbe&g suchprotectinggroupsthus are of imZI is hydrogen,or ZJ takeu togetherwith R4’ a is portanceprimaxily chemicalintermediates as (although cfllbonabon bond; somederivativesalso exhibit biological activity), their 30 Rr is hydrogenor a czarboxy protectinggroup; precise structureisnot criticaL Numerous reactioas for R3and R6 are as defimed above; the formationand removsl of such protectinggoups R”, when taken independently Zl, is hydrogen, of aredescrii in a numberof stqiard worb including, for example,“Protective Groupsin Organic C!bemismethyl, hyclroxymethyl, hydroxymetbylsubstior try”, Plemun Press, London and New York, 1973;35 tutedwithahydroxyprot&aggroup;and c3real~flb,‘ w.~teclive~oupsinorganicsynthe= R5’ ishydrogqalkyiof fto6carbonatoms,amino, sis”, Wiley, New York 1981;The Peptides”,Vol. I+ OrSJlZUUi3LOXblObCtieJoao. Schr6derand Lnbke, Academic Press, London and New York, l!%S;“Methodender organischea Chemie-, Ho&en-Weyl, 4th Edit& Vol.lS/I, Georg Tbietne40 oxidG,rhodiumoxlde,andthefkegoingonasupport Vexlag,’ Stuttgart 1974,the discSosures. which are SUChaSCkbOBOrcalcimnOXi& of in-ted hereinby reference. WheninFonnatam[,ZitakentogetherwithR~lsa With respect Rr, a carboxygroupcanbe prote&ed carbonabn bon& that is, whena triple bond is presto asan esterg.Mupwhich is sele&vely removable under entbetweeatbetwocarbonatomstowhichZ*andR4’ stiently mild ccmdidons to disrupt the de@ed45 arebouq~K~inthehy&ogenatioaproductwiUbe not stmctme of the mokcul~ espe&lly a lower aikyl ester hydrogen. Absentanycl&a&y in R3(or any pro&&q of 1 to 12 carbonatoms such as InetllylTE ethyl and liponp; encompassed RF, R*’and/or Rr)l the hydroby particularly one which is branchedat the I-positkm genationproductwillbf2asbglecni3nti~ha~thc suchast-but& andsuchlower alkyl estersubstituted in sconfiguratox~about the carbon the l- or 2-p&ion with (i) lower alkoxy, suchas for so This.alsoistruewhenZ~andR4’ atom designated.*. areeachhydrogea, example,metboxyme&yl, I-methoxyethyl,and ethox- tbatis,whenadoublebondispresentbetweenthe&vo ymethyb @iIlower alkylthio, such as for example metbylthiomethyl and l-etbyltbioethyl; (ii) balogeqsuch c&onatomstowhichZ~andR~arebouad. Wben,ontbeotberbaud,R~isotbertbaahydrogen, as2,2,2-Mdyl, 2-bromoetbyl, 2-iodoetboxa&d a mixtureof the R,S and S,S &stereomers.isobtained. ycarbouy~ oneor two phenyigroupseachof which 55 (ii) can be llllsubmittltedor mono-, di- or t&substituted ThC!ditiStWeOllleliCnnixtareC8IlbeusadtherapentiGalY as such(afterremovalof the protectinggroups)or c8n with, for example lower alkyl such as text.-butyl,lower mechaukslly as by chromatography. Aldkoxy suchasmethoxyjhydroxy, halo suchas cldoro, be separated tema~vely,the individuai d&tensmers can be sepaand nitro, such as for example,bemzyl,cl-&robe&, diphesyIm&yl, d&(4-methoxyphenyl)methyr; (v) 60 rated CM&Y or by fodg salts * a Chiral acid, of aroyf, such as phenacyf.A carboxy group also csinbe such as the individual estantiomers lO-camphon& fork acid,campboric a&& alphabTomocaB&o&acid, protect&kbtheformofanorganicsilylgroupsn&as trhuethylsilyl~ or @i-loweralkylsG* as fat exam- metkxyacetic aci& tartaric acid, diacetylktaric a&& malic acid, pyrrolidoae-mxylic a&$ and the like$ pie tzimethyl&lyloxycarboayL W~nspecttoR4;ahydroxy8lfoap’ canbepro-65ruadthenfreeinL5onoor’ bothoftljein~diastaeome&bases+optionaHyrepeatingtheproceas,soas teetedthroughthe formationof acetalsandketals,asfor exampletbrangb forma&n of the tetrabydropyr-2- obtaineithcrorboths&taatMyffeeQftheotber,i.ic, inaformhavinganopticalpurityof39546. yloxy (TEE) derivative.

5
by , l--hts ProttxtiDg group$ encomplsssed Rr, IV’ R5; and/or R6 oan be removed fidbwing hydrogenation throughaci&c or basichydrolysiqas for example with hydrogencbld to cleaveau w prom groupor w5thsodinmhydroxicietockaveR~orR+ote&ng group, therebyyklding the compounds FormulaL of Metbodsofremovingtbevmiousprotectivep;ranpsate desc&edinthestxmdardM&ences notedaboveand hwxpmed hereinby refermoe. CompoundsofFormulaII.Icanbepreparedut&ing lo procedures anatogous those descrii in U.S. Pat, to No. 4,818,819, ntiiizing howeve the corresponding habgenated pyrro10&3+3Jpyrimi&~c. Tims a pyrrolo[2$-djpyzimidkeof the form& Is

6

The product of FonnataVII then can be hydrogenated,hydrolysedto removethe Rr andR6 prot@kg groups, and,optiomtllywith intermediate protectionof any aminogroupencqmm by RF, andcoupled with a protectedglntamicacid derivativein the ma&r de+ srsrhed U.S. Pat. No. 6684,653 in asiag cmventiti condensation te&+ues for forming peptide bonds Iv suchasDCC or diphe@&lorophosphonate, followiug which the proteCtit@ groupsare removed Inafurtberva&mt,compotmdsofFormulaIIIcsn 2o be prepared utilizing the procedures dcscrii in U.S. Pat. No. 4,818,8X9. a compound the formubx Thus of

inwhichXisbromooriodo,R~,,,dR~areashwrcin 25 defiaed,is allowed to react with an unsanirated compoundof the formula:

iu which Z’ R4’Rs; andR6 aress hereindefined, , , is tiowed to react with a compound the form& of in which 251, andR4’am as hereindefined, R7 35 R3 and
is

X-R3-R'

lx

iu which X, R3, andRy are as hereindefined,in the
-c-OR%,

P

preseme of a palMum!txisuW~tcd phospbine cata40

lyst of tbc type descn’ bed~iu Pat. No. 4,818,819. U.S. l%isvariantcYfthepruceasisparticularlyauitabkf~, butisnotl&nitedto,preparationofthosecompoundsin which R4 is hydroxymethyl,in which caseRp in FormuIa Vi is a protectedhydroaymethylgroup, as for example tetrabydropynm-2-yloxymethyL 45 CompouodsofFoanalaWI&oambeobta@edby the methods0fU.S. Pat. No. 4,818,819 treat@ a by compbundof Form&~ IV with an unsatwated compond of the formalar

inwhichR~isashereinde&ed,~tbepzstmceofa H-c-c--RI* X pausdiazn/tKigubstit phosphille catalystof the type 50 descrii ia U.S. Pat. No. 4818,819, disclosure the of in which R*’is methyl, a pro&&d hydroxyme&yl., which 6 korporated hereinby n&mace. ora~trkm~~*lgroupinthepresenceofapslWhen R’ -XONHCH(CDORr\CX&ZH$XXJR~, is ladium/trisu~~ phospbinecatalyst of the. type . the product of this couplingreactkmis hydrogenated, dlscWedabov~lldsproced~isparticulattystlitablc andany protectinggroupremoved, descxii above.% far, but is not Jimitedto, preparation those camas of Alternatively, a compound ofFormula IV is allowed poundsin which R4 is hydroxymetbyL toreactwithacompouudoftbefinmuk Although not always the 688e,the compounds of FormuIaIVinwbichR~isbydrogencantendtobe somewhat insoluble solvents in suitablefor the reaction described U.S. Pat. No. 4,818,819. suchWancea, in In tbccompomukofFonnulaNinwbichR’ %shydrogen canbefkstreatedwithwithsodiumhydrideanda suitable ali@ alkauoate (such89chloromethylpivalate) inwhicb~l~Rr,R3,andR4’ areashutindefigtdin 65 tohtrodpceaa aEamykq groupin tbe 5-position aad the presenoe a paUadium/uisubstitutcd of phospbine increasesol~. AnsefPlsubckqsofcompounds&efuibotbasintercatdytgtof the type dcscrii in U.S. Pat.No. 4,818,819 medktcsandfor tbek effect on enzymes derivatives are to yield an intemxdiateof the foxmulaz

of Formula XI aud q chaim

lacking the glutaznicacid sidehydroxy&aminopyrrol~34iJp~ 3+(filr& ~l)ethyrJ-4-~droxyp~lok3-d~dk 3?25far%@&WJW~~w~~~~~m~~W~~3-22oethYl~hYdroxY~lmmnnvrrolo[2,3-d]PyrimWne, ~2-(fur-3-yl)ethylJ4h~xypyrrolo[2kWPyrin&k,. and 3+2-@~-3-yl)ethylJ4 hy~oxy~m~y~~o~[~~]p~~. As dii above,the compounds this invention of catt be prepared utiliziug the pa&&ml cataly!zed coupling of various tlnsatlXatedcompoundsdeskbed in U.S. Pat. No. 4,818,819 the glutamic acid coup&g and reactions descrii in U.S. Pat. No. 4,684,653, substWiug the amm>paiate pyrrolo[2,3dJpyrMdine foa the pyrido[2,3djpyrimidk therein disclosed. The pyrrolo[2,3djPy&idine intermediates of Formula Iv abovecan be obtainedby treating a cornPound the of formulaz
m~tWm=-W3-dlp+idh 3-@-Cf=2-~l)ethyfEe

8IKl et w

itt whiclx R4 is hydrogen,metbyk or hydroxymethyk Rs is. hydrogen, a&y1 of i to 6 carbon atoms, or 25 RfE?C,drogen, cltloro, fluoro, metbyL methoxy, trifluoromethy~or oarboe, and Y&-S-Or*ttttd 30 the pharnvaceuticauy acceptable saltstbereot inwhichRs’ andR~areashereindefiuedwithNCompounds FormulasXI and XII are obtainedby of iodosua5nimideto yield the correspondiug2,3-d& allowing a compoundof Formula VII to react with a odopyrrolo[2,3d]pyr;nidinewhich then is treatedwith compoundof the form& zinc and acetic acid to remove selectively the iodine the corre@ondingf 35 atom in the 2-posit& yielding ‘ R8 iod~yrroio@J-d]pyri@ine of Formula IV. According to the foregoing--PQ=lsof X Formulahinwl&hR~is-C3Hareob&ed.~Whena compoundof Porn&a I in which Rt is --NH2 is de. 40 sired,aoompo~diuwhic&R~is-OHcanbetreated or with 1GWriazole and .(4-&loroPhenyl)di~osphateandthe product of this reactionthen treatedwith cottcentratedammoni& A8 noted, the compoundsof this invention have an 45 effectononeormofe~eswhichutilkfolicaci& andin particuk metabolicderivativeaof folk acid, as a inwhich~Y,andRsareasherein~~,bytht For -m&s WHW-~Y~-Y-~ methodsof U.S. Pat. No. 4,818,819, namelyin the pres- ence of 8 palladillm/~bstituted PhosPhine e%taly& Iuninobvnolo%3d~~-3-~~yl~y~~ with the res&ittg coupledProductbeinghydrogenated gltttami~ aoid demonstra~ potent inbiiitory effkts~ and hydrolysed to remove the RX prote$ing gropp. 50 againstgrowth of human T-cell derived ly+Mastic leukemiacells (bin exhii an ICso of Typical compouttds FormulasXI and XZI are 3-Qof 0.004Hml. cytounricitr is not reversedby addition of phenyleWWv~v~~W,Wp~ M2-(3-fluoroPbenyl)ethyl]4hyclroxy-& puriues such as hypoxa&hine or by addition of dine, . *. by aminopynolo@&djpyrimi~ ~2-(4-fluorophenyl)e- ammomuMoleoaMxamidebut is reversed addition 55 0fthymidiiiRd.icatblg~c~illthe ~,~l~,..~,..~~olot~3-dlpvrimidine, 3-P tymidylate cycle and not ‘ de IIOVO in ptuine synthesis. e=bwPkJtY~YJ”~Y~~Y-6-~~Thecomppundscanbepsied,underthesopenGmof quaMedprofession&toinhiithegrowthofneopIas& includingcmoma, leuk& adenocar60 cittomaof the femalebreast,epidermidcaucersof the headandneok,sqaamoas small-celllung oancer,and or various lymphosa~comas. compoundscan also be The usedtotreatmycosisfbngoidesandpsoriak The eompotlttds catkbenAminiatnpAofauybUt~ 65 erablyare admi&e& parent.en~Uy, or in combialone nation with other therapendcagenls ittclttding other anti-~&geots,staoids,etc,toamammalsuff&g from neoplasmand ill need of treatment Paren-

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ted rontes of gdminirtratianin&de intram~, ofwater,andcooledsThesolidisco&ctedthron& illtra~,,tmvenousand~Dosageregifiltration- and dried under vaouUmOvctphOSp~ . mensmustbetitrated.tothepartiahneoplmqthe pentoxide 3-iodo4hydroxy-6. conditionof the patient,andthe response generally pivaloylaminop&lo[~yrcld&rimidine which c8n be hot doseswillbe&omaboutlOtoaboutl~mg/dayfor 5 purifiedfiuthex by chnm@ography over silica eluting i-10 daF or singledaily admi&tration of 25o-500 mg, with 2.5% methanol methylene ia chloride.mp >240* repeated pe&dicall~ e.g+ every 14days.While having c. ‘ &$It (d~-DMso)sl.2O@, 7.12 J- 1.8Hz, 1 I’ gHx’ (d, a low toxicity ascompared otherantimetabolites to now IQ, NM2 fs, II-I’ 11.79 lH), 11.89 1H).Anal. talc. ), (8, (4 inase,atoxicnspormeoften~beeliminatedbyeither fix C~IHI~N&E C, 36.69;H 3.64,N, 15.5a; 35.24. I, orbothofreduciugthedailydosageoradministeriug 10 Foundz 36.91; 3.58;N, 15.65; 35.56. C, Ii, I, the compound alternative on daysOT longerintervals at In a similar i&l&n &om 2,3diiodo-&hydroxy-& such as every three days.Oral dosage forms include m&ylpyrroloWd]py&idine and 2,3diiodo4 tabletsand caps&s containingfrom l-10 mg of drug W-m=WMle~~ there are rape+ per unit dosage.Isotonic dine solutionstively obtained3-iodo-4-hydroxy-6-methylpyrrol~3. 20-100mg/ml can be usedfor parenteral admi&ra- 15 dJpyrimidinemg 245’C, and 3-iodo4hyQoxypyrtioa rold2,3dlpyrimidine, mp >245”C (compound loses The following examples serveto farther ills will iodine). *NMR (&-DMso)wG!O (d, J-2.2 HZ, lH), trate the inventi~ In the NMR da@ “s” denotes sin- 7.82(a, Jr2.8 a lI$lL85 (a, J=l.l Hz, lH), 1217 glet, “d” denotes doublet,‘ denotes Y’ triplet, “q” denotesqaartet,‘ denotes h” multiplet, and ‘ denotes20 69 1H). W’ abroadpeak. EXAMPLE2 Dimethyl HXAMPLEl din-3-ylethynyl)bemyll&&mlmate To a mixtureof 3.6g (10 mmol)of welldried 3-iodoA mixture of 3:O g (0.02 mole) of 4hydroxy-6. 4-hydro~~~v~oylaminapyrtoro[~~~ in aminopyrroIo[2$d]pyrimidine 8.4 g (0.07mol) of and 40 mL of dimethy&rmamideare added4.0 g (13.19 pivaloyl chloridein 40 mL of pyridineis stirredfor 30 minutesat &om 8(r to 9[r C., the mixturethen evapo- mmol) of dimethyl N+ethynylbenzoyl)-Lglum ratedtodryness,andtheresiduedissolvedin30Iptof 30 0.38g of copper(I) iodide, 3 mL of triethylamiue,and 1.0 g of tetmk&(triphenylphosphine)@l&um.This methanol. Addition of 10%aqoeous ammonia yields4;2 mixtureis stirredat ambient tempemtures two hours for g (89%) of 4~0~~~3mL d]pyximidine which canbe further purifiedby cbroma- and then pouredinto SO0 of water. The solid is tography&rough silica get, elutingwith 8% me&an01 collectedby filtratiqn, air dried, and then refluxedin in metbylene chloride. mp 295 C WMR (&- 35 2CJDmLofmethauol~Themixtureiscooledandthe solid collected by fBtra$on,dissolvediu two liters of DMS0)61.20@, * 6.37(d, Js3.4 Hz; lH-), 6.92(d, 9H) 10% methanolin methylme cblorih and &omatoJ=3.4 Hz, ‘ 10.78(s, lH), 11.56(s, lH), 11.82(s, IH), grapbed over silica. Initial blackbands rechr<mnaboare 1H). AnaL Calc. for CnIi~iNsOz: C, 56.40, 6.02;N, H, graphedandtheeonrbinc36~l~leasbandsfromthefirst 23.92.FoundzC, 56.16H, 6.01;N, 23.67. To a mixture of 4.7 g (20 mmol) of 4-hydroxy-6.40 andsecondnmsareevaporatedtogive3.5gofdimdfl WWWrw~~~~~mlo~~ pivaloylami.uopyrrolo[2&djpyrimidine 200 mL of in ~~~-3-yle~~y~~y~~~~~w~~ dhuethylfonmamide added9.9 g (44 mmol) of Nare iodosucci+mid~ The mixtureis stirredat ambient tem- canbepmi&dfurtherby~ methanol in metbylene c&lox& mp W-285’ C peranucinthe~forl8honrs,MostofthedimethyE 2H), formamide removedby evaporation tlte residual45 *NMR fd&MSO)&l.21 (s,9H), 1.96-2.15.(m, 2.44 is and (t, 3~7.5 Hz, 2H) 3.56& 3H.),3.62(s, 3H), 4.40-4.45 slurrypourediato3oomLofwater.Thereslltingsolid (m, lH), 7.43(s, lH), 7.53(4 J=8.4 Hz, 2 H), 7.87(d, isco&ctedbyliltraticmanddriedundervacuumover J=8,4 Hz, 2 H& 8.82(a, Js7.4 Hz, 1 H), 10.95 lI3), (s, phosphoras pentoxide yield Z3-dWo-4hydroxy-6. to 11.95 lI1[). Anal. Calc. for CnH$I&z c, 6036; H (s, pivaloylaminopyrrolo&3-dlpyGnidine which can be Four& c, 60.55; 5.46;N, 1289. H, purifle&furtherby chmmatography over silica e+ing so 5.46;N, 13.08; Inasimilarf&hionbysubs&tisgauequi~t with 25% methanol inmethylenechloride.mp >290’ C. tNMR (&-DMSO)gl.l8@,9H), 10485 lw), 11.85 amountof dime&y1N-(pe&4ynoyl)Lglntemate, di(is, methyl N-(hept&enoyl)-L-glutamate, and dimethyl (s, lH), 1242(s, 1H).Anal. Calc. for CJrW~N409[2: G, N-(&x-5qmoyl).Lghamtue for dime&y1 N-(4 27.18;H 2.4%N, 11.53; 52.22.Found: C, 27.91;I& I, in 251; N; 1G&I, 52.02. 55 etbynylbenxoyl)glutemate the foregoingprooedare In a similar fashionbut start+ with Qhydroxy-6- there are obtsined dimethyl N-fs-leayat0ry-a methylpyrrolo@,3-dJpyrimidine and 4-hydroxypyr- pivaloylaminopynolo&3d@imidin-3-yl)pent4 rolo@,3&yzimidine (7deazahypoxanthinc) there are ynoyl]-L-glutamate, dimethyl N-@(4hydroxy-6reqectively obtained 2,3diiodo4hydroxy-6+nethyl- pivaloyl~op~lo~~~-p~~-~~)~t~ pyrrolo[2&djpyrin&W# mp 233’ and2&&odo4 60 enoyl~Lglutama& and dimethyl N-[6-(4hydroxy-6c,, hydroxypyzzolo@,3d]pyr&idine, >205* C. (com- p~y~opyrrolor~~p~~-~y~~-~ mp pound losesiodine). *NMR (&DMSQg7.79 (s, lH), ywYrl-W~Dime&y1 N-@ex-5-ynoyl)&glutamate be obcan 11.93 lH), 1274(s, 1H). (s, To a mia~ of 4.86 g of 2,3+odo-Ghydroxy-6- tainedin the mamjerdescrii generallyin U.S. Pat. issnqi Nov. 21, 1989,the disclosureof pivaloykm&opyrrolo@$-djpyrimk& in 100 mL of 65 No. 4,882,334 glacialaceticacidand25mLofwaterareaddedl3g whikh is incmposutkdhereinby reference, allowing by (2Ommol)ofziucpowder.Themixttureisstkedat hex-5-ynoicacid chloride (obtained treatinghex& by ambienttemperature 18hours,dilutedwith 500mL for ynoic acid with thionyl chloride)to reactwith dimethyl
25

x0

11.
L-giU~~hlthCpresenceOf~acidaGceptarsnchaS

5,344,932

12

XnAMPIB4 Dimethyl for example, by alkake hydrolysis of S-cyanopent-lN-[5-(4-hydroxy-6-pivaloylaminopyrrolo[2,3d]pyrimiYJ= 5 drn-3-yi}~~yl)thien-2vtcarbanvn-Gnlut EXAMPLE3 A mixture of 2.0 g of 3-iodo4hydroxy-6Die&y1 pivaloyiamiuopyrroio~~3dJpyrim&e# 1.2 g. of trimethylsnyh3cxty~ 0.1 g of pailadillm chloride, 0.23 g of triphenylphospbin~ 0.06 g of cuprous iodide, and 2.6 g 10 of triethylamine iu 100 niL of ac&onitriIe is heated in a A mixture of 14.6 g of 3-iodo4hydroxy-6sealedtubeforl.5hoursats(rCandthenat~~~fcK pivaloyiaminopyrrolo[2,3-djpy&nidine, 7.6 g of 2-(23 hours. The solvent is removed under reduced pressure propyny~oxy@ztrahydropyrark 798 mg (10%) of pallaand the residue t&mated with 1:l ethyl acetatehexanes. dium chloride, 236 g (20%) of triphenyl phosphine, 428 mg (5%) of cuprous iodide, 45 mi oftrietbyi amine and 1s and tiltered. The soiid thns coilected is dissolved in meihylene cidoride and this solution is passedthrough a 700 ml of acetonirile is heated at refiux under nitrogen psd of silica gel elating with 1% methanol on methyfor 12 houm. There then. are added to the hot reaction lene chioride. The eiuate is conce&ated to yieid 3mixture 33 g of 2-(2+ropynyioxy)$etrahydropyrall trimethy~yl~~y~hy~~~p~~oy~op~and retlux is continued for an additional 12 bouxs. AtIer rolof2,3dlpyrimidk heating for a total of 24 horns under reflua the solvent 20 To a soh~tiou of 1.5 g of 3-trimethylsilylethynyi4 is removed under reduced pressure, and the residue hydroxy-6.pivaloylamiuopyrrolo[2,3d]pyrimidine in fihered through silica gel using 2% me&a& in methyloo mL of a&ydr@us t&ahydrofunm cooied to 0. c. he chloride. This filtrate is concentrated and &roare added under nitrogen 4.75 mL of 1M tetrabutyiammatographed on silica gel eluting with ml kthyl acetamonium flaoridc in anhydrous tetrahydrofuran. After 5 te&sane mixture to give 3-(3-tetrabydropyr-2-yk1xy- 25 minutes, the reaction mixture is allowed to attain room prop-l -yn- 1-yl)-4-hydro4y-6-pivaloy~op~lo~%3temperature and is then stirred for 2 hours. The solvent dJpyrimidine which is further purified by recryst&zais removed uuder reduced pressure and the residue tion with ethyl acetate. purified by chromatography over siiica gel to yie3d A mixture of 2 g of 3+etrahydropyr-2-yloxyprop 30 ~~~~~~O~~~~OY~~~lOylaminopynolon

trlethylamirme. Hex&yn0icacidintmncanbepreparad,

dlp‘ yrimidine, 40 ml of methanol, 20 ml of chioroform, A mixture of 1.70 g. of 3-ethynyl4hydroxy-6. 40 mg ofS% palladium on barium sulfate, and 40 mg of pivsioylaminopyrrolo[2,3dJpyrimidin~ 230 g. of dimethyl synthetic quinoline is stirred under I atmosphere hydraN-(5aramoth;~-2-yl~yl~~~~ issued gen pressure for 40 min. ‘ be solvent then is removed by 35 (prepared as descrii in U.S. Pat. No. 4,882,333’ I’ Nov. 21,1939, the disciosure of which is incorpo~& evaporation and the residue diluted with metbylene herein by reference), 44 mg. of palladium &i&k& 130 chloride. The methyiene chlofide solution is filtered mg. of triphenylphospbine, 25 mg. of cuprous iodide, through silica gel with 2% methanol in ~ethylene cl& and1.13mLoftrietbyia&ein3OmL.ofacetonitrile ride to remove catalyst and the f’ iltrate then conceatrated to give au oil which upon adding ether yieids 40 is heated at reflux for 3 hours and then cooled to ambient temperature. The soivent is removed under reduced Y3-tetrabydtopyl-zyloxyproplen-I-~~hy&~pressnre and.the residue column cbromatographed 6-pivaloyIaminopyrrolo[2&d]pyrimidine wbicb can be (WaWs 500) eluting with 1:19 methanokmethyiene fiuther purified through column chromatography elutchlohie to yield dimetbyi N-[5+hydroxy-6igg with ethyl acetate and mcryM&ation rising ethyl 45 piv~y~~~lo[~3~p~-~yi~~l~acetate. ea-2-ylGWbonyij&ghz~te. A mixture containing 3.48 g of 3-(3-tetrahydxopyr-2. Eiy substituting eqnivakmt amounts of dkthyi N-(4yl6x~o~nen-l-yi~h~~~~v~oy~opytbromotbk&-yicarbony)&gS&mate, and diethyl Nrolo[2,3-d]pyrimidine, 3.12g (1.2 equiv.) of&ethyl N-(4(5-bromotbien-3-ylcarbony)-L-giutamate in the foregoiodobenzoyi~gWama~ 546 mg (20%) of tris-(2-methyiphenyl)phmphine, 201 mg (10%) of pailadium acetate 50 ing prwedm, there are respeaively obtained diethyi N-[4-(4-hy&o~~pi~o~~lo[~3d]p~and 85.5 mg (5%) of cuprous iodide in 15 ml of trietbyldin-3-yle-~~u~ and amineand24Omlofac&mMieisheatedatreflux diethyl N~~~hy~oxy~~~oy~p~lo~~ under nitrogen. After 12 hours., I.17 g of diethyl N-(4d]pyrimidin3 iodobenzoyQg&amate are added and the reaction mix- 55 ture is heated at reflux under nitrogen for an additional Didby . ~E4-c”brdroxyd-p’ ‘ YInmisopyr““ 12 hours, The reaction mixture then is co~~centrated ~~~” under redpressure and the residue chromatoN-[5-(4-hydroxy-6. diCthy1 graphed on silica ge& eiIltillg with 2ozl ethyl acetate:pi~oy~~~o~o~~3d~~~-~yl~~y~hexane. (by recoveredstarting material can be recy- 60 3-y@arbonyY]’ caubesindariyobtained cled through the fwegoing procedure.) The c(mcenfrom diethyl N@-bromofur-2-ylcarbony)-Lgiutamate tratedmateriaiisdissoivedin lz5ethylac!eta~and and diethyi N~5&romof~r-3-yicarbony)-L-gl~ this sol&on is &&rated for 15 hours. The solid respecdvely. which forms is collected by Ghration, washed with cold Siiy from d&&y1 N-(2-ff~o4iodobenxoyi)&yl acetate and dried to yield diethyi N-[4+(tetr&y65 Gglutamate and dimethyi N-(3-fluoro4iodobenzoyl)dropyr-2-yloxy>3-(4-hydroxy-6 -pivaloyiaminopyr” L-glutamate (prepared as descti in U.S. Pat. No. ~10[2,3~~-~y~~~-2en-2yl)b 4,889*859issued Dec. 26, ls89, the discrosme of which is incorporated herein by reference), there are respecmate.

.

hy~o~-4p~v~oyXaminopyrrolo[~~~.~ ylethyuyl)benxoyllftsrutamate. -5 iXmethy1


5

10

By allowing 3-iodo+hydroxypyrrolo~3d&imidine to react with dhuethyl N+ethynylbwzoyl)-L glutamatein the mannerdescrii iu Example2, there is obtained *ethyl N-@-(4-hydroxypyrrolc@,3d]pyrimidin-: which is 15 purikd by &romatogrqphy over s&i, m.p. 160 * C. (de@. lNMIR (dr+DMSO)81.98-2.15 2H), 2.45 (t, (XII, J-7.5 lis 2.w 3.57(% 3Q3.64 (s#3H), 4.40-4.4s(m, HZ), 7.51 ((d, Ja2.5 Hz, lH), 7.55(d, 3~8.2 Hz, 2 I-I), 7.87(8, lw), 7.90(6 J=8.2 Hz, 1 IQ, 11.97((d, J-3.7 20
-93342”3+AH),

C, 61.70;H 5.71;N, 9.m Four& C!,61.90;H, j.7l; N, 9.95. Use of 3-iodo4hydxoxy-5-pivaloyloxy4me&ylpyrrol~dIpyrimWne in plse of 3-iodo-Gydroxy4 pivaloylaminopyzroloR3-djpyrimid& with methyl eethynylbenzoate, 4-ethynYltol~ 4-ethynylberk zel& 4-etbyIlylcbJotobenzene, 4-ethyilylfl~ 3-ethynyIflaord>enzeM; I-methoxy-kthynylbenand zene yi* methyl 4-@-lIydroxy-5-pivaloyloxy4 methylp~]o~%3d~~-~yl~~y~~ 3~~m~~ph~yl)etb~~4h~~5-DivalovTcwtv-6meWpyrrok$Wd~pyrimk&e, 3-phenyleth~yl4 hydroxy-5 3+cblorophenyl)ethynyl4hydroxy-5fluorophenyl)ethyuyl4hydroxy-5-pivaloyloxy4 methylpynolo[~3-d&@iui*~ and 3+methoxyphe@ethynyl4hydroxy-5-pivaloyloxy4methylpyrrol~2,3dJpyrimidke.

_ _ EXAMPLE6 Altemetiv@iy,by substitutingequivalentamout~ts of methyl 4-ethjmylbenzoate+ 4&ynyltohmn~ 4-eth~y~Diithyl . benzen% 4”ethynylcblorobenzefl~ 4-ethynylfluorobenN&~-@-hydroxy4pivaIoylaminopyrro1o~ Zen& 3-ethynylfluorobenz4m~ I-methoxy-sethy-25 and d&imidin&y~)ethyl@enzo yl)-L-gkmate nylbenzenei the pmcedme of Example2, there are A mixture of 1.0 g of dimethyl N-[4+hydroxy4 obtained methyl 4+hydroxy4pivaloylaminopyrpivaloylaminopyrrolo[2,3dJpyrimidi&-ylethynyl)benrolo[%3-d]pyrimi~-~yle~~yl)~~ wia methylphenylF)ethynyl-4-bydroxy4pivaloyIaminopyr- zoyl]-L-glutamate 250mL of 50% methanolin methis rolo@3+Ijpyrimidine, 3-phenylet&ynyl4hydroxy4 30 ylene chloride and 0.8 g of 3% palladinm-on-carbon at pivaloyhtmiGpyrro~o[~~yrimi~ 3-@-cldoro- hydrogenated 50 psi for three hours, fikred, and under reducedpressure, solid is co& The phenyl)ethynyl4hydroxy4pivaloylaminopyrrolo[2,3- concentrated lectedby filtration anddried to yield 0.72g of dimethyl dfpyrimidin~ 3-(4 -fluoroplienyl)e,tb~yl4hydroxy4 pivaloylaminopyrrolo(2,3d]pyrimidine, 3-(34luoro- N-IA-‘ 2~~h.“M1..4~~oy~~~lo[~3pheny~~~y~h~xy~~oyLaminopy335 d~yrimidin-3-yl)ethyl&mzoy~~-L-glrrta dJpyrimi~ and 3-(4-methoxyphenyl)ethynyl4 C NMR (&-DMSd)s131 (s, 9X), 1.90-2.12 g 7; hydroxy4pivaloylaminopyrrolo[2,3+yrimidk 2.42 (t, J=7.4 Hz, 2%X), (t, J=4 Hx, m 297 (; 292 Use of 3-iodo4hydro~.,,lo[2,3-d]pyrWdine in J-4 Hz, 2H), 3.55 (st 3H), 3.61 (8, 3H), 4.38-4.45(m, place of 3-iodo4hydroxy4pivaIoylaminopyrrolo~~3- HI), 6.61(s,IH), 7.29(4. Jw8.2 Hx, 2I.Q 7.75(d, J18.2 dhpyrimiaine with methyl 4+thyny&enzo&e, 4- 40 Hz, 2 H), 8,64(d, Jm7.4Hz, 1 IQ, SO.75 III), 11.22 (s, (s, ethynyltoluene, 4-ethyny~ 4-ethy~ylchloroben- HI). AnaL Calc. for C27H4%07z C, 60.10;Ii 6.17;N, zene,4-ethynyllluoro~ 3-ethynylfluorm 12.98. Found:C, 59.aL,H, 6.u; N, 12.72. and l-methcsy4ethynyWnzene yields respectkly EWWPLE 7 methgl 4-@-W=m~4%~l~W~-3-~b thynyl)benzoa& 3+methylphenyf)ethynyl4hydrox- 45 DillWhy ypyrrolo@,3-aJpytimicrine, 3-phenylethynyl4hydroxN-(~2-(4-hydroxy4pivaloykuninopynolo[2,3wml@Mp~ W~Wzopbes~l)ethyn~ld~~--3 ~hydroxypyrroIo~2,3-@py+idine, 3-(4&orophexy~M+w~+v~yw+@Wl~~ am-~ W-methoxypherily~m~~~~~~yrr~~~~ 5o BY subjecting dimethyl W~WW=Y~ dlpyrimidine. pivaloylaminopunol[~~~~~~~yl~Ten gramsof 3&do4hydroxy4methyIpyrrolo[2,3en-2-ylcarkmyl]-Q@amate to the hydrogen&ion d&rimidiie BT~ allowed to react with 2.19 g of 80% procednreofEkzmple&tbereisobt&eddimetbyl sodium hydride.oil diqedon and 75 ml of dimethyl- N-~5-[~~hy~~4~~oy~~o[~ formamide with the exclusionof moisture. After 30 55 dJpyrim;rdin-3-yl~yl3tslien-2-ylcarb minutes, 6.02 g of chlorometbyl pivalqe are added. Tbismixtureisstirredf0rtbrezehourspouredintowaSiily the foknving compounds sub&ted to are ter,andneutr&edwith~acidThesolidis&rothe hydrogenationof &ample 6: matographedon silica gel with acetone-dichloromethaneto yield 3-iodo4bydroxy-l,5-bis-(pivaloy~oxy)-6 (a) dimethyl N-(2-fluoro4(4-hydroxy4pivaloyl60 amioopymilo[s3~]p~~~yl~~y~~l~ metbylpyrrolt#$-d]pyrimid& nap. 15s’C. iuitially, ‘ L-gtlttamate; followed by 3-iodo4hydroxy-5-pivaloyloxy4metbyldimethyl N-p-fluoro4(4hydroxy4 0 pyrrolo[2sdjpy m-p.236’c pivaloylaminop~lo~Jp~-3-yletllynyl)Use of ~i~A_hy~o~-~piv~~~4rne~y~~rolo[2,3d]py&nidine in the procedureof E&ample2 65 bf=WW-lW=@% (c) diethyl N-[q4hydroxy4pivaloylaminopyrthen yields dimethyi N#-(4-hydroxy-5-pkloyloxy4 rolo@,3d&rimidk~3-yletbynyl)tlden-2-ylcarmethylp~o[23d~~~y~~y~~~L+aamate, ‘ 196’ AnaL C!alc.for C&&N& lap. C bowwdtamatt;

5,344,932
(d) . diet&l N-[S-(4hydroxy-6-pi~Ioylrm$nopyrrolo[~~~~-3-y~e~~yl~-~y~pivaloyv Qr~~~~~~~~hy~~~v~y~~~boww-@=* (e) dhaethyl N-f ~lo[~~]p~-~y~~~oyl~~~~~ 5 0 3-[2-W=rQPh=YlMYWhYd=y?6. (0 dimethyl N~7-(4hydroxy&pivaloylaminopyrpivaloylaminopyrrolo&3dJpyrimid& rolo[S3~~~~y~h~t----.l~~~ 0 ,3-@W~~~~~W-=+ (s) diiethyl N+-(4hydroxy-6-piv&oySamin6pyrpiWloykWqyr&o ~lo[2;3d~~~~y~h~-S-~y~]-~~~~ s-t2-(3-auorophenyl)ethyll-4-hydroxy-6(m) @) methyl 4(4hydroxy-6-pivaloylaminopyrrolo[2,3- Pi.vaW~~WJdIp~diIlG 10 d]pyrimid&-3-ylethynyl)beozo9te; 3-[2~4methoxy (n) 3-(4methylpbenyl)ethynheoyr)ethydroxy-6pivaIoylamixopyrrolo[2,3d]pyrimidisq 0 pivaloylaminopyrro~o[2,3djpyrimM+g (0) methyl 4~2~4hyd~~~~ylp~io~~~ @ 3-p~yl~~~yl4-hy~oxy-6~~oytamin pyfMdin*3 -yl)etiylJbenzoa~ 15 op) rolo[2,3d]pyrimidiq 3-f;r-fsmetbyr~y~~yl]~y~y-S3-(4chlorophenyl)etbyny~4hydroxy-6- pivaloyloxy-6-m&ylpyrrolo[2,3d]pyximiding KJ pivaloylaminopyrrolo[2Jd&rimidk~ (9) 3-(2-ph~y~yl~hy~-5-~oylo~~~ 3<4~uorophenyl)cthynyl4hydroxy-60 ~Ybmot%3 pivaloykminopyrrolo@,3d]py&idixq 3(3 3-(3-fluor~h~yl~~y~4hy~~~ 20 pivaloyloxy-6-methylpyrrolo (ml [2,3d]pyrimid& pivaloylaminopynolo[2,3d]pyrimidine; 3-[2-(4-aaoroph~l~~~]~y~~-S6) ~3-(4m&hoxyphenyQethynyl4hydroxy-6- pivaloylo~~~y~~l~~3d~~~ 00 pivaloylaminopyrroloEs3-d2pyrimidine; ~2~4rn~~o~h~yl~y~~y~~-~ (0 (0) metbyl 4(4hydroxy-S-pivaloyloxy&-meihyl-pyrpiva.loyloxy-6-methylpyrrolo~~3dJpyrimidiaq 25 (u) methyl 4[2-(4bydroxypyrrolo[2,3dJpy&nidin-3rolo[2,3d~~~-~y~e~~y~b~~a~ 3-(4met.bylphenyl)et.hynyl4hydroxy-5- Yl)ethyllbenzoate; OI) pivaloyloxy-6.metbylpyrrolo[2,3d]pyrimidine; (v~~~~thylphesyl)ethyl]4hydroxypyrrolo2,3(4) 3-phenylethynyl4hydroxy-S-Pivaloyloxy-tjmethyL pyrrolo[2,3dJpyrimidiq (wzG-phenylethyl)-4hydroxypyrrolo[2,3 dlpyrimi. 3-@-chlorophenyl)ethynyl4hydroxy-S30 Q pi~oy~x~~rnethvravrrolo[~3~~~~ (x~~~~~~yl~yll4hy~o~~~~3(s) 3-(4fluorophenyl)ethynyl4hydroxy-S-pivaloyioxy6-metbylpyrrolo[2,3d]pyrimiaine; 6~~~~~~~h~yl~yl~h~o~~lo~33-(4metboxyphenyl)e&ynyl4hydroxy-5 (0 pivaloyloxy-6-metbylpyrroloa-methylpyrrolo[2,3afpyn’ 35 (z)3&2-@-~~oxyph~ylkthyl]4hydroxypyrrolo2,3mid (u) methyl q4hy~x~~olo[23d~~-3-yleWvl)b-w EXAMPLE8 (v~~~~~~~yl~~~y~h~o~~olo~3. Dietbyl N-[4-!!5 (wiDe;J-3d~~40 l~~y&~~-~~o~~3~4hy~~~~ pivaloylaminopyrrolo~p~~-~yl~~2(x~~~~~ph~~~~yl~hy~ox~~o~~~ Yl3WYl]gWa=te A solution of 1.16 g of dietbyl N-[4(1-(tetrahy(y) 3-(4fl~~~h~y~~~yl4hy~2cKophenyl)ethynyl4-hydroxypyrrolo2 45 dropvr-2-y10~~3~~h~~4pi~~~~~dlpyriniidiae;and rolo[~3~~m-3-y~~~~-2-yl)~l~(z)Y[~3mate and 174mg (20%) of amorphous platinum(IV) oxidein 150 of glacial-tic acidis hydrogenated ml for Thereare respectively obtained: 1OhoursatSOp&Thereactionmixhseisdiktedwith N-[2-&n-4(4-hydroxy-6. dimethyl 6) . pivaloylamkopyrrolo[2$djpy&nidin-3-ylethyl)bcn- SOmlofmetkolandfilteredthronghCelite.The SO fiitrate is concentrated diluted with ethyl acetate. and =Ml-L-dB N~3-fhtoro4#-hydroxy-6. The solid which forms aAn cooling for 15hour is coldimethyl .@I and pivaloyiaminopyrrolo[2Jd]pyrimidin-3-ylethyl)ben- lectedby filtmticm, washedwith cold ethyl acetate driedto give diethy N+k(.l +ctr8hydropyr-2-yloxy)-3zoYl]-Lglutamate; (c) diethyl N-[4(4hydroxy-6-pivakylmninopyr-55 (4hydroxy-6-pivaIoylaminopyrrolo~2,3d)pyrkidin-3rolo&3d]pyrimidin-3-y~ethyl)thien-2-ykarbonyl~ yl)prop-2*yl)belEoyl~~t.l= w-w EXAMPLE9 (d) diethyl N-[5-(4hydznxy-6-pivaloylaminopyr. rolo[~3d]primidin-3-yle~yl~~~yi~nyl~ N-~~2~4hy~o~~~~~]p~~-~y~60 wu-l-5 ’ thyl&ezGoyl3-L&tam8te (e) climetbyli N+5-(4hydroxy-6-pivaioylaminopyr~ A m&ure of 1.1g of &methyl N-Ey4hydroxypyrroloE3;3-d]p~~-~y~~n~l]-~~~ (0 dimethyl N-[7-(4bydroxy-6-pMoylami~pyrrolo[~3-alpyrimidin.3-ylethynyl)benm\ in1oOmLofSO%methat1olinme&ylenechloxideand roW3-4pIYrimidGW~epty~L-ghitama~ is hydrogenated SO at @) ~dimetbyi N-Es-(4-hydroxy+ivalo~kminopyr- 65 0.8 g of 3% palladium-& p.s.i. for 24 hours, f&crcd,.and concentrated under rolO(~33a-~)~l]-~~~~ reducedpressure. Etha: is addedto the residue the and 0 =W W-Wwirw~ti~~~Iaminopyrsolid is~colle&ed f&r&ion anddriedto yield 0.67g of by ro~o[2#3~yrimidin-3-yl)e&yljbWoatq

0

~W+-m~~;~~W=wj-

5,344,932

dimethyl N-{q2 -(4 -~;~opyrroIo &3roloP,3-dJ-@nidin-3-yl)prop-2-yl)bcnxoyI]gIutrmric e&d. dl~d--iMy~@W17V-172 C ~NMR ’ (dblDMSO)Eil.!W-2.14 2$$ (m, Similarlyfrom dimethylN-(2-nnorc-n-r 2.44(t7k7A Hx#2IQ 2.93-3.02 2li), 3.57(s#3Ii), (ub ~PivaWhnninop~oW2&dbyrhnidin-3-yl)-ethyl]and 3.63 (s#3l.Q 4.40-4.70 IQ 631($# 1l-Q 7.29 (a, 5 benzoj43-~&~tamatc dimethyl N-{3-flm2. (I& 3~8.2 Hz, 2 El& 7.77(m, 3 H), 8.66(d, Jt7.4 Hz, f H), (4~Yd=m5-P+=w~m~~tW~~11.52(q 1l.Q 11.71 1H). (q 3YlkWb=W0-L-gI=nxte there are respectively obtained,according the f-going pro&&m N-(2to In a siniiku firshion fkomdiiethyl N-[4(4hydroxy& fluolWq2+qXIro~~yrrolo[~3dJpYrimipivaIoyloxy&nethylpyrrolo[2,3djpyrimidin-3-y& tllynyI)benzoyl}-tglu~ thereis obtained accurd- 10 din-3-yl)ethylJbenxoyI)&giutamka&$ m.p. 230. 3o[r c (k) and N-{3&0~2-(4 ing to this proceduredimethyl N-(4[2-(4hydroxy-S- &miu& pivaIoyloxy-6-methylpyrrol~2,3~pYrimidin-3-yl)e- hy~~~~~lo~~3~~~~rn-~y~ylJbenxoylWghltamic aoid,IILp. >uxT c @cc.). ’ thyl]ben!zoYl)-L-ghl~ mp. 163.6. In an analogous fashicm the foregoingprocednq to EXAMPLE 10 15 therearemapective obtained from dietbyl N-<4[2-(4 hydro~Jp~~-~ N-~4[2-(4-hy~o~-6-pivaloylaminopyrrolo y~~yI~~2-yl~~y~~-~~~~ diethyl N-{5d]pyrimidb3-yQethyljkznoyl)-tglutami Acid [2~4h~~~piv~y~~~olo[~3d]-py A mixture of 1.5g of dimethYlN-(4[2-(4hydroxy6- din-3-yl~yl~~yl~~3-~dntamn~ pivaloylamioopyrrolo[2~~~~~~y~y~* uf methyl N-~S~2-(4hydroxY-6-pivaloylami.nopYrzoyI)-L-glutamate 10mL of IN sodiumby&oxide is in rolo[2,3d~~~3-y~~y~~-2-yl~~nyl~-~ stirred at ambienttemperatures three days to form for glntamatc, and dimethyl N-<5-[2+hydroxy& the sodium salt of N-(~-(4hydroxY&minopYrpivaloy~opyrrolofX3-alpyn$lidin-3-yl~yl]~rolo[~3~,~~aXp:yrimidio-2-yf)ethyl~~~u~ 2-ylcabonyl>-L-glWamatc, the compounds N-f412-(4 acid This is neutralized with glacial acetic acid The 25 hydroxy~~p~Io~,~~~~-3-yl)~yl~solid which forms is collectedby filtration and recrys- thien-2-yIc~bony1) acid, N-f s-12-(4 talked Tom 50% methanolin metbylenechloride to hydroxy~~~~oro~~~~~-3-yI)e~yl]~give 0.8 g (67%) of N-(e[2-(4hydroxy-&minq~~en-3-yIcarbonyl)&q$utas& acid, N-{5-@(4hydroxyrolo[2,3-d]pyrimidin-3-yI)ethyIJbenzoyI)-L-gIutamic 6-~~olo[2,3d~~m-3-yl~yl]~-2-yl)eth acid. INMR (d6-DMsO)6 1.80-2.00 2H’ 210-2.30 M bonyl&@amic acidsm.p. 2OOX!O3’ and N-f5 (m, ), C, (m, 2H.J 277-2820 (m, w), 289-2.93 (m, 2lQ, [2~4hYdroxy-6-aminopYrrolo[~3dJpYrimid&id&~ 4.13-4.19(m, 2H), 6.25 (d, J=1.3 wz, El), 7.23 (d, thyqthien-2+arboxlyl}-l&ltic m.p. . J=8.1 Hz, 2 IQ, 7.69(4 Jt8.I Hz, 2X), 8.13(a, Jx6.7 241’ -243” C
l

18

Hz, 1 Is), lU.55 (s, ISI).

Diethyl pivaEoriamiaopVnroloi23-d’ jpyrimidin-3-y N-[4cCl-hydroxy-3-(4hydroxy&‘ vaIoylaminopyrL-glutamate, and dimethyl N-[d(ehydroxy-a roIo&3-d)pyrkidin-3-yl)prop-2-ylbenxoyl&$Uanlate pivaIoylau3$opyxrok$~3~pyrimidin-3-vt’ F )-hexrmnvnThe solution of 0.94 g of diethyl N#+(tetrahy- 4o L-gIu~te, are, reqectively, N45-(4hydroxy-6i~oyl~~~o~. aminop~~[~3-~-3-yl)pen B,3-a)pu~~ in 40 glutamic acid, N~7-(4hyd1~~Y-6-aminop~rrolo[2$ ml of O.lN methanolic hydrogenchloride is stirred at dEpYrin&ik-3-yi)heptanoyl&gIutamic acid,and N-&ambient tqmperatnres 2 hours The reactionmixtnre (4hy~~~~~~~~~p~~-~yl~~for isnentratizedwithasolntionof2M*gofsodiumcar-4~ anoyl&L-glutaulic acid, bonateiniOmlofwateraddmostofm$banoIremoved byevapomtionunderreducedpmsnre.0nehundred nGllilim of methYSene chlorideareaddedandthe soInbenzoyl~&+tamic Acid tioniswa@dtwicewith2Omlofwater,driedover anhydrousmagnesium &fate, and concentrated..The S0 A mixtum of 0.5,g of dimethy N-ceEz(rhYdsoxresidueis tritumted with 1~2 ethyl acetateand ether, ~~olo~~3-dlpyimidin-3-vl)ethvrmenzovl iiltered, anddriedto give die&Y1 N-[4&l1ydroxy-3-(4 matein3mLofINs&iumhydroxideiss&edatambihy~~piv~~~~l~[~~p~-3ent temperatures threedaysto,fonn the sodiumsaIt for YDPffJP-2-YObauoY~M~ 55 of N-f4[~4hy~o~~~~[2~]p~~ 3-yI)ethy@ez1xoyI&&tamic acid This is nentmked EXAMPLE 12 with hydrochloric acid The solid which forms is collected by filtrzttionand.fkommethanolby additionof water to give 0.35 g (75%) of N-0-&(4 A solutionof 0.3 g. of diethyI N44{1-bydroxy-3-(4 60 by&o~~~~~,~~-~~I~Yl~~~ L-glutauk add. m-p. >230’C, IN’ (d,j-DMSO)gI.MR hydroxy+ivaloyIaminop~lo[2,3-djpYrimidin-3yI)prop-2-y0benxoyl@ntamate9 ml of IN aqueous 8&2.12 (mt ?.lQ,233 (k J-7.3 EIZ,2Ii& 2.97(L& 4EQ iu sodiumhydroxideis stirred undernitrogenat an&k& 4.33-4.40(a El), 6.70 (d, 511.2 Hz, IH), 7.28 (d, Ja7.0 Hz, 2 H), 7.76(m, 3H), 8.50(d, J-7.6 Hz, lH), t.eqemmfor72hours.Thereacdonmixtureiarenderedslightly acidic @El== with. 1N hydrocldoric 65 I 1.48(s, IH)s Il.67 (s, lH& 1240(br, lH) . -4) In a similar Won kom dimethyl N-f4Ez-(4 acidandillwedThesondthuscollectedbwashed witbwater(5mI)andcoIdethanoI(5mI)and&iedto h~~-~~~oy~-~~y~~Iot2~~ :F&(4@hydroxY-3-(4hydroxY&m&opyr- din-3-yl)ethyl)bqxo$3-~gIWnnate,there is obtained give

19 20 accordblg~tbeforegoing~urefirsttbeMxliam they do not iuhibit the pnrine de novo biosynthesis N-{~[2+lQdma+~&yl~~oiO~3salt of pathway,but is reversed thymidine,Wicatiug thyby dfpyrhndW-yl)etby@?nzoyl~-L-glutamic wh.kh acid midylatesynthetaseistbemaintargeLCytotoxic$tyis uponnetddiqtion with glmial acetkacia yieldsNd4 by [2-(4hydro -6-methylpynolo@,3d&&Gdin-3-yl)e- 5 alsoreversed add&n of leucxnmin,WW.ing the cytotoxicity is due to antagonism a folate-related, of tbyqbenzoy~ 7 q+tamic acid, mq. 291 * C WMR (ds-DhfSo)82.32 4w), 2.48 (s, 3H), 2% (mj 4K), meca (m, 4.26(m, Ill); 6.60(s,’ 7.26(d,J=8.W&, 1 H), 7.75 Hi), lntivoa&vityc2mbeseenfromthefollowingrepre(4 J-7.76 Hz, IH), 8.” (a, J=2.96 Hz, Hi’ 11.26 ), (s, sentative data fat N-+Q2-(4hydroxy&minopyrIH), 11.59 1H). (% 10 r~~~3-d~~~-~yl~yl~yl)c By subjecting methyl~2-(4hydroxy+pivaloyloxyacid againstthe WZ78WMC- tumor line in DBA/2 6-me~ylp~ralo(2723-~1~~~~~ 3-[2~4methjtlphenyI)ethylf-4hy~~ mice(female)* admin&&on beingip in a total volnme pivaloylaminopyrrolo&3d]pyrimid& 3-@phenyk= of OS mL daily for eight days:
Dose% S&ii&m Toxicity Tumor weight

ph~y~~y~~by&o~~~~oylami 0 W6 3606f2099 control 0.0 d]pyrEdirq. 3-I2-(3&orophenyl)etbyl”‘ -hydroxyh 0 W6 5533 f 1234 0.0 pivdoyIaminop~ooloR3-dlpyrimidine; W-W M) c!oaros 1OTJ Of0 O/l 2oom metbox~henyl)ethylJ4hydroxy-6-pivaloylaminopyr100 loaoo O/l Of0 rolo[2,3d]pyrimid+ and methyl 4[2-(4hydroxy-6ULOO 100 Of0 O/6 pivaloylaminopyrrolo[2&dJ-pyrimidin-3-yl)etbylJbenloo o/7 Of0 2s.w zoateto the foregoing proceduretherearerespectively 12.50 9s o/7 IMf 166 4[2-(4hydroxy-&metbylpyrrolo[2,325 obtained d]pyrimidin-3-yl)ethyl]benzoicaci& 3-[2-(4methylphenyl)etbyl]4-hydroxy-6aminopyrrolo[2,3-d]pyrimi- whatisclrdmedis: dine; 3-(2-pb~y~etby!\-bhy&o~~~~~lo[%31. A compound the formulaz of d]pyrimSne: 3-4hy~xy~ aminopyrrolo[Z3-a]pyrimiaine; 3-[2-(4fluorophenyl)e-3. ~yl]~hy~~xy~ad~~ 3#I (3-auoroph~ylk4hy~~~p~l~~ iI P #=N C-f-Cl&~-R3-CNH~&C--OR2 l d~yrimidine,m.p.29Y-298.;3-@-(4metboxyphenyl)ethyl]4hydroxy-6aminopyrrolo[2,3d]pyrimidine, m.p. C-OR2 28W-284" aud 4 [2-(4hy&oxy&minopyrrolo[2,3- 35 C; R’ RS ~pylimidin-3-yl)etbyl&$Ilzoic acid, nap. ,300” c. 8 -LE 14 Representative tion valuesagainst inhii’ CC!RF-C!EM inWhich: 5 cell culturesfor typical compounds as follows: ao R*is-OHor-NH% are Rz is hydrogen.or a plmrmaceutidy acceptable cstiom 2% R3 is L4pbenylene uns&stitutedor s&stituted with >10,00 chloro, flmro, methyl, methoxy, or tzifluoro45 meth&
0.004

the cxmfigmtion aboutthe carbonatomdesignated * is s. 2.Acmpon.ndacmrdingtoclaimlwbereinR~is 0.019 -0Ii; R3 is 1,4pbenykne, R4is hydrogen and 3. ‘ II&compoundaccording claim1 whichis N-{4 to 55 {2~4hydroxy-saminop~lo~~~]p~~~yl~ >uIxx) thyl]benzoyl&$uta& acid. 0.023 4. The cornpod according claim1 which is N-(4 to [l-hydrolrp-3-fehydroxy-scaminopyrrolo[23>20.00 acid.. 60 din-3-yl)prop-2-y~b~yl~ghztamic 5. The compound acmdiug to claim1 which is N-(20.0084 fluoro4~2-(4hydroxy-6-aminopyrrolo[2,3d]pyriu& din-3-yl)etbyl&nzoyl3-L-gllltamic acid. 6.Thecompoaadacco&ngtoclaimlwhichisN-{3fluoro-4&(4hydroxy-6&ninopyrrolo[2,3-dJpyrimiacid. The cytotoxicity of thesecompounds not revemed din-3-y1)e&yX&enzoyI3&gSutamic is 7. A compound the form& of by the additionof hypoxantbine AICA, suggesting or
0.008

>2MQ

50

21

5,344,932

r”

t’ ‘ g

P 43-aQui-Rs-b ,h b p

P

R*3s-OIior-NH~ Rr is hydrogen,& p-&y amptable cation,oraai&xyprotectbggroup: R3 is f&phenyke tmsuldtnted or s&s&ted with chloro, fluoro, methy& method, or. triflwro. ./ mcehyf R4’ l~ydrogm or methyl is R%uuninooraniinotibstitutedwithanaminoprotectiqg mm and 10 theconfiguratiou aboutthe carbouatomdesignated * is s. * * 8 I *

22

2s

30

35

40

45

50

55

60

65

POOZ/S/Z

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EXEIBIT IV

/**

!

Lilly Research L&oratories
A 2wsion @i El1 L~llv and ComDanv

July 8,1992

Food andDrug Administration Centerfor Drug Evaluation Research and CentralDocument Room2-14 12420Parklawn Drive Roclcville,Maryland 20852 Re: Initial Submission LY231514 Disodiumfor Injection- SerialNo. 000 -

In accordance CFR 0 312.20,we acre with subtitting an Investigational Drug New Application(in four volumes)for the new drugsubstance, LY231514Disodium.
(‘ ..

LY231514Disodiumis a folk acid antimetabolite a specificantagonist and of thymidylatesynthase will be testedas an oncolyticchemotherapeutic for solid and agent tl~j@ .sms. Accompanying letteris Form FDA’ this 1571informationsupporting Phase studiesof I for LY231514Disodium Section6(a) containsthe protocol(I-I3E-MC-JMAB-001) the with conversation initial safetyandpharmacokirietic study. In accordance the telephone with Ms. Ellen Cutler (CSO) on July 8,1992, theFormFDA 1572is beiig submitted for 6 (b), (c) and(d) with the exceptionof the curriculumvitae (item 2 of the Form 1572). In accordance the request with outlinedin the letter of April 27,1992,thefollowing informationis provided: 1.
2. 3.

ProtocolTitle: A PhaseI Trial of LY231514Administered a Bolus Infusion as Every Seven Days ProtocolNumber:W3E-MC-JMAB-001 M.inimumQualificationsof PrincipalInvestigator: Licensed, Boardcertified andPracticingOncologist

.

lY23 1514IND SerialNo. Ooo July 8,1992 Pap3 2

4.

DanielD. Von Hoff, M.D., F.A.%.P.,the principalinvestigator meets the above qualifications. Universityof TexasHealthScience Center Department MedicineOncology of Section Clin&alDrug Development of ‘ Floyd Curl Drive 7703 SanAntmici, Texas782844884

5.
6.

Namea&

of the InstitutionalReviewBoardsarelistedin the Form 1572andin item 3.3.4of theprotocol.
address

Names quaIi&zations subinvestigators and of workingunderthe supervision of Dr. Von Hoff: Thefollowing subinvestigators boardcertifiedand/orpracticing are oncologistsa Karen’ Bowen,M.D. HowardA. Burris, III, M.D. JohnR. Eckardt,M.D. Stephen Kalter, M.D. Pamela New, M.D. Tiiothy 3. O’ Rourke, M.D. PeterM. Ravdin,M.D. DavidA. Rinaldi,M.D. GladysI. Rodriguez, M.D. MaceL. R&c&erg, MD. Len Smith,M.D. James Wall, M.D. GeofferyR. Weiss,M.D. The following s&investigators licensedpharmacisG are experienced assisting in in clinical studies, James Koeller,M.S. John6. Kuhn, Pharm.D.

(.

.

THIS DOCUMENT CONTAINS TRADE SECRETS, OR COMMERCIAL OR FINANCIAL INFORMATION, PRtVlLEGED OR CONFIDENTIAL, DELlVERED IN CONFIDENCE AND RELIANCE THAT SUCH - INFORMATION WlLL NUT BE MADE AVAILABLE TO THE PUBLIC W ITHOUT EXPRESS WRITTEN , CONSENT OF ELI LlLLY AND COMPANY.

AMENDMENTS AND SUPPLEMENTS TO THIS DOCUMENT MAY CONlAiN TRADE SECRETS, OR COMMERCIAL OR,FINANCIAL INFORMATtON, PRlV&EGED OR CONFIDENTIAL, DELIVERED IN CONFtDENCE AND IN REIJANCE THAT SUCH INFORMATION W ILL NOT BE MADE AVAILABLE TO THE PUBLIC W ITHOUT THE EXPRESS WRITTEN CONSENT OF ELI LlLLY AND COMPANY.

DEPARTMENT OF HEALTH AND HUMAN SERVKES
FOOD ANQ ORUC ADMINISTRATION

PURLliZHEAL?ti SERVICE

INVESTiGATIONAL NEW DRUG A~WATON (MID) (TlTlE 2% CODE OF FEbER.41KEGUfAlYQffS (CFR)Paff 312)

Lilly Corparate Center Indianapolis, Indiana 46285

(317) 276-2000

I

8. PHASE (5) OF CLiNICAt lNVESTtGAT,TtONTO BE CONDUCTED: m PHASE 1

Q PHASE 2

0 PHASE 3

0 OTHER ISDetiho

9 I.61 NUMBERS OF ALL INVESTIGATIONAL NEW DRUG APPCICATIONS (21 CFff P,n312j, NEW DRUG OR ANTIBIOTIC APPLICATIONS (2 t CFR P4~3l4). DRUG MASTER FILES 91 CFR 314.420). AND PRODUCT LICENSE APPLICATIONS (21 CFR pdl't 601) REFERREDTO IN T! APPLICATION.

DMF4700 DMF1546 DMF5919
TO.

IND submissions should be ccansecutiveIynumbered. The initial IND shouldbe numbered “Seribl iNumber: 000. ” The next submission (e.g., amendment, report, of correspondence) should be numbered “Serial Number: 01. w Subsequent submissions should be numbered consecutive/y in the order in which they are Wunitted.
a RESPONSE TO CLINKAL HOLD IN0 SAFETY REPORT(S):

SERIAL NUb

000 --

11. THIS 5UEtMlSStON CONTAINS THE FOLLOWING: (Check all that apply) n INlTiAL INVESTIGATIONAL NEW DRUG APPUCATION (IND) PROTOCOL AMENOMENf6): 0 0 0 NEW PROTOCOL CHANGE IN PROTOCOL NEW rNVESTlGATOR 1tiFORMATlON AMENDMENTtS): f-J CWEMI5TRYIMKROBIOLOGY m PHARMACOLOGY~O~iCOCOGY 0 CLtNKAL

0 lNlTlAL WRITTEN REPORT 0 FOLLOW-UP TO A WRITTEN REPO;

(J RESF’ ONSE TO FDA REQUEST FOR INFORMATION DREQUEST FOR REINSTATEMENT OF IN0 THAT IS WITHDRAWN. lNACT1VAFED. TERMINATE0 OR DISCONTINUED

0 ANNUAL REPORT

0 GENERALCORRESPONDENCE

.

CONTENTSOF APPUCAllON This application contains the fokwing items: (check all that apply) m a # m a 1. Form FDA 1571 [2? CfR 312.23 (a) (?)J 2.Table of contents 121 CM 3 22.23 (a) (211 3. introductory statement I21 CFR312.23 (a)(311 4. General investigational plan /2l CFR312.23 (a) (311 5. Investigator’ brochure [2? CFR332.23 (a) ES]J s 6. Protocol(s) [21 CFR312.23 (a) (631 m a. Study protocol(s) [21 CFR312.23 (a) 161J m b. Investigator data.[2f 0% 312.23 (a) (li)(iii)&)J or completed Form(s) FDA 1572 a c. facilities data I21 CFR312.23(a)(6~(iii)(blJor completed Form(s) FDA 1572 m d. lnstjtutional Review Board data 121 CFR312.23 (a) (li;)(iii)(&>J& completed Form(s) FDA 1572 I 7. Chemistry, manufacturing, and control data l2l CFR312.23 (a) (7)J . 8 Environmental assessment or claim for exclusion f2,’ CfR 312.23 la) (7)(iv)(e)J m N 8. Pharmacotogy and toxicology data D? CFR3t2.23 (a) (8)J 9. Previous human experience 121 CFR312.23 (a) (9fl 121 CfR312.23(a)(lO)J *
fl YES

m 10. Additional information

13 IS ANY PART Of THE CLINICAL STUDY TO BE CONDUCTED BY A CONTRACT RESEARCH ORGANIZATION?

l

NO 0 NO lDENTlFlCATlON OF

IF YES, WILL ANY SPONSOR OBLIGATIONS BE TRANSFERRED TO THE CONTRACT RESEARCH ORGANIZATION?

0 YES

IF YES. ATTACH A STATEMENT CONTAINING THE NAME AND ADDRESS Of THE CONTRACT RESEARCH ORGANIZATION, THE CLlNIC4L STUDY, AND A 1lSliNG OF THE OBLIGATIONS TRANSFERRED. 14

NAME AND TITLE OF THE PERSON RESPONSIBLE FOR MONITORING THE CONDUCT ANDPROGRESS OF THE CLINICAL INVESTIGATIONS

J. )I. Holcombe, M.D.
15. F;EM;$i)tND T&TLE(S)OF THE PERSON(S) RESPONSrELE FOR REVIEW AND EVALUATION Of rNFORMATlON RELEVANT TO THE SAFETY OF

Sameas 14 above
I agree not to begin clinical investigations until 30 days after FDA’ receipt of the IN0 unless I receive earlier s notification by FDA that the studies may be in. t also agree not to begm ar continue clinical investigations covered by the tMD if those studies are piace ? on ctinicat hold. I agree that an Mstitutional Review Board (IRB) that complies with the requirements set forth in 21 CFR Part.56 will be responsible for the initial and continuing review and approval of each of the studies in the proposed clinical investigation. J agree to conduct the investigation m accordance with all other applicable regulatory requirements.
16 NAME OF SPONSbR OR SPONSOR’ AUTHORIZED S REPRESENTATIVE NSOROU SPONSQR’ AUTHORIZED S

M. W . Talbott, Ph.D., Director Medical ReNlatory Affairs
ADDRESS(Number,

18

Strttt,City,SrttttndZipCodt~

Eli Lilly and Company (MC598) (11/3) Lilly Corporate Center Indianapolis, Indiana 46285
(WARNIWC: A wdlfdly

fake statement

is Q krnmd

offem.

U.S.C. TiU

A copy of the Form FDA 1572and appropriate curriculum vitae for the primary investigator subinvestigators beingretainedin our fdes per your instructions and are in the April 27,1992, letter. Please me at (317)276-2574 Dr. Andy Stewartat (317) 276-4113 thereareany call or if questions.Than&you for your continuedcooperation assistance. and Sincerely, ELI LlLLYAND COMPANY

M. ‘ W,\TaIbott, Ph.D. DkXtor MedicalRegulatoryAfUrs

.

..*. .(-....

cc: Ms. E. Cutler, Consumer SafetyOfficer (letter only)

Elf Lilly and Company will notify Administration if the investigation the reason therefore.

the Food and Drug is discontinued and

Eli Lilly and Company will notify each investigator if a new drug application is approved or if the investigation is discontinued. The Institutional Review Boards will also be notified if the IND is withdrawn because of safety reasons. As a general rule, all materials for study are supplied to investigators without charge. If the drug is to be sold, the Food and Drug Administration will be so notified and an explanation of why sale is required will be rendered and should not be regarded as commercialization of the new drug. Clinical studies in humans will not be initiated prior to 30 days after the date of receipt of the Investigational New Drug Application by the Food and Drug Administration unless the 30-day delay is waived by the Food and Drug Administration upon showing by Eli Lilly and Company of good reason for such waiver. Eli Lilly and Company will defer or restrict clinical studies if requested to do so by the Food and Drug Administration prior to the expiration of such 30 days. Eli Lilly and Company will, when requested by the Food and Drug Administration, provide an environmental impact analysis report. All non clinical laboratory studies have been, or will be, conducted in compliance with the good laboratory practiceregulations or, if such studies have not been conducted in compliance with such regulations,a statemen,t will ,be provided that describes in detail all differences between the practices used in conducting the study and those required in the regulations. Very truly yours,

.(..._

Et1 LILLY AND COMPANY

Director Msdical MWT:sm

Ph.D. Regulatory Affairs

.: : . 0;i,;.:

. *

To the Reviewers:
.. f

To co-ordinate kZadm, :

our activities with yours , we suggest that any wires or regardless of subject, concerning this file be

M. W . Talbott, Ph.D., Director Medical Regulatory Affairs Lilly Research Laboratories Lilly Corporate Center Indianapolis, Indiana 46285 Any m g&,& relating
Miner

.

to manufacturing-controls 276-4509* 276-4248*

should be made to:

Dr. D. J. or in his absence to:

Dr. R. A. Raths

Any U relating to toxicology-pharmacology should be made to the Greenfield Laboratories of Eli Lilly and Company to:
Dr. D. M. Morton

467-4301* 467-4306*

or in his absence to: Dr. I?. L. Emmerson

_c. .

Any calls dealing with clinical reports or with labels and literature should be made to Dr. Talbott between 7:30 a.m. and 4:15 p.m. (EST). Dr. M. W . Talbott . or in his absence to: Dr. A. J. Stewart Dr. A. Pedersen * Area Code 317 On holidays, Saturdays, or Sundays, call using the telephone numbers indicated. the above personnel at home 276-4113* 251-8836* (Home) 276-2796* 253-5186f (Home) 276-2574* 846-2345* (Home) .

Ry way of explanation, Drs. Miner and Raths are in the Development Division; Drs. Rnmerson and Morton are in the Toxicology Division; and Drs. Talbott, Stewart, and Pedersen are in the Medical component. It is through Dr. Talbott's office that FDA submissions for this file are made. Close liaison among the three divisions will result matter how received, being brought to the attention MWT:sm in any messages, no of all concerned.

.““‘ i.. 0A,::.:

EXHIBIT

V

2136.P

--

September 10,1992 FoodandDrug Administration Centerfor Drug Evaluation Resear$ and Division of Oncology Pulmonary and Drug Products, l-ED-150 Attn.: Document ControlRoom 17B-20 5600Fishers Lane Rochville,Maryland 20857-1706
Re: IND 40,061- LY231514 (‘ Thymidylate SynthaseInhibitor) - Serial No.: 003

Please: to the conference held on August24,1992,andthe Memorandum refer cali of Agreement summarizing diskussion conclusions the and submitted August28,1992.
-

In accordance theagreement following documentation beingsubmitted: with the is 1. 2. 3. 4. Amended ProtocolH3E-MC-JMAB(a). Revised toxicologysummary the ConicalInvestigator for Brochure(pages - 3.14). 3.8 ToxicologyReport(Leucovorin Rescue BeagleDog Given of LethalDoses of LY231514 Disodiumin StudyD01692). Manufacturing responses points4 and5 in the to August7,1992, FAX from the FDA,

!

F&ryour convenience, copy of the following documents alsoattached: a are
*

Memorandum Agreement the August24,1992, of of conference call. Copyof the FDA FAX of .August 7,1992, notifying Eli Liiy of the clinical hold.

e

.Xn accordance theagreement the clinical studycould be initiatedconcurrently with that with the submission these of documents, cliiical trial materials beiig shipped the are to principalinvestigator DanielVon Hoff, Universityof Texas,SanAntonio,Texas). (Dr.

2136.
Pood andDrug Administtation

IND 40,061-- Lm31514 sepmber 10,1992
Page 2

PIease call me at (31’ 276-2574 Dr. Andy Stewart (317)276-4113 thereareany 7) or at if questions.Thankyou for your continue$i cooperation assistance. and

Sincerely, ELI LILLY AND C!OMPANY

MedicalRegulatory Affairs Enc.. cc: Ms. EllenCutler (I)

.r

.

-

DEPARTMENT OF HEALfH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION

PUBLICHEALTH SERVICE

INVESTlGAT’ lONAl NEW DRUG APPllCARDN (IND) (?-tTLE COOL OF FEDERAt REGULAl-tOtVS 21, (CFR)Part 312)

Lilly Corporate Center Indianapolis, Indiana 46285

(317) 276-2000

NA
8. PHASE (5) OF CLfNtCAL INMSTIGATION TO B E CONDUCTED: m PtlkSE 1 n PHASE 2 c] PHASE 3 a OTHER ISWft 9 LIST NUMBERS OF ALL INVESTlCATlONAL N E W ORUG APPCICATIONS (2t CFR PanJlfj, N E W ORUC OR ANTIBIOTIC APPLICATJONS (21 CFR Part 3141. DRUG M A S T E R FLLS (21 CfR 3 14.4201, AN0 PROOUCT LICENSE APPLlCATtONS (21 CFRPart 6011 REFERRED TO IN. APPLICATION.

I
IO.

NA

.

‘ i

IN0 submissionsshould be consecutive& numbered. The initial ttVU should be numbered “Serial Number: Ooo.” The next submission (e.g., amendmenf report, of corfespondence) should be numbered “Serial Number: 001. - Subsequentsubmissions should be numbered consecutively in the order in which they are submiited.
0 RESPONSE TO’ CLJNICAL HOLD tND SAFETY REPORT(S): 0

SERIAL NU‘

a- 00

11. THIS SUBMISSION CONTAINS THE FOLLOWING: &.%&a11 that l wl 0 INITIAL INVESTffiAflONAL N E W DRUG APPLICATION #ND) I PROTOCOL AMENDMENT(S): 0 N E W PROTOCOL INFORMATION AlWENOMENTg): m CHEMISTRYIMtCROSMLOGY H PHARMACOLOCYROXlCOLOGY a CLINJCAL

INJTJAL WRITTEN REPORT

m CHANGE IN PROTOCOt c] N E W tNVESTGATOR

0 FOLLOW-UP TO A WRITTEN REPC

l
I

RESPONSE TO FDA REQUEST FOR INFORMATION

0 ANNUAL REPORT D OTHER

[3CENERAlCORRESPONDENCE

E] REQUEST FOR REINSTATEMENTOF IN0 THAT IS WITHDRAWN, lNAC?lVATED, TERMINATED OR DISCONTINUED

6PUW~

.H--. . .#I

.

FORM FDA 15’ irl(6iSl)

PREVIOUS EOtTlON IS OBSOLETE.

i

213

THfS OOCLJMENT CONTAINS TRADE SECRETS, OR C3MMERCfAL OR FfNANCIJal INFORMATlON, PRlVl LEGEO OR CONFlOEP(TfAL~ OELIVERED IN CONFIOEP(CE AND RELIANCE ‘ U-UT SUCH INFORMATION WILL NOT 8E MADE AVA1LA8i.E TO THE PUBUC WiTHOUT THE EXPRESS WRI~EPJ CONSEIU Of Et1 LlLlY ANO COMPANY-

.

* .

,

EXIiItiIT VI
Publii Health Service

Food and Drug Administration Rockville MD 20857

IND 40,061

Eli Lilly and Company Zilly Corporate Center Indianapolis, Indiana 46285

SEP I I I992

Attention: Dear Dr. Tnlbott:

M. W . Talbott, Ph.D. Director, Medical Regulatory

Affairs

Please refer to your Investigational New Drug Application (IND) submitted pursuant to section 505(i) of the Federal FOOC~, Drug, and Cosmetic Act for Compound LY231514. We also refer'to our August 7, 1992 facsimile transmission in which you were notified that your IND is on clinical hold and to the August 24, 1992 telephone conference between members of your company and this Division. In that telephone conference you were notified that you may initiate the clinical investigzkion simultaneously upon submission of the following information to the FDA.
1.

A revised protocol including the rationale for the proposed 10 mg/m* starting dose of Compound LY231514, the criteria for leucovorin administration, and the dose, route and schedule of leucovorin. The extended toxioology study report.
The revised Xnvesdgzkor's

2. 3,

report

and the leucovorin

brochure.

We have the following 4. Provide starting diethyl

additional

comments and requests. for the acid

additional material ester.

information and controls N-4-iodobenzoyl-L-glutamic

5. Additional

The drug product should be formulated at 100% of the label claim. A 10% excess must be justified. comments may be forwarded as our review continues.

IND 40,061 Page 2

As sponsor of this IND, you are responsible for compliance with the Federal Food, Drug, and Cosmetic Act and the regulations promulgated thereunder. Those responsibilities include reporting any unexpected fatal or life-threatening experiences by telephone to this Agency no later than three working days after receipt of the information and the submission of annual progress reports. Sincerely yours,

Gregory Burke, M-D*, Ph.D. Director Division of Oncology and Pulmonary Drug Products Office of Drug Evaluation I Center for Drug Evaluation and Research

;

.a.

EXHIBIT

VII

A copy of-this

~.lill~wn

c

.

8UbmiS8iOn c&q

be found in 30 red books at the end of this
Ulb ResearchLaboratories A Olvisfonof EULIUyand Qtnpany Llliy Corporate Center Indianapolis,lndlana 46285U.S.A.

Phone 317 276 2000

October24,2002
Pre-Subm ission for Original Application, NDA 21-462

Central Docum ent Room and Centerfor Drug Evaluation Research Food and Drug Administration 12229W ilkins Avenue Rockville, M D 20852
Re: NDA 21-462, Aiimt.# (pemetrexed, LY2315i4) - Pre-Sabm issfon

This letter accom panies enclosed the pre-subm ission an originalNew Drug Application(NDA) of for A&&a* (pem etrexed, LY231514)in com bination cisplatinfor the indicationof with . m alignautpleuralm esotheliom a. This pm-subm ission providedin electronicform aton a digital tapeaccordingto the January is 1999 ‘ “Guidance Jndusuy for ProvidingRegulatorySubm issions FJectronic in Form at- NDAs.“. The electronicsubm ission is approxim ately gigabytes this portion of the subm ission. size 5.3 for All electronicm ediahavebeenchecked representatives lilly Jnform etion by of Technologyand havebeenverified to be free of known viruses.The virus chectingsoftwarewasNorton Antivirus Corporate Edition version 751.847 usingVirus Definitions4100% createdon October 9,2002 andScanEngine4.1l.6. As specifiedin the abovesUi$ance, paperreview copy a canting 37 volum es includedin this subm ission. is The Division of OncologyDrug Products(DODP)and Lilly havem etto discussthis NDA at PreNDA m eetings January30,2002 and againon Septem ber on 6,2002. This ND4 is beingsubm itted a “‘ as ro&ng”subm ission per the FastTrack Designation as for Alim ta in this indicationgrantedby the FDA on June 10,2002. As per agreem ents betweenLilly and DODP at the Septem ber 62002 Pre-NDA m eeting9 NDA subm ission be donein this will four stages indicatedbelow: as o StageA(October31,2002) o StageB(M arcb31,2003) o StageC (April 15.2003) o Stage (Septem ber D 30,2003) . - ._-Note: StageD subm ission is contingentuponreachingagreem eut FDA aate with DNDC I in Decem ber 2002 on the acceptabilityof the com patibilityand com parability package phrnnedstudiessupporting changeto a data and the com parable containerclosuresystem .

-.

. .

-

. .

.

,-. C’

As agreedinau October1,2002meetiug CDER andCBER personnel, with BioImagingTechnologies, (BIT&, Lilly’ vendorwho is prepa&g tbe imagingscau Inc. s data,win be submittinga setof DVD’ &%naining imagingdata(togetherwith a s tbe seton CD’ for archiving)for the patients the phase mesotbeboma s in 3 registration data 30,2002. Tbese trial (IMCH). BITI will submittbe imaging by December electronic mediacoutaining mediaimagingdatawill be sentdire&y to Debra tbe Vauseof DODP asper agreement thismeeting. at Tbis pre-submission containsStageA of therolling NDA. Stage containsthe foRowing: A 0 km 1 - index andcertaiuadministrative documents * Item 2 - draft labelingonly aud * Item 5 - complete n?ncIiui~aI armacology toxicology pb * Item 6 - all humanpbkrmacolvgy bioavaiIabiIity bioequiv&ence and / documentation witb tbe exception the two pbarmacokinetic of reportson the Alimtakpiriu and A.liruta/ibuprofen interaction studies (these be providedin StageB of tbe rolling wiII submission) * Item 8 - tbe following two critica C&XII studyreportsdemonstrating efficacy of Alimta in malignant pleuralmesothefioma: 3 studyof Alimta plus cisplatinversussingle CI JMCH - Phase registration agentCispIatin cbemonaive in malignant pleuraImesothelioma patients 2 malignant u JMDR - Phase studyof singleagentAIimta in cbemonaive pleuraJ mesotbelioma patients u Refereuce publications l Item 1 1 - datasets reIatingto cfinicaIpharmacology clinical studyreportsfor the and studiesidentifiedin Items6 and8 above l Item 12 -clinical reportfarms(CRFs)for notablepatients(deaths, seriousadverse events, discontinuation because adverse of events,andresponders) in tbe two clinical studiesidentifiedin Item 8 above Please thatAIimta for malignantpIeuraImesotbelioma grantedorphan Drug note was Desighation August 28,W.H. As a resultof the Orphan on Drug Desiguation, sponsoris: the to of (Prom 1) Not required provideevidence safetyandefficacyinpediatric populations tbe FDA meetingminutesof the January 30,2002Pre-NDA meetingsentfkomDODP to Lilly on March 6,2002, “PIease that you havebeengrantedOrphanDrug statuson note August28,2OfNtberefa tbe Pediatric Final Rule (63 PR 66632)doesnot apply.? s is 2) Exemptfrom submittingthePDUPA User’ fee. Tbe UserPeeID## 4249 as indicated on Form3397 which is providedin Item I of StageA In 0rd~T coordinate activitieswith yours,we suggest any facsimile(FAX) or other to our that writtencommunications regardingthis file, regardless subject,be directedto: of Debasisb Roycbowdbury, M.D. Director,U.S. Regulatory Affairs Eli LiIIy andCompany LiiIy Research Laboratories Ully Corprate Center
3ndiiIis, IN 46285

...*-. . i’ G

.

FAX number(317)433-2255

.-, c-

Telephone callsor E-Mailsregarding overallsubmission clinical-/precltical mattersshould or be madeto: l Mr. JohnF. WorzaUa Regulatory Research Scientist, U.S. Regulatory Affairs . ’ (317)2X-5052 (work) . (866)478-6616(pager) FAX (317)2X-1652 E-Mail address:worzalla@lillv.com (317)251-0957 (home) In Mr. WorzalIa’absence s pleasecontactz . Dr. Debasish Roychowdhury (317) 433-6604 (work) (317)332-4268(ceIh&r) FAX: (317)433-2255 E-mail address:dfi&liIiv.com (317)566-0935 (home) Telephone callsregarding chemistry,manufacting or controlissuesshouldbe madeto: 8 Mr. JeffreyR. Ferguson (317)433-5615(work) (317)502220%(cellular) FAX: (317)276-1887 E-mail address:fergusonJeffrey~r@liIly~com (317)81&907O(bome) In Mr. Ferguson’absence s pleasecontact: * Ditie Zezza,&ID., Dinector,GlobalRegulatory ABairs, CM&C (317)433-9882(work) (317)997-5491 @xdhrlar) cm 793-1062eager) FAX (317) 276-1887 23-mail ad&w zezza-dQlilly.com On holidaysor weekends, pleasecall Mr. Worzalla,Dr. Roychowdhury Mr. Ferguson hom& or at using the telephone numbrs provided. close liaisonbetween Lilly repnxentatives the listed abovetill resultin any messages, matter no how received, beingbroughtto the attentionof all concerned.. Pleaselet us know if thereare any your additionalwayswe may be of assistance during tbe review of this NDA. Lilly appreciates contiTAued assistance coope~tion. and The sponsor beeninformedthat DGDP will scheduie meetingapproximately daysafter has a 45 DODP receives StageA of the NDA wherethe sponsor give a pentation containingan .will overview of theNDA .andreasons the NDA shouldbe approv& The sponsor why reques&that the week of December be considered this presentation that meetswith FDA schedules. 9 for if

Sincerely, Eli Lilly & Company

John F. Woxzalla Regul,atoryResearchScientist U.S. Regulatory Affairs

Enclosures cc: Ms. Debra Vause, Regulatory Project Manager Food and Drug Administration Center for Drug Evaluation and Research Division of Oncology Dmg Products, HFD-IS0 1451 Roclcville Pike Rockville, Maryland 20852-1448

7

THIS SUBMISSION CAN BE FOUNDI# $2 RED BOOKSAT THB END OF THIS FILE i:
.-. c- . %

-:. . ..t
: ‘ ,* T ..*y . .. -.. . -. :
.

Rgel
www.liUycom l&y Research Leborawes
ADhrki#tefEUUUyand~ny Indlanapelle.Indiana 46285 U.SA

WW-tew

March24,2003.
.Pr&ubmission for Original Appkation, M IA 21462
..

Cc.ntralDocumcntRoom Center DrugEvsluation Resean& for and
Food and Dmg Adminiseation

.:

12229 d k insAverme W
Rockville, MD 20852 Re: NDA 21-462, Akata” (pemetrexed, LY231514)-Pm-Submission - StageB This lettesaccompanies endos~ pm-submission an orighl New Drug Applicaticm the of &DA)

: I .. I. _..._. c2. /

for~*@enrecrex_ed,x;yw15l4)~inco;mbioatianwi~cispIatinfwtbe~~~~of . malignant pleural ~otbelkma. This submission cons&u&s Stage of the ‘ E kcdling submission” of MDA 21-462 explained 8s beIow. Stage of theNDA wassubmitted October A on 24.2002.
Submtssionof StageB, completesthe non-clinical and dh%caiportions of NDA 21-462. W h e u Item 4 (Chemistry, Manufactmingand Conlrol) is providedthe MIA will be complete.Please aote’ drug substance tbat information for Item 4 will be providedas Stage C of th thing submksion”by April l&2003 and the drag product hformation for Item D by 4 will be providedas Stage of the % lllng submission” September30,2003.

’ This lm+submissionprovided ekckonk formatan a digitaltapeaccording theJanuary is in to 1999 Quidsncc Industry ‘ for Providing RegulatoqSubmissions Ektrc& Fkuat-ND&“. in Tbeelectmnic submiss&m is spproxiroately gigabytes this poation size 1.5 fa oftk submission. All tAectm& media havebeen thzked by xqrescnt&ives Lilly Information of Technology and havebecnverifiedtobe:freeofZrnownviruses,Tbevirus~~~sofrwarewasNoaam AntivirusCorpora& Editionversion751.847 usingVii DefiniitiaaFile 503124 created on March12,2003 Scan and Engine 4.1.0.6.As specified tht above in csuidance, apapanview copycoutaiuiug volumes included this submissi~ 27 is in TheDivisionof Uncolagy DrugProducts (DODP)andLjgy bsvemetto discuss NDA at Pre&is NDAmeetingsonJanuaqy30.2oMandagainonSeptembar6,2M)2.

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ThisNDAisbeingsubmitteda(a”roaing;”m~~aspcrtheFastTrackDesignatiosfor AlimtainthisindkaticmgmtedbytbemlAonfrme10,uxyL. AspexagnxmntabetweenEUy andDODPat the Septembex 6,2002Pre-NDAmeeting,.&% MIA submission be donein will four stages indicatedbelow: as . o Stage (bj 0ctober31,2002-actual A submission on 0ctober24,2002) was o StageB(byMarch31,2003) o StageC(by Aprif 15,2QO3j 0 stageD(ty septelnk30.2003)
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Thispre-submisGoncontainsStageB CdtherolXngND~ Stag~Binc1udesthefollowiq l km 1 -Table of cont.e&,i&x aadcertain a&&dstrativedoeumenta l Uem2-Aaposed~~~(pleasenotethat~packageimsertlabelingmaytre up&lteawh~StagcDissobmitledinSeptemberof2003torenect~ychanges Deeded fm:the drugproduct compatiity andstabilityportions thepackage of ins&). l ltem3-Applicatioasuuy l Item 6 -Two newp&umac&inetic (PK) reports (addendum andaddendum to 1 2 studyJMAW) on theAGmta/aspiria AE&a&buprofen and interaction studies.These two sew I% reports we p&d&l in aae&tro& version ahmgwith thepreviousm reportssubmitted Sqe A.of themuingNDA. Im l km 8 - S$udy repoxts thefive nx&ning critical clinicalstudies for (JMAP,JMAU, rtmaiibgclinimlmudyre~(6eeTabk of JMAw*;IMAYandJMk3z)aDdthe Contents Stem for thelistingof studies for 8 provided Stage T&e study In B). reparis~‘ ~~~inanelectronicversionalongwiththeprevioasstudy~ (SMCHandJMDR)sobm&dinStageAoft)lerolGngNDA. Item 8 also contains fo%ving to compler theclinicalpaclca8e: the cl IntegratcdSunmuryof~ 0 lutegratedsnnrmaryofsafety *. . 0 Snte~SmsmaryofB~ * ‘ Itenn11-I)atasetsn~to~clinicalpharmacollogy~forthefMAW ~anafraothaclinicals~notporeviouBfymibanittedinStegeA l Item 12 -C&&al rcpoafti (CI@6} fa notable patients (deaths, serious adverse events, di6qm~&bof6dvadverseevents, andrespo&m)forthefiv~ remnhdngtitical~(JMAP*IMAu,JMAFv,JMAY aDdJMt3Q . ltemlg-F~d~~farthe~cIinicsl:~(JMc133[,JMDR,~, -MAu,sMAFv,luAYaaifRulBz)asagreedtobyDoDP~ttJ~anuary3O,u)1)2 Pxe-NDAmeeting * 0 lteicm---theRisk-pleasenotethattheAlcmdamahignanpl~mRsottieaiamaindicafloeawas~oEphanDrog . DesignatijaoonArtgust~28,2oi)L AsaresukoftheOq&anDNgDesigoation,theqxmsoris: 1) Notrequindtoprovideevi~of safeQarideff5cacyinpediatsicpopnla6ons 2) Exemptfrom submitting PDUFAUse& fee. Tbr:USerFeeID# is 4249asindicated the onFoxm3397pn~idedinBemlofStageA

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The foRowing contact i~mmafion was previ~nsiy protided v&h Sage A in Odder ibon . . TherehaYebeenno~angesfnlhecontadM~llYl8flo~ lnordettoc~oIx8ctiYities with yams, we suggest eny facsimile(PAX) or otheawritten commtmicati~ regarding @at this Sle,regaxdIessofs~bjcct,bedinxtedtoz . . Ek&8&hRoychowdh~~UD. l3hecmu.s. R&llbryY l3i~8ndcomp8ny . . . LlllyResea.mhLinYcorparateQ=Qx I. rndhapokm46285 . FAX Imm~ (317)433-2255 Telephone calls or E-Mails iegaxriing oveall snbtission or c&&al / preclinicalmat&s shouId bemadetot l Mr.JohtiF.Worz.dlla ’ RegulatoryResearch Sciecntist, Regthtory Affairs US. (317) 276952 (work). (866)478-6616 @age@ FAX: (3 17) 276-1652 EXaiI address:worzalla@%i~.com (317)251-0957 &xne) l[n Mr. Worzall& absence pleasecontact l Dr. DebasishRoychowdbury . (317)433X504 (work) (317)332-4268@elh$ar) FAX (317)433-225s R-mail* (317)566-0935 (home) .’ *
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Telephone calls regan%ng &mistay, man&cuing or control issuesshouldbe madeto: . Mr.JefEeyRF~ . (317)433-5615(work) (317)5Q2-%Q8 fcellular) FAX: (317)2741887 Em8il acklni+* i??qmm&fffe~~@liny~~ (317) 818-9mQ ty+mIp) bnMr,Firgusonsa~apleaaecontac& * Di8neZixabpstD., l3imtor*aob8lRegnbktoxy~,cM&c (317)433-9882(work) (317)997-5491 (albllar) (877)793-1062(pager) FAX (3f7)276-1887 * E-maiI adtaiassz zezza~d@il&com

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On holidays cc wakend$, pleasecall Mr. Wmzab, Dr. Roychowdhuryor MT.perghsonat home . wingthetelep~onerurmbaspravi~ .

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JohuF. RegulatoxyResearchscientist U.S. Regulatcny Afhirs EhcloEum .

cc Ms. PatriciaGarvey, Reguhtoq B-o&t Manager FoodandDingAdrnin&t ’ Centerfor DrugBahatim andResekh DiYisimof ollcokIgy~g~u~~l50 1451RockvillcPike Ro&ville, Maryland208521448 .

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Lilly Research LaboratorIes A DiMi of Eti lilty and Company Lilly Corporate Canter Indianapolis. Indiana 46285 U.SJi.

THIS SDBMISSTON CAN BE FOUNDIN 3 RED BINDERS AT THE END OF TBIS FZLE
hme 317 276 2000

March 27,2003 Pre-Submission for Original Application, MDA 21-462 Central Document Room Center for Drug Evaluation and Research Food and Drug Administration 12229W ilkins Avenue b&viIle, M D 20852 Re: NDA 21-462, AlMa@ (pemetrexed, LY231514) - Pre-Submission - Stage C This letter accompanies encfosedpm-submissionof an original New Drug AppIication the (MDA) for Alimta” (pemetrexed,LY231514) in combination with cispiatin for the indication of malignant pleural mesothehoma.This submissionconstitutesStageC of the “roiling” submissionof NDA 21-462 and contains the completedrug substance chemistry, manufacturing and controI (CMC) information for pemetrexeddisodium heptahydrate. The specific content of StageC is outlined below. StageA and StageB of the EiDA were submittedon October 24,2002 and March 24,2003, respectively,and represent,collectively, the complete pre-cIinicaI and clinical sectionsof the NRA. StageD of the “rolling” submissionfor NDA 21-462 is targetedfor submissionby September30,2003 and will can&in the complete drug product sections,and thereby complete aU NDA submission content mquimments. StageA and StageB of the NDA were submitted orga&ed according to 21 and

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C m .3 14.50 and foIlowed the JanuaryI999 “Guidance IndustryProvidingRegulatory for Submissious Electronic in Format- NDAs”. Howeveraspreviously discussed agreed and with Division of New Drug Chemistry (DNDC I) personnel, CMC sections I the (Item 4) of
this NDA will be provided using the RX Common Technical Document (CID) format and C, the drug nmnbering~To combine both formatswithin Stage Item 4 contains compIete substance information using the CTD format that additionally incorporatesthe general principles of ektronic formatting outlined in the January 1999 “Cuklance for Industry Providing ReguIatory Submissionsin Electronic Format - NDAs”. Item 1 of StageC containsreview aides comparing the CTD to the standardNDA submissionformat and numkring to fa&iUte review of the CMC sectionsin Item 4. The StageC submission is supplied in electronic format on one CR-ROM. The size of the submissionis less 4 MB. The efectronic media has beencheckedand verified to be free of known viruses. The virus checking software was Norton Antivirus CorporateEdition version 7.51.847 using Virus Definition File 50312q createdon March 12.2003 and ScanEngine 4.1.0.6. As specified in the above Guidance, a paper review copy containing 3 volumes is included in this submission. .

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DqAdmidtratian Marcwt.2nm

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’ As agreed during the September6,200Z Pre-N5A meeting, Item I of this submissionalso

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contains qetication stat&gthat the drugsubstance a manufacturing, packaging con&o1 and siteslistedin StageC arereadyfor pre-approval inspections, R @ .RX&Additionally, if this pre+submission contains foflowingz the
Item Item Item Drug 1 (MIA Index and Administrative Documents) 3 (Appk&ion S-ryDrug Substance) 4 (chemistry, Manufactqing and Co&-00 .

substance sections protidedin CI’ format,consisting the Q&&y Overall D of Suxmnary (QOS- ModuIe2.3.S)andthe QualityBody of Data (ModuIe3.2.S) sections.

Item 7 (Microbiologg)

This se&u is not applicable this NDA submission. for
Item 14 (Patent Certifkation) Patent ce&fication was providd with StageA. Item 15 (Establishment Description)

This sectionis not applicable this M IA submission. in
Item 16 (Debarment Certification)

Debarment certificationwasprovidedwith Stage A.
Item 17 (Field Copy Ccrf.itication)

Held Copy Certificatidn the drugsubstance for contentis providedin Item 1.
1tenl20 (Other)

Note to Reviewer andStage reviewaid. C

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The submission contactinformation, previously providedwith Stage andStage is A B, includedbelow for your convenience. orderto coordinate activitieswith yours,we In our suggest any facsimile(FAX) or otherwritten communications that regarding file, this regardless subject,be &z&d to: of DebatishRoychowdhmy, I&D, Director, U.S. Regulatory Affairs Eli Lilly and Company ’ Lilly ReseaxchLabqratories LillytZ!orporatecedter Indianapolis,IN 46285
FAX number (3 17) 433-225s Tekphone c&s regarding chemistry, manufacturiigor control issues contained Stage in C should be madeto:

0 ’ M r. JefEeyR. Fergusan
(3 17) 433-5615 (WC&) (3 17) 502-2208 (cellular) FAX: (3 17) 276-1887

E-mail Bddress: fermson ieffrev r@,liHv.com
(317) 818-9070 (home)

In M r. Ferguson’absence s please contact: . Diane Zezza,P&D., Director, GlobalRegulatory Affairs, CM&C

(3 17) 433-9882 (work) (317) 997-5491 (cellular) (877) 793-1062 (pager) FAX (317) 2761887 E-mail address: zezza .d@IiUy .com Telephonecalls or E-Mails regarding overall submissionor cRnical / preciinical matters should be madeto: * Nr. John I? Worzalla ReguIatory ResearchScieatist, U.S. RegulatoryAffairs (317) 276-5052 (work) (866) 478-6616 (pager) FAX: (317) 276-1652 / E-Mail address: worzalla@lillv.com (317) 251-0957 (home) In Mr. Worzaha’ absencepleasecontact: s 0 Dr. DebFish Roychowdbury (317) 4336604 (work) (3 17) 332-4268 (cellular) FAX: (31’ 433-2255 7) E-mail address: dfr@lilk.com (317) 56643935(hQme) On holidays or weekends,please call Mr. Worzalla, Dr. Roycbowdhury or Mr. Fergusonat home using the telephonenumbersprovided, Cbse liaison betweenthe Lilly regulatory representatives listed above will result in any messages, matter how received, being brought to the attention of all concerned. Pleaselet no us know if them are any additicmd ways we may be of assistanceduring the review of this NDA. Lilly appreciatesyour continued assistanceand cooperation. Sincerely, EliLilly &company

John$!WorzaRa Re@atory ResearchScientist U.S. Regulatory Affairs

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cc: Ms. Patricia Garvey, Re#atory Project Manager Food and Drug Administration Centexfor. Drug Evah&ion and Research Division of Oncology Qrug Products, HFD-150 1451 Rockville Pike Rockville, Maryland 20852-1448

September 29,2003 Gompfetfon of Original Application, NDA 21462 CentralDocumentRoom Centerfor Drug EvaluationandResearch FoodandDzug Administration 12229Wilkins Avenue Roekvi.U~MD 20852 Re: NDA 21462, AlimtsQ @em&rexed,LY2.31514) Rna!-Submiss;fon StageD This letter accompanies enclosad the submission containingall outstanding contentof the chemistry,manufacturing control (C&G) sectionsand the&y completesali MIA and submission contentrequiqzments Alimta* (pemetrexed, fox LY231514)in combination with cispladnfor the indicationof malignantpleuralmesothelioma. This submission constitutesStageD of the “rolling” submission NDA 21-462aud of containsthe completedrug productCIVICinfonaaton for Pemetrexed Injection. for Additionally, updateddmg productlabeling and8 safetyupdateareprovidedin this submission.The specific contentof StageD is outlinedbelow. StageA andStageB of the MIA weresubmittedon Cktobe$24,2002andMarch 24, 2003,respectively,andrepresent, colkctively, the compkte pre-clinicalandclinical sectionsof the NDA. StageC of the NDA was submittedon March 27,203 and contained completedrug substance the portion of the ChK sectionsof the NIX StageC of NDA 21-462was amended with addition& drng substamxlot &&se datain the CMC information amendment datedSep&mber 3,2003. As pmvi&sly agreed during the DODP September 6,2002 Pre-HDA meeting informationprovidedin pmsubmissions StageA, StageB and Stage% arenot inch&d in this submissions. StageA andStageB of the NDA weresubmittedandorganized awording to 21 CFR.314.50and followed the Januaryt 999 “Guidancefor IndustryProvidingRegulatory Submissions ElectronicFormat- NDAs”. Koweveras previouslydiscussed in and agreed with Division of New Drug’ ChcmistryI @NIX! 9 personnel,the CMC sections

Answers That Matter.

(Item 4 submittedin StGges andD) of tbis NDA areprovidedusing the ICH Common C TechnicalDocument(CID) format andnumbering.To combinebotb foxmatswithin Stage Item 4 containsthe completedrug productinfurmationu&g the CID format D, thatadditionallyincqorates the general principlesof ekctmnic fonnattng outked in theJanuary1999“ Guidance IndustryProvidingRegulatorySubmissions Ekctronic ‘ for in .Format MIAS”. Rem20 contuinsa review aidecompting the CTD to the standard .NDA submission format andnumberingto facilitatereview of Rem 4. The StageD submit&m is suppliedin electmnkformat on one CD-ROM. The size of *the submission approximately is 79MB. The ek&ronic mediahasbeeucheckedand verifiedto be free of known viruses.The virus checkingsoftwarewas Norton Antivirus corporateEdition version7.51.847usingV&us DeBition File 5Q918g createdon September 4.2003 and ScsuEnginc4.l.Od. As specifiedin the aboveGuidance,a paper reviewcopy is includedwith this submission. As agreed during the September 6,2002 Pm-NDA meeting,Item 1 of this submission alsocontainsa certification statingthat the drugproductmanufacturing. packagingand controlsiteslisted in StageD em reedyfor pre-approval inspections, required. if Additionally,this submission containsthefollowing: Item 1 (NDA Index and AdmhWrative Documents) lltemz (UpdatedDrafiLabeIin~ The enclosed draft labelinghasbeenupdated with additionalCMC!information on tbe drugproduct. Also, Table 9 under“OtbexAdverseEvents” beenupd.at& as has explained the Wormation amendment NDA 21-462sentto FDA on April 3, UK)3 in to (copyof April 3,2003 amqndment providedinAp@ix 1 to Iteq 2). l&em3 (Application Summary- Drug Substanceand Drug Product) The ApplidationSummaryconsistsof the annobtedlabelingandCMC! summary information. LabeIingatmotations specificto drug substance sectionscontainedin Stage C do not containlive links within StageD. Appen&x 1 to the Application Summary *‘ ngtheaandatGd containsa “Manua?Cross-Reference l&&s Spreadsheet’ summ~l11w label cross-references the StageC (drugsubstance) to submission. Item 4 (Chemistry, Msumfaeturing and ContM Drug productsectionsprovidedin c13Dformat,consistingof the Quality Overall Summary(QOS - Module 2.3.P], Quality Rody of Data (Mod& 32.P). Appendices (IvfoduIi 3.2A), and US RegjonalInformation(Module3.2.R) sections. Htem7 (MicrobioIogy) This sectionis not applicablefor ihis NDA submission. Item 9 (Safety Update Report) The first safety updatewas providedas anamendment NDA 21-462 on JulyZ3,2&3. to A second updatedsafetyupdateis beingprovidedwith this submission;also a copy of the fmt safetyupdatethat was earlierprovidedon July 23 is beingprovidedwith this submission. / XtemW (Pate& Infonmation)

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P<atcnt informationwas providedback with StageA, but this did not includecompkted FDA 3542aforms. Compieted 3542aforms arebeingprovidedwith this submission. I&?m14 (Patent certrtrcatlsn) Patentcert%Wion was providedwith StageA. Item 15 (Establishmentwption) This sectionis not applicable this NDA submission. in Item X6 (Debarmentcer@la&on) Debim.mtcertificationwaspnovidcdwithStagek Itam 17 (Field Copy Certificatiw) Field Copy Certificationfor the drug productcontentis providedin Item 1. Item 20 (other) Note to ReviewerandStageD review aid The submission contactinfqrmation,previousIyprovidedwith StageA, StageB aod Ia our StageC is includedbelow for your convenience. orderto coordinate activities with yours,we suggest any facsixnilc(FAX) or otherwritten communicatious that regarding file, regardless subject,be directedto: this of Debasish Roychowdhury, M.D. Director,U.S. RegulatoryAffairs Bli Lilly andCompany Lilly Research Laboratories LiUy Corporate Center IildianapoI.is, 46285 IN FAX number(317)433-2255 Telephone calls segax&g chemistry~ manufacturing controlissuescontained Stage or in C!andDshouldbemadeto: Mr. JeffreyR Ferguson ReguIatmy Research Scientist,OlobaIReguktory CM&C (317)433&15 (w&k) (317-J 502-2208(CeuuIar) FAX (317)276-1887 EmaiI address:f&gggg&& &filIv.com
(317) 818~9070 (horn) In Mr. l%qpsoD’ absmcc pleaseCons s Diane ztzza, Ph.D.,

Director, GIobalRegulatoryAffairs, CM&C (317)433-9882(work) (317)997-5491(ce3Illiar) FAX (317)276-1887 E-maiI address:M d9lillv.con-t (317)733-8604(home)

Telephone calls or E&Mailsregardingoverall submission clinical / preclinical matters or shouldbe made~0: Mr. JohnF. Worzn?k RegulatoryResearch Scientist,U.S. RegulatoryAff& (317) 276-5052(work) (~6) 478-6616 @aget) FAX: (317)276-1652 E-Mail addnm: yq&la@lillv.cq (317) 251-0957(hoqe) lrdMr. Woxzalhx’ s absence pleasecontact: Dr. DchasishRoychowdhury (317) 433-6604(work) (32’ 332-4268 7) fcelhdsr) FAX: (3 17)433-2255 Email address:dfr8iillv.com (317) !%6-0935(home) On holidaysor weekends, pleasecall Mr. Woxzalla, Roychowdbmy,A&. Fergusonor Dr. Dr. !Zkza at homeusingtbe t&qtbone numhcrsprotided. CSose liaison betweenthe Lilly regulatoryrepreseitatives listed abovewill result in any messages, matterbow wived, being broughtto the attentionof all concerned.. no PIease us know if therearc any additionalways we may be of assistance let during the continuedassistance cooperation. and mtiew of this NDA. Lilly appreCia~~your SiUdY, E!Jimy 4% company . ?f Jo F. Wonalla i!f RegulatoryResearGh Scien~ U.S. RegulatoryAffairs .

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CC:

Ms. PatriciaGarvey,RegulatoryPrqjcct Manager Food andDrug Adminktration Centerfor Drug Evaluationand Research Division of OncologyDnq4Mducts, HFD-150 1451RockMe Pike RockviNe,Maryland 2OgS2-‘ 1448

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Note to Reviewer NDA 21,462
Alimta@ (pemetrexed, LY23f 514) for the Indication of Malignant Pleural Mesothelioma
This Note to Reviewersaccompanies StageD of a “rolling submission” underFast Track d&g&on as agreedto by Division of OncologyDrug Productsat the September 6, 2002 Pre-NDA Meeting.

Introduction
Lilly is submittingthis NDA to gain approvalto marketAlimta (pemetrexed, LY231514) in combinationwith cisplatin for the indicationof treatmentof patientswith malignant pleural mesothelioma.Alimta is an antifolateagentthat targetsseveralkey folatedependent enzymesin the de novo biosynthesis thymidineandpurine nucleotides. of Malignantpleural mesothelioma a rare type of cancerfor which thereis no current is standard treatmentand thereis no FDA approved of therapy. Alimta was granted orphan-drug designation the indication of malignantpleural mesothelioma the for by Office or OrphanProductsDevelopmenton August 28,2OOl(request#W-1451). Alimta was grantedFast Track designation malignantpleuralmesothelioma the Division for by of OncologyDrug Products(DODP) on June 10,2002. This submission constitutesStageD of the “rolling” submission NDA 21-462and of containsthe completedrug product CMC informationfor Pemetrexed Injection. for Additionally, updateddrug product labeling and a safetyupdateare providedin this submission.The specif&c contentof StageD is outlinedbelow. StageA and StageB of the NDA were submittedon October24,2002 and March 24,2003, respectively,and represent, collectively,the completepre-clinical and clinical sectionsof the NDA. StageC of the NDA was submittedon March 27,2003 and contained completedrug substance the portion of the CMC sectionsof the MIA. StageC of NDA 21-462was amended with additionaldrug substance release lot data in the CMC informationamendment datedSeptember 3,203, As previouslyagreedduring the DODP September 6,2002 Pre-NDA meeting,informationprovided in pre-submissions StageA StageB and StageC arenot includedin this submissions.

Pemettexed Disodium IInitialNDA 21462 (Chsniswy, t,bnvfacnttin& and Conttol)

September. 2003 Eli tilly and Company

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Mming Convefftions
Drug Substance and Product
Throughoutthis document,Alimta may be referredto by a variety of terms including LY23 1514,pemetrexeddisodium(WAN), pcmetmxed(INN) or Alimta (proprietary name). In its early stagesof development, Alimta was also referredto as MTA (for Multi-TargetedAntifoIate) or TSI (for Thymidylate SynthaseInhibitor), and thus these terms may also have beenused. The Division of Medication Errors and TechnicalSupport(DMETS)~compIeted a preliminary review of the proposeproprietaryname,Alimta. On June 14,2002 DMETS statedthat it hasno objection to the useof the proposedproprietary drug name. DMETS cautionedthat the FDA would m-review the proprietaryname during the NDA review process.

hIDA Submission hformation: Stage D Final Submission Gmtaining Drug Product GMG Inform&on
Format and Organization of Stage D
StageA and StageB of.the NDA were submittedandorganizedaccordingto 21 CFR.314.50and followed the January1999 “Guidancefor Industry Providing Regulatory Submissions Electronic Format - NDAs”. However as previously discussedand in agreedwith Division of New Drug ChemistryI (DNDC I) personnel,the CMC sections (Item 4 submitted in StagesC and D) of thii NDA areprovided using the ICI-I Common TechnicalDocument (CTD) format and numbering. To combineboth formats within StageD, Item 4 contains the completedrug productinformation using the C’ D format I’ that additionally incorporatesthe genera1 principles of electronic formatting outlined in the January1999 “Guidance for Industry Providing Regulatory Submissionsin Electronic Format - NDAs”. Item 20 containsa review aide comparingthe CTD to the standard NDA submissionformat and numberingto facilitate review of the CMC sectionsin Item 4.

Pemetrexed Oiiodium Initial NDA 21462 (Chemistry, tt#anufacturing,end Control)

September. !a03 Eii Lilly and Company

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Stage D Submission Content
StageD of the NDA containsthe following sectionsand content:

Cover Letter Sponsorcontactinformation is provided in the cover letter.

Item t (NDA Index and Administrative

Documents)

Item 2 (Updated Draft Labeling) 7I’ encloseddraft labeling has beenupdatedwith additional CMC information on the he drug product. Also, Table 9 under “Other AdverseEvents”has beenupdatedas explainedin the information amendmentto NDA 21-462 sent to FDA on April 3.2003 (copy of April 3,2003 amendmentprovided in Appendix I at the end of this section). Item 3 (Application Summary- Drug Substance and Drug Product) T’ Application Summaryconsistsof the annotatedlabeling and CMC summary be information. Labeling annotationsspecific to drug substance sectionscontainedin StageC do not containIlive links within StageD. Appendix 1 to the Application Summarycontainsa “ManualCross-Reference ‘ Links Spreadsheet” summarizingthe annotatedlabei cross-references the StageC (drug substance) to submission.

Item 4 (Chemistry, Manufacturing and Control) Drug product sectionsprovided in CTD format, consjstingof the Quality Overall Summary(QOS- Moduie 2.3.P), Quality Sody of Data (Module 3.2.P). Appendices (Module 3-2.A), and US RegionalInformation (Module 3.2-R) sections.

Item 7 (Microbiology) I’ sectionis not applicablefor this NDA submission. his

P6tMrexed Oisodilim lrliial NOA 21462 (chemistry. Manufaduring,

s~-.2003
and Control) Eli Lilly and Company

note.pdf Item 9 (Safety Update Report)

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.As. agreedbetweenDODP and Lilly at the September 6,2002 Pre-NDA meeting,this submission (StageD) containsa secondsafetyupdatereflecting updatessince the f?rst isafetyupdatedsubmittedto NDA 21-462on July 23,2003. A’ copy of the first safety updatethat was earlierprovided on July 23 is beingprovidedwith this submission. Item 13 (Patent information) Patentinformationwas provided~back StageA, but this did not include completed with .FDA 3542aforms. Completed3542aforms are beingprovided with this submission.

ttem 14 (Patent Certification) Patentcertification was provided with StageA.

#tern 15 (Establishment Description) This sectionis not applicablein this NDA submission. iltem 16 (Debarment ,CertificatZon) Debarment Certification was provided with StageA.

Item 17 (Field Copy Certification) Reld Copy Certification for the drug productcontentis provided in Item 1.

Item 20 (Other) Note to Reviewerand StageD review aid.

IPemetrexfid Diii

Septembef. 2003

Initial NDA 21-462 fChemistry, Manufaduring, and Control)

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EXEIBIT VT.11

DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Sewice Food and Drug AdminWation Rockville, MD 20857

NDA 21462 Eli Lilly & Company Attention: JohnF. Worzalla RegulatoryResearch Scientist,U.S. RegulatoryAffairs Lilly Corporate Center Indianapolis,IN 46285 Dear Mr. Worzzalla: We have received your new drug application(NDA) submittedundersection505(b)of the FederalFood,Drug, and CosmeticAct for the following: * Name of Drug Product: Alimta@(pemetrexed, LY23 1514)

Review IPriorityClassification: Priority (P) Date of d4pplication: Date of Receipt: Our Retkence Number: September 29,2003 September 30,2003 NDA 21-462

Unlesswe notify you within 60 daysof the receiptdatethat the applicationis not sufficiently completeto permit a substantive review, we will file the applicationon November29,2003 in accordance 21 CFR 3 14.101 If we file the application,the user fee goal datewill be with (a). March 3 1,2003. Under 28 CFR 3 14.102(c), may requesta meetingwith this Division (to be held you approximately days from the abovereceiptdate)for a brief reporton the statusof the review 90 but not on the ultimateapprovabilityof the application, Alternatively,you may chooseto receivea reportby telephone. Pleasecite theNDA numberlisted aboveat the top of the fmt pageof any communications concerningthis application. Addressa11 communications concerning NDA as follows: this

RECEIVED 20 2003 OCT

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N D A 2 II-4 6 2 Page 2 U .S .P o s tal Service: C e n ter D r u gE valuatio a n dR e s e a r c h for n Divisiono f O n c o l o g D r u gP roducts, F D - 1 5 0 y H A tte n tio n :DivisionD o c u m e n t o o m 3 0 6 7 R , 5 6 0 0Fishers a n e L Roclwille,M a r y l a n d2 0 8 5 7 Courier/O vernight il: Ma F o o da n dD r u gA d m inistration C e n ter D r u gE valuatio a n dR e s e a r c h ffor n Divisiono f O n c o l o g D r u gP roducts, F D -1 5 0 y H A tte n tio n :D o c u m e n t o o m3 0 6 7 R 1 4 5 RockvilleP ike 1 Rockville,M a r y l a n d2 0 8 5 2 If y o u h a v ea n yq u e s tio n s , P a ttyG a r v e yR e g u l a tory roject a n a g e r ,t (301)W - 5 7 6 6 . call , P M a S incerely,
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Richard a z d u r P Director Divisiono f O n c o l o g y r u gP roducts D O fficeo f D r u gE valuatio n I C e n ter D r u gE valuatio n n dR e s e a r c h for a
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FILiNG COMMUNICATION NDA 21-462 Eli Lilly & Company Attention: John F. Worzalla RegulatoryResearch Scientist,US. RegulatoryAffairs LilIy CorporateCenter Indianapolis,IN 46285 Dear Mr. w0lza1laz Pleaserefer to your September 29,2003 new drug application@IDA) submitted undersection 505(h) of the FederalFood, Drug, and CosmeticAct for Al&a@ (pemetrexed,LY231514). We also refer to your submissions datedOctober24, November22, December6.2002; January 10,.28, February 13,27, March 24,27, April 3, May 9, 12,29, June l&26, July 29,30, August 8, l&21,28, September 2,3,4,9, 12, 15, 16, 19,22,29, October6, 7,20, and November4,5,6, and 7,2003. We have completedour filing review and have determinedthat your application is sufliciently completeto permit a substantive review, Therefore,this applicationwill be tiled under section 505(b) of the Act on November29,2003 in accordance with 21 CFR 314.101(a). At this time, we have not identified any potential filing review issues. Cur filing review is only a pr&minary evaluationof the applicationand is not indicative of deficienciesthat may be identified during our review. If ‘ have any questions,call Patty Carvey, RegulatoryProject Manager,at (301) 594-5766. you Sincerely,
{Seeappentkd electronic s@ohtn’ pugef

Doni Pease Chief, Project ManagementStaff Diviaioll of oncology Drug Products Office of Drug EvahrationI _ Centerfor Drug Evaluation and Research

Thir; is a representation of an, electronic record that waS signed electronically and this page is the menlfestation of the electronic signature. -ii/ --__----------_-I---Patricia Garvey 11/13/03 ol.:41:35 PM Signed for Dotti Pease

,

EXHIBIT IX

IIEPARTMENT OFHEALTH 4% HUMAN SERVICES

Public Health Service f ocd and Drug AcMMWon Rockville, MD 20857

NDA 21462

Eli Lilly & Company Attention: JohnF. Worzalla RegulatoryResearch Scientist,U.S. ReguIatoryAffairs Lilly CorporateCenter Indianapolis,IN 46285 Dear Mr. Wonalla: Pleaserefer to your new drug applicatian (NDA) datedSeptember 29,2003, receivedSeptember 30,2003, submittedundersection 505(b)of the FederalFood,Drug, and CosmeticAct for AlimtaQ (pemetrexed, LY23 1514). We acknowledge receiptof your submissions datedOctober24, November22, December6, 2002; January10,28, February13, March 24,27, April 3, May P9l&29, June 18,26,30, July 29,30, August 8,15,21,28, September 2,3,4,9,12,15,16, 19,22,29, October6,7,20, November4,5,6,14, 18,24,26, December1,4,5,10,11,12, 15,16,29,2003, and 3anuary12,
2004.

This new drug applicationprovides for the useof AlimtaQ (pemetrexed, LY231514) in the treatmentof patientswith malignantpleural mesothelioma whosedisease is either unresectable or who areotherwisenot candidates curativesurgery. for We havecompletedour review of this application,as amended,It is approved,effective on the date of this letter, for useas recommended the agreed-upon in attachedlabeling text. The final printed labeling(FPL),must be identicalto the enclosedlabeling (text for the package insert and the patientpackageinsert). Marketing the product(s)with FPL that is not identical to the approvedlabeling text may renderthe productmisbranded an unapprovednew drug. and Pleasesubmitan electronicversion of the FPL accordingto the guidancefor industry titled Providing RegulutotySubmissi& in Electronic Format- NDA. Alternatively, you may submit 20 papercopiesof the FPL as soon as it is availablebut no more than 30 days after it is printed. Individually mount 15 of the copies on heavy-weight paperor similar material. For administrativepurposes, designatethis submission “FPL for approved NDA 21462.” Approval of this submissionby FDA is not required before the labeling is used.

NDA 21-462 Page2 In addition, submit threecopiesof the introductorypromotionalmaterialsthat you propose use to for this product. Submitat1proposed materialsin drafi or mock-up form, not final print. Send one copy to the Division of OncologyDrug Productsand two copiesof both the promotional materialsand the packageinsertdirectly to: Division of Diug Marketing,Advertising And Communications, HFD-42 Food andDrug Administration 5600 FishersLane Rockville, MD 20857 Pleasesubmit one marketpackage the drug product when it is available. of We have not completedvalidationof the regulatorymethods. However,we expectyour continuedcooperation to-resolve problemsthat may be identified. any We remind you that you mustcomply with reportingrequirements an approvedNDA (2 1 for CFR 314.80and 314.81). The Me&Watch-to-Manufacturer Programprovidesmanufacturers with copiesof serious adverseeventreportsthat arereceiveddirectIy by the FDA. New molecularentitiesand importantnew biologics quaI@ for inclusion for threeyears after approvat. Your furn is eligible to receivecopiesof reportsfor this product. To participatein the program,pleaseseethe enrollmentinstructionsand programdescriptiondetails at www.fda.~ov/medwatchuort/mmu.htm. If you have any questions, Patty Garvey,RegulatoryProjectManager,at (301) 594-5766. call

Robert Temple,M.D. Director Of&e of Drug EvaluationI Centerfor Drug Evaluationand Research Enclosure: labeling

, ,.

Thlsa representation of an electronic record that was signed electronicaMy and this page is the manifestation of the electronic signature,
IS/ --L---.-------,-------

Robert: Z/4/04

Temple 07:52:20

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EXHIBIT

X

3.H.2.1..

Regulaitory History

Regulatory History and Agreements 3.H.2.1 .I. The original IND for LY23 1514 was submitted on 8 July 1992and was assignedIND number 40,061 by the FDA on 14 July 1992. The first human doseof LY23 1514 was administeredon 29 September1992. Four End of Phase2 (EOP2) meetingshave occurred betweenthe Division of Oncology Drugs (DODP) and Lilly at which the malignant pleura1mesothelioma(MPM) indication was discussed. The initial EOP2 meetings on MPM took place on 23 September1998 (Biopharmaceutics)and 25 September1998 (Clinical). Lilly requestedan additional EUP2 meeting to discussthe possibility for acceleratedapprovalin MPM, and this meeting was heId on 25 June1999. Another EOP2 meeting was held betweenDODP and Lilly on 1 March 2000 to discussthe ramifications of the addition of folic acid and vitamin BQ supplementationfor the ongoing registration trial (JMCH) in MPM. LY23 1514 for MPM receivedOrphan Drug designationfrom the Office of Orphan Drug Products on 28 August 2001. The first pre-NDA meeting for the MPM indication was held on 3 1 January2002. LY23 151,4for MPM receivedFast Track Designation by the FDA on 10 June 2002, and thus a secondpre-NDA meeting was held on .6 September2002 to discussthe mechanism for a rolling submissionfor the LY23 1514 MPM NDA. The first portion of the LY23 15Id4rolling NDA was sent to the FDA on 24 October 2002. Lilly made a 45-day presentationto DODP on 3 December2002, during which the sponsorpresentedthe basis for approval of the LY23 1514 MPM NDA. Table 3.H.3 summarizesthe significant FDA meetings, communications,and IND submissionsover the dinical developmenthistory of LY23 1514 for the MPM indication.

Table 3.H.3.
Date

History of Regulatory Correspondence
IND Serial # or Type of Communication MOO submittedlND FDA Letter to Lillv Comments

Lilly submittedthe original IND application for LY23 1514
IliSOdium.

)7/l 3/98

#125 Request for EOP2Meeting

#I26 Briefing Document

)9/08/98

#130 Revisionsto Briefing Document EOP2Meeting #I (Biopharm) betweenLilly and the FDA

FDA assignsIND # 40,061to LY23 1514 disodium receivedby Lilly on 7/2 l/92). [communication First humandoseof LY23 1514 given in the Phase1 study H3EMC-JMAB. Lilly requested EOP2 Meeting to discussdoseand scheduleof an LY23 1514 andthe MPM, NSCLC, and headand neck cancer indications. Lilly proposeddiscussionson efficacy endpoints, active controls,analysisplans, a&safety relatedto patient exposure, theseissuesrelatedto the timing and quality of an as NDA submissionand review. Lilly providedthe scientific rationalefor the use of LY231514 and gavethe development history. Lilly posedquestionsto the FDA regarding MPM, NSCLC, head and neck cancer,NSALD usage, populationPK, renal impairment,hepaticimpairment,multivariate analysis,risk to benefit ratio, andthe use of unidimensional measurements. Lilly told the FDA it wantedthe EOP2 Meeting to focus on MPM andNSCLC, andLilly is withdrawing the questionsrelatedto the headand neck cancerindication. Lilly posedsomeadditional questionsrelatingto the use of concentrated solution for injection andthe use off-the-shelf vitamins in place of folic acid. At the EOP2 Biopharmaceutics meetingbetweenthe FDA and Lilly, the FDA saidthat PK data will be reviewed,but it may be inadequate rule out the absence interactionbetween to of LY 231514 and ibuprofen,and that further animal datawould be considered with examplesfrom eachclass of NSAIDs. The FDA was interestedin having PK populationdata as soonas possible for review, and Lilly will follow guidelinesfor analysisof renal impairmentstudy. Lilly agreedthat patientswill be followed for liver fimction, and the FDA agreedthat the preclinical studies were in order concerning toxicity and PK studies. (continued)

Table 3.H.3.

History of Regulatory Correspondenctb (continued)

endpointin MPM, and that clinical shortnessof breath,etc.) shouldbe use r gainingapprovalif survival advantage cannotbe demonstrated. FDA said unidimensionalmeasurements uncertainto provide were information to determineresponse rate. The FDA saidthat it in a blinded trial, and that accelerated approvalbasedon response rate was unlikely in MPM. The FDA said that althoughapproval for a first indication usually requirestwo studies,the FDA might be willing to grant approval(depending the quality of the data) on basedon a single trial in MPM with supportingevidencefrom a the addition of vitamins to the LY23 1514 arm without datathat

trial, JMCH. This protocol amendment incorporated changes the suggested the FDA in the End of Phase2 Meeting on 25 by September1998. This is the versionof the protocol usedto enroll the initial patients. The major changes this amendment in included: (1) the starting dosewas reducedto 500 mglm2; (2) survival was madethe new primary endpoint;(3) the secondary endpointswere redefined,(4) the trial was single-blinded(at the toms; and (5) administration (continued)

Table 3.H.3,
Date

History of Regulatory Correspondence
ND Serial # or rype of Zommunication ;AX &om FDA 0 Lilly Zomments

(continued)

33/08/99

03129199

SN 158 ZMC Meeting Package

FDA FAX regarding briefmg documentdated 29 March 1999 FAX from FDA to Lilly

Ihe FDA sentLilly their medicalreview of the 08 February1999 submission (rationalefor single-blinding)and the 12 February 1999submission protocol amendment JMCH(a). The FDA wanted know when fmal survival analysiswould occur for to IMCH. The FDA also said that the clinical benefit endpointwas notvalidated. The FDA againpointed out that JMCH must be double-blind “Since the FDA is consideringone positive trial in MPM plus a positive trial in a closely-relatedmalignancyas the basisfor approval,the one MPM trial must be rigorous and above reproach.” IDA wantedto know the minimum time The requirement 50% of patientsmust have achievedto be that avaluable the numberof patientsenrolled!evaluable the and for interim analysis. The FDA said that if JMCH is single-blind,then clinical benefit assessment not be consideredan option for will 111approval. The FDA strongly urgedLilly to designand performa second,randomized pivotal trial in MPM, e.g., cisplatin f LY23 1514 compared with cisplatin + gemcitabine. Lilly submitteda pm-meeting information packagefor the scheduled April 1999teleconference 14 betweenFDA and Lilly representatives. focus of the teleconference the selection The was of startingmaterialsfor the LY23 1514 disodium septahydrate process. FDA repliedto Lilly’ CMC meetingpackagedated29 March s 1999(SN 158)to cancelthe 14 April I999 teleconference to and confirm that the FDA agreed with Lilly’ proposedselectionof s startingmaterialsfor the septahydrate (heptahydrate) drug substance synthesis. The FDA completedtheir review of amendment JMCH(a) submittedon 12 February1999. The FDA statedthat (1) the rationalefor the interim analysiswas unclear,particularly because the interim was basedon clinical benefit endpointsratherthan survival (the primary endpointfor the final analysis). Thus, an efficacy advantage the interim might not be sufficient for at approval. (2) The interim Type I error level, basedon assumptions aboutcorrelationbetweenchnical benefit and survival, may be too high or low. (3) Although the stratification schemeis acceptable, theremay be someproblems in the actual analysis. (4) Theremay not be enoughpatients for balancing againstsuch a largenumberof randomizationfactors. (5) Lilly must be explicit as to whetherthe final survival analysisis an adjustedor unadjusted log-ranktest. (Note this FAX was sentto Lilly originally on 20 April 1999and re-senton 24 June 1999.) (continued)

Table 3.H,3.
Date

History of Regulatory Correspondence
(ND Serial # or Type of Communication #170 Briefing Document

(continued)

06fI O/99

meetingon 25 &me 1999. The briefing documentposedquestions relatedto accelerated approval,the use of unidimensional measurements, to tumor progression a surrogate time as for survival, clinical benefit as a valid endpointandthe single agent Phase trial in MPM. An attachment the briefing document 2 to o the FDA statistical review of

06125199

EOP2Meeting (Responses and Accelerated Approval) betweenLilly and the FDA

convincingly demonstrated thereare clinically relevantand and statistically significant differenceson all threeendpoints(response rate,time to progression clinical benefit),the resultswould be and suffkient for accelerated approval.”Lilly statedits commitment to completethe 280 patient trial in MPM evenif the resultswere positive at interim analysis. The FDA will consider unidimensional measurements provideddatasupporta correlation between unidimensionaland bidimensionallesionsin patientswho exhibit both types. For clinical benefit,FDA said it would give moreweight to separate assessment eachcomponentof of proposed compositeclinical benefit endpoint. Also if clinical benefitis to suffice for approval,thendouble-blindingis strongly advised. FDA requested Lilly submit written statisticalplan for We analysisof clinical benefit. FDA stated,‘ remind you of our ementthat the randomizedcontrol trial in NSCLC is essential

9/l 5199

#182 Response Stat to Review #l91 Annual Report

rmationand algorithm for ssesFDA statistical concerns

safety analysis(pp. l-5), and cover letter pointedout relationship betweenhigh baselinehomocysteine levels and severetoxicity collection of notedin LY23 1514 trials. Lilly will recommend

(continued)

c

Table 3.H.3.

History 6f Regulatory Correspondence

(continued)

correlatedwith increased of hematologicand nonrisk

LY23 1514 safetyanalysisshowing details of relationshipbetween

than JMCH inform ing them to no longer excludepatients with high baselinehomocysteine, rather to supplement but patientswith folic acid and vitam in Br2. This submissionalso included a copy of the abbreviated safety analysisthat was sent to the investigators. The letter to investigatorand the abbreviatedsafety report was not sentto investigatorson JMCH, JMAF, JMAS, JMAW and JMBV andthe reasons theseinvestigatorswere

the FDA along with protocol amendments specifying vitam in

studiesto institute vitam in supplementation theseprotocols in

and the Medical Officer doesnot supportadding vitam ins to the ongoingpivotal, randomized trial in M P M . He gave several

completeJMCH even if the results are positive at interim analysis, and (3) the informationin the annualreport for LY23 1514toxicity doesnot appearto supportthe addition of vitam ins. The FDA Medical Omcer addedthat Lilly “may want to designa (continued)

.

.

Table 3.l-i.3.
Date

History of Regulatory Correspondence
IND Serial # or Type of Communication #200 Protocol Amendment JMCH(c)
Comments

(continued)

lW2W99

#2OI Lilly Response toFDA Communication

01/06/00

FAX from FDA to Lilly #206 Protocol Amendments JMCWO, JMDR (b) and JMDR(c)
#207

2/14/00

Amendment(c) to the MPM registrationtrial, JMCH, was submitted This amendment instituted addition of folic acid and vitamin Bl2 for patientson JMCH and gives instructions for vitamin supplementation new patientsor for continuationon for patientswho beganwithout vitamin supplementation.The amendment specifieswhat constitutesfolic acid supplementation complianceand additionally gives a plan for a safety analysisin which the toxicity would be comparedfor cycles in which patients did and did not receivefolic acid. In response 2 1 December 1999FDA communication,Liliy to provided rationalefor adding vitamins to the ongoingMPM registrationtrial -this included (1) Lilly statistical analysisplan [SAP] for JMCH, (2) Lilly’ commitment to completingJMCH s and (3) updateddataon mortality in both arms of JMCH (five deathson LY231514 plus cispiatin arm versusone deathon cisplatin alone arm). FDA Medical Officer reiteratedthat after reviewing submissions #ZOO #201, he still did not supportthe addition of vitamins to and the ongoing pivotal MPM trial. Protocol AmendmentJhKH(d) provided re-wordingto increase clarity. Protocol AmendmentJMDR(b) instituted folic acid and vitamin B12 supplementation the single agentPhase2 for LY23 1514trial in MPM. Protocol AmendmentJMDR(c) provided re-wordingto increaseclarity.

02/l 6/00

Lilly provided briefing documentfor upcoming 01 March 2000 Briefing meetingto discussvitamin supplementation ongoingMPM in Documentfor 01 registrationtrial, JMCH. Included with this briefing documentas March Meeting an attachmentwas a list of communicationsbetweenthe FDA and Lilly concerningLY23 1514 for MPM. EOP2 Meeting EOP2 Meeting was held to discussaddition of vitamins to ongoing #3 (Vitamins) MPM registrationtrial. Lilly agreedto continuethe MPM registrationtrial with vitamins using a recalculatedsamplesize to provide adequate power (see06 April 2000 entry for FDA minutes of this meeting). After 150 patientsare treatedon revised protocol, a pooled survival analysiswill be done with the approximately 150 patients not supplemented with vitamins.. Lilly will provide vitamin dosing information and a new statistical plan for Study JMCH. (continued)

.

T a b l e 3 .X .3 .
D a te

History O f R e Q y l a tory C o r r e s p o n d e n c e (continued)
N D Serial# o r r y p eo f S m m u n ication f2 1 2 :0 1 1 o w - u p suestions to viarch1 M e e tin g h m m e n ts

1 3 /0 8 /0 0

3 3 /2 0 /0 0

@ t/0 6 /0 0 7

4 /2 5 /0 0

4 /2 6 /0 0

X ly m a d e x p e d i te R e v i e wR e q u e sfo r D O D Pr e s p o n s e E d t e g a r d i n g e issue f s u p p o r tintrials. A t th e M a r c h 1 m e e tin g th o g vith th e F D A , Dr. P a z d u sta te d th e c o n s e n s uasn s w e to r in r & e s tio n # 3 ,th a tth e “F D A will g e tb a c kto th e s p o n s oo n th e r l u m b e ro f trials in N S C L Ca n dn o c o m m i tm e nis m a d ea t this t n e e tin g . Lilly s u b m i tte d e i rversian f th e m e e tin g inutes th o m from th e #216 Lilly V e r s i o n f o % a r c h1 ,2 0 0 O e e tin g Lilly a s k e d a tseveral m sb e n o te d m . th ite Ih a tw e r en o t c a p tu r e in m inutes k e nb y th e F D A d u r i n gth e d ta M a r c h1 . a s l M e e tin g inutes m e e tin g A lso Lilly p r o v i d e d n s w e r to “A d d i tio n a C o m m e n ts M l% o m e F D A ” th a tw e r ep r o v i d e d writing a t th e 0 1 M a r c h th in m e e tin go n ec o m m e not n clinicalb e n e fit e s p o n sa n da n o th e r ( r e c o m m e not njustificationfo r u s eo f vita m ins).A d d i tionally Lilly p r o v i d e d n s w e rto F D A c o m m e n ts n p r o tocola m e n d m e n t a s o IM C H ( d ) th a tw a sS u b m itte 1 4F e b r u a r2 0 0 0(serial 2 0 6 )a n d d y # a revised A P fo r J M C H . S F D A s e n tto Lilly th e o fficial m e e tin g inutes f th e 0 1 M a r c h m o F A X from F D A 2 0 0 0m e e tin g h e r e m ins u p p l e m e n ta tio nth e o n g o i n g w vita in to Lilly M P M registration w a sdiscussed. h e F D A m inutes i d n o t trial T d i n c o r p o r a ta n yo f th e n o te so r clarifications r o p o s eb y Lilly in e p d th e Lilly version f th e m e e tin g inutes o m (submission 21 6o n 2 0 # M a r c h2 0 0 0 ) . e # r F A X from F D A F D A r e s p o n sto Lilly submissionZ1 2(Lilly q u e s tio ne g a r d i n g s u p p o r tin trials); F D A saidth a t2 n d N S C L C c o u l dservea s g line to Lilly th e s u p p o r tin trial fo r M P M indication, u t th a tP h a s e trials g b 2 w o u l dn o ts u p p o rth e M P M indication t P r o tocol m e n d m e J M D R ( d )sta te dth e s a m p l e w a s a nt size #224 i n c r e a s eto a s s u r th a tth e trial w o u l dc o n ta i n 1 vita m in d e 4 P r o tocol s u p p l e m e n te d tie n ts; e l u n gdensityd a taw o u l dn o l o n g e r e pa th b Amendment collected this trial in JMDR(d) F A X from F D A F D A r e s p o n d ewith sta tisticalc o m m e n ts th e Lilly 2 0 M a r c h d to to Lilly 2 0 0 0submissionf th e Lilly sta tisticalp l a nfo r J M C H . F D A o a s k e d r clarification f th e interimsurvivalfo r J M C H a n dth e fo o e ffectso f th e interimanalysis n th e fin a l survivalanalysis.T h e o F D A a s k e d r clarification n th e p r i m a r yanalysis r a n o o fo acceleratedp p r o v aa n dd e m o n s trationa t a T y p e I e r r o r a l th inflationwill n o t resultwithoutth e a p p r o p r i a a l p h a te adjustment. A lso th e F D A a s k e d Lilly to specifyeitherl o g r a n k r W ilcoxon o analysis r th e interima n dfin a l analyses; b o th analyses b e fo if will c o n s i d e r ea s primary, e nth e a l p h a d th levels h o u l d e a d j u s t e d r b fo m u ltip l eanalyses. (continued)

Table 3.H.3.
Date

History of Regulatory Correspondence
IND Serial # or Type of Commudcation SN 233 EOP2 CMC Questions Comments

(continued)

06/U8/00

6/21/00

7/12/00

8i23fOO -

Lilly submittedan amendment the IND to confirm its planned to approach threetopics: the API stability simulator,the matrixing on 3f upright and inverted vials for drug productprimary stability (for solutionformulation), andthe inclusion of two long-termstorage renditionsin the API primary stability study. Teleconference A teleconference held betweenFDA and Lilly to discuss was betweenDODP supporting trials. The FDA agreedthat the secondline and Lilly registration trial in NSCLC could supportthe MPM indication. FDA strongly discouraged‘MPM submissionon interim analysis s of the secondary endpoints(response rate,time to tumor progression “symptom benefit”without maturesurvival data. or FDA also statedthat “survival data would leadto a definitive conclusionregardingLY231514’ clinical benefit.” s Protocolamendment JMCH(e) increased samplesize to allow the #242 Protocol for 280 patientsthat had beensupplemented vitamins (per 01 with Amendment March2000 EOP2 meeting);also amendment statedthat lung JMCH(e) densitymeasurements were no longerbeing collectedin this trial as sufficient datahas beenobtained. Additionally the amendment presented revisedprimary efficacy analysis. a FDA FAX FDA (Ms. Vause)FAX dated 11 August 2002 providedFDA’ s response to responses Lilly’ questionsdated08 June02 (SN 233). FDA to s EOP2 agreed the API stability simulatorandprimary stability study that CMC Questions test conditions [(Lilly Questions(1) and(3)]. Further,FDA recommended modification to our proposed a matrix designfor the drug productprimary stability plan (Lilly Question2). SN 253 This submissionwas madein response the FDA FAX received to Response to 11 August 2000. s in to ‘ FDA FAX dated Lilly agreedto FDA’ suggestion response question2 and 11 August 2000 reversed upright/invertedschedules the 25 mL the for presentation.We have revisedthe Pl protocol from page 19 of the original briefing documentas shown. FAX from FDA FDA response Lilly’ 06 July 2000 requestfor a special to s to Lilly protocol assessment Study JMEI (LY231514vs docetaxeiin for secondline NSCLC). In the submissionof July 6, Lilly askedif JMFI will supportthe MPM claim. The’ FDA responded the that study is well controlled and will supportthe MPM claim, but that the proposedassessment non-inferiority is not acceptable.Thus of Study JMEI would needto demonstrate superiorityto supportthe MPM claim (continued)

._ .

.

Table 3.H.3.
Date

History of Reguiatory Correspondence

(continued)

amendment JMCH(f). If lung densityis droppedas a secondary endpoint,the resultsof the exploratoryanalysisof the 170patients not all patientsmay havesuffkient tissue for review of histopathology, slidesshouldbe availablefor review by an the independent pathologist. The rigor to the study will be decreased without independent review of all cases. FDA recommends a uniform, singledoseof folic acid and vitamin Bl2, otherwisethe resultsare subjectto bias anduncertaintyfor review of the NDA and labeling. Pleuralrind when considered assessment for of tumor response progression or shouldbe prospectivelyidentified at baseline. FDA wantedclarification of the interim analysispvalue. The final analysison survival shouldbe basedon the protocol-specified numberof deaths(also the interim analysis). lysis basedon secondary 21610 1 CH would be based on the primary endpointof survival ratherthan on the secondary endpoints. In additionthe alphaspendat the interim analysiswas loweredto 0.01 to preserve higher significancelevel testing at a the final analysis. Lilly reiteratedthat the interim analysiswill be performedunderthe auspices a Data Monitoring Board of comprisedexclusively of membersexternalto Lilly andthat any decisionto submit an NDA a&r the interim analysiswill be basec 3/20/01

ly Advancedor Metastatic
(continued

Table 3.M.3.
Date

History of Regulatory Correspondence
IND serial # or Type of Communication FAX from FDA to Lilly Comments

(continued)

s/01/01

DODP requested Lilly addrossseveralissuesin NDA for LY231514. The first issue involved drug-druginteractionsin conjunctionwith the 02 May 2001 EGPZmeetingto discussthe proposed registrationtrial of LY23 1S14 plus gemcitabine in pancreatic cancer. DGDP also asked,“What is the statusof in vitro studiesto determinewhetherLY23 1S14 is an inhibitor, substrate an inducerof cytochromeP-450 isozymes?”DODP or alsobroughtup the topic of organdysfunction studies: “At the End-of-Phase meetingwith FDA on 23 September 2 1998,the sponsor committedto conductingrenal impairmentstudieswith LY23 1514 in accordance with the FDA Guidancefor Industry on RenalImpairmentstudies, What is the currentstatusof these studies?’ Communication Lilly received(11 May 2001)the FDA communicationdated07 May 2001 with DODP specialclinicaLprotocol assessment the for from FDA to Lilly second MPM trial, JMEW submittedas SN 298 on 20 March line 2001. DODP agreedwith the designof JMEW, the patient population,the comparatorand also that Study JMEW could be supportiveto a front line claim in MPM. DODP recommended thatthe numberof stratification factors in JMEW be reduced. Lilly submittedcharterfor Data Monitoring Board (DMB) for #314 Charterfor Data MPM registrationStudy JMCH. The DMB will overseethe interim analysisof JMCH. Membersof the DMB are all external Monitoring Board to Lilly and only the DMB is authorizedto review completely unblindedthe interim efficacy and safety analysis. The interim analysison JMCH will be basedon primary endpointof overall survival and the trial will not be stoppedbasedon the resultsof the interim analysis. Lilly Submission Lilly submitted requestfor OrphanProductDesignationfor to the Office of LY23 IS 14 for MPM to the Office of OrphanProducts OrphanProducts Development. This submissionwas basedon (1) the prevalence of MPM has beenestimatedat only 3930 casesin the US and (2) scientific rationalefor the use in MPM. (continued)

Table 3.H.3.
Date

History of Regulatory Correspondence
IND Serial # or Type of Communication #320 Response to 01 May FDA Biopha& issues Comments

(continued)

6/20/01

Lilly responded the 01 May FDA biopharmissues. ( 1) to Regardingthe drug-drug interactionstudiesfor LY23 1514 with gemcitabine,Lilly statedthat a trial is alreadybeing doneusing the generalcancerpatientpopulationto study interactionsbetween LY23 1514 andgemcitabine.(Z).Regarding vitro studiesof in cytochromeP-450isozymes,Lilly statedthat LY23 1514 would be predictedto not cause‘ significantinhibition of the metabolic clearance drugsmetabolized CYP3A, CYP2D6, CYP2C9 of by and CY P 1A2. Because LY23 1514 is excretedlargely unchanged in humanurine, studiesto determine whetherLY23 1514is a substratefor CYP-450enzymes havenot beencarriedout. Also enzymeinduction studieshavenot beencarried out with LY2315 14 since any significantenzymeinduction in humansis not likely with a onceevery 21 day schedule. (3) LiIly gave an updateon the clinical renalinsufficiency Study IMAW and asked if the completedPK andchnical safety analysescould be submittedas part of the 120 day safety updateratherthan at the time of the NDA submission. Lilly submitteda safety updateon the effects of folic acid and #323 vitamin B 12supplementation was promisedin SN 195 (03 that Safety Update December1999)and againin the briefing document(SN 207 on 16 February2900) for the 01 March 2000 EOP2 meeting. The results of this analysisshowedthat folic acid and vitamin B 12 supplementation to a profoundreductionin LY231514-related led deathsas well as significant reductionsin episodesof Grade3 hematologicand Grade3/4 nonhematologic toxicities associated with LY231514. Teleconference Teleconference held between was FDA and Lilly to discuss Biopharm issues. FDA statedthat Lilly’ 29 May 2001 responses s with FDA regarding to Issues#l (drug-druginteractionsbetweenLY231514 and Biopharm issues gemcitabine)and #2 (in vitro cytochromeP-450 studies)were acceptable responses.Regarding third issue(organ the dysfunction) FDA statedthat the renal insufficiency study is potentially relevantto the drug’ approval,and that FDA will wait s for the results of the MPM interim analysisbeforemaking their decision and that this issuewill be revisited at the pre-NDA meeting. The FDA againstatedthat the endpointfor the interim analysis of the MPM registrationtrial, JMCH, must be survival. (continued)

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