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Presented at the American Society of Clinical Oncology, Chicago, IL, May 30–June 3, 2014

• Veliparib in combinaon with FOLFIRI chemotherapy was generally well tolerated without drug-drug PK interacons.
• The RP2D is veliparib 200 mg BID with bimonthly FOLFIRI (irinotecan 150 or 180 mg/m
2
without 5-FU bolus).
• Paents with ovarian and breast cancer experienced the greatest antumor acvity, with an ORR of 38% and 22%, respecvely, but prior treatments/
exposures and/or BRCA status could have influenced these results.
• This study supports further evaluaon of veliparib in combinaon with FOLFIRI in several tumor types.
CONCLUSIONS
A Phase 1 Dose-Escalaon Study of Veliparib With Bimonthly FOLFIRI in Paents With Advanced Solid Tumors
Jordan Berlin
1
, Ramesh K. Ramanathan
2
, John H. Strickler
3
, Deepa Suresh Subramaniam
4
, Herbert Hurwitz
3
, Yoon-Koo Kang
5
, Tae-You Kim
6
, Stacie Peacock Shepherd
7
, Hao Xiong
7
, Robert Hetman
7
, Caroline Nickner
7
, Mahew W. Dudley
7
, Vincent L. Giranda
7
, Heinz-Josef Lenz
8

1
Vanderbilt-Ingram Cancer Center, Nashville, TN, USA;
2
Translaonal Genomics Research Instute – Virginia G. Piper Cancer Center, Scosdale, AZ, USA;
3
Duke University Medical Center, Durham, NC, USA;
4
Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA;
5
Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea;
6
Department of Internal Medicine and Cancer Research Instute, Seoul Naonal University Hospital, Seoul Naonal University College of Medicine, Seoul, South Korea;
7
AbbVie Inc., North Chicago, IL, USA;
8
Division of Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA
2574
INTRODUCTION
To view an electronic version of
this poster, scan QR code or visit
abbviescience.com/614119315/6
OBJECTIVE
METHODS
RESULTS
ACKNOWLEDGEMENTS
This presentaon was supported by AbbVie. AbbVie
parcipated in the design and conduct of the study
and in the analysis and interpretaon of the data as
well as the wring, review, and approval of the poster.
Medical wring support was provided by Jennifer Han
of Complete Publicaon Soluons, LLC; this support was
funded by AbbVie.
1. Chiarugi A. Trends Pharmacol Sci. 2002;23(3):122-129.
2. Virag L and Szabo C. Pharmacol Rev. 2002;54(3):375-429.
3. Curn NJ, et al. Clin Cancer Res. 2004;10(3):881-889.
4. Davidson D, et al. Invest New Drugs. 2013;31(2):461-468.
5. Shelton JW, et al. Int J Radiat Oncol Biol Phys. 2013;86(3):469-476.
6. Goodman SN, et al. Stat Med. 1995;14(11):1149-1161.
7. O’Quigley J and Zohar S. Br J Cancer. 2006;94(5):609-613.
8. Piantadosi S, et al. Cancer Chemother Pharmacol. 1998;41(6):429-436.
9. Eisenhauer EA, et al. Eur J Cancer. 2009;45(2):228-247.
REFERENCES
DISCLOSURES
Jordan Berlin, Heinz-Josef Lenz, Ramesh K. Ramanathan
and John Strickler received research funding fromAbbVie.
Yoon-Koo Kang and Tae-You Kimhave no conflicts to disclose.
Deepa Subramaniam, Stacie Shepherd, Hao Xiong, Robert
Hetman, Caroline Nickner, Ma Dudley, and Vincent Giranda
are AbbVie employees and may hold AbbVie stock or opons.
• Poly(ADP-ribose) polymerase (PARP)-1 and PARP-2 are nuclear enzymes
that recognize DNA damage and facilitate DNA repair.
1,2
• Genec deficiencies and the acon of DNA-damaging chemotherapies
render cancer cells more dependent on PARP-1 and PARP-2 for DNA
repair and therefore more sensive to PARP inhibion.
3
• Veliparib (ABT-888) is a potent, oral, compeve PARP-1 and PARP-2
inhibitor that enhances the acvity of genotoxic agents, such as
irinotecan, in preclinical tumor models (Figure 1).
4,5
Figure 1. Veliparib + Irinotecan in a Preclinical Model
Veliparib (ABT-888) and/or irinotecan (irino) was administered to 14 groups of 10 mice in a HCT116 model of human colorectal carcinoma.
• To determine the maximum tolerated dose (MTD) and recommended
phase 2 dose (RP2D) of veliparib in combinaon with various regimens
of bimonthly folinic acid + 5-fluorouracil (5-FU) + irinotecan (FOLFIRI) in
paents with solid tumors
STUDY DESIGN
• This ongoing, phase 1, open-label, mulcenter, dose-escalang study
included dose-escalaon and safety-expansion phases in which paents
received veliparib and bimonthly FOLFIRI in 28-day cycles (Figure 2).
– Veliparib was administered on Days 15–19 in Cycle 1 and on Days 1–5
and 15–19 in subsequent cycles.
– Subjects with stable disease or beer status could connue veliparib
and FOLFIRI unl progressive disease (PD), unacceptable toxicity, or
FOLFIRI disconnuaon.
Figure 2. Study Design
Part 1
n = 67
Velipariba 10, 20, 40, 80, or
130 mg BID
+
Folinic acid 400 mg/m2 2-h infusion
+
5-FU 2400 mg/m2 46-h infusion
+
Irinotecan 150 mg/m2 90-min infusion
Part 2
n = 8
Velipariba 160, 200, or 270 mg BID
+
Folinic acid 400 mg/m2 2-h infusion
+
5-FU 2400 mg/m2 46-h infusion
[+ bolus]
+
Irinotecan 150 mg/m2 90-min infusion
Part 3
n = 25
Velipariba 100, or 200 mg BID
+
5-FU 2400 mg/m2 46-h infusion
[no bolus]
+
Irinotecan 180 mg/m2 90-min infusion
ÞauenLs evaluaLed for uL1s: n = 41
uL1s: n = 3
ÞauenLs ln Lhe expanslon cohorL: n = 14
ÞauenLs LreaLed aL 8Þ1u: n = 20
ÞauenLs evaluaLed for uL1s: n = 4 ÞauenLs evaluaLed for uL1s: n = 12
uL1s: n = 1
ÞauenLs ln Lhe expanslon cohorL: n = 7
ÞauenLs LreaLed aL 8Þ1u: n = 11
1reaLed pauenLs
N = 92
FOLFIRI = folinic acid + 5-fluorouracil + irinotecan; PARP = Poly(ADP-ribose) polymerase.
aThe bolus 5-FU dose was not tolerated during the first 2 weeks of C1, before veliparib administraon. P2 dose escalaon was consequently
disconnued and, although paents could connue veliparib, they were considered not evaluable. Data from Part 2 were combined with
those from Part 3.
METHODS CONTINUED
Table 1. Key Study Entry Criteria
All Patients
• Age 18 years
• Eastern Cooperative Oncology Group performance status score of 0–1
• Received 3 prior DNA-damaging agents/cytotoxic chemotherapy within the past 2 years
Dose Escalation Safety Expansion
• Patients with histologically/cytologically
confirmed solid tumors that are metastatic or
unresectable and 1 of the following:
• Patients with histologically confirmed,
advanced/metastatic cancer with
irinotecan-based regimen as standard therapy
- FOLFIRI as a viable option - ~50% of whom have histologically confirmed
gastric cancer and no previous treatment with
a PARP inhibitor - No standard curative/therapeutic options
- Refractory disease to standard therapy
DOSE ESCALATION AND DETERMINATION OF MTD AND RP2D
• Dose escalaon was conducted in 3 parts; a minimum of 3 paents per
dose level were included for dose-toxicity modeling:
– Part 1 (P1) regimen: Dose escalaon began with veliparib 10 mg
twice daily (BID) + bimonthly FOLFIRI (folinic acid + 5-FU + irinotecan
150 mg/m
2
)
– Part 2 (P2) regimen: Veliparib 160 mg BID + bimonthly FOLFIRI (folinic
acid + 5-FU [+bolus] + irinotecan 150 mg/m
2
)
– Part 3 (P3) regimen: Veliparib with dose escalaon starng at
100 mg BID or MTD + bimonthly FOLFIRI (5-FU + irinotecan 180 mg/m
2
)
without bolus 5-FU
– Folinic acid was administered as 400 mg/m
2
over 2 hours on Days 1
and 15 and connuous infusion 5-FU was administered at a dose of
2400 mg/m
2
over 46 hours beginning on Days 1 and 15
• A connual reassessment method
6-8
that uses Bayesian methods to
incorporate informaon fromall prior events (e.g., doses and tolerability)
into a dose-response model in real me guided dose escalaon.
• Dose-escalaon paents who did not require FOLFIRI dose reducon by
Cycle (C) 1 Day (D) 15 were evaluated for DLT in the second half of C1;
those who required dose reducon were replaced to ensure ≥3 evaluable
paents per dose cohort.
• MTD was defined as the largest dose for which the probability of DLT
was <0.33.
SAFETY EXPANSION
• Safety expansion was conducted in 2 cohorts to further evaluate the
RP2D; ~50% of paents were to have a diagnosis of gastric cancer.
SECONDARY OBJECTIVES
• Safety and tolerability
• Pharmacokinecs (PK)
– In dose-escalaon cohorts, samples were collected on C1D15 for
veliparib PK and on C1D1 and C1D15 for FOLFIRI components PK
(irinotecan, irinotecan acve metabolite [SN-38], leucovorin, and
5-FU).
• Exploratory effi cacy
– Objecve response rate (ORR: confirmed complete response + paral
response [PR] by Response Evaluaon Criteria in Solid Tumors,
version 1.1)
9
– Time to progression (TTP)
– Best percentage change from baseline in tumor size
BASELINE CHARACTERISTICS
• 97 paents were enrolled across the escalaon and expansion
cohorts, and 92 received veliparib. Baseline demographic and clinical
characteriscs are listed in Table 2.
Table 2. Baseline Demographic and Clinical Characteriscs
(N = 92)
Variable
Sex, n (%) Female 42 (46)
Male 50 (54)
Mean (SD) age, y 55 (12)
Race, n (%) White 68 (74)
Asian 13 (14)
Black 8 (9)
Other 3 (3)
ECOG status Grade 0 37 (41)
Grade 1 54 (59)
Missing 1 (1)
Tumor type, n Breast 9
Colorectal 10
Gastric 20
Ovarian 9
Pancreatic 14
Other* 30
Number of lines of prior therapy 0 2 (2)
1 18 (20)
2 25 (27)
>3 47 (51)
Patients who received cisplatin or carboplatin, n (%) 42 (46)
Patients who received oxaliplatin, n (%) 44 (48)
Median (range) prior lines
of therapy
Overall group (n = 92) 3 (0-10)
Patients with colorectal cancer (n = 6)
or gastric cancer (n = 14)
1.5 (0-4)
Median (range) cycles of veliparib 4 (1-48)
*Other types of tumor include: esophageal (n = 4); head and neck (n = 2); hepatocellular carcinoma (n = 1); non-small cell lung cancer (n = 3);
other adenocarcinoma (n = 1); other adenoid cysc tumor (n = 1); other cholangiocarcinoma (n = 2); other common bile duct tumor (n = 1);
other malignant neoplasm (n = 1); other papillary serous tumor (n = 1); other pseudomyxoma peritonea (n = 1);other squamous carcinoma
(n = 1); other unknown primary tumor (n = 1); skin cancer (n = 1); small cell lung cancer (n = 2).
SAFETY
• 86 paents disconnued veliparib: 83 due to PD, 7 withdrew consent,
3 due to adverse events (1 PD-related), and 9 for other reasons. (Paents
who disconnued study drug are counted under each reason given for
disconnuaon. Therefore, the sum of the counts given for the reasons
may be greater than the overall number of disconnuaons).
• Adverse events and grade 3/4 toxicies that occurred in ≥30% paents
overall are reported in Table 3.
Table 3. Treatment-Emergent Adverse Events Reported in
≥30% of All Paents
Part 1
n = 67
Parts 2a and 3
n = 25
Combined RP2Db
n = 31
Total
N = 92
Adverse Events
All
Grades
Grade
3/4
All
Grades
Grade
3/4
All
Grades
Grade
3/4
All
Grades
Grade
3/4
Diarrhea 60 36 68 28 58 29 62 34
Neutropenia 57 43 72 60 77 68 61 48
Nausea 61 40 56 32 71 52 60 38
Vomiting 48 28 48 24 45 23 48 27
Fatigue 39 25 68 44 42 29 47 30
Anemia 39 22 52 28 45 29 42 24
Alopecia 45 25 28 4 45 26 40 20
Decreased appetite 15 9 52 28 23 16 33 15
RP2D = recommended phase 2 dose.
a Paents in Part 2 did not tolerate the 5-FU bolus as part of the FOLFIRI regimen. Therefore, dose escalaon was disconnued and, although
paents could connue veliparib, they were considered not evaluable. Data fromthe 8 paents in Part 2 were combined with Part 3.
b Includes 20 paents from Part 1 and 11 paents from Part 3.
• Grade 3/4 toxicies that were considered possibly or probably related to
veliparib (in ≥2% of the overall study populaon) included neutropenia
(29%), anemia (4%), febrile neutropenia (3%), dehydraon (2%),
diarrhea (2%), leukopenia (2%), and voming (2%).
DLTS AND RP2D
• Four DLTs occurred: 3 DLTs of neutropenia (at veliparib 160 and 270 mg
BID in P1, and at veliparib 100 mg BID in P2) and 1 DLT of gastris and
voming (at veliparib 270 mg BID in P1).
• In P2, the 5-FU bolus of the FOLFIRI regimen was not tolerated during the
first 2 weeks of C1, before veliparib administraon. P2 dose escalaon
was consequently disconnued, and P2 was moved into P3.
• The RP2D was determined to be veliparib 200 mg BID in both P1 and P3.
• 2 safety-expansion cohorts were enrolled at the RP2D + FOLFIRI with
either irinotecan 150 mg/m
2
(gastric cancer, n = 14) or 180 mg/m
2

(colorectal cancer, n = 7).
PHARMACOKINETICS
• Veliparib exposure was approximately dose proporonal in combinaon
with FOLFIRI (Figure 3).
• Veliparib PK parameters are comparable to those in other ongoing
veliparib phase 1 studies, suggesng no significant effect of FOLFIRI on
veliparib PK.
• Irinotecan/SN-38, folinic acid (leucovorin), and 5-FU PK were comparable
with or without veliparib administraon.
Figure 3. Mean ± SD Cmax and AUC0–8 of Veliparib Aer a Single
Dose of Veliparib in Combinaon With FOLFIRI
0 50 100 150 200 250 300
0.00
0.25
0.50
0.75
1.00
1.25
1.50
1.75
0 50 100 150 200 250 300
0
1
2
3
4
5
6
7
8
9
Veliparib Dose (mg) 10 20 40 80 100 130 160 200 270
N 10 5 5 4 11 4 9 4 5
Veliparib Dose (mg) Veliparib Dose (mg)
A
U
C
0-8 (μ
g
h
/
m
L
)
C
m
ax (μ
g
/
m
L
)
AUC0–8 = area under the plasma concentraon-me curve from me 0 to 8 hours; Cmax = maximum observed plasma concentraon.
EXPLORATORY EFFICACY
• Response rates, mes to disease progression, and best percentage
change frombaseline in tumor size by veliparib dose are shown by tumor
type in Table 4 and Figures 4 and 5, respecvely.
Table 4. ORR and TTP Rate
Ovarian
n = 8
Breast
n = 9
Pancreatic
n = 14
Gastric
n = 20
Colorectal
n = 10
Other
n = 30
ORRa (CR+PR), n (%)
[95% CI]
3 (38)
[8.5–75.5]
2 (22)
[2.8–60.0]
2 (14)
[1.8–42.8]
3 (15)
[3.2–37.9]
1 (10)
[0.3–44.5]
2 (7)
[0.8–22.1]
PR, n 3 2 2 3 1 2
TTP rateb at 6 mo
[95% CI]
63.5
[23.8–86.6]
22.2
[3.4–51.3]
26.8
[7.3–51.5]
45.9
[22.8–66.4]
50.8
[15.7–78.1]
21.9
[8.2–39.8]
CR = complete response; ORR = objecve response rate; PR = paral response; TTP = me to progression.
a ORR was esmated for all paents with ≥1 measurable lesion; the corresponding 95% CI was constructed using exact binomial distribuon.
b The distribuon of TTP was esmated using Kaplan-Meier methodology.
One ovarian paent was unevaluable.
• The median TTP was longest in paents with ovarian cancer at 361 days, with the upper bound of the 95% CI not reached (Figure 4A).
• The median TTP was 195 and 157 days, respecvely, in paents with colorectal or gastric cancer (Figure 4B).
Figure 4. Kaplan-Meier Curve for Time to Disease Progression
a
(A) Paents With Breast
b
, Ovarian
b
, or Other Cancer and for
(B) Paents With Colorectal, Gastric
c
, or Pancreac Cancer in the Dose-Escalaon and Safety-Expansion Cohorts
P
ro
b
a
b
ility
o
f R
e
m
a
in
in
g

P
ro
g
re
s
s
io
n
-fre
e
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Ovarian
Breast
Other Censored
Days Since First Dose
1140 1020 960 900 840 780 720 660 600 540 480 420 360 300 240 180 120 60 0 1080
Pt at Risk
Ovarian 9 7 6 5 4 3 3 2 2 2 2 2 2 2 2 2 2 2 1 1
Breast 9 6 4 2 2 2 2 2 2 2 2 2 2 0
Other 30 21 12 5 3 3 3 3 3 3 1 1 0
Ovarian Breast Other
(N = 9) (N = 9) (N = 30)
Event (%) 6 (66.7) 9 (100.0) 25 (83.3)
Median Days (95% CI) 361 (1, - ) 107 (36, 730) 113 (92, 154)
P
ro
b
a
b
ility
o
f R
e
m
a
in
in
g

P
ro
g
re
s
s
io
n
-fre
e
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Gastric
Colorectal
Þancreauc
Censored
Days Since First Dose
780 720 660 600 540 480 420 360 300 240 180 120 60 0
Pt at Risk
Gastric 20 10 9 7 6 6 4 3 1 1 0
Colorectal 10 8 4 4 1 1 0
Þancreauc 14 S 3 3 3 2 1 1 1 1 1 1 1 0
CasLrlc ColorecLal Þancreauc
(N = 20) (N = 10) (N = 14)
Event (%) 13 (65.0) 6 (60.0) 13 (92.9)
Median Days (95% CI) 157 (51, 568 ) 195 (43, -) 42 (32, 295)
A. B.
a The distribuon of me to progression (median me to progression and corresponding 95% CI) was esmated using Kaplan-Meier methodology.
b 4 paents with breast cancer and 4 paents with ovarian cancer were BRCA+.
c Median PFS was longer in the safety-expansion cohort for gastric cancer paents at 223 (95% CI, 57, not reached).
• The majority of safety-expansion paents experienced some reducon in tumor size from baseline (Figure 5A and B).
Figure 5. Best Percentage Change FromBaseline in Tumor Size by Veliparib Dose for A) Paents With Breast, Ovarian, or Other
Cancer and for B) Paents With Colorectal, Gastric, or Pancreac Cancer in the Dose-Escalaon and Safety-Expansion Cohorts
-100
-75
-50
-25
0
25
50
75
B
e
s
t P
e
rc
e
n
t C
h
a
n
g
e
F
ro
m
B
a
s
e
lin
e
Breast
(N = 8)
Ovarian
(N = 6)
Other
(N = 23)
10 mg (non-bolus)
10 mg (bolus)
20 mg
40 mg
80 mg
100 mg (non-bolus
100 mg (bolus)
130 mg
160 mg
200 mg (150 mg/m2 irinotecan)
200 mg (180 mg/m2 irinotecan)
270 mg
300 mg
* *
*
*
*
*
*
*
*
*
A.
Colorectal
(N = 11)
Gastric
(N = 19)
Pancreac
(N = 13)
-100
-75
-50
-25
0
25
50
75
B
e
s
t P
e
rc
e
n
t C
h
a
n
g
e
F
ro
m
B
a
s
e
lin
e
10 mg (non-bolus)
10 mg (bolus)
20 mg
40 mg
80 mg
100 mg (non-bolus
100 mg (bolus)
130 mg
160 mg
200 mg (150 mg/m2 irinotecan)
200 mg (180 mg/m2 irinotecan)
270 mg
300 mg
*
*
*
*
B.
Bolus = 5-FU bolus as part of the FOLFIRI regimen; Non-bolus = no 5-FU bolus as part of the FOLFIRI regimen. Evaluable paents had at least one CT scan following the start of therapy.
*BRCA+.
NCT01123876