Protocol Document

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TITLE PAGE STUDY PROTOCOL
Protocol Title:
A Phase III multicenter, international, randomized, double-blind, placebo-controlled study of doxorubicin plus palifosfamide-tris vs. doxorubicin plus placebo in patients with front-line metastatic soft tissue sarcoma. The PICASSO III Study IPM3001 III Amendment 3: 17 January 2011 Amendment 2: 21 May 2010 Amendment 1: 22 April 2010 Original protocol: 03 March 2010
Protocol Number: Phase: Date of Protocol:
Sponsor:
ZIOPHARM Oncology, Inc. One First Avenue, Parris Building 34 Boston, MA 02129 USA John Hunter, MD (PPD, Primary) Brian L. Hamilton, MD, PhD (ZIOPHARM) ZIOPHARM Oncology, Inc. One First Avenue, Parris Building 34 Boston, MA 02129 USA
Medical Monitor(s):
Safety Reporting:
Not for Distribution Do Not Copy This study protocol contains confidential information and is the proprietary property of ZIOPHARM Oncology, Inc. The protocol is for use by the Principal Investigator and his/her designated representatives participating in this investigational trial. This protocol may not be copied or made available for review by an unauthorized person or firm without the prior written authorization of ZIOPHARM Oncology, Inc.
Protocol IPM3001 Palifosfamide-tris
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ZIOPHARM Oncology, Inc.
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TABLE OF CONTENTS Page
Section 1. 2. 3. 4. 5. 6.
TITLE PAGE ................................................................................................................. 1 TABLE OF CONTENTS .............................................................................................. 2 ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................. 6 SYNOPSIS ...................................................................................................................... 8 TABLE 1: SCHEDULE OF STUDY PROCEDURES AND ASSESSMENTS..... 10 BACKGROUND .......................................................................................................... 13 6.1. Palifosfamide (IPM) .............................................................................................14 6.2. Clinical Experience with Palifosfamide ...............................................................15 6.2.1. Clinical Experience with Palifosfamide (lysine salt formulation) ........15 6.2.2. Clinical Experience with Palifosfamide (tris salt formulation) .............16 6.3. Rationale for Phase III Study ...............................................................................18 6.4. Rationale for Dose of Palifosfamide-tris ..............................................................18
7.
OBJECTIVES AND DESIGN .................................................................................... 19 7.1. Objectives .............................................................................................................19 7.2. Design and Treatment Regimen ...........................................................................19
8.
SCREENING AND REGISTRATION ...................................................................... 20 8.1. Number of Patients ...............................................................................................20 8.2. Informed Consent .................................................................................................20 8.3. Inclusion and Exclusion Criteria ..........................................................................21 8.3.1. Inclusion Criteria ...................................................................................21 8.3.2. Exclusion Criteria ..................................................................................22 8.4. Protocol Eligibility Waivers .................................................................................23 8.5. Registration ..........................................................................................................24 8.6. Assignment of Patients to Treatment Groups.......................................................24 8.7. Removal of Patients from Study Therapy ............................................................24 8.8. Removal of Patients from Study Follow-up .........................................................26
9.
TREATMENT PROCEDURES ................................................................................. 26 9.1. Schedule of Assessments and Procedures According to Visit/Study Day ...........26 9.1.1. Baseline Evaluations (at the time of Screening) ...................................26 9.1.2. Schedule of events by Cycle and Day ...................................................27 9.1.3. Electrocardiogram (ECG)......................................................................28 9.1.4. Quality of life ........................................................................................28 9.1.5. Tumor Response Evaluations, Even Cycles (e.g., 2, 4, 6), Days 1521 ...........................................................................................................28 9.1.6. Post-treatment Safety Assessment Visit (21 days 3 days after last
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dose) ......................................................................................................28 9.1.7. Long-term Follow-up ............................................................................29 9.1.8. Overall Survival Follow-up after PD until patients death....................29 9.2. Missed Visits ........................................................................................................30 9.3. Protocol Violations ...............................................................................................30 9.4. Blinding/Unblinding Procedures ..........................................................................30 10. STUDY MEDICATION SUPPLY, DOSING PROCEDURES, AND DISPOSITION (ADDITIONAL DETAILS CAN BE FOUND IN THE PHARMACY MANUAL) ........................................................................................... 31 10.1. Palifosfamide-tris Supply and Dispensation ........................................................31 10.1.1. Accountability .......................................................................................31 10.1.2. Receipt of Drug .....................................................................................31 10.1.3. Storage ...................................................................................................31 10.1.4. Handling ................................................................................................31 10.1.5. Vial Inventory and Dispensation ...........................................................31 10.2. Palifosfamide-tris Reconstitution and Dose Preparation......................................32 10.3. Palifosfamide-tris Matching Placebo Dose Preparation .......................................32 10.4. Doxorubicin Supply and Dose Preparation ..........................................................33 10.5. Dosing Regimen and Dosing Instructions ............................................................33 10.6. Dose Delays and Modifications ...........................................................................33 10.7. Treatment of Nausea and Vomiting .....................................................................35 10.8. Disposition of Unused Drug .................................................................................35 11. CONCOMITANT THERAPY.................................................................................... 35 11.1. Permitted Therapies ..............................................................................................35 11.2. Therapies Not Permitted During Study Drug Dosing ..........................................36 12. SAFETY AND EFFICACY VARIABLES AND ASSESSMENTS ......................... 36 12.1. Efficacy ................................................................................................................36 12.1.1. Primary Efficacy Variable .....................................................................36 12.1.2. Secondary Variables ..............................................................................36 12.2. Tumor Response ...................................................................................................36 12.3. Safety Assessments and Adverse Event Reporting ..............................................36 12.4. Definitions ............................................................................................................37 12.4.1. Adverse Event (AE) ..............................................................................37 12.4.2. Suspected adverse reaction ....................................................................38 12.4.3. Expectedness .........................................................................................38 12.4.4. Serious Adverse Event (SAE) ...............................................................38 12.4.5. Serious Adverse Event (SAE) Collection .............................................39 12.4.6. Adverse Event Collection ......................................................................40 12.4.7. Adverse Event Term ..............................................................................40 12.4.8. Start Date ...............................................................................................40
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12.4.9. Stop Date ...............................................................................................40 12.4.10. Intensity .................................................................................................40 12.4.11. Action taken regarding Study Drug Administration .............................41 12.4.12. Relationship to Study Drug ...................................................................41 12.4.13. Pregnancies ............................................................................................42 12.4.14. IND Safety Reports ...............................................................................42 12.4.15. Reporting of Adverse Events to IRB/EC ..............................................42 12.4.16. Adverse Event Record Retention ..........................................................42 12.4.17. Data Monitoring Committee (DMC) .....................................................43 12.4.18. Central Pathology Review .....................................................................43 12.4.19. Central Radiology Reads .......................................................................43 13. STATISTICAL PROCEDURES ................................................................................ 43 13.1. Overview ..............................................................................................................43 13.2. Historical Data ......................................................................................................44 13.3. Study Populations .................................................................................................44 13.4. Study Endpoints ...................................................................................................44 13.4.1. Primary Efficacy Endpoints ..................................................................44 13.4.2. Secondary Endpoints .............................................................................45 13.4.3. Other Endpoints .....................................................................................45 13.4.4. Safety Endpoints....................................................................................45 13.5. Analyses ...............................................................................................................46 13.5.1. Patient Status .........................................................................................46 13.5.2. Baseline Demographics and Clinical Characteristics ............................46 13.5.3. Primary Efficacy Analyses ....................................................................46 13.5.4. Secondary Analyses ..............................................................................47 13.6. Safety Analyses ....................................................................................................47 13.7. Sample Size Determination ..................................................................................48 13.7.1. Overall Survival (OS) ............................................................................48 13.7.2. Progression-free Survival (PFS) ............................................................48 13.8. Interim Analysis ...................................................................................................49 13.9. Procedures for Handling Missing, Unused, and Spurious Data ...........................50 14. ADMINISTRATION OF THE STUDY..................................................................... 50 14.1. Electronic Case Report Forms and Source Documentation .................................50 14.2. Good Clinical Practice..........................................................................................51 14.3. Monitoring ............................................................................................................51 14.4. Duration of the Study ...........................................................................................52 14.5. Record Retention ..................................................................................................52 14.6. Institutional Review Board/Ethics Committee .....................................................52 15. INFORMED CONSENT ............................................................................................. 53
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15.1. ICH/GCP Informed Consent Requirements .........................................................53 15.2. Informed Consent Form .......................................................................................53 16. PROTOCOL APPROVAL ......................................................................................... 54 APPENDIX 1. EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE STATUS ....................................................................................... 55 APPENDIX 2. COCKCROFT AND GAULT FORMULA FOR CREATININE CLEARANCE .............................................................................................................. 56 REFERENCES ...................................................................................................................... 57
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3.
ABBREVIATIONS AND DEFINITIONS OF TERMS

HN2 .................... Nitrogen mustard hr ........................ Hour(s) ICF ..................... Informed Consent Form ICH..................... International Committee on Harmonisation IFOS ................... Ifosfamide in ........................ Inch(es) INR..................... International normalized ratio IPM .................... Isophosphoramide mustard; palifosfamide IRB/EC............... Institutional Review Board/ Ethics Committee ISN ..................... Investigator Study Notebook ITT ..................... Intent-to-treat IV ....................... Intravenous(ly) kg ....................... Kilogram(s) L ......................... Liter lb ........................ Pound(s) LD ...................... Longest diameter LDH ................... Lactate dehydrogenase LVEF ................. Left ventricular ejection fraction m2 ....................... Square meters MCV .................. Mean corpuscular volume mg ...................... Milligram mL ...................... Milliliter(s) mm ..................... Millimeter(s) MRI .................... Magnetic resonance imaging MTD................... Maximum tolerated dose mTOR ................ Mammalian target of rapamycin MUGA ............... Multiple gated acquisition scan NCI..................... National Cancer Institute Palifosfamide ..... Isophosphoramide mustard Palifosfamide-tris.Isophosphoramide mustard with tris salt; ZymafosTM PD ...................... Progressive disease PET-CT .............. Positron emission tomography
g........................ Microgram GT ..................... Gamma Glutamyltransferase C........................ Degrees Celsius AA ...................... Accelerated approval AE....................... Adverse event AGC ................... Absolute granulocyte count ALT .................... alanine aminotransferase [SGPT] ANC ................... Absolute neutrophil count AST .................... Aspartate aminotransferase BSA .................... Body surface area BUN ................... Blood urea nitrogen CBC .................... Complete blood count CO2 ..................... Carbon dioxide CFR .................... Code of Federal Regulations cm ....................... Centimeter(s) CNS .................... Central nervous system CPA .................... Cyclophosphamide CR....................... Complete response CRO .................... Contract research organization CT ....................... Computed tomography CTCAE ............... Common terminology criteria for adverse events DHHS ................. Department of Health and Human Services dL ....................... Deciliter(s) DNA ................... Deoxyribonucleic acid DMC ................... Data Monitoring Committee eCRF................... Electronic case report form ECG .................... Electrocardiogram ECOG ................. Eastern Cooperative Oncology Group EC ....................... Ethics Committee EORTC ............... European Organisation for Research and Treatment of Cancer FDA .................... Food and Drug Administration G-CSF................. Granulocyte colony-stimulating factor GIST ................... Gastrointestinal stromal tumor GLP .................... Good laboratory practices HCT .................... Hematocrit Hgb ..................... Hemoglobin HIPAA ................ Health Insurance Portability and Accountability Act
- computed tomography
PFR .................... Progression-free rate PFS ..................... Progression-free survival PI ........................ Principal investigator PO ...................... By mouth (oral) PR ..................... Partial response PT ....................... Prothrombin Time
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PTT ..................... [Activated] partial thromboplastin time QoL..................... Quality of Life RBC .................... Red blood cell RECIST .............. Response evaluation criteria in solid tumors SAE .................... Serious adverse event SC ....................... Subcutaneous(ly) SD ....................... Stable disease STS ..................... Soft tissue sarcoma TTP ..................... Time to progression ULN .................... Upper limit of normal USA .................... United States of America US ....................... Ultrasound USP..................... United States Pharmacopeia VEGF ................. Vascular endothelial growth factor WBC ................... White blood cell WHO-DD ........... World Health Organization Drug Database ZIO-201 .............. Lyophilized lysine salt formulation of isophosphoramide mustard ZIO-201-T .......... Lyophilized tris/mannitol salt formulation of isophosphoramide mustard ZIOPHARM ....... ZIOPHARM Oncology, Inc.
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4.
Title
SYNOPSIS
A Phase III multicenter, international, randomized, double-blind, placebocontrolled study of doxorubicin plus palifosfamide-tris vs. doxorubicin plus placebo in patients with front-line metastatic soft tissue sarcoma. Primary: The primary objective is to assess overall survival (OS) with an assessment of progression-free survival (PFS) as an accelerated approval endpoint. Secondary: The secondary objectives are to assess quality of life (QoL), and safety and tolerability.
Objectives
Study Drugs Anticipated No. of Patients
Palifosfamide-tris (isophosphoramide mustard-tris; IPM-tris, Zymafos), placebo (normal saline), doxorubicin. Approximately 424 patients will be enrolled to attain 406 evaluable patients; 330 progression events (radiological) and 318 death events will be required for completion of the study. This is an international, randomized, double-blind, placebo-controlled trial to evaluate the clinical efficacy of palifosfamide-tris administered with doxorubicin in combination, compared with doxorubicin administered with placebo in frontline patients diagnosed with metastatic soft tissue sarcoma (STS). Patients who meet the entry criteria will be randomized equally into 1of 2 arms: either to receive doxorubicin plus palifosfamide-tris or doxorubicin plus placebo. Prior to randomization, patients will be stratified by tumor type (leiomyosarcoma, synovial sarcoma or other), and age (65 or <65 years old). Pathology reports will be reviewed and verified by independent central pathology reading and radiology will be reviewed by the independent Central Imaging Core Lab prior to randomization. After randomization, histology slides will be read by the independent central pathologists to confirm their agreement with the local pathology report. After 6 treatment cycles, no additional study medication will be administered. All patients will continue to be followed for PFS and OS.
Design
Population
The population for this study is adult patients with metastatic soft tissue sarcomas who have not received prior chemotherapy or immunotherapy for the treatment of metastatic disease. Certain histologic subtypes are not eligible for this study, specifically: alveolar soft-part sarcoma, chondrosarcoma, dermatofibrosarcoma, Ewing sarcoma, GIST, Kaposi sarcoma, mixed mesodermal tumor/carcinosarcoma, osteosarcoma, radiation induced sarcomas, and low grade (histologic grade 1) sarcomas. (Myxoid liposarcoma with t(12; 16) or t(12;22) is permitted). On Day 1 of each cycle (21 days), 150 mg/m2 IV (intravenous) palifosfamide-tris or placebo (normal saline) and 75 mg/m2 IV doxorubicin are administered on the same day. Palifosfamide-tris or placebo alone is administered on Days 2 and 3, every 3 weeks (one 21-day cycle). A maximum of 6 cycles will be permitted. Patients may be taken off study 1 therapy for unacceptable toxicity, progression per RECIST (version 1.1) , clinical progression based on signs and symptoms, or death. The principal
Dose and Schedule
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investigator or designee will make the determination to take a patient off of study therapy due to a progression event. Copies of all scans will be provided to the independent Central Imaging Core Lab on an ongoing basis. All scans will be reviewed using RECIST (version 1.1) in conjunction with the Imaging Charter to determine if a progression event has occurred. Final progression determinations will be made by the independent Central Imaging Core Lab. In the instance that there is discordance between the progression determination made by the independent Central Imaging Core Lab and the principal investigator, scans should be obtained per protocol until there is concordance. Every effort should be made to continue study therapy through 6 cycles, or until radiologic progression has been confirmed by the independent Central Imaging Core Lab, whichever comes first. Route of Administration Palifosfamide-tris or matching placebo will be given by IV infusion over approximately 30 minutes on Days 1-3. Doxorubicin will be given by IV infusion over approximately 5 to 30 minutes. Doxorubicin administration will be initiated approximately 1 hour ( 30 minutes) after the completion of palifosfamide-tris/placebo dosing. Note: Each palifosfamide-tris/placebo administration must be completed within 1 hour of reconstitution in IV bag. Duration of Treatment Safety Evaluations Patients will receive up to six 21-day cycles of study therapy followed by a Posttreatment safety assessment 21days ( 3 days) after the last dose of study drug. Safety will be monitored throughout the study by the Data Monitoring Committee (DMC). The following parameters in each patient will be assessed for safety: serious adverse events (SAEs), adverse events (AEs), physical examinations, electrocardiograms (ECGs), MUGA and/or cardiac ultrasound, vital signs, clinical laboratory evaluations, medical history, and prior/concomitant medications. All patients who receive any amount of study drug (palifosfamidetris/placebo or doxorubicin) will be included in the safety analysis population. Efficacy Evaluations The primary analyses for OS and PFS will be conducted on the intent-to-treat (ITT) population. The primary analysis of PFS will use progression assessments as determined by the independent Central Imaging Core Lab. Scans should be obtained per protocol by the principal investigator until there is agreement from the independent Central Imaging Core Lab that a progression event has occurred. Assessments of disease status will be conducted every 6 weeks ( 1 week) while receiving study medications, then every 8 weeks ( 1 week) for the next 6 months and then every 12 weeks ( 1 week) (additional scans may be obtained as clinically indicated) until progression of disease. Patients will be followed for overall survival status every 12 weeks ( 1 week) from progression to death.
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5.
TABLE 1: SCHEDULE OF STUDY PROCEDURES AND ASSESSMENTS

Procedure Screening Visit1 (28 days before 1st dose) X X X X X
6
Cycle 1 (Day 1-21) Days 2&3 Days 8 &15 ( 1 day) Day 1 ( 1 day)
Cycles 2-6 (Day 1-21) Days 2&3 Day 8 ( 1 day) Days 15-21
Day 1
Post-treatment safety assessment (21 days 3 days post last dose)
Longterm FU
Informed consent2 Medical History Cancer History

3
X X X X X X X X X X X X
Concomitant medications Adverse events

5
LVEF (MUGA or US) Physical Exam Vital Signs Weight Height

8 7
X X X X X
9 10
ECOG status Hematology
X X
11, 13
X X X X X X X X X X X X X X
X X X X X X X X X X
X X X X X X X
11, 12
Coagulation panel
X X X
Chemistry panel11, 14 Urinalysis

11,15 16
Pregnancy test
X X
Electrocardiogram, 12-lead17 Palifosfamide-tris or placebo dosing18 Doxorubicin dosing

19
X X X
EORTC QLQ C30/EQ-5D questionnaires20 Imaging Studies/Tumor Assessment21 Survival Assessment

22
X X X
X X X
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2 3 4 5 6
7 8 9 10 11 12 13 14
15 16
All Screening assessments are to be performed within 28 days prior to the first dose of study drug, with the exception: laboratory evaluations, which are to be performed within 14 days prior to study drug administration; and biopsy, which may have been obtained earlier. Screening lab tests may be used in place of Day 1 assessments if performed within 7 days before first dose (exception: pregnancy test.) A written informed consent must be signed by the patient before any protocol required procedures and assessments are performed. Standard of care evaluations that were performed as part of the patients routine treatment prior to signing consent can be used if they were conducted in the timeframe allowed for Screening. Includes medical and surgical history. The medical history is to be updated on Day 1 of Cycle 1. Cancer history includes all cancers, treatment regimens (regimen, doses, start and stop dates), and best response for each treatment. Cancer history is to be updated on Day 1 of Cycle 1. Pathology reports are to be sent to the Central Pathologists for review. Pathology slides or tissue samples need to be available for Central Pathology review (to be submitted post randomization.) Adverse Events (AEs) and SAEs will be collected from the first dose of study drug through the Post-treatment safety assessment visit. AEs/SAEs that occur after informed consent is obtained and prior to the first dose of study drug will be entered into the patients medical history. Left ventricular ejection fraction (LVEF) assessment by multiple gated acquisition scan (MUGA) or ultrasound (US) will be performed at baseline (up to 28 days prior to first dose of study drug) and at the Post-treatment safety assessment visit. For patients who do not receive at least 2 cycles of doxorubicin, Post-treatment safety assessment visit MUGA/US can be waived at the investigators discretion. Additional LVEF assessments should be performed when clinically indicated. The same technique for obtaining LVEF should be used throughout the patients participation in the study. A complete physical exam is required at Screening; Cycle 1, Day 1; and the Post-treatment safety assessment visit. Otherwise, a symptom-directed physical exam should be performed if indicated. A weight is obtained at Screening and at the Post-treatment safety assessment visit. Height is obtained and recorded only at baseline. ECOG (Eastern Cooperative Oncology Group) performance status is assessed at Screening, on Day 1 of every cycle, and at the Post-treatment safety assessment visit Laboratory samples (hematology, coagulation, chemistry and urinalysis) should be drawn at Screening, Days 1 and 8 of each cycle, Day 15 of Cycle 1, and at the Post-treatment safety assessment visit and sent to the Central Laboratory. Labs drawn on Day 1 of Cycles 2-6 may be drawn within 3 days prior to Day 1 and sent to the Central Laboratory for analysis. Hematology panel includes hemoglobin, hematocrit, red blood cell count, mean corpuscular volume (MCV), white blood count, differential (expressed as absolute counts), and platelets. Coagulation panel includes PT, PTT, and INR. Chemistry panel includes glucose, creatinine, alkaline phosphatase, BUN (blood urea nitrogen), total bilirubin, AST, ALT, calcium, magnesium, phosphorus, LDH (lactate dehydrogenase), albumin, total protein, sodium, potassium, chloride, CO2, and GT (glutamyltransferase) The creatinine clearance will be calculated (Cockcroft and Gault equation) from the serum creatinine at each chemistry time point. Urinalysis panel (dipstick) should be obtained on Screening, Days 1 and 8 of each cycle, Day 15 of Cycle 1, and at the Post-treatment safety assessment visit. It should be analyzed locally and includes appearance, pH, specific gravity, glucose, protein/albumin, blood, ketones, bilirubin, nitrates, and leukocyte esterase; a microscopic exam for casts, crystals, and will be done at Screening and
the Post-treatment safety assessment. Additionally it will be done when dipstick is abnormal..
17 18 19 20 21
Required for women of childbearing potential only; must be a serum pregnancy test at Screening and the Post-treatment safety assessment visit. At other time points may be a urine or serum pregnancy test (assessed locally); a positive urine pregnancy test must be confirmed by a serum pregnancy test (a blood sample should be sent to the Central Lab for analysis.) Additional pregnancy tests may be performed when clinically indicated. Single ECGs will be done on at Screening, Day 1 of cycle 1 within 1 hour prior to the start of the palifosfamide-tris/placebo infusion, and within 5 minutes prior to the end of the palifosfamidetris/placebo infusion ), and at the Post-treatment safety assessment visit. . Palifosfamide-tris or placebo (normal saline) is administered by intravenous infusion over approximately 30 minutes on Days 1, 2, and 3 of every cycle. Doxorubicin is administered by IV infusion over approximately 5-30 minutes on Day 1 (only) of each cycle. Begin approximately 1 hour ( 30 minutes) after end of palifosfamide-tris/placebo infusion. The EORTC QLQ C30 and the EQ-5D questionnaires will be administered at Screening; on Day 1 of Cycles 3 and 5; during the Post-treatment safety assessment visit; the questionnaires should be administered approximately every 8 weeks for the first 6 months after coming off study therapy, and then approximately every 6 months until death. Screening scans must be performed 28 days prior to Cycle 1, Day 1. Tumor assessments are to be performed every 6 weeks ( 1 week) during the study. All patients on active treatment will have tumor assessments performed during the last week of every even-numbered cycle (i.e., 2, 4, 6: between days 15 and 21) for the 6 cycles of study therapy. NOTE: If Day 1 of one or more cycles is delayed, then tumor assessment should continue to be performed at six-week intervals during the active treatment period, despite the delay in treatment. Tumor assessments will continue (in all patients coming off study therapy without documented radiological progression) every 8 weeks ( 1 week) (starting from the last scan obtained) for the next 6 months and then every 12 weeks ( 1 week) (additional scans may be obtained as clinically indicated) until documented radiological progression of disease. Scans should be obtained per protocol by the principal investigator until there is agreement from the independent Central Imaging Core Lab that a progression event has occurred. All attempts will also be made to obtain information regarding other therapies a patient may start once coming off study therapy until documented progression. Every effort should be made to confirm clinical progression of disease with CT/PET-CT/MRI scans. If significant neurological signs and/or symptoms are noted, a head CT or MRI scan should be performed to assess the patient for brain metastasis. Other imaging studies may be performed as clinically indicated. All scans will be retrospectively reviewed by an independent Central Imaging Core Lab. The same imaging technique should be used through the patients participation on study. Radiological studies should be repeated at the Post-treatment safety assessment visit if greater than 6 weeks since the last radiological studies.
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Patients will be monitored for survival throughout the study. After progression of disease has been documented, survival status will be obtained (e.g., by telephone contact occurring every 12 weeks ( 1 week) after disease progression, and the date of death will be recorded. Every effort should be made to document further courses of therapy. Additionally, any surgical or radiotherapy procedures the patient may undergo in relation to their soft tissue sarcoma should be documented.
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6.
BACKGROUND
Soft tissue sarcomas (STS) are rare and account for less than 1% of all solid tumors in adults. They are heterogeneous and likely arise from pluripotential mesenchymal stem cells. They can develop at any site in the body, but occur predominantly in the extremities (43%), internally (34%), the trunk wall (10%) and head & neck and elsewhere (13%) 2,3. Despite their heterogeneity, once metastatic, they are similarly treated, with the exception of: gastrointestinal stromal tumors (GIST), the Ewing-like sarcomas, other small, blue-round cell tumors, and certain other histopathologic subtypes. Indeed, with the logical exclusion of certain rarer subtypes together with relevant limited stratification, biological homogeneity is attainable for the purposes of a rigorous randomized clinical trial and treatment algorithm.2 For patients presenting with localized disease, optimal treatment consists of surgical resection sometimes followed by adjuvant radiation. Despite improvements in local control, many patients still develop metastatic disease or present initially with metastatic disease. Despite improvements in our molecular and biologic understanding, it has been very difficult, and near impossible to improve the outcome in this disease 4. Systemic chemotherapy is used for patients presenting with metastatic disease or with locally advanced disease that is not treatable by local measures. In some cases (site dependent), cure may still be possible if chemotherapy can induce tumor shrinkage, which in turn renders the tumor resectable. In general for patients with metastatic disease, chemotherapy is regarded as palliative, although in a very small subset of patients, long-term survival is achieved2,4. In STS, it is strongly considered that progression-free survival (PFS) is biologically relevant as CR = PR = SD 5,6, and the duration of non-progression is clinically very relevant. In clinical trials, there is also a very strong correlation between measurement of PFS at 3 and 6 months and drug activity 7. With chemotherapy there can often be a disconnect between clinical vs. radiographic improvement: that is, patients can report substantial symptom improvement (e.g., pain or well-being); even when measureable disease does not show decrease in size on radiographic evaluation. In this difficult to treat cancer, symptom improvement is often the clinical goal. In a clinical study setting, when biologic homogeneity is attained between treatment groups 8, positive outcome in PFS correlates with positive outcome in overall survival. Currently, doxorubicin is approved for the treatment of sarcoma and is considered to be the standard of care for front-line patients either as a single agent or in combination with other agents. When administered as a single agent, the reported response rate is approximately 6% to 27%, with median overall survival ranging from 7.7 to 12.0 months7. A dose-response
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relationship of doxorubicin has been evaluated. Doxorubicin, at doses >70 mg/m2 administered in 3-week intervals, is standard dosing and has served as a control treatment for most randomized studies performed to date 9. The use of doxorubicin is limited primarily by myelosuppression and cardiomyopathy. The latter side effect is cumulative and occurs more frequently at total lifetime doses exceeding 450 mg/m2. In addition to doxorubicin, ifosfamide (IFOS) has consistently shown activity against advanced STS. IFOS, as a single agent, yields response rates ranging between 1% and 25%, and a median overall survival of 1 year in metastatic disease9,10. Similar to doxorubicin, IFOS shows a dose-response relationship, with higher doses correlating with higher response rates. A randomized study comparing IFOS to two different doses of doxorubicin was prematurely terminated due to the fact that similar efficacy rates were reported, although the IFOS-treated groups reported significantly more toxicities than those treated with doxorubicin 11. 6.1. Palifosfamide (IPM)
Palifosfamide (isophosphoramide mustard, IPM), is a bi-functional DNA alkylator and crosslinker; and is the functional active metabolite of IFOS. IFOS is a pro-drug and must be metabolized in order to be active (Figure 1). The clinical utility of IFOS is often quite limited by toxicities associated with IFOS metabolites unrelated to DNA-alkylation and by development of resistance conferred by decreased pro-drug activation. In contrast, these toxic metabolites are not present with palifosfamide and there is no need for pro-drug activation. There may be additional advantages to IPM as well. Palifosfamide has demonstrated broad activity against human sarcoma cell lines in vitro and in human xenograft models. In addition, palifosfamide is active in IFOS- and cyclophosphamide-resistant human osteosarcoma cell lines and xenografts. Figure 1. Metabolic Products from IFOS
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Palifosfamide, either as the tris salt (palifosfamide-tris, ZIO-201-T) or as the lysine salt (palifosfamide-lysine, ZIO-201) are proprietary formulations of IPM. Palifosfamide-tris is currently in clinical development. Administration of palifosfamide-tris does not result in toxicities such as encephalopathy and hemorrhagic cystitis that are associated with IFOS. Coadministration of mesna or other hydration therapies commonly used with IFOS are not required with palifosfamide, thereby reducing overall treatment time and expense. Thus, the rationale for the use of palifosfamide-tris as an anticancer therapy is based on current understanding of molecular mechanism of action, in vitro and in vivo experimental evidence of efficacy, and low toxicities observed at therapeutic doses in both preclinical and clinical studies. This rationale follows the reported efficacy of single-agent IFOS, particularly at high IFOS dose levels (>10 g/m2 per 21-day cycle). Palifosfamide, administered as with lysine (referred to as ZIO-201), has demonstrated in vitro cytotoxic effects against human sarcoma cell lines as well as in vivo in several mouse and rat models, including CPA-sensitive and -refractory tumors9. In these experiments, palifosfamide-lysine inhibited tumor growth and increased survival. 6.2. 6.2.1. Clinical Experience with Palifosfamide Clinical Experience with Palifosfamide (lysine salt formulation)
Two studies, a Phase I study in patients with solid tumors (Study IPM1001) and a Phase I/II study in patients with advanced sarcomas (Study IPM2001), have been conducted. They were designed to investigate the safety of palifosfamide (lysine salt formulation) when administered to patients diagnosed with advanced cancers who had not responded to standard therapies. An amendment to the Phase I/II clinical study IPM2001 was added to investigate the safety of the new tris salt formulation of palifosfamide (also referred to as ZIO-201-T) when administered IV to patients diagnosed with advanced sarcomas who have not responded to standard therapies. In this study, 6 patients received palifosfamide-tris, administered as a single IV dose of 178 mg/m2. The majority of the reported AEs using the lysine formulation were considered to be mild to moderate in severity and included gastrointestinal (nausea), general (fatigue), renal (increased creatinine, hypophosphatemia, and hypokalemia), and hematological (anemia). Severe toxicities were reported primarily at doses higher than the recommended Phase II dose (these were DLTs) and included Fanconi syndrome and acute renal failure. Preliminary efficacy has been reported in the Phase II portion of the IPM2001 study conducted in patients diagnosed with sarcoma. In 2nd, 3rd and 4th line sarcoma patients, one partial response was reported in a patient with liposarcoma. In addition, stable disease (SD) was observed in 44% of evaluable patients. At 3 months, 45% of patients were progressionAmendment 3: 17 January 2011 Page 15
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free, consistent with an active drug in sarcoma. At 6 months, PFS was 23%. Furthermore, in IFOS-nave patients, 55% were progression-free at 3 months. (Based on the EORTC experience and database, 40% PFS at 3 months, in front-line patients, is consistent with an active drug in sarcoma) 12. 6.2.2. Clinical Experience with Palifosfamide (tris salt formulation)
Two studies of palifosfamide-tris in combination with doxorubicin have been conducted in patients with soft tissue sarcoma. 6.2.2.1. IPM1002
IPM1002, was a Phase I combination study with palifosfamide-tris and doxorubicin in patients diagnosed with advanced, refractory solid tumors for which no standard therapy exists and for whom doxorubicin therapy is medically acceptable. This study has been completed and the study report is being drafted. It was a dose-escalation study administering palifosfamide-tris doses of 100 to 150 mg/m2 IV daily for 3 consecutive days, repeated every 3 weeks, in combination with doxorubicin doses of 60 to 75 mg/m2 administered IV once every 3 weeks. Thirteen patients were treated in this study. The most frequently reported adverse events were anemia, neutropenia, febrile neutropenia, (85% each) thrombocytopenia, hypokalemia and nausea (69% each) urinary tract infection and hypocalcemia (62% each), increased aspartate aminotransferase and hypoalbuminemia (46% each). Fanconi Syndrome was not reported in patients receiving the palifosfamide-tris formulation. There were 3/12 PRs in evaluable patients, and the median PFS was 18+ weeks. 6.2.2.2. IPM2002 Randomized Data
IPM2002, A Phase II Randomized Controlled Trial of Palifosfamide Plus Doxorubicin vs. Doxorubicin In Patients with Soft Tissue Sarcoma (PICASSO), evaluated the safety and efficacy of palifosfamide-tris, in combination with doxorubicin vs. doxorubicin alone in patients with metastatic/unresectable soft tissue sarcoma (STS) in the front- and second-line setting. Patients were stratified by age (65 or <65) and histologic subtype (leiomyosarcoma, synovial sarcoma or other). Patients received up to 6 cycles until disease progression or unacceptable toxicity occurs. Patients who progressed on doxorubicin alone before or during cycle 6 were eligible to receive single agent palifosfamide-tris. In addition, those patients who completed 6 cycles of the combination arm were eligible to continue receiving single agent palifosfamide-tris. The primary end-point was PFS; the secondary end-points were safety and survival.
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Preliminary Efficacy Results: The primary endpoint of the study was Progression Free Survival (PFS). PFS is defined as time from randomization to the date of documented, objective progressive disease, (radiological or clinical findings) whichever is earlier, or death. Patients who came off study for a reason other than progression or death were censored 30 days after coming off of study, or at the start of a new therapy, whichever is earlier. Patients who are ongoing at the time of final analysis will be censored at the last known study date. In an interim analysis of this study, 62 patients were determined to be evaluable for efficacy. Of the 62 patients, 30 who received the combination of palifosfamide-tris plus doxorubicin (Arm A) and 32 who received doxorubicin alone (Arm B), 28 had progression events (10 Arm A and 18 Arm B). The median PFS was 7.8 months (34 weeks) for the combination vs. 4.4 months (19 weeks) for doxorubicin alone; the hazard ratio was 0.427 (95% c.i.: 0.191 , 0.951) in favor of the combination with significance achieved. These data are consistent with an active drug in STS. Figure 1 PFS: Eligible, Treated Patients, Progression-Free Survival
palifosfamide-tris + doxorubicin doxorubicin
Front-Line Second-Line
Arm A 21 9
Arm B 22 10
p=0.019
In addition, this combination may have better activity in leiomyosarcoma. This has been observed in small numbers of patients in both single arm and randomized studies, including front-line. The Kaplan-Meier curve from the randomized Phase II study is presented below for leiomyosarcoma patients.
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Figure 2 PFS: Eligible, Treated Leiomyosarcoma Patients, Progression-Free Survival

palifosfamide-tris + doxorubicin doxorubicin
Front-Line Second-Line
Arm A 5 3
Arm B 5 6
Adverse events which occurred in more than 10% of patients treated with palifosfamide-tris in combination with doxorubicin included nausea, fatigue, (58% each); vomiting, anemia, and neutropenia (33% each); alopecia (27%); leukopenia, constipation, and hypokalemia (24% each); mucosal inflammation (21%); dehydration (18%); thrombocytopenia, diarrhea, hypomagnesemia, and headache (15% each); hypophosphatemia, dizziness, stomatitis, and peripheral edema (12% each). Please refer to the IB for additional information. 6.3. Rationale for Phase III Study
The current Phase III study was designed from the efficacy results and safety profile of the randomized Phase II IPM2002 study. In this Phase III study, we will additionally limit the patient population to those who are front-line for their metastatic soft tissue sarcoma in an effort to increase homogeneity. All other eligibility criteria are similar. The study will be randomized, placebo-controlled, blinded to the patients and investigators, and rigorously conducted. 6.4. Rationale for Dose of Palifosfamide-tris
The recommended palifosfamide-tris single-agent regimen is 150 mg/m2/day3, every 3 weeks. In order to maximize efficacy, therapeutic doses of both drugs are utilized. The dose of palifosfamide-tris in combination with doxorubicin is based on a Phase I single-agent experience and Phase I and Phase II studies of palifosfamide-tris with doxorubicin. The toxicities observed with single-agent palifosfamide-tris do not appear to overlap with those of
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doxorubicin.The recommended dose of 150 mg/m2/day palifosfamide-tris3 consecutive days, and 75 mg/m2 IV doxorubicin1 day, every 3 weeks will be administered. 7. 7.1. OBJ ECTIVES AND DESIGN Objectives
The objectives of this study are to evaluate efficacy and safety of doxorubicin plus palifosfamide-tris versus doxorubicin plus placebo in patients with front-line metastatic STS. Primary objective: to assess overall survival (OS) with an assessment of progression-free survival (PFS) as an accelerated approval endpoint. Secondary Objectives: to assess quality of life (QoL), and safety and tolerability. 7.2. Design and Treatment Regimen
This is a randomized, double-blind, placebo-controlled trial. All patients who meet all entry criteria will be equally randomized to receive either doxorubicin 75 mg/m2 IV once (Day 1) plus palifosfamide-tris 150 mg/m2 IV for 3 consecutive days (Days 13) every 21 days, or doxorubicin 75 mg/m2 IV once (Day 1) plus placebo IV for 3 consecutive days (Days 13) every 21 days for 6 cycles. Approximately 424 patients will be randomized into the study. Prior to randomization, patients will be stratified by tumor type (leiomyosarcoma, synovial sarcoma or other) confirmed by independent Central Pathology review, and age (65 or <65 years old). The study will employ a blocked randomization scheme featuring institution balancing with a fixed key size. The expected distribution of strata is: Histology: Leiomyosarcoma: Synovial Sarcoma: Other Tumors: Age: Age < 65: Age 65: 30% 10% 60% 80% 20%
Treatment will continue for a maximum of 6 cycles. During all study visits, patients will be evaluated for safety. Tumor measurements will be calculated at baseline (within 28 days prior to treatment initiation) and in the last week of every even numbered cycle (i.e., every 6 weeks 1 week) for the 6 cycles of study therapy. After discontinuing study therapy, tumor measurements will be calculated every 8 weeks ( 1 week) for the next 6 months and then every 12 weeks ( 1 week) until progression occurs. For patients who have clinical progression of disease, objective confirmation of progression by CT or MRI scan should be
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obtained. In the instance that there is discordance between the progression determination made the independent Central Imaging Core Lab and the principal investigator, scans should be obtained per protocol until there is concordance. A Post-treatment safety assessment visit will be conducted 21 days ( 3 days) after the last dose of study drug for all patients. Every effort should be made to document further courses of therapy. Additionally, any surgical or radiotherapy procedures the patient may undergo in relation to their soft tissue sarcoma should be documented. Once patients have completed their treatment and the Post-treatment safety assessment visit, they will continue to be followed for progression every 8 weeks ( 1 week) (starting from the last scan obtained) for the next 6 months and then every 12 weeks ( 1 week) by radiographic studies consistent with those that occurred while on study. Patients will enter into the longterm follow-up period at the time of progression of disease. Upon progression, patients will be followed every 12 weeks ( 1 week) to assess survival status and the date of death will be recorded for patients who died. A death certificate and/or autopsy results will be requested. This information will be collected by the investigator and provided to ZIOPHARM to ensure the OS endpoint is assessable. 8. SCREENING AND REGISTRATION
The population for this study is adult patients with metastatic soft tissue sarcomas who have not received prior chemotherapy or immunotherapy for the treatment of metastatic disease. The principal investigator (PI) at each site is responsible for maintaining a record of all patients screened, including both those who enter the study and those who are excluded, as well as the reason for exclusion or screen failure. 8.1. Number of Patients
It is anticipated that approximately 424 patients will be enrolled to reach 406 evaluable patients. 330 progression events (radiological) and 318 death events will be required for completion of the study. 8.2. Informed Consent
Each potential patient must sign a written informed consent form (ICF) prior to the initiation of any Screening procedure related to the study. Standard of care evaluations that were performed as part of the patients routine treatment prior to signing consent can be used if they were conducted in the timeframe allowed for Screening.
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8.3.
Inclusion and Exclusion Criteria
Screening for enrollment must be completed within 28 days prior to study drug administration with the exception of labs, which must be completed within 14 days. Biopsy for histology may have been obtained earlier. If radiographic studies for tumor measurements, ECG, and MUGA or cardiac ultrasound have been performed within 28 days prior to the first dose of study drug as part of standard of care, they will be accepted in place of Screening assessments. All Screening procedure(s), with the exception of the pregnancy test, may be used as Day 1 if performed within 7 days of start of treatment (if an assessment was done prior to 7 days before the first dose of study drug, the assessment will need to be repeated prior to study drug administration in order to re-confirm eligibility). Inclusion and exclusion criteria will be reviewed for each enrolled patient prior to randomization and documented in the eCRF. Pathology reports will be reviewed by an independent Central Pathology Read. After randomization, histology slides will also be sent to and read by the independent central pathologists to confirm their agreement with the local pathology report. Radiology will be reviewed by the independent Central Imaging Core Lab. Once the site has received confirmation that the patient meets enrollment criteria and this process has been documented in the eCRF, registration is complete and patients will be assigned to a Treatment Arm (doxorubicin plus palifosfamide-tris or doxorubicin plus placebo). 8.3.1. Inclusion Criteria
To be eligible, each patient must meet EACH of the following criteria: 1. Age 18 years. 2. Histological documentation of soft tissue sarcoma (biopsy may be obtained from primary tumor or metastatic site). Pathology reports will be reviewed and approved by an independent Central Pathology Read prior to each patients registration. After randomization, histology slides will also be sent to and read by the independent central pathologists to confirm their agreement with the local pathology report. Please see Exclusion Criterion #1 for subtypes that are to be excluded. 3. Metastatic disease for which the patient has not received any prior treatment, and for whom treatment with doxorubicin is considered medically acceptable. 4. Measurable disease as per RECIST (version 1.1). 5. ECOG Performance Status of 0,1or 2 (Appendix 1). 6. Adequate bone marrow, liver, and renal function, as assessed by the following laboratory requirements conducted within 14 days prior to dosing: a. b. c. d. Hemoglobin 9.0 g/dL. Absolute neutrophil count (ANC) 1,500/mm3. Platelet count 100,000/mm3. Total bilirubin 1.5ULN (upper limit of normal).
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e. ALT and AST 2.5ULN. For patients with documented liver metastases, ALT and AST 5ULN. f. International Normalized Ratio (INR) and activated partial thromboplastin time [PTT] <1.5ULN, if not therapeutically anticoagulated. Patients who are being therapeutically anticoagulated with an agent such as Coumadin (warfarin sodium) or subcutaneous heparin may be included provided there is no prior evidence of underlying abnormality in coagulation parameters, Screening test results are in appropriate therapeutic range, and anticoagulation regimen is stable and closely monitored. g. Calculated creatinine clearance > 60 mL/minute as per the Cockcroft and Gault formula (Appendix 2). 7. Written informed consent must be obtained from a potential patient prior to the conduct of any study-specific procedures (see Section 8.2). 8. Male and female patients must agree to use a highly reliable method of birth control (expected failure rate less than 5% per year) from the Screening visit through 21 days after the last dose of study drug. 8.3.2. Exclusion Criteria
A potential patient will be excluded from the study if he or she meets ANY of the following criteria: 1. Has any one of the following sarcoma histological subtypes: alveolar soft-part sarcoma, chondrosarcoma, dermatofibrosarcoma, Ewing sarcoma, GIST, Kaposi sarcoma, mixed mesodermal tumor/carcinosarcoma, osteosarcoma, radiation induced sarcomas, and low grade (grade 1) sarcomas. (Myxoid liposarcoma with t(12;16) or t(12;22) is permitted). Pathology reports will be reviewed, and approved by an independent Central Pathology Review prior to each patients registration to ensure that subtype is allowed. 2. Anticancer chemotherapy, anticancer immunotherapy, or any investigational drug therapy for the treatment of metastatic sarcoma, prior to or during the study. However, patients may have received neo-adjuvant/adjuvant Gemzar and Taxotere (aka gem/tax) chemotherapy for their primary sarcoma, prior to the development of metastatic disease concluding at least 3 months prior to the start of the study drug dosing. 3. Any prior anthracycline use. 4. Known allergy to any of the study drugs or their excipients. 5. Unstable or clinically significant concurrent medical condition that would, in the opinion of the investigator, jeopardize the safety of a patient and/or their compliance with the protocol. Examples include, but are not limited to, unstable angina, congestive heart failure, recent (within 6 months of Screening) myocardial infarction, ongoing maintenance therapy for life-threatening ventricular arrhythmia, uncontrolled asthma, AIDS or HIV infection not adequately treated with antiretrovirals, evidence of hepatic pathology due to or consistent with infection with a chronic hepatitis virus, and uncontrolled major seizure disorder.
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6. Myocardial dysfunction defined as scintigraphically- (MUGA [multiple gated acquisition scan], myocardial scintigram) or ultrasound-determined left ventricular ejection fraction (LVEF) <50%. 7. Presence of, or history of any illness or injury to the urinary tract (renal or post-renal) which may make the patient more susceptible to acute renal insufficiency in the case of potential renal adverse events. Types of injury or illness might include a history of congenital renal or ureteric abnormalities, history of chronic, severe or frequent kidney infections, or prostatic hyperplasia causing obstruction. 8. Active infection requiring systemic antibacterial/antibiotic, antifungal, or antiviral therapy (except HIV treated with appropriate antiviral therapy). Potential patients on chronic therapy for latent infections (such as tuberculosis) should also be excluded, or therapy must be completed at least 28 days prior to study drug dosing. However, patients with chronic herpes infections who use intermittent suppressive antiviral therapy for viral outbreaks may be included. 9. Any major surgery within 4 weeks prior to the first dose of study drug. 10. Minor surgery within 2 weeks prior to the first dose of study drug. 11. Documented metastases to brain or meninges. [Note: If there are any neurological signs or symptoms, imaging of the brain should be performed as clinically indicated.] 12. Any malignancy other than sarcoma within the last 5 years prior to Screening, with the exception of cervical carcinoma in situ, basal cell carcinoma, or superficial bladder tumors (Ta, Tis, or T1) that have been successfully and curatively treated with no evidence of recurrent or residual disease. If prior malignancy, the investigator should ensure, based on histology or clinical information, that metastatic sites are sarcoma and not recurrence of the original malignancy. 13. Currently pregnant or nursing. 14. Substance abuse or medical, psychological, or social conditions that may interfere with the patients participation in the study or evaluation of the study results, in the opinion of the investigator. 15. Radiotherapy with curative intent within 4 weeks of first dose of study drug, however, palliative external beam radiation to bone lesions is permitted if started or planned prior to Cycle 1, Day 1. 8.4. Protocol Eligibility Waivers
No waivers of inclusion or exclusion criteria will be granted by ZIOPHARM or the Study Medical Monitors. All prospective patients must meet all entry criteria prior to randomization in the study. If there are questions regarding the interpretation of a criterion for a specific potential patient, the investigator should immediately contact the Study Medical Monitors to discuss the potential patient prior to confirming eligibility.
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8.5.
Registration
Each patient eligible to enter the study must be registered with ZIOPHARM Oncology, Inc. (ZIOPHARM) prior to the initiation of study therapy by having all required enrollment information entered into the electronic case report form (eCRF) module (to include: inclusion/exclusion criteria, demographics, history of malignant disease and target lesion data.) This information will be reviewed by ZIOPHARM or designee upon the sites data submission. Pathology reports will be provided to and reviewed by an independent Central Pathology Review prior to determining final eligibility. The site will then receive notification that the randomization information can be accessed. After randomization, histology slides will also be sent to and read by the independent central pathologists to confirm their agreement with the local pathology report. If a patient discontinues from the study, the patient identifier will not be reused and the patient will not be allowed to re-enter the study. 8.6. Assignment of Patients to Treatment Groups
Once deemed eligible for randomization, patients will be stratified by tumor type and age. All patients will receive blinded treatment. They will be randomly assigned on a 1:1 basis to receive doxorubicin plus palifosfamide-tris or doxorubicin plus placebo, and issued a randomization number using a computer-generated schema within the eCRF system. 8.7. Removal of Patients from Study Therapy
The investigator and/or the patient have the right to withdraw from study therapy at any time. Patients who withdraw from study therapy, unless due to death or withdrawal of consent, should continue to have all follow-up evaluations completed. A patient will be withdrawn from treatment in the event of any of the following: Withdrawal from treatment requested by the patient; If, in the investigators opinion, continuation of the treatment would be detrimental to the patients wellbeing; Severe allergic reaction; Development of significant heart failure, defined as decline in LVEF to 45%, or a 20% decline from baseline in LVEF; Significant renal insufficiency, defined as calculated creatinine clearance that is <50 mL/minute (repeated and confirmed); Study drug administration is delayed more than two weeks; Need for more than two dose reductions; Need for permanent discontinuation of any of the study drugs;
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Patient undergoes any therapeutic surgical resection of tumor; Investigators determination that the patient has substantial noncompliance with the requirements of the study; Patients with a positive pregnancy test (pregnancy will be reported via the form(s) within the pregnancy data collection packet); Documented radiological progression of disease (as per RECIST (version 1.1)).
Every effort should be made to continue study therapy through 6 cycles, or until radiologic progression has been confirmed by the independent Central Imaging Core Lab, whichever comes first. Patients who are withdrawn from study drug dosing without disease progression confirmed via review by the independent Central Imaging Core Lab should be followed for radiological progression that is confirmed via central review and for survival. In the instance that a patient is withdrawn from study drug dosing due to investigator determined progression and there is discordance between the progression determination made by the independent Central Imaging Core Lab and the principal investigator, scans should be obtained per protocol until concordant assessment of objective disease progression occurs. In the event that a patient is judged by the principal investigator to be surgically resectable (with complete or partial metastasectomy) prior to the completion of Cycle 6, and if it is judged by the treating physician to be medically acceptable, surgery should not be performed until the patient has completed all planned study therapy per protocol through final cycle (i.e., Cycle 6 of study therapy). These patients should subsequently be followed per protocol for radiological progression as determined by the independent Central Imaging Core Lab and for survival. If it is deemed not to be medically acceptable to wait until the end of study therapy and a patient is taken off study therapy for resection prior to the completion of Cycle 6, the patient should continue to get scans per protocol until there is radiological progression as determined by the independent Central Imaging Core Lab. All patients who have not been judged to have exhibited confirmed disease progression via central imaging review should be followed per protocol for subsequent radiological progression and survival. All patients who have been judged to have exhibited confirmed disease progression via central imaging review should be followed per protocol for subsequent overall survival. Patients who are withdrawn from study drug dosing, regardless of timing or reason, should be followed for resolution of adverse events. As required by protocol all patients should be followed for radiological progression and for survival. In the event that a patient withdraws consent for follow-up contact, this should be documented in writing, and should only be done after thoughtful discussion with the investigator.
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8.8.
Removal of Patients from Study Follow-up
The investigator and/or the patient have the right to terminate the patients participation in the study at any time. A patient will be withdrawn from the study in the event of any of the following: Formal withdrawal of consent by the patient; Patient Death.
9. 9.1.
TREATMENT PROCEDURES Schedule of Assessments and Procedures According to Visit/Study Day
Refer to the tabular Schedule of Study Procedures and Assessments (Table 1) in Section 5 for the overall study trial schematic. 9.1.1. Baseline Evaluations (at the time of Screening)
The following Screening assessments must be performed within 28 days prior to study drug administration with the exception of lab tests which must be conducted within 14 prior to study drug administration (laboratory results may be used as Day 1 if performed within 7 days of first dose except for the urine/serum pregnancy test): 1. Complete medical and surgical history, including history of any prior cancers, including therapies received.
Pathology reports will be provided to and reviewed by an independent Central Pathology Review prior to determining final eligibility. The site will then receive notification that the randomization information can be accessed. After randomization, histology slides will also be sent to and read by the independent central pathologists to confirm their agreement with the local pathology report.
2. Concomitant medications with indications. 3. MUGA or cardiac ultrasound to obtain LVEF (the same technique should be used to obtain LVEF throughout the patients participation in the study). 4. Complete physical examination including ECOG performance status and vital signs (temperature, pulse, respirations, and blood pressure), and complete review of systems. 5. Measurement of height (cm/in) and weight (kg/lb). 6. AEs/SAEs occurring from time between signing of informed consent and first administration of study drug should be added to the medical history. 7. Hematology
Complete blood count (CBC), including hemoglobin, hematocrit, WBC with differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), platelet count, and red blood cell count with mean corpuscular volume (MCV).
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8. Coagulation panel
PT /INR, PTT. Chemistry panel that includes glucose, creatinine, alkaline phosphatase, BUN (blood urea nitrogen), total bilirubin, AST (aspartate aminotransferase [SGOT]), ALT (alanine aminotransferase [SGPT]), calcium, magnesium, phosphorus, LDH (lactate dehydrogenase), albumin, total protein, sodium, potassium, chloride, CO2, and GT (glutamyltransferase); calculated creatinine clearance using the Cockcroft and Gault equation (Appendix 2).
9. Chemistry
10. Urine or serum pregnancy test (woman of childbearing potential only); a positive urine test must be confirmed by a serum test. 11. Urinalysis
Dipstick: pH, specific gravity, appearance, protein/albumin, glucose, ketones, blood and bilirubin, nitrites and leukocyte esterase; additionally, microscopic analysis will be done for crystals, casts, and cells if clinically indicated.
12. Single ECG (electrocardiogram), 12-lead. 13. Radiological studies/tumor assessment
The preferred imaging modality is a contrast enhanced computed tomography scan (CT). Positron emission tomography - computed tomography (PET-CT) or magnetic resonance imaging (MRI) may be used per RECIST (version 1.1). Scans of the Chest/Abdomen/Pelvis (and any additional anatomical regions with known disease) must be obtained to assess overall tumor burden. If the patient has a known allergic reaction to contrast medium then a MRI scan of the same anatomical regions indicated above shall be performed. If the patient develops an allergic reaction to contrast medium after Baseline (and the Baseline imaging provided was a contrast enhanced CT) then both an MRI and a non-contrast CT scan shall be performed. Tumor measurements using RECIST (version 1.1) To ensure comparability, baseline x-ray/scans and the subsequent x-ray/scans for response assessment must be performed using identical techniques, unless medically contraindicated, (i.e., scans performed immediately following bolus contrast administration using a standard volume of contrast, the identical contrast agent, and preferably the same scanner). Screening tumor scans must have been performed no more than 28 days prior to Cycle 1, Day 1. If significant neurological signs and/or symptoms are noted, a head CT or MRI will also be performed in order to exclude brain metastasis. Other imaging studies should be performed as clinically indicated. Schedule of events by Cycle and Day
9.1.2.
Refer to Table 1 Schedule of Study Procedures and Assessments and its footnotes in Section 5.
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9.1.3.
Electrocardiogram (ECG)
ECGs will be done on at Screening, Day 1 of cycle 1 within 1 hour prior to the start of the palifosfamide-tris/placebo infusion, and within 5 minutes prior to the end of the palifosfamide-tris/placebo infusion (this must be obtained prior to the initiation of doxorubicin), and at the Post-treatment safety assessment visit. 9.1.4. Quality of life
The EORTC QLQ C30 and the EQ-5D questionnaires will be completed by each patient at Screening, on Day 1 in Cycles 3 and 5, at the Post-treatment safety assessment visit; the questionnaires should be administered every 8 weeks ( 1 week) for the first 6 months after coming off study therapy, and then every 6 months until death. Sites will be provided copies of these documents with instructions for their use. 9.1.5. Tumor Response Evaluations, Even Cycles (e.g., 2, 4, 6), Days 15-21
Tumor response assessments are to be performed approximately every 6 weeks ( 1 week) until documentation of disease progression. Scans should be obtained per protocol by the principal investigator until there is agreement from the independent Central Imaging Core Lab that a progression event has occurred. During the active treatment period, tumor assessments should be performed during the last week of every even-numbered cycle (Days 15-21 of cycles 2, 4, 6). NOTE: If Day 1 of one or more cycles is delayed, then tumor assessment should continue to be performed at six-week intervals during the active treatment period, despite the delay in treatment. The primary determination of PFS will use progression assessments as evaluated by the independent Central Imaging Core Lab. All scans will be reviewed by the independent Central Imaging Core Lab using RECIST (version 1.1) in conjunction with the Imaging Charter to obtain concurrence on whether or not a progression event has occurred. 9.1.6. Post-treatment Safety Assessment Visit (21 days 3 days after last dose)
A Post-treatment safety assessment visit will be conducted 21 days ( 3 days) after the last dose of study medication to complete the safety assessments described in Section 5, Table 1. In addition, for any patient with a drug-related medical event, including an abnormal ECG, requiring additional follow-up, these events must be monitored as long as is medically appropriate, or until resolution or stabilization in the event that resolution is not possible. The following lab studies and procedures will be performed at the Post-treatment safety assessment visit: Review concomitant medications since last dose
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Collect AEs MUGA or cardiac ultrasound (LVEF) (if the patient did not receive at least 2 cycles of doxorubicin. The window for post treatment assessment MUGA is 1 week. Complete physical examination, vital signs, ECOG Weight Hematology Coagulation panel Chemistry panel; calculated creatinine clearance (Cockcroft and Gault equation) Pregnancy test (woman of childbearing potential only) Urinalysis (including microscopic) ECG, 12-lead Radiological studies as appropriate for tumor assessment for patients taken off study therapy for reasons other than radiological progression (if greater than 6 weeks since the last radiological studies) 9.1.7. Long-term Follow-up
Patients who discontinue study drug with stable disease or better will continue to have tumor assessments every 8 weeks ( 1 week) for the next 6 months and then every 12 weeks ( 1 week) (additional scans may be obtained as clinically indicated) until documentation of disease progression. Every effort should be made to confirm clinical progression of disease by CT/MRI scans. In the instance that there is discordance between the progression determination made by the independent Central Imaging Core Lab and the principal investigator, additional scans should be obtained per protocol until there is concordance. Copies of all scans will be provided to the independent Central Imaging Core Lab on an ongoing basis. Details regarding subsequent treatment (medical or surgical) will be obtained. Every effort should be made to document further courses of therapy. Additionally, any surgical or radiotherapy procedures the patient may undergo in relation to their soft tissue sarcoma should be documented. 9.1.8. Overall Survival Follow-up after PD until patients death
Patients will continue to be followed for survival at the time of progression of disease. Patients will be monitored via medical records, public records, and contact with the patient or patients family every 12 weeks ( 1 week) to assess survival status and the date of death. Additionally, documentation of death (e.g., a death certificate or autopsy results) will be requested as appropriate. For patients who are unable to be contacted, documentation of three
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phone calls and one certified letter attempt should be recorded before the site confirms the patients status as lost to follow up. 9.2. Missed Visits
If a patient misses a scheduled study drug administration visit, he/she will continue on the protocol and the visit should be rescheduled within 3 days. If a patient misses two scheduled visits, his/her continued participation in the study should be re-evaluated. 9.3. Protocol Violations
Deviations from this protocol are considered protocol violations and are not allowed. If for some reason, a deviation must be made, ZIOPHARM and the IRB/EC must be notified as required. 9.4. Blinding/Unblinding Procedures
In order to maintain the blind, all study site personnel (except the investigational pharmacist or designee) will be blinded to the treatment assignments for the duration of the study. It will be the responsibility of all study personnel to ensure that the study blinding is maintained during the clinical phase of the study. ZIOPHARM will remain blinded for the duration of the study. ZIOPHARM will appoint unblinded designees to perform certain procedures as necessary (e.g., study drug accountability) and will ensure that the proper steps are taken to separate blinded and unblinded staff in order to ensure the integrity of the blind is maintained. Treatment assignments will be obtained through the web randomization system and for dose preparation according to the procedures outlined in the Study Manual. Information regarding the treatment assignments will be kept securely per a standard operating procedure. Emergency unblinding, if necessary, will be conducted via the web based randomization system. Records of the patient number, the date study drug was dispensed, and the study drug/cohort assignment will be maintained by the unblinded pharmacist. If the treatment assignment must be revealed for the safety of the patient or to treat an AE, the investigator will contact the medical monitor (contact information is in the Investigator Study Notebook). A decision to break the blind must be reached by the medical monitor or designee, and the investigator. The investigator or designee may break the blind through the web based randomization system independent of the medical monitor only if it is considered an emergency by the investigator. The event requiring breaking the blind must be documented in the eCRF, including the date the blind was broken. In addition, the patient will be discontinued from further study drug administration in this study.
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10.
STUDY MEDICATION SUPPLY, DOSING PROCEDURES, AND DISPOSITION (ADDITIONAL DETAILS CAN BE FOUND IN THE PHARMACY MANUAL) Palifosfamide-tris Supply and Dispensation Accountability
10.1. 10.1.1.
The investigational materials are to be prescribed only by the PI or the sub-investigators named in the Form FDA 1572. Under no circumstances will the PI allow the investigational drug to be used other than as directed by the protocol. 10.1.2. Receipt of Drug
The PI must maintain accurate records accounting for the receipt of the investigational materials (ZIOPHARM and/or distributor provides a copy of the Clinical Trial Material Shipment Receipt form for this purpose). Each vial will be labeled with the name of the drug, strength, and lot number. 10.1.3. Storage
Palifosfamide-tris should be stored frozen (approximately -20C or colder) except when being prepared for injection. 10.1.4. Handling
All necessary precautions and institutional guidelines for handling potentially toxic compounds must be strictly followed. 10.1.5. Vial Inventory and Dispensation
A responsible person(s) designated by the PI must maintain an accurate record of study drug dispensation (Drug Accountability Log). This designated person(s) will be unblinded team member(s) responsible for documenting drug dispensation and keeping this information blinded to the remainder of the study team. The patient(s) initials/number, and dates and amounts dispensed and returned, must be included in the log. ZIOPHARM and/or designee will provide forms to facilitate inventory control; these forms must be used unless the investigator has previously established a system that adequately complies with Food and Drug Administration (FDA) regulations and local county requirements, and is approved by ZIOPHARM. The study drug(s) must be dispensed only from the institution(s) specified on the Form FDA 1572. Authorized pharmacy personnel by the investigator will dispense the drug.
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10.2.
Palifosfamide-tris Reconstitution and Dose Preparation
Palifosfamide-tris has been developed in one dosage strength of 250 mg of IPM active ingredient per vial. Each vial contains tris and mannitol as excipients. The preparation and reconstitution of palifosfamide-tris should be performed by an unblinded person at the clinical site (usually, the site pharmacist or research pharmacist). Each 250 mg vial of palifosfamide-tris is reconstituted with 5 mL of 14.6% Sodium Chloride for Injection, to a final concentration of 50.0 mg per mL. If the 14.6% sodium chloride diluent is not available, sites may use either 5.0% or 0.9% sodium chloride for injection as the diluent used for reconstitution utilizing the same reconstitution instructions. However the 14.6% sodium chloride is the recommended diluent to use for reconstitution of palifosfamide-tris. Reconstituted vials are stable for two hours at room temperature prior to being added into the IV bag. The reconstituted drug is then introduced into the 250 mL 0.9% sodium chloride IV infusion bag. This IV bag will be given to a blinded study staff member in such a manner as to not break the blind. NOTE: If using 14.6% Sodium Chloride for Injection for vial reconstitution: Within one hour of being removed from the freezer, palifosfamide-tris is reconstituted with 5 mL of 14.6% Sodium Chloride for Injection, to a final concentration of 50.0 mg per mL; Within two hours of being reconstituted in the vial with 14.6% Sodium Chloride for Injection, the reconstituted drug should be introduced into the 250 mL 0.9% sodium chloride IV infusion bag; Within one hour of being reconstituted in the IV infusion bag, the infusion of palifosfamide-tris must be started. Palifosfamide-tris is to be administered over approximately 30 minutes.
In the event that 14.6% Sodium Chloride for Injection is not available at the time of vial reconstitution, you may use 5% or 0.9% Sodium Chloride for Injection, however, please note that in this case, the reconstituted vial should be introduced into the 250 mL 0.9% sodium chloride IV infusion bag within one hour. 10.3. Palifosfamide-tris Matching Placebo Dose Preparation
An IV bag containing 250 mL normal saline should be prepared by an unblinded person at the clinical site (usually, the site pharmacist or research pharmacist).
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10.4.
Doxorubicin Supply and Dose Preparation
Doxorubicin is commercially available and will be supplied by the hospitals pharmacy. The investigator is required to consult the doxorubicin Product Monograph available in his/her country. Doxorubicin should be prepared according to the manufacturers instructions. 10.5. Dosing Regimen and Dosing Instructions
On Day 1 of each cycle, 150 mg/m2 IV palifosfamide-tris/placebo and 75 mg/m2 IV doxorubicin are administered. Palifosfamide-tris or matching placebo will be given by IV infusion over approximately 30 minutes. The infusion of palifosfamide-tris/placebo should occur as soon as possible after reconstitution and be completed within 1 hour of reconstitution in IV bag. The dose of doxorubicin should commence approximately 1 hour ( 30 minutes) following the completion of the palifosfamide-tris/ placebo infusion. Doxorubicin should be administered over 5-30 minutes. Palifosfamide-tris or placebo alone is administered on Days 2 and 3 of each 3-week (21-day) cycle as described above. Patients must be adequately hydrated with at least 500 mL of fluids orally or IV as appropriate, in addition to the infusion administered, on each day of palifosfamidetris/placebo dosing. Patients should be cautioned to maintain good oral hydration in between dosing days. The dose of palifosfamide-tris/placebo and doxorubicin for each patient should be calculated by the pharmacist based on the dose level and the patients body surface area (BSA) at Screening. BSA should be calculated using their Institutional guidelines for calculating BSA or, the calculation for BSA by the Mosteller formula may be used (note: SQRT=square root): BSA (m) = ([height (cm) weight (kg)]/3600) e.g., BSA = SQRT ([cm*kg]/3600); or in inches and pounds: BSA (m) = ([height (in) weight (lbs)]/3131) 10.6. Dose Delays and Modifications
Doses reductions and delays in the administration of doxorubicin and/or palifosfamidetris/placebo are allowed, and should follow the guidance in Table 2 (below) for palifosfamide-tris/placebo and the approved country specific Product Monograph as applicable for doxorubicin. Any dose reduction may be based on local or central lab results as available on Day 1 of Cycles 2-6).
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An unblinded study team member responsible for preparation of study drug must receive notification that a dose reduction is necessary in order to prepare the study drug(s) for administration. Once the dose has been reduced for a patient, all subsequent cycles should be administered at that dose, unless further dose reduction is required. The reduced dose will be considered the maximum dose for all subsequent cycles for that patient. A maximum of 2 dose reductions for toxicity will be permitted per patient. Dose administration may be delayed no more than 2 weeks to allow for recovery from toxicity. If the dose is delayed more than 2 weeks for toxicity, the patient will be withdrawn from the treatment phase of the study, but will continue to undergo all follow-up evaluations. If either of the study drugs needs to be delayed, then both should be delayed on the same schedule. If either of the study drugs needs to be discontinued, then all study drug dosing should be discontinued and the patient will be considered off study therapy. Details of dose delays and modifications are presented below. Table 2. Dose Modifications for study drug-related toxicity1
ADVERSE EVENT Hematologic Platelet count <100 X 109/L ANC 1500 Delay dose of palifosfamide-tris/placebo up to 14 days or until platelet count 100 X 109/L, then reduce by 20% For patients who are not currently being treated with growth factors, delay dose of palifosfamide-tris/placebo up to 14 days or until ANC returns to 1500, then maintain dose when restarted and add growth factors For patients who are already being treated with growth factors, delay dose of palifosfamide-tris/placebo up to 14 days or until ANC returns to 1500 , then reduce by 20% Neutropenic fever Any Grade 4 hematologic toxicity Calculated creatinine clearance >30 mL/minute but 40 mL/minute <30 mL/minute Grade 3 if unresponsive to appropriate therapy. Grade 4 Reduce dose of palifosfamide-tris/placebo by 20% Discontinue palifosfamide-tris/placebo Delay dose of palifosfamide-tris/placebo for up to 14 days, until Grade 1 or baseline, then reduce by 20% Delay dose of palifosfamide-tris/placebo up to 14 days until Grade 1 or baseline, then reduce by 20% Delay dose of palifosfamide-tris/placebo up to 14 days or until Grade 1 or baseline, then reduce by 20% Delay dose of palifosfamide-tris/placebo up to 14 days and then reduce by 20%. PALIFOSFAMIDE-TRIS/PLACEBO
Nonhematologic (other than creatinine or urinary electrolyte wasting)
1 The investigator is required to consult the doxorubicin Product Monograph available in his/her country in order to make dose modification or discontinuation decisions.
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10.7.
Treatment of Nausea and Vomiting
Anticipatory, breakthrough, and delayed-onset regimens are recommended. Antiemetic medication must be provided consistent with the institutions standard practice for a chemotherapy of moderate emetic risk, with delayed emetic potential, as long as the institutions standard practice is consistent with the guidelines of the American Society for Clinical Oncology and/or the European Society for Clinical Oncology, which were summarized in a recent review 13. For a chemotherapy in this class of emetic risk, this should include at least a 5-HT3 antagonist medication and dexamethasone on the day of doxorubicin administration, with additional 5-HT3 antagonist and/or dexamethasone administration on Day 2 and 3 of the dosing cycle13. A multi-national meeting was held in June 2009 in Perugia, Italy (The 2009 ESMO- MASCC Consensus Conference) to review recent literature on studies of antiemetic regimens, to harmonize recommendations across organizations, and to assess whether changes to the current guidelines (described above) are indicated. The working group recommended no changes for the current standard of antiemesis for chemotherapies of this class and emetic risk, based on personal communication with Dr. Lawrence Einhorn, working group member (report of the meeting is being submitted for publication). 10.8. Disposition of Unused Drug
At the termination of the study or at the request of ZIOPHARM, all unused study drug must be destroyed per facility procedure after a full accountability has been documented. This destruction will be fully documented and the records maintained in the Investigators Study Notebook (ISN). 11. 11.1. CONCOMITANT THERAPY Permitted Therapies
Palliative and supportive care for any underlying illness including palliative external beam radiation to bone lesions (the latter is permitted only if started or planned prior to the first day of study drug dosing; if it is initiated after study drug dosing has started, it will be considered evidence of progression of disease).
Dexrazoxane when associated with doxorubicin administration for patients who have received a cumulative doxorubicin dose of 300 mg/m2. Anti-diarrheal therapy for study drug-induced diarrhea. Treatment with nonconventional therapies and vitamin/mineral supplements, provided that they do not interfere with the study endpoints, in the opinion of the investigator.
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G-CSF may be administered as per institutional standard of care when giving doxorubicin. Either filgrastim or pegfilgrastim may be chosen per the discretion of the treating physician. It is expected that toxicity due to doxorubicin in the absence of hematopoietic growth factors will be myelosuppression; therefore, growth factors may be utilized for all patients on this study. Erythropoietin/Darbopoietin. 11.2. Therapies Not Permitted During Study Drug Dosing
Other investigational therapy or other approved anticancer therapy. 12. 12.1. 12.1.1. SAFETY AND EFFICACY VARIABLES AND ASSESSMENTS Efficacy Primary Efficacy Variable
The primary efficacy variable is OS. There is also an assessment of PFS as an accelerated approval endpoint. OS is defined as the time from randomization to the date of documented death or date of last follow-up. PFS is defined as the time from randomization to the date of documented, objective PD, radiological or clinical findings or death (if prior to progression). Patients without PD at the time of analysis will be censored as of the last date of disease evaluation. All patients will be followed for survival. Secondary Variables
12.1.2.
Secondary variables are defined as the following: Quality of Life: The EORTC QLQ C 30 questionnaire will be used. Safety and tolerability: safety and tolerability will be evaluated using CTCAE (version 4.0). 12.2. Tumor Response
MRI and/or CT scans must meet the standard of care for imaging of lesions in the respective organ system(s). 12.3. Safety Assessments and Adverse Event Reporting
Complete, accurate and timely safety information from clinical trials is crucial for the protection of patients and is mandated by regulatory agencies. It is the responsibility of the
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investigator to document all AEs occurring during the clinical trial. All clinical trials sponsored by ZIOPHARM Oncology will be conducted in accordance with Good Clinical Practices for collecting and reporting safety information. Safety and tolerability will be evaluated based on AEs, vital signs, physical examination and laboratory tests (including ECGs). 12.4. 12.4.1. Definitions Adverse Event (AE)
An adverse event can be any unfavorable and unintended sign, symptom or disease temporally associated with the use of a drug, without any judgment about causality. An AE can be a new occurrence or an existing process that increases significantly in intensity or frequency. An AE of a patient in a clinical trial may be any of the following: An unfavorable and unintended symptom reported by the patient - patients will be encouraged to report treatment-emergent AEs (any adverse event that begins or worsens with study treatment) spontaneously; general, non-directed questioning may also be used to elicit reports of AEs; or An abnormal result from laboratory studies or other diagnostic procedures that meets at least one of the following criteria: o Results in termination of study drug; o Leads to corrective treatment; o Leads to further diagnostic tests (other than simple repeat for confirmation); o Is considered to be clinically significant by the investigator The following considerations apply when identifying an AE:
Anticipated day-to-day fluctuations of pre-existing conditions including the disease under study that do not represent a clinically significant exacerbation or worsening need not be considered adverse events; In the event that a constellation of symptoms results in a confirmed diagnosis, the diagnosis (not the symptoms) should be recorded as the adverse event term; If a diagnosis cannot be established, the symptoms should be recorded as the adverse event(s);
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If a symptom has been included in the medical history, an associated severity grade and frequency should also be documented so that a worsening in severity or frequency of a symptom can be readily identified as an AE; Progression of disease is not itself an AE however, the event(s) leading to disease progression should be documented as an AE (e.g., increase in pain). Suspected adverse reaction Suspected adverse reaction means any adverse event for which there is reasonable possibility that the drug caused the adverse event. Reasonable possibility means there is evidence to suggest a causal relationship between the drug and adverse event. Examples include: A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure (ie. Angioedema, hepatic injury, Stevens-Johnson Syndrome); One or more occurrences of an event that is not commonly associated with drug exposure, but is otherwise uncommon in the population exposed to the drug (ie. Tendon rupture); An aggregate analysis of specific events (such as known consequences of the underlying disease or condition under investigation or other events that commonly occur in the study population independent of drug therapy) that indicates those events occur more frequently in the drug treatment group than in a concurrent or historical control group.
12.4.2.
12.4.3.
Expectedness An adverse event or suspected adverse reaction is considered unexpected if it is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed. Unexpected, as used in this definition, also refers to adverse events or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmaceutical properties of the drug, but are not specifically mentioned as occurring with the particular drug under investigation.
12.4.4.
Serious Adverse Event (SAE)
An AE is serious when the event meets one or more of the following: Death;
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NOTE: Death should not be reported as the verbatim term, the event(s) that led to death should be reported as the SAE(s). Death is an outcome. Life-threatening, meaning that the patient was at immediate risk of death from the event at the time that the event occurred. It does not include an event which hypothetically might have caused death if it occurred in a more severe form; Hospitalization, initial or prolonged, meaning that a hospital admission and/or prolongation of a hospital stay was required for the treatment of the AE, or occurred as a consequence of the event. It does not include a pre-planned hospital admission (scheduled prior to enrollment) for treatment or diagnostic procedures (unless the condition deteriorated in an unexpected manner during the study), or, in general, a hospital admission of less than 24 hours duration; Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions (such as mobility, communication, self-care, self-direction, interpersonal skills, work tolerance or work skills); A congenital anomaly or birth defect; An important medical event that, although not immediately life-threatening, requires intervention in order to prevent one of the other serious outcomes listed above. Examples of such events are allergic bronchospasm requiring intensive treatment in an emergency room or at home; blood dyscrasias or convulsions that do not result in hospitalization; or the development of drug dependency or drug abuse. Serious Adverse Event (SAE) Collection
12.4.5.
All SAEs must be reported by the investigator or designee within 24 hours of becoming aware of the event. SAEs, which occur following informed consent but prior to administration of the first dose of study drug, will be added to the patients medical history. All SAEs (initial and follow-up reports) will be collected via the eCRF system. Source documents will be uploaded into the database in PDF format. Should the eCRF system be unavailable or inaccessible, a protocol specific paper SAE form will be provided to all study sites. A SAE form, in paper format, as well as the SAE completion guidelines, is provided in the investigator study notebook (ISN). Please refer to the ISN for instructions on how to complete the form. SAE collection continues up to 21 days after the last dose of study drug administration (inclusive). SAEs will to be followed until resolution or stabilization. Investigators must submit followup information as it becomes available. A discharge summary with an end date and outcome
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should be provided/uploaded into the eCRF. A SAE form will be considered finalized once all data fields are source data verified by the monitoring team and a final narrative is generated. 12.4.6. Adverse Event Collection
All AEs which occur following the administration of the first dose of study drug will be reported in the eCRF. If an AE occurs following informed consent, but prior to starting the first dose of study drug, the event should be added to the patients medical history. AEs should be followed until the event has stabilized or resolved. 12.4.7. Adverse Event Term
Whenever possible, NCICTCAE (version 4.0) (National Cancer InstituteCommon Terminology Criteria for Adverse Events) terms should be utilized; signs and symptoms due to a common etiology will be reported as an integrated diagnosis; for example, cough, runny nose, sneezing, sore throat, and head congestion would be reported as upper respiratory infection. The diagnosis will be as specific and complete as possible (e.g., lower extremity edema, rather than just edema). 12.4.8. Start Date
The date at which the event was first apparent to the patient or investigator 12.4.9. Stop Date
The date applicable to the reported outcome If the AE resolved, record the date on which the event resolved as determined by the patient or the investigator. If the AE was ongoing at the time of death, the event should be captured as ongoing. Intensity
12.4.10.
The intensity (synonym: severity) of AEs will be assessed according to the NCICTCAE (version 4.0) (National Cancer InstituteCommon Terminology Criteria for Adverse Events). The criteria can be found at: http://ctep.cancer.gov/reporting/ctc.html. Adverse events should be reported using the maximum intensity of the event (e.g, if a patient reported nausea lasting 3 days, one start date and stop date should be recorded along with the maximum intensity experienced for that event over that 3 day timeframe). In those cases where the NCI-CTCAE criteria do not apply, intensity should be defined according to the following criteria:
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Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental Activities of Daily Living (ADL); Grade 3: Severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL; Grade 4: Life-threatening consequences; urgent intervention indicated; Grade 5: Death related to AE. Action taken regarding Study Drug Administration
12.4.11.
For each AE, the investigator will indicate which one of the following actions regarding the administration of study drug was taken as a result of the event. None no change in study drug administration. Discontinued permanently study drug was stopped due to the AE. Reduced study drug administration was modified due to the AE. Interrupted study drug administration interrupted but not stopped due to AE. Relationship to Study Drug
12.4.12.
The relationship (synonym: causality) is based on the investigators clinical judgment regarding the likelihood that the study drug caused the AE and may include consideration of some or all of the following factors: Alternative possible causes of the AE, including the patients underlying disease or co-morbid conditions, other drugs, other host and environmental factors; The temporal sequence between the exposure to study drug and the AE; Whether the clinical or laboratory manifestations of the AE are consistent with known actions or toxicity of the study drug; Whether the AE resolved or improved with decreasing the dose or stopping the study drug (i.e., dechallenge); or recurred or worsened with re-exposure to the drug (i.e., rechallenge).
The relationship between the study drug and the AE will be described using one of the following categories: Unrelated another factor is clearly the cause of the AE;
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Possibly Related there is a reasonable possibility that the study drug is the cause of the AE, including that the study drug and another factor(s) are equally likely as causes of the AE; Related the AE can be fully explained by the administration of study drug.
The investigator will complete the relationship (causality) for the combination therapy of palifosfamide-tris/placebo and doxorubicin. 12.4.13. Pregnancies
If a patient becomes pregnant while participating in the study, study treatment must be discontinued immediately. ZIOPHARM Drug Safety will provide the site with an Initial Pregnancy Report and Pregnancy Outcome Form to be completed by the investigator or designee and entered into the clinical database. Completion guidelines will be provided in the investigator study notebook (ISN). Please refer to the ISN for details on how to complete these forms. 12.4.14. IND Safety Reports
ZIOPHARM and/or designee will notify the investigator, via an IND Safety Report, of the following: Any AE associated with the use of study drug or study procedures in this or any study which meets the following criteria: Suspected adverse reaction (Related SAE except in US); Serious; Unexpected.
Any finding from tests in laboratory animals that suggests a significant risk for human patients, including reports of mutagenicity, teratogenicity, or carcinogenicity. 12.4.15. Reporting of Adverse Events to IRB/EC
The investigator shall notify his/her IRB/EC promptly of all serious and suspected unexpected adverse reactions/events (synonym: SUSAR) or any other significant risks to patients should such information become available. The investigator will inform ZIOPHARM of any local regulatory or IRB requirements not covered by the procedures in this or the prior section. 12.4.16. Adverse Event Record Retention
The investigator must keep on file copies of all AE information, including correspondence with ZIOPHARM and/or designee and the IRB/EC.
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12.4.17.
Data Monitoring Committee (DMC)
A Data Monitoring Committee (DMC) will be in place to assess the safety and efficacy of the interventions during the trial and to monitor the overall conduct of the clinical trial. The DMC will provide recommendations about stopping or continuing the trial. To contribute to enhancing the integrity of the trial, the DMC may also formulate recommendations relating to the selection/recruitment/retention of participants, their management, improving adherence to protocol-specified regimens and retention of participants, and the procedures for data management and quality control. The DMC will be comprised of external medical experts and a statistician. The DMC will hold an Organizational Meeting at the beginning of the study to approve the DMC Charter which will guide their activities. The DMC will meet approximately every 4-6 months during the conduct of the clinical trial to review data regarding measures of quality of trial conduct, as well as patient safety and efficacy. ZIOPHARM or the DMC Chair can request a DMC meeting or consultation at any time during the study, based on new information or safety data. In formulating its recommendations regarding trial continuation, the DMC will implement monitoring guidelines that are specified in the DMC Charter and the Statistical Analysis Plan. 12.4.18. Central Pathology Review
A team of independent pathologists with specific sarcoma expertise will review and approve histology prior to a patient being deemed eligible. Pathology reports will be reviewed and verified prior to randomization. After randomization, histology slides will be read by the independent central pathologists to confirm their agreement with the local pathology report. A Central Pathology Charter will be developed to provide guidance and consistency. 12.4.19. Central Radiology Reads
An independent Central Imaging Core Lab will review reported responses and progression events using RECIST (version 1.1) criteria. In the case of a dispute, adjudication will be implemented. This team will include external medical experts with specific experience in STS. An Imaging Charter will be developed to provide guidance and consistency. 13. 13.1. STATISTICAL PROCEDURES Overview
This is a Phase III multicenter, international, randomized, double-blind, placebo-controlled study of doxorubicin plus palifosfamide-tris vs. doxorubicin plus placebo in patients with front-line metastatic soft tissue sarcoma.
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All analyses will be conducted as defined in a formal statistical analysis plan (SAP) for the analysis and presentation of data. The SAP will be finalized prior to study launch. Deviations from the statistical analyses outlined in this protocol will be indicated in this plan; any further modifications will be noted in the final clinical study report (CSR). All statistical analyses will be performed using SAS (version 8.2 or later) or using StatXact (version 7.0 or later). 13.2. Historical Data
The recent randomized ZIOPHARM Phase II study which compared palifosfamide-tris + doxorubicin vs. doxorubicin alone is relevant for sample size and follow-up determination. The ZIOPHARM Phase II study evaluated PFS. An interim analysis of evaluable patients (n=62) suggested improved PFS (10/30 for the combination vs. 18/32 for doxorubicin alone). The median PFS was 7.8 months (34 weeks) for the combination vs. 4.4 months (19 weeks) for doxorubicin alone; the hazard ratio was 0.427 (95% c.i.: 0.191 , 0.951) in favor of the combination. 13.3. Study Populations
The Intention-to-Treat (ITT) population is defined as all randomized patients. Patients will be analyzed as randomized. The modified ITT (mITT) population is defined as all ITT patients who are eligible and treated with study-directed therapy. Patients will be analyzed as randomized. The Safety population is defined as all randomized patients who were treated with one of the two study therapies. Randomized patients who do not receive at least one dose of study treatment are excluded from this population. Patients will be analyzed as treated. Patients will be allowed to be randomized based on review of pathology reports by independent central pathologists prior to centralized review of the histology slides. Upon central pathology review, patients may be found to be ineligible for the study or improperly classified, but still eligible. Ineligible patients will be included in the ITT population, but will be excluded from the mITT. Misclassified patients will be placed according to the central pathology review stratum. In the event that >5% are found to be ineligible, the sample size will be increased to ensure that at least 406 patients are in the mITT population. 13.4. 13.4.1. Study Endpoints Primary Efficacy Endpoints
The primary efficacy endpoint is overall survival (OS) with an assessment of progressionfree survival (PFS) as an accelerated approval endpoint.
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OS is defined as the time from randomization to the date of documented death or date of last follow-up. PFS is defined as the time from randomization to the date of documented, objective PD, radiological or clinical findings or death (if prior to progression). Patients without PD at the time of analysis will be censored as of the last date of disease evaluation. All patients will be followed for survival. Secondary Endpoints
13.4.2.
Secondary variables are defined as the following: Quality of Life: The EORTC QLQ C 30 questionnaire will be used. Safety and tolerability: safety and tolerability will be evaluated using CTCAE (version 4.0).
No formal hypothesis tests will be used for these secondary efficacy endpoints. 13.4.3. Other Endpoints
The nature of any subsequent disease-directed therapies will be displayed. 13.4.4. Safety Endpoints
The safety endpoints will include adverse events, vital signs, physical examinations, laboratory data, and concomitant medications. All adverse events will be coded according to Medical Dictionary for Regulatory Activities (MedDRA, version 13.0) or National Cancer Institue-Common Terminology for Adverse Events, version 4.0 (NCI-CTCAE version 4.0) Concomitant medications will be coded using WHO-DD (World Health Organization Drug Dictionary, September 2006 or later). The incidence, onset timing, duration, severity, relationship, and resolution will be presented for each adverse event. All adverse events occurring on-study until the Post-treatment safety assessment (21 days ( 3 days) after last dose of any study drug) will be analyzed by treatment group and listed in by-patient data listings. Treatment-emergent events are defined as any adverse event that occurs after administration of the first dose and until going on any subsequent STS-directed therapy or any adverse event that is present at baseline and continues after the first dose of study treatment but worsens in intensity. Events that are considered related to treatment (possibly or definitely drug-related) also will be tabulated. Adverse events to be reported will include pre-existing events as well as treatment-emergent events, serious adverse events, related adverse events, the severity of events. Timing relative to study treatment administration will also be reported. Treatment-related serious adverse
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events (SAEs), including potential cardiac and renal toxicities as well as deaths, will also be presented on a case-by-case basis. Dosing and study drug tolerability will also be assessed. This will include total dose per drug, percent of planned vs. actual dose per study drug, need for dose modifications, and need for delayed doses. 13.5. 13.5.1. Analyses Patient Status
Patient status will be summarized for all randomized patients by treatment group. The numbers of patients in the ITT, Safety, and mITT populations will be provided together with exclusions. Analyses will address follow-up duration, missed follow-up, and reasons for removal of patients from study therapy or from study follow-up. In addition, patient categories for major protocol violations will be identified in a listing. Categories will include misdiagnosis of disease, misclassification of a stratification factor, not fulfilling other inclusion/exclusion criteria, disallowed medications during the study, missed follow-up, and lack of progression confirmation by the independent Central Imaging Core Lab. Length of follow-up, timing of removal from study therapy, and withdrawal reason, including adverse events, tolerability, and lack of efficacy, will also be displayed. Kaplan-Meier life tables will be used to compare the time to onset and the duration of any adverse events with >10% incidence. The cumulative enrollment and numbers still at risk will also be presented. The percents and timing of those proceeding to subsequent STS-directed therapies will also be displayed. 13.5.2. Baseline Demographics and Clinical Characteristics
Patients randomized to doxorubicin plus palifosfamide-tris versus doxorubicin plus placebo will be compared regarding demographic and baseline characteristics within the ITT, mITT, and Safety populations. Demographic categories for evaluation will include age, gender, race, weight, country/region, while clinical characteristics will include STS histology, Initial Performance Status (ECOG, BSA, disease sites, interval since STS surgery, and any prior disease-directed therapies.) Categorical data (e.g., STS histology, gender) will be compared using a two-sided Fisher Exact test or a singly ordered exact test (e.g., disease extent), while continuous data (e.g., age, BSA) will be compared using an unpaired t-test. 13.5.3. Primary Efficacy Analyses
Standard statistical methodology will be used to assess the time to event endpoints, such as OS and PFS. The Kaplan-Meier estimate will be used to display time to death or time to
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disease progression. A log rank test will be used to evaluate treatment effects on groups as randomized; a stratified log rank test and a stratified proportional hazard model will be used to control for the stratification factors (histology, age, and region) as well as additional baseline covariates. An additional proportional hazard model will also examine treatment interactions between treatment and these three stratification factors. The proportional hazards model analysis conducted in the ITT population will be used for primary analyses of efficacy, while the mITT and Safety populations will be used in supportive analyses. Subgroup analyses will be displayed; any p-values for individual strata will be regarded as descriptive statistics. 13.5.4. Secondary Analyses
The Quality of Life outcomes will be analyzed using an unpaired t-test. The ITT, mITT and Safety populations will be used in these analyses. 13.6. Safety Analyses
Safety tables will be presented for all safety parameters including adverse events, dosing, tolerability, vital signs, ECGs, x-rays, and clinical chemistries. The Safety population will be used for these analyses. Adverse event tables will display the number of patients and the corresponding number of events per treatment group. MedDRA data (patients, events) will be presented by System Organ Class and Preferred Term; NCI-CTCAE (version 4.0) events will also be displayed at the patient level. Adverse events to be presented by patient and event for each treatment group include adverse events, serious adverse events, related adverse events, adverse events leading to withdrawal, and the severity of events. Timing relative to study treatment administration will also be provided in figures. SAEs as well as treatment-related SAEs, plus any potential cardiac or renal toxicities as well as treatment-related deaths, will also be presented in narratives. Deaths unrelated to STS and premature treatment withdrawals due to toxicity or drug intolerance will be presented in separate listings providing reasons. Descriptive methods will be used to assess the incidence of any expected adverse events in the two treatment groups. There will be a comparison of the total number of adverse events, treatment-emergent adverse events, treatment-emergent moderate to severe adverse events, SAEs. Dosing and study drug tolerability will also be displayed for each treatment group as percents and means for each treatment group. This will include mean total dose per drug, percent of planned vs. actual dose per study drug, percent needing dose modifications, and percent needing delayed doses.
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Vital signs, clinical chemistries, ECGs, and x-rays will be displayed serially as normal/abnormal (or low vs. high, if appropriate) relative to baseline. A listing of clinically significant laboratory values for relevant laboratory parameters will be provided. Additional safety analyses may be requested at any time by the DMC, in order to depict toxicities and to further define the safety profile of doxorubicin plus palifosfamide-tris vs. doxorubicin plus placebo. 13.7. 13.7.1. Sample Size Determination Overall Survival (OS)
In a retrospective exploratory analysis of data collected on advanced soft tissue sarcoma patients who were treated with first-line ifosfamide containing chemotherapy compared to doxorubicin monotherapy, patients treated with doxorubicin achieved a 19 week median PFS and 52 week median survival 14. An additional retrospective analysis of data collected on first-line palliative chemotherapy in advanced soft tissue sarcoma, suggests that using a doxorubicin-based combination regimen may be associated with superior survival outcomes than those treated with doxorubicin alone4. The study is powered to detect clinically meaningful effects on OS. OS events include death from any cause including advancing disease, other cancers, heart disease, and accidental deaths. The trial will have 85% power to detect a 0.667 hazard ratio advantage for doxorubicin plus palifosfamide-tris, when using a stratified log rank statistic having (one sided) 0.005 false positive error rate. This hazard ratio corresponds, approximately, to an increase in median survival from 52 to 78 weeks. In turn, this will require the primary analysis of OS to be conducted on the calendar date when L=318 deaths have occurred. Statistical significance at (one-sided) 0.005 will be achieved when the estimated hazard ratio for OS is 0.749, corresponding to an increase in median survival of approximately 52 versus 69 weeks, (i.e., a 4 month increase in overall survival). With an overall sample size of 2N = 406 evaluable patients who would be enrolled over 18 months, then 24 months of additional follow-up will be required to achieve the targeted L=318 events. 13.7.2. Progression-free Survival (PFS)
The DMC will formulate a recommendation to ZIOPHARM regarding whether to release evidence to enable possible filing for Accelerated Approval (AA). This recommendation will be based predominately on results from the primary analysis of PFS. Since a statistically significant (i.e. one-sided p=0.005) OS outcome will be obtained for an estimated hazard ratio of 0.749, corresponding to a clinically significant 4-month estimated improvement in
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OS, it is judged that a reliably estimated increase on PFS in the range of a 3 to 4 month improvement then would be reasonably likely to predict clinical benefit. If patients treated with doxorubicin achieve a 19 week median PFS and if the estimated hazard ratio for PFS is 0.60, this corresponds to an increase in median PFS from approximately 19 weeks on doxorubicin plus placebo to 32 weeks on doxorubicin plus palifosfamide-tris, (i.e., a 3 month increase in PFS). The primary analysis of PFS will occur when L*=330 patients have had PFS events. With L*=330 PFS events and an estimated hazard ratio of 0.60, then the upper limits of 95% and 99.9% confidence intervals for the PFS hazard ratio are, respectively, 0.745 and 0.861. Hence, the data would establish, at the 1sided p=0.0005, that the true reduction in rate of PFS events is at least 14%, and would rule out, at the 1-sided p=0.00001, that the addition of palifosfamide-tris provides no reduction in the rate of PFS events. If the true hazard ratio for PFS is 0.50, then with L*=330, the trial has 95% power to achieve an estimated hazard ratio 0.60. With an overall sample size of 2N = 406 evaluable patients who would be enrolled over 18 months, then 6 months of additional follow-up will be required to achieve the targeted L*=330 PFS events. Hence, this analysis for PFS and potential release of data for AA would occur approximately 18 months before the trial achieves its target of L=318 OS events. When formulating its recommendation regarding release of evidence to enable possible filing for AA, the DMC also will consider all available efficacy and safety data, including an interim efficacy analysis of survival data at the time of the final analysis of PFS, using the standard O'Brien-Fleming monitoring guideline, set to preserve the false positive error rate of (one-sided) 0.005 as specified in the DMC Charter and the Statistical Analysis Plan. Should the DMC recommend release of evidence regarding effects on PFS, secondary endpoints and safety, in order to file for AA, the survival data will remain confidential either until there is definitive evidence of a survival benefit (i.e., likely requiring evidence that a monitoring boundary for OS has been crossed), or until the achievement of the targeted L = 318 deaths. In the event that ZIOPHARM does file for AA, the DMC will provide the FDA the available OS data while maintaining the study blind. The anticipated total sample size of the trial will be 424 patients to achieve 406 evaluable patients (after a loss of 18 patients due to withdrawal for reasons other than efficacy, safety, or tolerability) to evaluate the effect of the addition of palifosfamide-tris on the PFS and OS endpoints. 13.8. Interim Analysis
A Data Monitoring Committee (DMC) will be in place, with responsibilities for safeguarding the interests of trial participants, for assessing the safety and efficacy of the interventions
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during the trial, and for monitoring the overall conduct of the clinical trial. The DMC will provide recommendations about stopping or continuing the trial. The DMC will meet approximately every 4-6 months during the conduct of the clinical trial to review data regarding measures of quality of trial conduct, as well as patient safety and efficacy. In formulating its recommendations regarding trial continuation, the DMC will follow its monitoring guidelines that are specified in the DMC Charter and the Statistical Analysis Plan. 13.9. Procedures for Handling Missing, Unused, and Spurious Data
No imputation of values for missing data will be performed. Whenever possible, the ITT population will be used. Time to event analyses will utilize censoring rules to deal with withdrawals and losses to follow-up, whether on- or off-study. Every reasonable effort will be made to ensure that all patients will be followed until the complete documentation of OS and PFS events and secondary endpoint outcomes including QoL assessments, even after patients have discontinued their randomized treatment arm or initiated supportive care. 14. 14.1. ADMINISTRATION OF THE STUDY Electronic Case Report Forms and Source Documentation
For each patient, pre-study, on-study, and off-study forms will be maintained, with accurate records of: Drug treatment (including dose levels and dates administered); Concomitant drug therapies; Follow-up evaluation data; Records related to SAEs (including clinical and autopsy dates, when applicable); Other pertinent data.
Case report forms will be in electronic form (eCRF). They should be completed in a timely manner, and every effort should be made to have forms completed and up-to-date in anticipation of a visit by the monitor. Specific instructions will be provided to the site. All requested information must be entered into the eCRF in the spaces provided. If an item is not available or is not applicable, it should be documented as such. The completed eCRF must be promptly reviewed and signed where required by the investigator. It is the obligation of the investigator to review each page of the eCRF. E-CRF completion may be delegated to other study personnel; however, this should be documented as part of the delegation of authority process at the site. If, for any reason, certain data are lacking to complete an
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individual report form, the site will be prompted to explain the missing information on the eCRF. 14.2. Good Clinical Practice
The study will be conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with the International Committee on Harmonisation (ICH)/Good Clinical Practice guidelines, applicable regulatory requirements, and ZIOPHARM Oncology, Inc. policies. 14.3. Monitoring
After satisfactory receipt of all necessary paperwork, the monitor will arrange for all study material be delivered to the study site at a mutually agreed upon date. The monitor will conduct a site initiation visit. At the initiation, all personnel who will be involved in the conduct of the study will undergo an orientation to include review of the study protocol, instruction for eCRF completion and overall responsibilities, including those for drug accountability and study file maintenance. Throughout the course of the study, the monitor will make frequent contact with the investigator. This will include telephone and/or on-site visits at approximately 6 to 8 week intervals, or more frequently if necessary. During these visits, eCRFs will be reviewed for completeness and adherence to protocol. As part of the data audit, it is expected that source documents (e.g., hospital records, office records) will be made available for review by the monitor. An unblinded monitor also will perform drug accountability checks periodically. The monitor(s) may periodically request review of the investigators study file to assure completeness of documentation in all respects of the study conduct. Upon completion of the study, the monitor will arrange for a final review of the study files, after which the files should be secured by storage for the appropriate period as specified in Section 14.5 (Records Retention). Electronic copies of the completed eCRFs will be sent to the site for review and confirmation of accuracy. In addition, paper copies will be sent upon request. The investigator or appointed delegate will receive the sponsors representative during these on-site visits and will cooperate in providing the documents for inspection and responding to inquiries that may arise as part of this review. In addition, the investigator will permit inspection of the study files by authorized representatives of the FDA, local Health Authorities and/or ZIOPHARM audits.
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14.4.
Duration of the Study
The study is estimated to complete enrollment within 18 months. The expected total duration of the study is 22 months for the active treatment phase. Patients will be followed until death. 14.5. Record Retention
Records of drug disposition and any reports of the investigation must be maintained by the investigator for a period of at least 2 years following the date on which the test article is approved by FDA for marketing for the purposes that were investigated in the clinical study. If no application is to be filed or if the application is not approved for such indication, the records will be stored for two more years, and then returned to ZIOPHARM. No records will be destroyed, but will be stored indefinitely. 14.6. Institutional Review Board/Ethics Committee
This protocol and the study consent form must be reviewed and approved by the Institutional Review Board (IRB)/Ethics Committee (EC) prior to the start of the study with a copy of the approval letter supplied to ZIOPHARM and/or designee. Following approval, an IRB/EC Assurance Statement must be completed and submitted to ZIOPHARM and/or designee. During the course of the study, the investigator shall make timely and accurate reports to the IRB/EC on the progress of the trial, at intervals not exceeding one year, as well as satisfying any other local IRB/EC regulations regarding reporting. Copies of all reports to, and correspondence with, the IRB/EC must be provided to ZIOPHARM and/or designee, as well as filed in the site study file. Further, within 3 months of the completion or early termination of the study, a final report should be made to the IRB/EC and ZIOPHARM by the investigator. All protocol revisions must originate with, and be documented by, ZIOPHARM and/or designee. If the requested revision is an amendment, the investigator will sign it. The FDA/local Health Authorities will be notified of all revisions by ZIOPHARM unless instructed otherwise. The investigator must submit each amendment to the IRB/EC(s) for review and approval prior to implementation. Documentation of approval signed by the chairperson or designee of the IRB/EC must be promptly submitted to ZIOPHARM and/or designee. It is the investigators obligation to maintain an IRB/EC correspondence file and to make this available for review to ZIOPHARM representatives and/or designee as part of the routine study monitoring process.
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15. 15.1.
INFORMED CONSENT ICH/GCP Informed Consent Requirements
The investigator or his/her staff will explain the nature of the study, its purpose and associated procedures, the expected duration and the potential risks involved to the patient prior to enrollment. It should also indicate that, by signature, the patient or where appropriate, legal guardian, permits access to relevant medical records by ZIOPHARM and designees and by representatives of the FDA. If the patient does not understand English, an appropriate translation into their language must be made available. The PI or designee will obtain written, informed, witnessed consent. The patient must be given ample time and opportunity to ask questions, and will be informed about the right to withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Once the patients questions have been answered, the patient will be asked if he/she is willing to sign and personally date a statement of informed consent. A patient may enter the study only if he/she voluntarily agrees to sign the informed consent statement and has done so. A copy of the signed and dated informed consent will be provided to the patient. The original signed informed consent form is to remain in the investigators study file. The ICF and any other written information provided to the patients will be revised whenever important new information becomes available that may be relevant to the patients consent, or if there is an amendment to the protocol which necessitates a change to the content of the patients informed consent. The investigator will inform the patient of changes in a timely manner and will ask the patient to confirm continuation of their participation in the study by their signature on the revised ICF (if applicable). Any written ICF and written information must receive the IRB/ECs approval/favorable opinion in advance of use. The ICF will be accompanied by or will include a separate document incorporating Health Insurance Portability and Accountability Act (HIPAA)-compliant wording by which the patients authorize the use and disclosure of their protected health information. 15.2. Informed Consent Form
ZIOPHARM will provide a sample patient ICF for modification, as appropriate, by the PI. Any modifications to the ICF should be sent to ZIOPHARM and/or designee for review and approval prior to submission to IRB/EC.
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16.
PROTOCOL APPROVAL
A Phase III multicenter, international, randomized, double-blind, placebo-controlled study of doxorubicin plus palifosfamide-tris vs. doxorubicin plus placebo in patients with front-line metastatic soft tissue sarcoma. With the exception of a change intended to eliminate an immediate hazard to patients, the study shall be conducted as described in the approved protocol. All deviations from the protocol will be documented in the eCRF. Any significant deviation or deviation related to dosing or safety evaluation will be reported to ZIOPHARM and documented in the eCRF. I agree to the terms of this study protocol. I will conduct the study according to the procedures specified herein, and according to principles of Good Clinical Practice and local regulations and requirements.
Center Name: ______________________________ Principal Investigator Print Name: Signature: Date: ______________________________ ______________________________ ______________________________
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APPENDIX 1. EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE STATUS
ECOG PERFORMANCE STATUS* Grade 0 1 2 3 4 5 ECOG Fully active, able to carry on all pre-disease performance without restriction Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. Capable of only limited self-care, confined to bed or chair >50% of waking hours Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. Dead
* As published in Am J Clin Oncol: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-55, 1982.
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APPENDIX 2. COCKCROFT AND GAULT FORMULA FOR CREATININE CLEARANCE The creatinine clearance (CrCL) will be calculated from the serum creatinine using the Cockcroft and Gault Formula: CrCL (mL/minute) for males = ((140-age in years) x ideal body weight (kilograms))/(72 x serum creatinine (mg/dL)). Multiply the result by 0.85 for females.
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REFERENCES
1
3 4
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13 14
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer 2009; 45: 228-247. Brennan MF, Singer S, Maki RG, OSullivan B. Sarcomas of the Soft Tissues and Bone. Cancer Principals & Practice of Oncology; 7th Edition, edited by V DeVita, Jr, S Hellman, Steven Rosenberg, 1581- 1686. Lippincott Williams & Wilkins. http://www.cancer.gov/templates/doc.aspx?viewid=24A7086E-252C-433B-B0C1-8CFD4EA06030 Karavasilis V, Seddon BM, Ashley S, Al-Muderis O, Fisher C, Judson I. Significant Clinical Benefit of First-Line Palliative Chemotherapy in Advanced Soft-Tissue Sarcoma; Retrospective Analysis and Identification of Prognostic Factors in 488 Patients. Cancer 2008; (112, 7)1585-1591. Schuetze S. Assessing Response in Sarcoma: Clear Methods, Murky Results. Oral Presentation CTOS 2009. Chawla/Rosenfeld Developmental Therapeutics Symposium- SARC. Verweij J. Other Endpoints in Screening Studies for Soft Tissue Sarcomas. The Oncologist 2008; 13(suppl 2):27-31. Van Glabbeke M, Verweij J, Judson I, Neilsen OS, et al. Progression-free rate as the principal end-point for Phase II trials in soft-tissue sarcomas. European Journal of Cancer 2002; 38: 543-549. Maki RG, Wathen JK, Patel SR, Priebat DA, Okuno SH, Samuels B, Fanucchi M, Harmon DC, Scheutze SM, Reinke D, Thall PF, Benjamin RS, Baker LH, Hensley ML. Randomized Phase II Study of Gemcitabine and Docetaxel Compared With Gemcitabine Alone in Patients With Metastatic Soft Tissue Sarcomas: Results of Sarcoma Alliance for Research Through Collaboration Study 002. Journal of Clinical Oncology 2007: 25, 19: 2775-2763. Sleijfer S, Seynaeve C, Verweij J. Using single-agent therapy in adult patients with advanced soft tissue sarcoma can still be considered standard care. Oncologist 2005 Nov;10(10):833-41. Tascilar M, Loos WJ, Seynaeve C, Verweij J, Sleijfer S. The pharmacologic basis of ifosfamide use in adult patients with advanced soft tissue sarcomas. Oncologist 2007 Nov;12(11):1351-60. Lorigan P, Verweij J, Papai Z, Rodenhuis S, Le CA, Leahy MG, et al. Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol 2007 Jul 20;25(21):3144-50. Maki RG, Morgan RA, Lewis JJ. Palifosfamide: A Novel Molecule for the Treatment of Soft Tissue Sarcoma (STS). Electronic Sarcoma Update Newsletter 2009; 6, 3. Hesketh PJ, Chemotherapy Induced Nausea and Vomiting . NEngl J Med 2008; 358:2482-94. Sleijfer S, Ouali M, van Glabbeke M, Krarup-Hansen A, Rodenhuis S, Le Cesne A, Hogendoorn PCW, Verweij J, Blay JY. Prognostic and predictive factors for outcome to first-line ifosfamide-containing chemotherapy for adult patients with advanced soft tissue sarcomas. An exploratory, retrospective analysis on large series from the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG). European Journal of Cancer 2010; 46: 72-83.
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TITLE PAGE STUDY PROTOCOL

Protocol Number: Phase: Date of Protocol:

Protocol IPM3001 Palifosfamide-tris

ZIOPHARM Oncology, Inc.

TABLE OF CONTENTS Page

Amendment 3 17 January 2011

Protocol IPM3001 Palifosfamide-tris

ZIOPHARM Oncology, Inc.

Amendment 3 17 January 2011

Protocol IPM3001 Palifosfamide-tris

ZIOPHARM Oncology, Inc.

Amendment 3 17 January 2011

Protocol IPM3001 Palifosfamide-tris

ZIOPHARM Oncology, Inc.

Amendment 3 17 January 2011

Protocol IPM3001 Palifosfamide-tris

ZIOPHARM Oncology, Inc.

ABBREVIATIONS AND DEFINITIONS OF TERMS

Amendment 3 17 January 2011

Protocol IPM3001 Palifosfamide-tris

ZIOPHARM Oncology, Inc.

Amendment 3 17 January 2011

Protocol IPM3001 Palifosfamide-tris

ZIOPHARM Oncology, Inc.

Study Drugs Anticipated No. of Patients

Dose and Schedule

Amendment 3 17 January 2011

Protocol IPM3001 Palifosfamide-tris

ZIOPHARM Oncology, Inc.

Amendment 3 17 January 2011

Protocol IPM3001 Palifosfamide-tris

ZIOPHARM Oncology, Inc.

TABLE 1: SCHEDULE OF STUDY PROCEDURES AND ASSESSMENTS

Post-treatment safety assessment (21 days 3 days post last dose)

Informed consent2 Medical History Cancer History

Concomitant medications Adverse events

LVEF (MUGA or US) Physical Exam Vital Signs Weight Height

ECOG status Hematology

Chemistry panel11, 14 Urinalysis

Electrocardiogram, 12-lead17 Palifosfamide-tris or placebo dosing18 Doxorubicin dosing

EORTC QLQ C30/EQ-5D questionnaires20 Imaging Studies/Tumor Assessment21 Survival Assessment

Amendment 3: 17 January 2011

Protocol IPM3001 Palifosfamide-tris

ZIOPHARM Oncology, Inc.

Amendment 3: 17 January 2011

Protocol IPM3001 Palifosfamide-tris

ZIOPHARM Oncology, Inc.

Amendment 3: 17 January 2011

Protocol IPM3001 Palifosfamide-tris

ZIOPHARM Oncology, Inc.

Protocol IPM3001 Palifosfamide-tris

ZIOPHARM Oncology, Inc.

Amendment 3: 17 January 2011

Protocol IPM3001 Palifosfamide-tris

ZIOPHARM Oncology, Inc.

Protocol IPM3001 Palifosfamide-tris

ZIOPHARM Oncology, Inc.

Amendment 3: 17 January 2011

Protocol IPM3001 Palifosfamide-tris

ZIOPHARM Oncology, Inc.

Amendment 3: 17 January 2011

Protocol IPM3001 Palifosfamide-tris