Clinical trial NCT01846611
Conditions: Ovarian Neoplasms Peritoneal Neoplasms Fallopian Tube Neoplasms
Keywords: Ovarian neoplasms Peritoneal neoplasms Fallopian tube neoplasms Advanced-relapsed epithelial ovarian cancer Advanced-relapsed primary peritoneal cancer Advanced-relapsed fallopian tube cancer Trabectedin Yondelis Doxil Caelyx Platinum sensitive Tthird-line BRCA Patient related outcome
Sponsor: Janssen Research & Development, LLC
Start date: 2013-10-16; Completion date: 2018-11-16
Enrollment: 581 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the efficacy and safety of trabectedin+DOXIL as a third-line chemotherapy regimen (treatment) in patients with platinum-sensitive advanced-relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer who received 2 previous lines of platinum-based chemotherapy.

Detailed description:
This is a randomized (individuals assigned to study treatment by chance), open - label (identity of assigned study drug will be known), active - controlled study in adult female patients with platinum-sensitive advanced - relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer who received 2 previous lines of platinum - based chemotherapy. Approximately 670 participants will be enrolled. Patients will be stratified by 4 criteria defined in the protocol and randomly assigned in a 1:1 ratio to the trabectedin+DOXIL combination therapy group (Arm A) or to the DOXIL (pegylated liposomal doxorubicin) monotherapy group (Arm B). During the treatment phase, patients will receive study drug infusions according to 21 - day cycles in Arm A and 28 - day cycles in Arm B. Treatment will continue until the occurrence of disease progression or unacceptable treatment toxicity, or until 2 cycles after assessment of a complete response (CR). Efficacy assessments will be evaluated using Response Evaluation Criteria in Solid Tumors. Disease assessments, including assessments for patients who discontinue treatment for reasons other than disease progression, will be performed until disease progression, the start of subsequent anticancer therapy, withdrawal of consent, or the clinical cutoff date. Collection of survival status will continue until at least 514 deaths have been observed or until the clinical data cutoff date. Serial pharmacokinetic (PK) samples will be collected in a subset of patients who voluntarily consent to the PK portion of the study. Safety will be monitored throughout the study. An interim analysis of overall survival (OS) will be performed after approximately 308 participants have died. The final analysis of OS will occur when approximately 514 deaths have been observed or until the clinical cutoff date. As of Amendment 6, no new participants will be randomized to study treatment, and treatment with trabectedin should be immediately discontinued for participants assigned to Arm A (trabectedin+DOXIL). All study participants (Arm A or Arm B) currently on study who, in the opinion of the investigator, are deriving clinical benefit may continue treatment with single-agent DOXIL as per the local standard of care.

Arms: arm 1: Participants will receive DOXIL 30 millgram per meter square (mg/m\^2) administered as an intravenous (IV) infusion over approximately 90 minutes followed by trabectedin 1.1 mg/m\^2 administered as an IV infusion over approximately 3hours, every 3 weeks. Participants will be pretreated with 20 mg dexamethasone IV (or the IV equivalent) approximately 30 minutes before DOXIL study drug. As of Amendment 6, treatment with trabectedin will be discontinued for participants on treatment with trabectedin and no new participants will receive trabectedin. Participants who, in the opinion of the investigator, are deriving clinical benefit may continue treatment with single-agent DOXIL as per the local standard of care. arm 2: Participants will receive DOXIL, 50 mg/m\^2 administered as an IV infusion over approximately 90 minutes every 4 weeks.
Interventions: intervention 1: Trabectedin intervention 2: DOXIL intervention 3: Dexamethasone intervention 4: DOXIL
Intervention descriptions: intervention 1: 1.1 mg/m\^2 administered intravenously over approximately 3 hours on Day 1 of each 21-day treatment cycle. intervention 2: 30 mg/m\^2 administered intravenously over approximately 90 minutes on Day 1 of each 21-day treatment cycle. intervention 3: 20 mg administered intravenously on Day 1 of each 21-day treatment cycle approximately 30 minutes prior to study drug infusion. intervention 4: 50 mg/m\^2 administered intravenously over approximately 90 minutes on Day 1 of each 28-day treatment cycle.

Protocol documents:
Prot_000.pdf: 
1
Approved, 9 January 2018
Janssen Research & Development*
Clinical Protocol
A Randomized, Open-Label Study Comparing the Combination of YONDELISand 
DOXIL/CAELYXwith DOXIL/CAELYXMonotherapy for the Treatment of 
Advanced-Relapsed Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer
Protocol ET743-OVC-3006; Phase 3
AMENDMENT 6
R279741 (trabectedin)
* YONDELIS, ET-743 (trabectedin), is being co-developed by Janssen Research & Development, LLC 
pursuant to a licensing arrangement with Pharma Mar, S.A. Janssen Research & Development is a global 
organization that operates through different legal entities in various countries. Therefore, the legal entity 
acting as the sponsor for Janssen Research & Development studies may vary, such as, but not limited to 
Janssen Biotech, Inc.; Janssen Products, LP; Janssen Biologics, BV; Janssen-Cilag International NV; 
Janssen, Inc; Janssen Infectious Diseases BVBA; Janssen Sciences Ireland UC; or Janssen Research & 
Development, LLC. The term “sponsor” is used throughout the protocol to represent these various legal 
entities; the sponsor is identified on the Contact Information page that accompanies the protocol.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
EudraCT NUMBER: 2012-004808-34
Status:
Approved
Date:
9 January 2018
Prepared by:
Janssen Research & Development, LLC
Document No:
EDMS-ERI-41719962; 8.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements.
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged 
or confidential.
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
2
Approved, 9 January 2018
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 22
TIME AND EVENTS SCHEDULE (No Longer Applicable After Amendment 6) - TREATMENT 
ARM A (30 MG/M2 DOXIL ADMINISTERED AS AN IV INFUSION OVER 
APPROXIMATELY 90 MINUTES FOLLOWED BY 1.1 MG/M2 TRABECTEDIN 
ADMINISTERED AS AN IV INFUSION OVER APPROXIMATELY 3 HOURS EVERY 3 
WEEKS)............................................................................................................................................. 27
TIME AND EVENTS SCHEDULE (No Longer Applicable After Amendment 6) - TREATMENT 
ARM B (50 MG/M2 DOXIL ADMINISTERED AS AN IV INFUSION OVER 
APPROXIMATELY 90 MINUTES EVERY 4 WEEKS)...................................................................... 31
TIME AND EVENTS SCHEDULE – AMENDMENT 6................................................................................ 35
ABBREVIATIONS ...................................................................................................................................... 36
1.
INTRODUCTION................................................................................................................................ 38
1.1.
Trabectedin .................................................................................................................................... 39
1.1.1.
Human Pharmacokinetics of Trabectedin................................................................................... 39
1.1.2.
Metabolism of Trabectedin ......................................................................................................... 39
1.2.
Combination Therapy - Trabectedin + DOXIL ............................................................................... 40
1.2.1.
Pivotal Efficacy Study ................................................................................................................. 40
1.2.2.
Pivotal Safety Study.................................................................................................................... 42
1.3.
Comparator DOXIL ........................................................................................................................ 43
1.4.
Overall Rationale for the Study...................................................................................................... 43
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 44
2.1.
Objectives ...................................................................................................................................... 44
2.2.
Hypothesis ..................................................................................................................................... 45
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 45
3.1.
Overview of Study Design.............................................................................................................. 45
3.2.
Study Design Rationale.................................................................................................................. 49
4.
SUBJECT POPULATION.................................................................................................................. 50
4.1.
Inclusion Criteria ............................................................................................................................ 50
4.2.
Exclusion Criteria ........................................................................................................................... 52
4.3.
Prohibitions and Restrictions ......................................................................................................... 54
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 54
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 55
6.1.
Criteria for Continuation of Treatment............................................................................................ 56
6.2.
Dose Modification........................................................................................................................... 57
6.2.1.
Dose Reductions Due to Hematologic Toxicity ....................................................................... 58
6.2.2.
Dose Reductions Due to Nonhematologic Toxicity ................................................................. 58
7.
TREATMENT COMPLIANCE............................................................................................................ 59
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
3
Approved, 9 January 2018
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 60
9.
STUDY EVALUATIONS .................................................................................................................... 61
9.1.
Study Procedures........................................................................................................................... 61
9.1.1.
Overview..................................................................................................................................... 61
9.1.2.
Screening Phase ........................................................................................................................ 62
9.1.3.
Open-Label Treatment Phase .................................................................................................... 63
9.1.3.1.
Clinical Laboratory Tests......................................................................................................... 64
9.1.3.2.
Cardiovascular Safety ............................................................................................................. 64
9.1.3.3.
Physical Examination .............................................................................................................. 65
9.1.3.4.
Tumor Assessment.................................................................................................................. 65
9.1.3.5.
Patient Reported Outcomes Assessments.............................................................................. 66
9.1.3.6.
Other Assessments ................................................................................................................. 66
9.1.4.
Posttreatment Phase (Follow-Up) .............................................................................................. 66
9.2.
Efficacy........................................................................................................................................... 67
9.2.1.
Evaluations ................................................................................................................................. 67
9.2.2.
Endpoints.................................................................................................................................... 68
9.3.
Pharmacokinetics........................................................................................................................... 68
9.3.1.
Evaluations ................................................................................................................................. 68
9.3.2.
Analytical Procedures................................................................................................................. 69
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 69
9.4.
Pharmacogenomic Evaluations ..................................................................................................... 69
9.4.1.
Mandatory BRCA 1 and BRCA 2 Mutation Analysis .................................................................. 69
9.4.2.
Optional Pharmacogenomic Analyses........................................................................................ 69
9.5.
Safety Evaluations ......................................................................................................................... 70
9.6.
Sample Collection and Handling.................................................................................................... 72
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 72
10.1.
Completion ..................................................................................................................................... 72
10.2.
Discontinuation of Treatment ......................................................................................................... 73
10.3.
Withdrawal From the Study............................................................................................................ 73
11.
STATISTICAL METHODS................................................................................................................. 74
11.1.
Subject Information ........................................................................................................................ 74
11.2.
Sample Size Determination ........................................................................................................... 74
11.3.
Efficacy Analyses ........................................................................................................................... 75
11.4.
Pharmacokinetic Analyses............................................................................................................. 76
11.5.
Patient Reported Outcomes........................................................................................................... 77
11.6.
Pharmacogenomic Analyses ......................................................................................................... 77
11.7.
Safety Analyses ............................................................................................................................. 77
11.8.
Interim Analysis.............................................................................................................................. 78
11.9.
Independent Data Monitoring Committee ...................................................................................... 78
12.
ADVERSE EVENT REPORTING ...................................................................................................... 79
12.1.
Definitions ...................................................................................................................................... 79
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 79
12.1.2.
Attribution Definitions.................................................................................................................. 80
12.2.
Special Reporting Situations.......................................................................................................... 81
12.3.
Procedures..................................................................................................................................... 81
12.3.1.
All Adverse Events...................................................................................................................... 81
12.3.2.
Serious Adverse Events ............................................................................................................. 82
12.3.3.
Pregnancy................................................................................................................................... 83
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 84
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 84
13.1.
Procedures..................................................................................................................................... 84
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 84
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
4
Approved, 9 January 2018
14.
STUDY DRUG INFORMATION......................................................................................................... 84
14.1.
Physical Description of Study Drug(s) ........................................................................................... 84
14.2.
Packaging ...................................................................................................................................... 85
14.3.
Labeling.......................................................................................................................................... 85
14.4.
Preparation, Handling, and Storage............................................................................................... 85
14.5.
Drug Accountability ........................................................................................................................ 86
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 87
16.
ETHICAL ASPECTS ......................................................................................................................... 87
16.1.
Study-Specific Design Considerations........................................................................................... 87
16.2.
Regulatory Ethics Compliance....................................................................................................... 89
16.2.1.
Investigator Responsibilities ....................................................................................................... 89
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 89
16.2.3.
Informed Consent ....................................................................................................................... 91
16.2.4.
Privacy of Personal Data ............................................................................................................ 92
16.2.5.
Long-Term Storage of Samples for Future Research ................................................................ 92
16.2.6.
Country Selection ....................................................................................................................... 93
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 93
17.1.
Protocol Amendments.................................................................................................................... 93
17.2.
Regulatory Documentation ............................................................................................................ 93
17.2.1.
Regulatory Approval/Notification ................................................................................................ 93
17.2.2.
Required Prestudy Documentation............................................................................................. 94
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 94
17.4.
Source Documentation................................................................................................................... 95
17.5.
Case Report Form Completion ...................................................................................................... 95
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 96
17.7.
Record Retention ........................................................................................................................... 96
17.8.
Monitoring ...................................................................................................................................... 97
17.9.
Study Completion/Termination....................................................................................................... 97
17.9.1.
Study Completion ....................................................................................................................... 97
17.9.2.
Study Termination....................................................................................................................... 97
17.10.
On-Site Audits ................................................................................................................................ 98
17.11.
Use of Information and Publication................................................................................................ 98
REFERENCES.......................................................................................................................................... 100
INVESTIGATOR AGREEMENT ............................................................................................................... 118
LIST OF ATTACHMENTS
Attachment 1:
Evaluation of Response According to CA-125 (GCIG Criteria)................................ 102
Attachment 2:
RECIST Guidelines .................................................................................................. 103
Attachment 3:
EORTC QLQ – OV28 ............................................................................................... 110
Attachment 4:
EQ–5D-5L Health Questionnaire.............................................................................. 112
Attachment 5:
New York Heart Association Classification .............................................................. 115
Attachment 6:
Cockcroft-Gault Method............................................................................................ 116
Attachment 7:
Study Procedures as Outlined in Amendment 6 ...................................................... 117
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
5
Approved, 9 January 2018
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Criteria for Continuation of Treatment ...................................................................................... 57
Table 2:
Dose Level Reductions – Trabectedin + DOXIL Group............................................................ 58
Table 3:
Dose Level Reductions – DOXIL Group................................................................................... 58
Table 4:
Dose Reductions for Hematologic Toxicity............................................................................... 58
Table 5:
Dose Reductions for Nonhematologic Toxicity......................................................................... 59
Table 6:
Statistical Operating Characteristics......................................................................................... 78
FIGURES
Figure 1:
Kaplan-Meier Plot of Progression-Free Survival ...................................................................... 40
Figure 2:
Kaplan-Meier Plot of Overall Survival....................................................................................... 41
Figure 3:
Overall Survival by Platinum-Free Interval ............................................................................... 42
Figure 4:
Study Design............................................................................................................................. 48
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
6
Approved, 9 January 2018
PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
19 December 2012
Amendment INT-1
25 March 2013
Amendment INT-2
29 August 2013
Amendment INT-3
26 August 2015
Amendment INT-4
17 December 2015
Amendment INT-5
18 March 2016
Amendment 6
9 January 2018
Amendments are listed beginning with the most recent amendment.
Amendment 6 (9 January 2018)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The sponsor’s decision to amend the study protocol was based on the 
Independent Data Monitoring Committee (IDMC) recommendation to discontinue the study based on the results of 
a futility analysis of overall survival (OS), in which the prespecified futility threshold was crossed. In addition, the 
amendment will allow study subjects deriving clinical benefit to continue on single-agent DOXIL® per local 
standard of care.
Applicable Section(s)
Description of Change(s)
Rationale: Study conduct was changed due to the IDMC recommendation to discontinue the study.
Synopsis; Section 3.1, 
Overview of Study 
Design; Section 6, 
Dosage and 
Administration; 
Section 9, Study 
Evaluations; Section 
9.1.3, Open-Label 
Treatment Phase; 
Section 9.1.4, 
Posttreatment Phase 
(Follow-up); Section 
9.5, Safety 
Evaluations; Section 
10.1, Completion; 
Section 10.2, 
Discontinuation of 
Treatment; Section 
11.9, Independent 
Data Monitoring 
Committee; Section 
14, Study Drug 
Information; Section 
16.1, Study-Specific 
Design 
Considerations; 
Attachment 7
Text was added in full or in part to reflect the following: On 26 June 2017, the IDMC 
requested a futility analysis of OS to be performed at the time of the next meeting 
6 months later. Following the review of the study data by the IDMC on 15 December 
2017, the HR for OS was 0.962, crossing the previously agreed upon threshold for futility 
of 0.93. In view of this result and the observed and expected higher toxicity in Arm A as 
compared with Arm B, the IDMC recommended discontinuing the study. Therefore, as of 
Amendment 6, no new subjects will be randomized to study treatment, and treatment with 
trabectedin should be immediately discontinued for subjects assigned to Arm A 
(trabectedin+DOXIL). All study subjects (Arm A or Arm B) currently on study who, in the 
opinion of the investigator, are deriving clinical benefit may continue treatment with 
single-agent DOXIL as per the local standard of care. Treatment for these subjects may 
continue as long as the subjects comply with protocol-specified prohibitions and 
restrictions for treatment and as long as they experience clinical benefit in the opinion of 
the investigator. DOXIL will be provided by JR&D as needed until post-trial access to 
DOXIL is available or until disease progression, whichever occurs first.
Accordingly, the end of study data collection is defined as when all subjects on study 
treatment have completed treatment termination visit assessments as specified in the Time 
and Events Schedule for Amendment 6 or by 18 January 2018, whichever occurs first. For 
subjects continuing treatment with single-agent DOXIL, as per the local standard of care, 
only serious adverse events should be reported to JR&D.
All subjects still on study treatment should be informed of the reasons for the 
discontinuation of the study, and the potential risks and benefits of continued treatment 
with single-agent DOXIL should be discussed.
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
7
Approved, 9 January 2018
Applicable Section(s)
Description of Change(s)
Rationale: To indicate that subjects in screening will not be randomized to study treatment and that no new subjects 
will be screened.
Section 3.2, Study 
Design Rationale; 
Section 4, Subject 
Population; Section 5, 
Treatment Allocation 
and Blinding; 
Attachment 7
Text was added in full or in part to reflect the following: Following Amendment 6, 
subjects will not be randomized to study treatment, and no new subjects will be screened. 
Subjects currently in screening are be eligible to receive treatment with single-agent 
DOXIL, if the investigator confirms that such treatment would be a clinically appropriate 
therapeutic option.
Rationale: To indicate that subjects in screening who are eligible to receive treatment with single-agent DOXIL 
should meet study inclusion and exclusion criteria as specified in Amendment 6.
Section 4, Subject 
Population; Section 
4.1, Inclusion 
Criteria; Section 4.2, 
Exclusion Criteria, 
Attachment 7
Text was added to indicate that: Following Amendment 6, in those instances where the 
investigator confirms that single-agent treatment with DOXIL would be a clinically 
appropriate therapeutic option for subjects currently in screening, those subjects in 
screening would need to meet study inclusion and exclusion criteria as specified in 
Sections 4.1 and 4.2.
In addition, inclusion criteria #7 and #9 and exclusion criteria #3 and #5 no longer apply 
for these subjects per Amendment 6 for the following reasons: efficacy will not be 
monitored for subjects receiving single-agent DOXIL after Amendment 6, IV 
administration of dexamethasone is only applicable for subjects receiving trabectedin and 
trabectedin treatment ends with Amendment 6, central venous catheter access is only 
needed for trabectedin administration (no longer applicable), hypersensitivity to 
trabectedin and it’s excipients is no longer applicable.. 
Rationale: Text was added regarding the reporting of serious adverse events. 
Synopsis; Section 3.1, 
Overall Study Design; 
Section 9.5, Safety 
Evaluations; Section 
10.1, Completion; 
Section 12, Adverse 
Event Reporting; 
Section 12.3.2, 
Serious Adverse 
Events; Attachment 7
Text was added to indicate that: Following the IDMC recommendation to stop the study
(clinical cutoff date of 18 January 2018), only serious adverse events for subjects 
continuing to receive single-agent DOXIL should be reported to JR&D. Text was also 
added, where appropriate, to indicate when the reporting of serious adverse events for 
subjects receiving single-agent DOXIL would end.
Rationale: To provide a Time and Events Schedule for study procedures following Amendment 6.
Time and Events 
Schedule –
Amendment 6
All study procedures at the time of Amendment 6 are summarized in Time and Events 
Schedule. A summary of study conduct in text format is provided in Attachment 7.
Rationale: To indicate that concomitant therapies and monitoring of overall survival will end at the clinical cutoff 
date (18 January 2018).
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
8
Approved, 9 January 2018
Applicable Section(s)
Description of Change(s)
Synopsis; Section 3.1, 
Overview of Study 
Design; Section 8, 
Prestudy and 
Concomitant 
Therapy; Section 
9.1.4, Posttreatment 
Phase (Follow-up); 
Section 9.2.1, 
Evaluations; Section 
11.3, Efficacy 
Analyses
Text was updated to indicated that the collection of survival status will continue until at 
least 514 deaths have been observed or until the clinical data cutoff date. In addition, 
concomitant therapies must be recorded throughout the study beginning from the time the 
ICF is signed to 30 days after the last dose of study drug or until 18 January 2018, 
whichever occurs first.
Rationale: To provide data collection guidance regarding adverse event reporting and special reporting situations.
Section 12.2, Special 
Reporting Situations; 
Section 12.3.1, All 
Adverse Events
Updated text was provided to indicate that adverse events and special reporting situations, 
will be reported up to the clinical cutoff date of 18 January 2018.
Rationale: To indicate that follow-up data collection will end with Amendment 6.
Synopsis; Section 
9.1.4, Posttreatment 
Phase (Follow-up); 
Section 12.3.1, All 
Adverse Events
Text was added to indicate that follow-up data will no longer be collected. Text regarding 
follow-up for significant declines in LVEF was deleted.
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment INT-5 (18 March 2016)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.
The overall reason for the amendment: The overall reason for the amendment is to add text regarding the 
monitoring and recording of significant declines in left ventricular ejection fraction.
Applicable Section(s)
Description of Change(s)
Rationale: To clarify the timing of LVEF assessments for subjects experiencing a significant decline in LVEF that 
has not resolved by the end of treatment.
Synopsis, Safety 
Evaluations; Time 
and Events 
Schedules; Section 
9.1.4, Posttreatment 
Phase (Follow-up); 
Section 12.3.1, All 
Adverse Events
The following text was added: Subjects experiencing significant LVEF decline (defined as 
absolute decrease ≥15%, or less than LLN and absolute decrease ≥5%) not recovered to 
less than Grade 2 (or baseline) by the end of treatment should have follow up assessments 
of LVEF every 2 months until recovered or up to 6 months after discontinuation of study 
treatment (whichever occurs first).
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
9
Approved, 9 January 2018
Applicable Section(s)
Description of Change(s)
Rationale: To clarify the dose reduction guidelines to be followed if DOXIL is discontinued due to cardiac toxicity.
Section 6.2.2, Dose 
Reduction Due to 
Nonhematologic 
Toxicity
The following text was added: If DOXIL is discontinued due to cardiac toxicity, then refer 
to Table 5 for treatment guidelines for trabectedin monotherapy. 
Rationale: To clarify the reporting of significant decreases in LVEF.
Section 6.2.2, Dose 
Reduction Due to 
Nonhematologic 
Toxicity
The following text was added: Any significant decrease in LVEF (defined as absolute 
decrease ≥15%, or less than LLN and absolute decrease ≥5%) should be captured as an 
adverse event regardless of assessed clinical significance or action taken. The 
supplemental cardiac adverse events form should also be completed for these adverse 
events.
Rationale: To clarify that subsequent LVEF assessments may be required during the follow-up period.
Section 9.5, Safety 
Evaluations
The following text was added: Subsequent LVEF assessments may be indicated during the 
follow-up period if significant LVEF decline is noted (Section 9.1.4) at the time of end of 
treatment.
Rationale: To clarify the reporting of LVEF assessments conducted during the follow-up period.
Section 12.3.1, All 
Adverse Events
The following text was added: These assessments of LVEF are to be reported in the eCRF.
Rationale: To clarify the reporting of data for subjects who discontinue study drug due to cardiotoxicity or 
significant decreases in LVEF.
Section 12.3.1, All 
Adverse Events
The following text was added: For study subjects who discontinue a study drug for 
cardiotoxicity or who have a significant decrease in LVEF, all cardiac adverse events and 
relevant concomitant therapies must be recorded until the events resolve or for 6 months 
after the last dose of study drug (whichever occurs first). Any significant decrease in 
LVEF should be captured as an adverse event regardless of assessed clinical significance 
or action taken. The supplemental cardiac adverse events form should also be completed 
for these adverse events.
Rationale: To clarify the no change in dose is required for the first occurrence of an LVEF decline ≥10% and 
<LLN or clinical evidence of cardiomyopathy.
Table 5
Text was added indicating no change in dose is required for the first occurrence of an 
LVEF decline ≥10% and <LLN or clinical evidence of cardiomyopathy.
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment INT-4 (17 December 2015)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.
The overall reason for the amendment: The overall reason for the amendment is to add additional left ventricular 
ejection fraction evaluations.
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
10
Approved, 9 January 2018
Applicable Section(s)
Description of Change(s)
Rationale: To add the United States regulatory approval of trabectedin.
Synopsis; Section 1, 
Introduction
The approved United States indication was added.
Rationale: To include 2-dimensional echocardiograms as an evaluation choice regardless of the availability of 
multigated acquisition scans.
Synopsis, Overview 
of Study Design and 
Safety Evaluations; 
Time and Events 
Schedule; Section 3.1 
Overview of Study 
Design; Section 9.1.2, 
Screening Phase; 
Section 9.1.3.2, 
Cardiovascular 
Safety; Section 9.5, 
Safety Evaluations; 
Section 11.7, Safety 
Analyses
The protocol was changed to reflect that either MUGA scans or 2D-ECHOs can be used 
for LVEF assessments; with the understanding that the same imaging technique should be 
used consistently throughout the study. 
Rationale: To include the final cardiac analysis and report.
Section 3.1, Overview 
of Study Design; 
Section 11.7, Safety 
Analyses
Text was added to indicate that a final cardiac analysis will be conducted and a report will 
be provided.
Rationale: To add additional LVEF assessments.
Synopsis, Safety 
Evaluations; Time 
and Events Schedule; 
Section 9.1.3.2, 
Cardiovascular 
Safety; Section 9.5, 
Safety Evaluations
Additional assessments of LVEF were added to reflect the following complete LVEF 
assessment schedule:
Left ventricular ejection fraction assessments (MUGA scans or 2D-ECHOs) will be 
performed for all subjects at screening (baseline), after an approximately 100 mg/m2 
cumulative dose of planned anthracycline treatment with DOXIL (ie, after Cycle 3 for 
treatment Arm A and after Cycle 2 for treatment Arm B) and as part of end-of-treatment 
assessments (ie, end-of-treatment termination visit). In addition, those subjects who 
receive a total cumulative dose of anthracycline exceeding 300 mg/m2 (including previous 
and on-study treatments) or have a clinically significant history of cardiomyopathy should 
have follow-up LVEF assessments after every 2 cycles of therapy, or as clinically 
warranted. The same methodology (MUGA scans or 2D-ECHOs) should be used to assess
scheduled LVEF assessments throughout the study. Additional LVEF assessments 
performed during the study should be reported as unscheduled LVEF assessments.
Rationale: To specify that waivers to inclusion and exclusion criteria are not allowed.
Section 4, Subject 
Population
Text was added to indicate that any questions regarding the inclusion/exclusion criteria 
should be resolved before enrolling a subject, and to indicate that waivers to the 
inclusion/exclusion criteria are not allowed.
Rationale: To reiterate that the use of prophylactic granulocyte-colony stimulating factor is strongly recommended.
Section 6, Dosage and 
Administration; 
Section 6.2.1, Dose 
Reductions Due to 
Hematologic Toxicity
Text was added noting that the use of prophylactic granulocyte-colony stimulating factor is 
strongly recommended for subjects randomized to treatment Arm A.
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
11
Approved, 9 January 2018
Applicable Section(s)
Description of Change(s)
Rationale: To add the LVEF assessment to the list of criteria to be met for continuation of treatment (as noted in 
Table 1) and to update the corresponding text regarding this criterion.
Section 6.1, Criteria 
for Continuation of 
Treatment
Table 1 was updated to reflect that the most recent LVEF assessment must be ≥ the lower 
limit of normal [LLN] for treatment to continue. In addition, the following corresponding 
text regarding continuation of treatment based on the LVEF assessment was updated: 
Subjects must discontinue DOXIL for clinical evidence of cardiac toxicity or if the LVEF 
is compromised (ie, any absolute decrease in LVEF ≥10% and an LVEF value below the 
institutional lower limit of normal [LLN]). However, dosing with trabectedin should 
continue if the criteria for continuation of treatment are met (Table 1) at the same dose. For 
those subjects on treatment Arm A who continue with trabectedin as a monotherapy after a 
cumulative anthracycline dose of 300 mg/m2 has been exceeded or due to cardiotoxicity, 
regular monitoring of LVEF every 2 cycles of treatment should continue, regardless of the 
cumulative dose of anthracycline. All subjects in Arm A should undergo LVEF 
assessments after Cycle 3 of study treatment, even if DOXIL has been discontinued.
Rationale: To add parameters for dose reductions in cases of LVEF decline or cardiomyopathy.
Section 6.2.2, Dose 
Reductions Due to 
Nonhematologic 
Toxicity
Table 5 was updated to reflect dose reductions at first and subsequent occurrences of 
LVEF decline ≥10% and <LLN or clinical evidence of cardiomyopathy.
Rationale: To add text indicating the follow-up procedures to potential cases of cardiac toxicity and the 
documentation required.
Section 9.5, Safety 
Evaluations
The following text was added:
In selected cases of cardiac adverse events, investigators may be asked to complete a 
supplemental CRF section in order to provide more detailed information relating to the 
event. Any additional LVEF assessments should be reported as unscheduled assessments.
Rationale: Text added for clarification regarding local requirements.
Section 16.2.2, 
Independent Ethics 
Committee or 
Institutional Review 
Board
Text was changed from: “This study will be undertaken only after the IEC/IRB has given 
full approval of the final protocol, amendments (if any, excluding the ones that are purely 
administrative, with no consequences for subjects, data, or study conduct)…” to “This 
study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data, or study conduct, unless required locally)…”.
Rationale: For clarity, minor wording changes were made regarding the contact information page.
Section 17.1, Protocol 
Amendments
Minor wording changes were made to clarify that the Contact Information page will be 
provided as a separate document. 
Rationale: For clarity, minor wording changes were made regarding source documentation.
Section 17.4, Source 
Documentation
The following text was moved from the beginning of the 3rd paragraph to the beginning of 
the first paragraph: “At a minimum, source documents consistent in the type and level of 
detail with that commonly recorded at the study site as a basis for standard medical care.”
Rationale: To add text regarding the verification of inclusion/exclusion criteria.
Section 17.4, Source 
Documentation
The following text was added: “Inclusion and exclusion criteria not requiring documented 
medical history must be verified at a minimum by subject interview or other protocol 
required assessments (eg, physical examination, laboratory assessment) and documented in 
the source documents.”
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
12
Approved, 9 January 2018
Applicable Section(s)
Description of Change(s)
Rationale: To ensure the recording and accuracy of data in the CRF.
Section 17.5, Case 
Report Form 
Completion
The following text was added:
“All CRF entries, corrections, and alterations must be made by the investigator or 
authorized study-site personnel. The investigator must verify that all data entries in the 
CRF are accurate and correct.”
Rationale: To update the method for correcting the CRF.
Section 17.5, Case 
Report Form 
Completion
The method for correcting the CRF was updated to the following: “If corrections to a CRF 
are needed after the initial entry into the CRF, this can be done in either of the following 
ways:
•
Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).
•
Sponsor or sponsor delegate can generate a query for resolution by the investigator and 
study-site personnel.”
Rationale: For clarity, minor wording changes were made to ensure: 1) the sponsor review of the CRFs after 
transmission to the sponsor and 2) verification for accuracy and consistency with data sources after the upload of the 
data into the study database.
Section 17.6, Data 
Quality 
Assurance/Quality 
Control
The wording was revised to: “The sponsor will review CRFs for accuracy and 
completeness during on-site monitoring visits and after transmission to the sponsor; any 
discrepancies will be resolved with the investigator or designee, as appropriate. After the 
upload of the data into the study database, they will be verified for accuracy and 
consistency with the data sources.”
Rationale: For clarity, additional examples of source documents were specified.
Section 17.8, 
Monitoring
The following examples were provided as source documents: hospital/clinic/physician’s 
office medical records.
Rationale: Minor editorial changes were made.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made. 
The terms multiple gated acquisition scan and multi gated acquisition scan were corrected 
to multigated acquisition scan. The MedDRA version number was deleted.
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
13
Approved, 9 January 2018
Amendment INT-3 (26 August 2015)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.
The overall reason for the amendment: The overall reason for the amendment is to add to and revise study 
inclusion and exclusion criteria to allow greater flexibility in demonstrating eligibility based on response to previous 
therapy.
Applicable Section(s)
Description of Change(s)
Rationale: To clarify that study treatment will continue until 2 cycles after assessment of a complete response.
Synopsis, Overview of 
Study Design; Section 
3.1, Overview of Study 
Design
The following statement was changed from “Treatment will continue until the 
occurrence of disease progression or unacceptable treatment toxicity, or until 2 cycles
beyond a confirmed complete response” to “Treatment will continue until the occurrence 
of disease progression or unacceptable treatment toxicity, or until 2 cycles after 
assessment of a complete response (CR).”
Rationale: To clarify that disease progression is to be radiographically confirmed.
Synopsis, Overview of 
Study Design, Efficacy 
Evaluations/Endpoints; 
Time and Events
Schedule footnotes; 
Section 3.1, Overview 
of Study Design, Figure 
4; Section 9.1.3.1, 
Clinical Laboratory 
Tests; Section 9.1.3.4, 
Tumor Assessment; 
Section 9.1.4, 
Posttreatment Phase
(Follow-up); Section 
9.2.1, Evaluations
Specified that disease progression is to be confirmed radiographically.
Rationale: To clarify that documentation of all subsequent anticancer therapy, survival status, and safety 
evaluations are required for all subjects discontinuing study treatment and not just those subjects with disease 
progression at the time of treatment discontinuation.
Synopsis, Overview of 
Study Design; Section 
3.1, Overview of Study 
Design; Section 9.1.4, 
Posttreatment Phase 
(Follow-up)
The following statement was changed from “For subjects with disease progression at the 
time of treatment discontinuation, documentation of all subsequent anticancer therapy, 
survival status, and safety evaluations as outlined in the Time and Events Schedule will 
be required.” to “For subjects discontinuing study treatment, documentation of all 
subsequent anticancer therapy, survival status, and safety evaluations as outlined in the 
Time and Events Schedule will be required.” Related text/statements were also changed.
Rationale: Inclusion criterion #5 was changed to specify serum CA-125 levels.
Synopsis, Subject 
Population; Section 4.1, 
Inclusion Criteria
Inclusion criterion #5 was changed to specify that a subject was to have received second-
line treatment with a platinum-based regimen, with progression of disease after attaining 
a response. A response could have been determined by imaging or by serum CA-125 
levels. Reference to the Gynecologic Cancer Intergroup outline was deleted.
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
14
Approved, 9 January 2018
Applicable Section(s)
Description of Change(s)
Rationale: For clarity, editorial changes were made to inclusion criterion #11 regarding subjects receiving 
recombinant erythropoietin therapy.
Section 4.1, Inclusion 
Criteria
Inclusion criterion #11 was changed to reflect that subjects may be enrolled into the 
study while receiving recombinant erythropoietin provided that they have received 
recombinant erythropoietin for at least 4 weeks before the first dose of study drug.
Rationale: Inclusion criterion #18 was changed to define postmenopausal and surgical sterility, to indicate that male 
and female condoms should not be used together, and to note that if childbearing potential changes after the start of 
the study, 2 effective methods of birth control must be used.
Section 4.1, Inclusion 
Criteria
Inclusion criterion #18 was revised to “Be postmenopausal (>45 years of age with 
amenorrhea for at least 2 years or any age with amenorrhea for at least 6 months and a 
serum follicle stimulating hormone level >40 IU/L or mIU/mL), surgically sterile (have 
had a hysterectomy or bilateral oophorectomy, bilateral salpingectomy, bilateral tubal 
occlusion ligation [which includes tubal ligation procedures as consistent with local 
regulations], or otherwise be incapable of pregnancy), abstinent (acceptability of this 
method is at the discretion of the investigator who will ensure and document that the 
subject understands the definition of "abstinence", and who will periodically remind and 
counsel the subject on this topic), or if heterosexually active, be practicing two effective 
methods of birth control (eg, prescription hormonal contraceptive, intrauterine device, 
double-barrier method [eg, condoms, occlusive cap (diaphragm or cervical/vault caps) 
with spermicidal foam, cream, gel, film, or suppository]), before enrollment, and must 
agree to continue to use the same two methods of contraception throughout the study and 
for 6 months thereafter. Note: a female condom and a male condom should not be used
together as friction between the two can result in either product failing.
Note: If the childbearing potential changes after the start of the study (eg, woman who is 
not heterosexually active becomes active), then the woman must begin two effective 
methods of birth control, as described above”.
Rationale: To include inclusion criterion #22.
Section 4.1, Inclusion 
Criteria
Inclusion criterion #22 was added and states: Each subject “must agree not to donate 
eggs (ova, oocytes) for the purposes of assisted reproduction”.
Rationale: Exclusion criterion #2 was changed to clarify the number and type of prior lines of therapy.
Synopsis, Subject 
Population; Section 4.2 
Exclusion Criteria
Exclusion criterion #2 was changed from: “A subject who had more than 2 prior lines of 
chemotherapy” to “A subject who had more than 2 prior lines of systemic therapy. 
Maintenance therapies and hormonal therapies are not considered additional lines of 
therapy.” Related text/statements were also changed.
Rationale: Exclusion criterion #7 was revised to clearly state the time period between study treatment and other 
specified therapies.
Section 4.2, Exclusion 
Criteria
Exclusion criterion #7 was changed from “A subject who is less than 3 weeks from 
radiation therapy, experimental therapy, hormonal therapy, prior chemotherapy, or 
biological therapy” to “A subject who would receive study treatment within 3 weeks 
from radiation therapy, experimental therapy, hormonal therapy, prior chemotherapy, or 
biological therapy; use an invasive investigational device; or is currently enrolled in an 
investigational study”.
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
15
Approved, 9 January 2018
Applicable Section(s)
Description of Change(s)
Rationale: To change neoplastic disease to invasive malignancy in exclusion criterion #8.
Section 4.2, Exclusion 
Criteria
Exclusion criterion #8 was changed from “A subject who has a history of another 
neoplastic disease (except non-metastatic basal cell carcinoma or squamous cell 
carcinoma of the skin or cervical carcinoma in situ adequately treated) unless in 
remission for 5 years” to “A subject who has a history of another invasive malignancy 
(except non-metastatic basal cell carcinoma or squamous cell carcinoma of the skin 
adequately treated) unless in remission for ≥5 years, or a non-invasive malignancy 
requiring ongoing therapy”.
Rationale: To clarify the dosing administration for Treatment Arm A and Treatment Arm B and to add approximate 
durations of infusions.
Synopsis, Dosage and 
Administration; Time 
and Events Schedule; 
Section 3.1, Overview 
of Study Design Figure 
4; Section 6, Dosage 
and Administration
Changes were made to the dosing administration of DOXIL and trabectedin.  The revised 
text reflects the following:
Treatment Arm A: DOXIL 30 mg/m2 administered as an IV infusion over 
approximately 90 minutes (per package insert) followed by trabectedin 
1.1 mg/m2, administered as an IV infusion over approximately 3 h, via central 
venous access, every 3 weeks. If no infusion-related reaction is observed with 
DOXIL after the first infusion, DOXIL may be administered as a 60- to 90-
minute infusion in subsequent cycles.
Treatment Arm B: DOXIL, 50 mg/m2 administered as an IV infusion over 
approximately 90 minutes (per package insert) every 4 weeks. If no infusion-
related reaction is observed with DOXIL after the first infusion, DOXIL may be 
administered as a 60- to 90-minute infusion in subsequent cycles.
Rationale: To add text indicating that investigators should review adverse events before each dose of study drug.
Synopsis, Dosage and 
Administration
The terms “adverse events” were added to the following sentence and related text: 
“Investigators will review physical findings, adverse events, and the results of clinical 
laboratory tests before each dose of study drug and, if required, delay administration or 
reduce the dose according to the protocol-defined guidelines”.
Rationale: To clarify the timing of the CA-125 evaluations.
Synopsis, Efficacy 
Evaluation/Endpoints; 
Time and Events
Schedule Footnotes; 
Section 9.1.3.1, Clinical 
Laboratory Tests; 
Section 9.2.1, 
Evaluations
The text regarding CA-125 evaluations now reflects that the evaluations should coincide 
(±5 days) with the scheduled tumor assessments. The ±5 day window for the assessment 
was added for clarity.
Rationale: To clarify the timing of the clinical laboratory evaluations.
Synopsis, Safety 
Evaluations; Time and 
Events Schedule; 
Section 9.1.3.1, Clinical 
Laboratory Tests
The timing of the clinical laboratory evaluations was clarified and now reflect the 
following:
Clinical laboratory test results will be evaluated before dosing (ie, within 2 
days prior to dosing) on Day 1 of each cycle; and 
Blood samples will also be collected for clinical laboratory testing on +/- 2 
days on Days 8 and 15 (Treatment Arm A) or Days 8, 15, and 22 (Treatment 
Arm B) of each cycle and at the end of treatment. 
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
16
Approved, 9 January 2018
Applicable Section(s)
Description of Change(s)
Rationale: To add text regarding the capping of body surface area (BSA) utilized for dosing calculations.
Time and Events 
Schedule Footnotes; 
Section 6, Dosage and 
Administration
The text regarding the capping of BSA utilized for dosing calculations was added. 
Example text: For those subjects with a body mass index (BMI) ≥30, the use of ideal 
body weight for dose calculation and capping of BSA utilized for dosing calculations 
will be left to the discretion of the investigator and to institutional guidelines.
Rationale: To clarify that all subjects who discontinue study treatment will be monitored for survival.
Section 3.1, Overview 
of Study Design
The following text was changed from “Subjects who discontinue study treatment due to 
evidence of disease progression or unacceptable toxicity will be monitored for survival” 
to “All subjects who discontinue study treatment will be monitored for survival”.
Rationale: To delete text regarding alopecia from Table 1.
Section 6.1, Criteria for 
Continuation of 
Treatment, Table 1 
Footnote
The term “alopecia” was deleted from footnote “b” in Table 1.
Rationale: To clarify the dexamethasone premedication is not required if trabectedin treatment is discontinued.
Section 6.2, Dose 
Modification
The following text was added to the protocol: “If trabectedin is discontinued for a subject 
in Treatment Arm A, premedication with dexamethasone is no longer required”.
Rationale: To clarify that investigators may reduce the dose of either or both study drugs for any toxicity and 
subjects who experience toxicities that require more than 2 dose reductions of the same drug must discontinue study 
treatment with that drug.
Section 6.2, Dose 
Modification; Section 
6.2.1, Dose Reductions 
Due to Hematologic 
Toxicity; 6.2.2, Dose 
Reductions Due to 
Nonhematologic 
Toxicity
Text was added to clarify that:
Investigators may also reduce the dose of either or both study drugs for any 
toxicity as clinically warranted, and 
Only 2 dose reductions of each study drug will be allowed. Subjects who 
experience toxicities that require more than 2 dose reductions of the same drug 
must discontinue study treatment with that drug.
Rationale: To clarify the parameters for dose reductions for nonhematologic toxicity.
Section 6.2.2, Dose 
Reductions Due to 
Nonhematologic 
Toxicity, Table 5
In Table 5, the footnotes were updated, direct bilirubin was changed to bilirubin, criteria 
for a dose reduction due to alkaline phosphatase were updated, and criteria for creatine 
phosphokinase were added.
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
17
Approved, 9 January 2018
Applicable Section(s)
Description of Change(s)
Rationale: To clarify the start of the screening phase and activities to be completed during this study phase.
Section 9.1.2, Screening 
Phase
Text was revised to reflect the following: “The Screening Phase begins with the signing 
of the informed consent and should not last longer than 30 days. During the Screening 
Phase, the medical monitors will confirm subject eligibility based on previous therapy 
history, according to inclusion criteria #4 through #8 [Section 4.1, Inclusion Criteria]). 
Response to second-line platinum-based therapy will be confirmed either based on 
imaging demonstrating at least a 30% decline in tumor burden or on a 50% reduction of 
elevated baseline serum CA-125 levels (≥2 x ULN, measured within approximately 4 
weeks prior to the first dose of second-line platinum-based therapy that is maintained 
after at least 28 days as modified from Gynecologic Cancer Intergroup [GCIG] criteria 
[Attachment1]).”
In addition, the following screening procedures to be completed within 30 days before 
randomization were revised or added:
Submission of redacted source documents supporting subject eligibility relevant 
to inclusion criteria #4 through #8.
On or prior to Day 1 of Cycle 1, all subjects will be provided with a “wallet 
(study) card” and instructed to carry this card with them for the duration of the 
study.
Rationale: To clarify the timing of absolute neutrophil count (ANC) determination.
Section 9.1.3.1, Clinical 
Laboratory Texts
Text was revised to reflect that: If a subject has an ANC of <500/µL, the ANC for this 
subject should be repeated at most 5 days later to document recovery to >500/µL.
Rationale: To clarify disease assessments should be performed at the treatment termination visit.
Section 9.1.3.4, Tumor 
Assessment
Text was revised from: “disease assessments must be performed at the treatment 
termination visit…” to disease assessments should be performed at the treatment 
termination…”.
Rationale: To clarify assessment required in case of clinical progression.
Section 9.1.3.4, Tumor 
Assessment
Text was changed from: “In case of clinical or symptomatic progression, the same tumor 
assessments will be performed to document the progression. If progression is not 
confirmed at this unscheduled radiologic assessment, subsequent radiologic assessments 
should proceed according to the original Time and Events Schedule” to In case of 
clinical progression, radiologic assessments should proceed according to the original 
Time and Events Schedule, or as clinically indicated”.
Rationale: To clarify that the treatment termination visit should occur 30 days (+3 days) after the last dose of study 
drug.
Section 9.1.4, 
Posttreatment Phase 
(Follow-up)
Text was revised to state that the treatment termination visit should occur 30 days (+3 
days) after the last dose of study drug.
Rationale: Text was added regarding CA-125 use.
Section 9.2.1 
Evaluations
The following text was added: “CA-125 shall not be used as a basis to assess disease 
response or progression during study treatment and should not guide treatment 
decisions.”
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
18
Approved, 9 January 2018
Applicable Section(s)
Description of Change(s)
Rationale: To add/delete criteria for subject discontinuation from treatment.
Section 10.2, 
Discontinuation of 
Treatment
The following was deleted from the list criteria for treatment discontinuation:
The investigator believes that for safety reasons (eg, adverse event) it is in the 
best interest of the subject to stop treatment.
The following were added to or revised in the list of criteria for treatment 
discontinuation:
The subject meets protocol prescribed criteria for drug discontinuation due to 
toxicity after appropriate dose reduction (Section 6.2).
The subject develops a concurrent medical condition (adverse event) that 
precludes further participation.
The subject completes 2 cycles of treatment after assessment of CR.
Rationale: To add text regarding the reporting of suspected unexpected serious adverse reactions.
Section 12.3.1, All 
Adverse Events
The following text was added: “The sponsor will also report to the investigator (and the 
head of the investigational institute where required) all suspected unexpected serious 
adverse reactions (SUSARs). The investigator (or sponsor where required) must report 
SUSARs to the appropriate Independent Ethics Committee/Institutional Review Board 
(IEC/IRB) that approved the protocol unless otherwise required and documented by the 
IEC/IRB”.
Rationale: To add to the list of abnormal pregnancy outcomes.
Section 12.3.3, 
Pregnancy
The following were added to the list of abnormal pregnancy outcomes: fetal death and 
ectopic pregnancy.
Rationale: To add text regarding study monitoring.
Section 17.8, 
Monitoring
The following text was added:
“The sponsor will use a combination of monitoring techniques (central, remote, or on-
site monitoring) to monitor the study.”
“In addition, to on-site monitoring visits, remote contact can occur. It is expected that 
during these remote contact, study-site personnel will be available to provide an update 
on the progress of the study at the site.”
“Central monitoring will take place for data identified by the sponsor as requiring central 
review.”
Rationale: Minor editorial changes were made throughout the protocol.
Throughout the protocol
Minor editorial, grammatical, formatting, or spelling changes were made. Changes 
terminology were also made (eg, 48 h changed to 2 days; study medication changed to 
study drug)
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
19
Approved, 9 January 2018
Amendment INT-2 (29 August 2013)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The overall reasons for the amendment are to extend the use of 
contraceptives from 3 months to 6 months after the study, to increase the creatinine clearance rate from 
40 mL/min/1.73 m2 to 60 mL/min/1.73 m2, and to add a prohibition regarding subjects receiving a yellow fever 
vaccine.
Applicable Section(s)
Description of Change(s)
Rationale: Inclusion criterion 11 was modified to increase the calculated glomerular filtration rate from 
40 mL/min/1.73 m2 to 60 mL/min/1.73 m2.
Section 4.1, Inclusion 
Criteria
The following statement was changed from “either a serum creatinine 1.5 mg/dL or a 
calculated glomerular filtration rate 40 mL/min/1.73 m2 (Cockcroft-Gault)” to “either a 
serum creatinine 1.5 mg/dL or a calculated glomerular filtration rate 60 mL/min/1.73 m2
(Cockcroft-Gault)”.
Rationale: Inclusion criterion 18 was modified to extend the period of contraceptive use from 3 months after the 
study to 6 months.
Section 4.1, Inclusion 
Criteria
The following statement was changed from “must agree to continue to use the same two 
methods of contraception throughout the study and for 3 months thereafter” to “must agree 
to continue to use the same two methods of contraception throughout the study and for 
6 months thereafter”.
Rationale: To add a prohibition (#6) for yellow fever vaccination.
Section 4.3, 
Prohibitions and 
Restrictions
The following prohibition was added: “Subjects may not receive yellow fever vaccine 
during this study”.
Rationale: To clarify BRCA testing procedures when the mutation status of BRCA 1 or BRCA 2, and not both, is 
known.
Section 9.4.1, 
Mandatory BRCA 1 
and BRCA 2 
Mutation Analysis
The following phrase was deleted from the first sentence of the first paragraph in 
Section 9.4.1: “for subjects who have previously been tested for BRCA 1/2 mutations”.
The following paragraph was added to the end of Section 9.4.1: “For subjects with a 
known mutation status for either BRCA 1 or BRCA 2, but not for both genes, the result 
from the single gene tested will be captured in the CRF. If the status of the reported gene 
indicates a mutation, the status will be used for randomization. However, if the single gene 
tested indicates no mutation, then BRCA testing for the other gene is to be conducted and 
reported within 30 days prior to randomization.”
Rationale: To reflect the recent United States Food and Drug Administration approval of generic doxorubicin 
hydrochloride (HCl) liposome injection, and it’s potential to be used in the United States of America (USA) as a 
treatment for ovarian cancer.
Throughout the 
protocol
DOXIL refers to DOXIL/doxorubicin hydrochloride (HCl) liposome injection (USA 
only) and CAELYX/pegylated liposomal doxorubicin (PLD) (non-USA).
Rationale: To change the EQ-5D-3L Health Questionnaire to the current EQ-5D-5L Health Questionnaire
Attachment 4, 
EQ-5D-5L Health 
Questionnaire
The 3L questionnaire was deleted and the 5L questionnaire was added.
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
20
Approved, 9 January 2018
Applicable Section(s)
Description of Change(s)
Rationale: To simplify the Time and Events Schedule.
Time and Events 
Schedule
The randomization column was deleted.
Rationale: To change the wording regarding clinically significant abnormalities persisting during follow-up.
Time and Events 
Schedule; Section 
9.1.4, Posttreatment 
Phase (Follow-Up); 
Section 9.5, Safety 
Evaluations
Text was changed to indicate that clinically significant abnormalities persisting 30 days 
after the last dose of study drug would be followed, rather than clinically significant 
abnormalities persisting at the end of the study.
Rationale: To update the text regarding the study card.
Section 12.3.1, All 
Adverse Events
The information to be listed on the “wallet (study) card” was revised. Text instructing the 
subject to carry the “wallet (study) card” with them for the duration of the study was 
added.
Rationale: To update the title page.
Title page
Document and version number provided. Approval date changed.
Rationale: Minor edits for clarity and consistency.
Throughout the 
protocol
Minor edits were made throughout the protocol.
Amendment INT-1 (25 March 2013)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union. 
The overall reason for the amendment: The overall reason for the amendment is to revise inclusion criterion #6.
Applicable Section(s)
Description of Change(s)
Rationale: To modify the subject inclusion criterion #6 and to clearly identify the subject population.
Synopsis; Section 4.1, 
Inclusion Criteria
The stipulation that progression of disease must occur 6 months from the start of second-
line therapy was deleted from inclusion criterion #6. The bullet regarding second-line 
therapy for subjects treated with a pegylated liposomal doxorubicin was changed to 
“Subjects treated with a pegylated liposomal doxorubicin-containing regimen as a second-
line therapy are eligible if subsequent disease progression occurs 9 months from the first 
dose”.
Rationale: To add text regarding the rare incidence of secondary oral cancer after the long-term exposure to 
DOXIL.
Section 1.3, 
Comparator DOXIL 
(doxorubicin HCL)
Text was added regarding rare cases of secondary oral cancer after long-term exposure to 
DOXIL. 
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YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
21
Approved, 9 January 2018
Applicable Section(s)
Description of Change(s)
Rationale: To clarify the timing of the follow-up survival.
Synopsis; Time and 
Event Schedule; 
Section 3.1, Overview 
of Study Design; 
Section 9.1.4, 
Posttreatment Phase 
(Follow-up)
Text was modified to state: Subjects will be followed for survival at least every 8 weeks 
for the first 2 years after the treatment termination visit and approximately every 12 weeks 
thereafter.
Rationale: To specify that subjects who complete 2 cycles of treatment after confirmed CR should discontinue 
treatment. 
Synopsis, Overview 
of Study Design; 
Section 3.1, Overview 
of Study Design
Section 10.2, 
Discontinuation of 
Treatment
The following text was revised to include the condition noted in Section 10.2: “Treatment 
will continue until the occurrence of disease progression or unacceptable treatment 
toxicity, or until 2 cycles beyond a confirmed complete response (CR).”
The following condition was added: “The subject completes 2 cycles of treatment after 
confirmed CR”.
Rationale: To add pegylated liposomal doxorubicin (PLD) to the text.
Section 1.3, 
Comparator – DOXIL
(pegylated liposomal 
doxorubicin)
Pegylated liposomal doxorubicin (PLD) was added to the description of DOXIL.
Rationale: To change the blood sample collection for the optional pharmacogenomics analysis from randomization 
to Day 1 of Cycle 1.
Time and Events 
Schedule; Section 
9.1.2, Screening 
Phase
The time and events schedules were modified and the footnotes updated to indicate “The 
optional pharmacogenomics blood sample collection is scheduled for Day 1 of the first 
cycle of treatment. However, it will not be considered a protocol deviation if the blood 
sample is collected at any time following this timepoint.”
In Section 9.1.2, text regarding the optional pharmacogenomics portion of the study was
updated to note that the pharmacogenomics blood sample collection is scheduled for Day 1 
of Cycle 1.
Rationale: To update the time interval for reporting PQCs.
Section 13.1, 
Procedures
The reporting of PQCs was changed from as soon as possible to within 24 hours. 
Rationale: To update the title page.
Title page
Document and version number provided. Approval date changed.
Rationale: Minor edits.
Throughout the 
protocol
The OV28 questionnaire designation was changed to QLQ-OV28. In addition, there are 
minor edits throughout the document.
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
22
Approved, 9 January 2018
SYNOPSIS
A 
Randomized, 
Open-Label 
Study 
Comparing 
the 
Combination 
of 
YONDELIS
and 
DOXIL/CAELYXWith DOXIL/CAELYXMonotherapy for the Treatment of Advanced-Relapsed 
Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer
EudraCT NUMBER: 2012-004808-34
Trabectedin (YONDELIS) is a tris, tetrahydroisoquinoline alkaloid initially isolated from the marine 
ascidian ecteinascidin turbinate. It has a unique mechanism of action that involves the transcription-
dependent nucleotide excision repair system and is currently under development as an antineoplastic 
agent. Trabectedin has been approved in the European Union and other countries outside the United 
States of America (USA) for the treatment of soft tissue sarcoma (STS) and ovarian cancer, and it has 
been approved in the USA for the treatment of unresectable or metastatic liposarcoma or leiomyosarcoma 
in patients who received a prior anthracycline-containing regimen.
Trabectedin and DOXIL (as per protocol, DOXIL refers to DOXIL/doxorubicin hydrochloride [HCl] 
liposome injection [USA only] and CAELYX/pegylated liposomal doxorubicin [PLD] [non-USA]), 
2 agents with different mechanisms of action, have shown efficacy in treating women with advanced 
ovarian cancer. The combination of trabectedin and DOXIL has previously been demonstrated to improve 
progression-free survival (PFS), as compared with DOXIL monotherapy, in the second-line treatment of 
refractory ovarian cancer. Median overall survival (OS) was also increased by 3.3 months in the 
combined trabectedin+DOXIL treatment arm, but this result did not reach statistical significance 
(p=0.0835). Retrospective analysis suggested that the efficacy of the trabectedin+DOXIL combination 
was greatest in subjects with platinum-sensitive disease (subjects with a platinum-free interval 
6 months), and that the lack of statistical significance for OS may have resulted from an imbalance in 
prognostic factors. Thus, limiting treatment to patients with platinum-sensitive disease is expected to 
result in improved demonstrated efficacy, as well as an improved risk-benefit ratio.
Currently, there are few prospective studies that have examined the third-line treatment of patients with 
refractory epithelial ovarian cancer. Study ET743-OVC-3006 is designed to investigate the activity of 
trabectedin+DOXIL for the treatment of subjects with platinum-sensitive advanced-relapsed epithelial 
ovarian, primary peritoneal, or fallopian tube cancer who have received 2 previous lines of 
platinum-based chemotherapy.
OBJECTIVES AND HYPOTHESIS
Primary Objective
To compare the OS after treatment with trabectedin+DOXIL combination therapy to that observed after 
treatment with DOXIL monotherapy for subjects with platinum-sensitive advanced-relapsed epithelial 
ovarian, primary peritoneal, or fallopian tube cancer who have received 2 previous lines of 
platinum-based chemotherapy.
Secondary Objectives

To evaluate PFS.

To evaluate the objective response rate (ORR).

To characterize the plasma pharmacokinetics of trabectedin using a sparse sampling scheme in the 
trabectedin+DOXIL treatment group.

To evaluate the safety of the trabectedin+DOXIL combination therapy and DOXIL monotherapy.
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
23
Approved, 9 January 2018
Exploratory Objectives

To conduct pharmacogenomic evaluations of OS, PFS and other endpoints in subjects with and 
without mutations in BRCA1 or BRCA2.

To evaluate patient-reported outcomes (PROs).
Hypothesis
Trabectedin in combination with DOXIL will improve OS compared with DOXIL monotherapy in the 
treatment of subjects with platinum-sensitive advanced-relapsed epithelial ovarian, primary peritoneal, or 
fallopian tube cancer who received 2 previous lines of platinum-based chemotherapy.
OVERVIEW OF STUDY DESIGN
This is a randomized, open-label, active-controlled, multicenter study designed to assess the efficacy and 
safety of trabectedin+DOXIL as a third-line chemotherapy in subjects with platinum-sensitive 
advanced-relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer who received 
2 previous lines of platinum-based chemotherapy. Approximately 670 subjects will be enrolled in this 
study, with 335 subjects per planned treatment group.
During the Screening Phase, potential subjects will be assessed for study eligibility after providing 
informed consent to participate in the study. Baseline radiographic disease assessments must be 
performed within 30 days before randomization. 
At randomization, subjects will be stratified by 4 criteria: 1) the time from the last dose of first-line 
platinum therapy to disease progression (6 months to 12 months vs >12 months to 24 months vs 
>24 months), 2) Eastern Cooperative Oncology Group (ECOG) performance status grade (0 vs 1), 
3) BRCA 1/2 status (mutation vs no mutation), and 4) prior DOXIL therapy (no vs yes). Subjects will 
then be randomly assigned in a 1:1 ratio to the trabectedin+DOXIL combination therapy group (Arm A) 
or to the DOXIL monotherapy group (Arm B).
During the Treatment Phase, subjects will receive study drug by IV infusion on Day 1 of a 21-day cycle 
in Arm A and on Day 1 of a 28-day cycle in Arm B. Treatment will continue until the occurrence of 
disease progression or unacceptable treatment toxicity, or until 2 cycles after assessment of a complete 
response (CR). Subjects assigned to the trabectedin+DOXIL group (Arm A) will be pretreated with 
20 mg of IV dexamethasone (or an equivalent IV corticosteroid) approximately 30 minutes prior to 
initiation of infusion of DOXIL IV, on Day 1 of each treatment cycle. Treatment efficacy endpoints will 
be evaluated using Response Evaluation Criteria in Solid Tumors (RECIST, Version 1.1). Scheduled 
assessments of disease status will be performed within 30 days before randomization, every 8 weeks 
(5 days) after randomization for the first 4 assessments, and then every 12 weeks (5 days) thereafter. 
Disease assessments, including assessments for subjects who discontinue treatment for reasons other than 
disease progression, will be performed until disease progression is radiographically confirmed, the start of 
subsequent anticancer therapy, withdrawal of subject consent, or the clinical cutoff date. For subjects
discontinuing study treatment, documentation of all subsequent anticancer therapy, survival status, and 
safety evaluations as outlined in the Time and Events Schedule will be required. Survival status follow-up 
should be done at least every 8 weeks for the first 2 years after the treatment termination visit and 
approximately every 12 weeks thereafter. Collection of survival status will continue until at least
514 deaths have been observed or until the clinical data cutoff date. Treatment safety will be assessed 
using laboratory test results and the incidence and severity of adverse events. Left ventricular ejection 
fraction (LVEF) assessments (either multigated acquisition [MUGA]
scans or 2-dimensional 
echocardiograms [2D-ECHO]) and electrocardiograms (ECGs) will be used to monitor cardiac function.
An Independent Data Monitoring Committee (IDMC) will assess safety and efficacy data. Safety data 
will be reviewed approximately every 6 months. An interim analysis of OS will be performed after 
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YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
24
Approved, 9 January 2018
approximately 308 subjects have died. The final analysis of OS will occur when approximately 
514 deaths have been observed or until the clinical cutoff date. A study steering committee composed of 
physicians will periodically review issues related to study conduct and offer advice as needed. 
On 26 June 2017, the IDMC requested a futility analysis of OS to be performed at the time of the next 
meeting 6 months later. Following the review of the study data by the IDMC on 15 December 2017, the 
HR for OS was 0.962, crossing the previously agreed upon threshold for futility of 0.93. In view of this 
result and the observed and expected higher toxicity in Arm A as compared with Arm B, the IDMC 
recommended discontinuing the study. Therefore, as of Amendment 6, no new subjects will be 
randomized to study treatment, and treatment with trabectedin should be immediately discontinued for 
subjects assigned to Arm A (trabectedin+DOXIL). All study subjects (Arm A or Arm B) currently on 
study who, in the opinion of the investigator, are deriving clinical benefit may continue treatment with 
single-agent DOXIL as per the local standard of care. Treatment for these subjects may continue as long 
as the subjects comply with protocol-specified prohibitions and restrictions for treatment and as long as 
they experience clinical benefit in the opinion of the investigator. DOXIL will be provided by JR&D as 
needed until post-trial access to DOXIL is available or until disease progression, whichever occurs first.
Accordingly, the end of study data collection is defined as when all subjects on study treatment have 
completed treatment termination visit assessments as specified in the Time and Events Schedule for 
Amendment 6 or by 18 January 2018, whichever occurs first. For subjects continuing treatment with 
single-agent DOXIL, as per the local standard of care, only serious adverse events should be reported to 
JR&D.
SUBJECT POPULATION
Eligible women must fulfill all study inclusion and exclusion criteria. Subjects will be at least 18 years of 
age at screening, with histologically proven advanced-relapsed epithelial ovarian cancer, fallopian tube 
cancer, or primary peritoneal cancer. Subjects must have:

ECOG performance status Grade 0 or 1.

First-line treatment with a platinum-based regimen, and no evidence of disease progression for 
6 months after the last dose.

Second-line treatment with a platinum-based regimen, with progression of disease after attaining a 
CR or partial response (PR). Complete response or PR could have been determined by imaging or by 
serum CA-125 levels. 

Progression of disease based on imaging after the second-line platinum-based regimen.

Subjects treated with a DOXIL-containing regimen as a second-line therapy are eligible if 
subsequent disease progression occurs 9 months from the first dose.

No more than 2 prior lines of systemic therapy.
DOSAGE AND ADMINISTRATION
Study treatment occurs on Day 1 (+2 days) of each 21-day cycle for subjects assigned to Treatment 
Arm A and on Day 1 (+2 days) of each 28-day cycle for subjects assigned to Treatment Arm B.

Treatment Arm A: DOXIL 30 mg/m2 administered as an IV infusion over approximately 
90 minutes (per package insert) followed by trabectedin 1.1 mg/m2 administered as an IV infusion
over approximately 3h, via central venous access, every 3 weeks. Central venous access is required 
for administration of trabectedin. If no infusion-related reaction is observed with DOXIL after the 
first infusion, DOXIL may be administered as a 60- to 90-minute infusion in subsequent cycles. All 
subjects assigned to Treatment Arm A will be premedicated with 20 mg dexamethasone, 
administered IV approximately 30 minutes before the start of the DOXIL infusion, to reduce the 
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
25
Approved, 9 January 2018
incidence of transaminase elevation related to trabectedin. If dexamethasone is not available, an 
equivalent IV dose of another corticosteroid may be substituted.

Treatment Arm B: DOXIL, 50 mg/m2 administered as an IV infusion over approximately 
90 minutes (per package insert) every 4 weeks. If no infusion-related reaction is observed with 
DOXIL after the first infusion, DOXIL may be administered as a 60- to 90-minute infusion in 
subsequent cycles.
Investigators will review physical findings, adverse events, and the results of clinical laboratory tests 
before each dose of study drug and, if required, delay administration or reduce the dose according to the 
protocol-defined guidelines.
EFFICACY EVALUATIONS/ENDPOINTS
Efficacy will be assessed by a determination of OS, PFS, and ORR. Measurable disease and the response 
criteria based on measurable disease used in this protocol are defined in the RECIST (Version 1.1)
guidelines. Radiological disease assessments (thoraco-abdominal and pelvic computed tomography [CT]
scan or magnetic resonance imaging [MRI] measurements and evaluation of extent of disease) will be 
performed within 30 days before randomization, every 8 weeks (±5 days) after randomization for the first 
4 assessments, and then every 12 weeks (±5 days) thereafter. Disease assessments, including assessments 
for subjects who discontinue treatment for reasons other than disease progression, will be performed until 
disease progression is radiographically confirmed, the start of subsequent anticancer therapy, withdrawal 
of subject consent, or the clinical cutoff date.
Assessments must be done consistently in both treatment arms to ensure an unbiased assessment of tumor 
response and progression. The CA-125 analyses will be performed at a local laboratory. The initial 
CA-125 evaluation will be performed within 30 days before randomization, approximately every 8 weeks 
after randomization for the first 4 evaluations, and then approximately every 12 weeks until disease 
progression is radiographically confirmed, the start of subsequent anticancer therapy, withdrawal of 
subject consent, or the clinical cutoff date. CA-125 evaluations should coincide (5 days) with the 
scheduled tumor assessments. Survival follow-up will continue for all enrolled subjects until at least 
514 deaths are observed or until the clinical cutoff date.
As of Amendment 6, follow-up data will no longer be collected.
PHARMACOKINETIC EVALUATIONS
Sparse samples for measurement of trabectedin concentrations in plasma will be collected from at least 
40 subjects administered trabectedin+DOXIL. 
PHARMACOGENOMIC EVALUATIONS
BRCA 1/2 mutation data will be collected at screening. If BRCA 1/2 mutation status has not been 
determined, a blood sample (10 mL) will be collected for BRCA 1/2 analysis. In addition, an optional
pharmacogenomic blood sample (4 mL) will be collected from consenting subjects to allow for 
pharmacogenomic research (where local regulations permit).
SAFETY EVALUATIONS
The incidence and severity of adverse events will be assessed for all subjects who receive study drug. 
Clinical laboratory test results will be evaluated before dosing (ie, within 2 days prior to dosing) on Day 1 
of each cycle. Blood samples will also be collected for clinical laboratory testing on +/- 2 days on Days 8
and 15 (Treatment Arm A) or Days 8, 15, and 22 (Treatment Arm B) of each cycle and at the end of 
treatment. Electrocardiograms and LVEF assessments (either MUGA scans or 2D-ECHO) will be 
performed for all subjects at screening (baseline), after Cycle 3 for treatment Arm A and after Cycle 2 for 
treatment Arm B, and as part of end-of-treatment assessments. In addition, those subjects who receive a 
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
26
Approved, 9 January 2018
total cumulative dose of anthracycline exceeding 300 mg/m2 (including previous and on-study treatments) 
or have a clinically significant history of cardiomyopathy should have follow-up LVEF assessments after 
every 2 cycles of therapy, or as clinically warranted.
Following the IDMC recommendation to stop the study (clinical cutoff date of 18 January 2018), only 
serious adverse events for subjects continuing to receive single-agent DOXIL should be reported to 
JR&D.
STATISTICAL METHODS
Sample Size Justification
It is assumed that failure will follow an exponential distribution with a constant hazard rate. Assuming a 
median OS of 16 months for the active control group (DOXIL monotherapy), a planned sample size of 
approximately 670 subjects will provide 80% power to detect a hazard ratio (HR) of 0.78 (16 months vs
20.5 months) at a 2-tailed significance level of 0.05 and an enrollment duration of approximately 
52 months (13 subjects/month enrollment) over a total study duration of 64 months to obtain the required 
514 events.
Efficacy Endpoints
All efficacy endpoints will be analyzed using the All Randomized population. The Kaplan-Meier product 
limit method and un-stratified Cox proportional hazards model will be used to estimate the time-to-event 
variables and to obtain the HR and their 95% confidence intervals. The un-stratified log-rank test will be 
used as the primary analysis for treatment comparison. The response rate variables will be evaluated using 
the Chi-square statistic (un-stratified). Sensitivity analyses for the primary endpoint using the stratified
log-rank test will also be performed. Subgroup analyses will be carried out to assess if the treatment effect 
is consistent across clinically relevant subgroups.
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
27
Approved, 9 January 2018
TIME AND EVENTS SCHEDULE (No Longer Applicable After Amendment 6) - TREATMENT ARM A (30 MG/M2 DOXIL 
ADMINISTERED AS AN IV INFUSION OVER APPROXIMATELY 90 MINUTES FOLLOWED BY 1.1 MG/M2 TRABECTEDIN 
ADMINISTERED AS AN IV INFUSION OVER APPROXIMATELY 3 HOURS EVERY 3 WEEKS)
Phase
Screeninga
Each Treatment Cycle
Period
Within 
30 days prior 
to 
randomization
Dosing on Day 1 (with a 
dosing window of +2 
days) of each 
21-day treatment cycle. 
Each treatment cycle 
being at least 
21 days apart.
Cycle 3 
(within the 
21 day period 
after Cycle 3 
Day 1)
Every 2 cycles 
when the 
cumulative dose 
of anthracyclines 
exceeds 
300 mg/m2
First 4 evaluations 
every 8 wks after 
randomization and then 
every 12 wks until 
disease progression 
Treatment 
Termination
Visit
(30 to 33 
days after 
the last 
dose)
Follow-up 
Phase
Day
Day 1
Day 8
Day 15
Study Procedure
Screening/Administrative
Informed consent (ICF)
X
Pharmacogenomic ICF (optional)
X
Inclusion/exclusion criteria
X
Medical history and 
demographics
X
Prestudy therapy
X
Preplanned surgery/procedure(s)
X
Pregnancy test
X
Study Drug Administration
Randomization
X
Body Surface Area (BSA)b
X
X
Premedication with 
dexamethasone (20 mg IV) or an 
equivalent IV corticosteroid 
approximately 30 min prior to 
DOXIL. Combination Arm A 
ONLY
X
DOXIL 30 mg/m2, IV infusion, 
approximately 90 min
X
Trabectedin 1.1 mg/m2, IV 
infusion, approximately 3h
X
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
28
Approved, 9 January 2018
Phase
Screeninga
Each Treatment Cycle
Period
Within 
30 days prior 
to 
randomization
Dosing on Day 1 (with a 
dosing window of +2 
days) of each 
21-day treatment cycle. 
Each treatment cycle 
being at least 
21 days apart.
Cycle 3 
(within the 
21 day period 
after Cycle 3 
Day 1)
Every 2 cycles 
when the 
cumulative dose 
of anthracyclines 
exceeds 
300 mg/m2
First 4 evaluations 
every 8 wks after 
randomization and then 
every 12 wks until 
disease progression 
Treatment 
Termination
Visit
(30 to 33 
days after 
the last 
dose)
Follow-up 
Phase
Day
Day 1
Day 8
Day 15
Study Procedure
Safety Assessments
Physical examination
X
Vital signs
X
ECOG Performance Status
X
X
ECGc
X
X
LVEF assessmentc
Xc
Xc
Xc
Xc
Xc
Efficacy Assessments
Tumor assessments
Xd
Xd
Xd
Xd
Survival Status
At least 
every 
8 weeks for 
the first 
2 years after 
the 
treatment 
termination 
visit, then 
≈every 12 
weeks
Subsequent anticancer therapy
X
Patient Reported Outcomes (PRO) – Always complete before any tests, procedures, drug administration, or other consultations
QLQ-OV28
X
X
EQ-5D-5L
X
X
≈ every 8 
weeks until 
the start of 
subsequent 
anticancer 
treatment
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
29
Approved, 9 January 2018
Phase
Screeninga
Each Treatment Cycle
Period
Within 
30 days prior 
to 
randomization
Dosing on Day 1 (with a 
dosing window of +2 
days) of each 
21-day treatment cycle. 
Each treatment cycle 
being at least 
21 days apart.
Cycle 3 
(within the 
21 day period 
after Cycle 3 
Day 1)
Every 2 cycles 
when the 
cumulative dose 
of anthracyclines 
exceeds 
300 mg/m2
First 4 evaluations 
every 8 wks after 
randomization and then 
every 12 wks until 
disease progression 
Treatment 
Termination
Visit
(30 to 33 
days after 
the last 
dose)
Follow-up 
Phase
Day
Day 1
Day 8
Day 15
Study Procedure
Clinical Laboratory Assessments - Obtain within 2 days prior to drug administration on Day 1 and +/- 2 days on Days 8 and 15 of each treatment cycle
CA-125
X
X
X
Xi
Hematology
X
X
X
X
X
Chemistry and Liver Panel
X
X
X
X
X
Pharmacokinetics
Blood sample collection
Xe
Xe
Pharmacogenomics
Blood sample collection
Mandatory for subjects who do 
not have a BRCA 1/2 status at 
screening.
A separate blood sample for 
subjects who consent to the 
optional pharmacogenomics 
research.
X
Xf
Ongoing Subject Review
Concomitant therapyg
X
X
X
X
X
X
Adverse eventsg,h
X
X
X
X
X
X
BMI=body mass index; BSA=body surface area; ECG-electrocardiogram, ECOG=Eastern Cooperative Oncology Group; ICF=informed consent; LVEF=left ventricular 
ejection fraction; QLQ=quality of life questionnaire.
a
It is expected that BRCA 1/2 analysis will require approximately 10 to 14 days. In the case of delayed BRCA 1/2 mutation reporting, the screening period may be 
extended for up to 14 days (with medical monitor approval). In such cases, only screening clinical laboratory assessments (hematology, clinical chemistry, and liver 
panel) will need to be repeated.
b
Body surface area (BSA) to be calculated either during Screening or on Day 1 of Cycle 1. It is not necessary to recalculate BSA each cycle unless required to comply 
with institutional guidelines or a subject has a weight gain or loss of approximately >10% of body weight. For those subjects with a body mass index (BMI) 30, the 
use of ideal body weight for dose calculation and capping of BSA utilized for dosing calculations will be left to the discretion of the investigator and to institutional 
guidelines.
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
30
Approved, 9 January 2018
c
For the left ventricular ejection fraction (LVEF) assessment, multigated acquisition scans (MUGA) or 2-dimensional echocardiograms (2D-ECHO) can be used.
However, the same procedure should be used to assess LVEF during the study. The screening LVEF assessment and ECG must be performed within 30 days before 
randomization, and the LVEF must be within normal range according to the institutional guidelines. Each subject must also have a LVEF assessment after Cycle 3 
and at the treatment termination visit. Subjects’ who have received a cumulative dose of anthracyclines that exceeds 300 mg/m2 (including previous and on-study 
treatments) or have a clinically significant history of cardiomyopathy, must have a follow-up LVEF assessment after every 2 cycles of therapy. In addition, subjects 
experiencing significant LVEF decline (defined as absolute decrease ≥15%, or less than lower limit of normal and absolute decrease ≥5%) not recovered to less than 
Grade 2 (or baseline) by the end of treatment should have follow up assessments of LVEF every 2 months until recovered or up to 6 months after discontinuation of 
study treatment (whichever occurs first).
d
Perform disease assessments using the same radiographic technique (computed tomography [CT] scans or magnetic resonance imaging [MRI]) every 8 weeks 
(5 days) after randomization for the first 4 assessments and then every 12 weeks (5 days) until disease progression is radiographically confirmed, the start of 
subsequent anticancer therapy, withdrawal of subject consent, or the clinical cutoff date. The disease assessments should include radiographic imaging of the chest 
(with lung views), abdomen, and pelvis.
e
Plasma samples obtained within 1 h before the start of trabectedin infusion, at 1 h after start of infusion, at 10 minutes before the end of infusion, and 0.5 h, 24 h and 
168 h after the end of infusion on cycle 1 only.
f
The optional pharmacogenomics blood sample collection is scheduled for Day 1 of the first cycle of treatment. However, it will not be considered a protocol 
deviation if the blood sample is collected at any time following this timepoint.
g
To be reported from the time the informed consent document is signed until 30 days after the last dose of study drug.
h
Any clinically significant abnormalities persisting 30 days after the last dose of study drug will be followed by the investigator until resolution or until a clinically 
stable endpoint is reached. Drug-related Grade 3 or Grade 4 toxicities will be monitored until Grade 2 or less, or for a maximum of 6 months after the last dose of 
study drug, whichever, occurs first. Grade 2 to 4 liver or cardiac toxicities will be monitored until Grade 1 or less, or for a maximum of 6 months after the last dose 
of study drug, whichever occurs first.
i
For subjects who terminate treatment prior to disease progression, CA-125 samples will continue to be collected during the follow-up phase approximately every 
8 weeks for the first 4 evaluations and then approximately every 12 weeks until disease progression is radiographically confirmed, the start of subsequent anticancer 
therapy, withdrawal of subject consent, or the clinical cutoff date. CA-125 sample collections should coincide (±5 days) with the scheduled tumor assessments.
NCT01846611


YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
31
Approved, 9 January 2018
TIME AND EVENTS SCHEDULE (No Longer Applicable After Amendment 6) - TREATMENT ARM B (50 MG/M2 DOXIL 
ADMINISTERED AS AN IV INFUSION OVER APPROXIMATELY 90 MINUTES EVERY 4 WEEKS)
Phase
Screeninga
Each Treatment Cycle
Period
Within 
30 days prior 
to 
randomization
Dosing on Day 1 (with a dosing 
window of +2 days) of each 
28-day treatment cycle. Each 
treatment cycle being at least 
28 days apart.
Cycle 2 
(within the
28 day 
period after 
Cycle 2 
Day 1)
Every 2 
cycles when 
the 
cumulative 
dose of 
anthracyclines 
exceeds 
300 mg/m2
First 4 
evaluations 
every 8 wks 
after 
randomization 
and then every 
12 wks until 
disease 
progression 
Treatment 
Termination
Visit
(30 to 
33 days 
after the last 
dose)
Follow-up 
Phase
Day
Day 1
Day 8
Day 15
Day 22
Study Procedure
Screening/Administrative
Informed consent(ICF)
X
Pharmacogenomic ICF (optional)
X
Inclusion/exclusion criteria
X
Medical history and 
demographics
X
Prestudy therapy
X
Preplanned surgery/procedure(s)
X
Pregnancy test
X
Study Drug Administration
Randomization
X
Body Surface Area (BSA)b
X
X
DOXIL 50 mg/m2, IV infusion, 
approximately 90 min
X
Safety Assessments
Physical examination
X
Vital signs
X
ECOG Performance Status
X
X
ECGc
X
X
LVEF assessmentc
Xc
Xc
Xc
Xc
Xc
Efficacy Assessments
Tumor assessments
Xd
Xd
Xd
Xd
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Phase
Screeninga
Each Treatment Cycle
Period
Within 
30 days prior 
to 
randomization
Dosing on Day 1 (with a dosing 
window of +2 days) of each 
28-day treatment cycle. Each 
treatment cycle being at least 
28 days apart.
Cycle 2 
(within the
28 day 
period after 
Cycle 2 
Day 1)
Every 2 
cycles when 
the 
cumulative 
dose of 
anthracyclines 
exceeds 
300 mg/m2
First 4 
evaluations 
every 8 wks 
after 
randomization 
and then every 
12 wks until 
disease 
progression 
Treatment 
Termination
Visit
(30 to 
33 days 
after the last 
dose)
Follow-up 
Phase
Day
Day 1
Day 8
Day 15
Day 22
Study Procedure
Survival Status
At least 
every 
8 weeks for 
the first 
2 years after 
the treatment 
termination 
visit, then 
≈every 
12 weeks
Subsequent anticancer therapy
X
Patient Reported Outcomes (PRO) - Always complete before any tests, procedures, drug administration, or other consultations
QLQ-OV28
X
X
EQ-5D-5L
X
X
≈ every 8 
weeks until 
the start of 
subsequent 
anticancer 
treatment
Clinical Laboratory Assessments - Obtain within 2 days prior to drug administration on Day 1 and +/- 2 days on Days 8, 15, and 22 of each treatment cycle
CA-125
X
X
X
Xh
Hematology
X
X
X
X
X
X
Chemistry and Liver Panel
X
X
X
X
X
X
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Phase
Screeninga
Each Treatment Cycle
Period
Within 
30 days prior 
to 
randomization
Dosing on Day 1 (with a dosing 
window of +2 days) of each 
28-day treatment cycle. Each 
treatment cycle being at least 
28 days apart.
Cycle 2 
(within the
28 day 
period after 
Cycle 2 
Day 1)
Every 2 
cycles when 
the 
cumulative 
dose of 
anthracyclines 
exceeds 
300 mg/m2
First 4 
evaluations 
every 8 wks 
after 
randomization 
and then every 
12 wks until 
disease 
progression 
Treatment 
Termination
Visit
(30 to 
33 days 
after the last 
dose)
Follow-up 
Phase
Day
Day 1
Day 8
Day 15
Day 22
Study Procedure
Pharmacogenomics
Blood sample collection
Mandatory for subjects who 
do not have a BRCA 1/2 status 
at screening.
A separate blood sample for 
subjects who consent to the 
optional pharmacogenomics 
research.
X
Xe
Ongoing Subject Review
Concomitant therapyf
X
X
X
X
X
X
X
Adverse eventsf,g
X
X
X
X
X
X
X
BMI=body mass index; BSA=body surface area; ECG-electrocardiogram, ECOG=Eastern Cooperative Oncology Group; ICF=informed consent form; 
MUGA=multigated acquisition scan; QLQ=quality of life questionnaire.
a
It is expected that BRCA 1/2 analysis will require approximately 10 to 14 days. In the case of delayed BRCA 1/2 mutation reporting, the screening period may be 
extended for up to 14 days (with medical monitor approval). In such cases, only screening clinical laboratory assessments (hematology, clinical chemistry, and liver 
panel) will need to be repeated
b
Body surface area (BSA) to be calculated either during Screening or on Day 1 of Cycle 1. It is not necessary to recalculate BSA each cycle unless required to comply 
with institutional guidelines or a subject has a weight gain or loss of approximately >10% of body weight. For those subjects with a body mass index (BMI) 30, the 
use of ideal body weight for dose calculation and capping of BSA utilized for dosing calculations will be left to the discretion of the investigator and to institutional 
guidelines.
c
For the left ventricular ejection fraction (LVEF) assessment, multigated acquisition scans (MUGA) or 2-dimensional echocardiograms (2D-ECHO) can be used. 
However, the same procedure should be used to assess LVEF during the study. The screening LVEF assessment and ECG must be performed within 30 days before 
randomization, and the LVEF must be within normal range according to the institutional guidelines. Each subject must also have a LVEF assessment after Cycle 2 
and at the treatment termination visit. Subjects’ who have received a cumulative dose of anthracyclines that exceeds 300 mg/m2 (including previous and on-study 
treatments) or have a clinically significant history of cardiomyopathy, must have a follow-up LVEF assessment after every 2 cycles of therapy. In addition, Subjects 
experiencing significant LVEF decline (defined as absolute decrease ≥15%, or less than lower limit of normal and absolute decrease ≥5%) not recovered to less than 
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Grade 2 (or baseline) by the end of treatment should have follow up assessments of LVEF every 2 months until recovered or up to 6 months after discontinuation of 
study treatment (whichever occurs first).
d
Perform disease assessments using the same radiographic technique (computed tomography [CT] scans or magnetic resonance imaging [MRI]) every 8 weeks 
(5 days) after randomization for the first 4 assessments and then every 12 weeks (5 days) until disease progression is radiographically confirmed, the start of 
subsequent anticancer therapy, withdrawal of subject consent, or the clinical cutoff date. The disease assessments should include radiographic imaging of the chest 
(with lung views), abdomen, and pelvis.
e
The optional pharmacogenomics blood sample collection is scheduled for Day 1 of the first cycle of treatment. However, it will not be considered a protocol 
deviation if the blood sample is collected at any time following this timepoint. 
f
To be reported from the time the informed consent document is signed until 30 days after the last dose of study drug.
g
Any clinically significant abnormalities persisting 30 days after the last dose of study drug will be followed by the investigator until resolution or until a clinically 
stable endpoint is reached. Drug-related Grade 3 or Grade 4 toxicities will be monitored until Grade 2 or less, or for a maximum of 6 months after the last dose of 
study drug, whichever, occurs first. Grade 2 to 4 liver or cardiac toxicities will be monitored until Grade 1 or less, or for a maximum of 6 months after the last dose 
of study drug, whichever occurs first.
h
For subjects who terminate treatment prior to disease progression, CA-125 samples will continue to be collected during the follow-up phase approximately every 
8 weeks for the first 4 evaluations and then approximately every 12 weeks until disease progression is radiographically confirmed, the start of subsequent anticancer 
therapy, withdrawal of subject consent, or the clinical cutoff date. CA-125 sample collections should coincide (5 days) with the scheduled tumor assessments.
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Clinical Protocol ET743-OVC-3006 – Amendment 6
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TIME AND EVENTS SCHEDULE – AMENDMENT 6
Treatment Termination Visit Assessments
(within 30 days after the last dose of study drug or by 18 January 2018)
Study Procedure
ECOG Performance Status
X
ECGa
X
LVEF assessmenta
Xa
Tumor assessmentsb
Xb
QLQ-OV28
X
EQ-5D-5L
X
CA-125
X
Hematology
X
Chemistry and Liver Panel
X
Concomitant therapy
X
Adverse events
X
Survival Status
Single-Agent DOXIL per Local Standard of Carec
Report serious adverse eventsd
Note: See Attachment 7 for a consolidated summary study termination procedures.
ECG-electrocardiogram, ECOG=Eastern Cooperative Oncology Group; MUGA=multigated acquisition scan; QLQ=quality of life questionnaire.
a
For the left ventricular ejection fraction (LVEF) assessment, multigated acquisition scans (MUGA) or 2-dimensional echocardiograms (2D-ECHO) can be used. 
However, the same procedure should be used to assess LVEF during the study. Each subject must also have a LVEF assessment at the treatment termination visit. 
b
Perform disease assessments using the same radiographic technique (computed tomography [CT] scans or magnetic resonance imaging [MRI]). The disease 
assessments should include radiographic imaging of the chest (with lung views), abdomen, and pelvis.
c
Subjects continuing treatment with single-agent DOXIL as per the local standard of care. Treatment for these subjects may continue as long as the subjects comply 
with protocol-specified prohibitions and restrictions (Section 4.3) for treatment and as long as they experience clinical benefit in the opinion of the investigator.
DOXIL will be provided by the JR&D as needed until post-trial access to DOXIL is available or until disease progression, whichever occurs first.
d
Serious adverse events are to be reported as specified in Section 12.3.2.
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ABBREVIATIONS
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
β-HCG
β-human chorionic gonadotropin
BMI
body mass index
BSA
body surface area
BUN
blood urea nitrogen
CI
confidence interval
CPK
creatine phosphokinase
CR
complete response
CRF
case report form
CT
computed tomography scan
D5W
5% dextrose in water
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eDC
electronic data capture
EMA
European Medicines Agency
EU
European Union
fax
facsimile
GCIG
Gynecologic Cancer Intergroup
GCP
Good Clinical Practice
G-CSF
granulocyte-colony stimulating factor
HCl
hydrochloride
HFS
hand and foot syndrome
HR
hazard ratio
HRR
homologous recombination repair
ICF
informed consent form
ICH
International Conference for Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IVRS
interactive voice response system
IWRS
interactive web response system
JR&D
Janssen Research & Development
LC-MS/MS
liquid chromatography-mass spectrometry/mass spectrometry
LLN
lower limit of normal
LVEF
left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MUGA
multigated acquisition scan
NCI-CTCAE
National Cancer Institute – Common Terminology Criteria of Adverse Events
NER
nucleotide excision repair
NYHA
New York Heart Association
ORR
objective response rate
OS
overall survival
PD
progressive disease
PFI
platinum-free interval
PFS
progression free survival
PK
pharmacokinetics
PLD
pegylated liposomal doxorubicin
PQC
Product Quality Complaint
PR
partial response
PRO
patient-reported outcome(s)
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YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
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Approved, 9 January 2018
QLQ
quality of life questionnaire
RECIST
Response Evaluation Criteria in Solid Tumors
STS
soft tissue sarcoma
SUSAR
suspected unexpected serious adverse reaction
TTP
time-to-progression
2D-ECHO
2-dimensional echocardiogram
ULN
upper limit of normal
USA
United States of America
US FDA
United States Food and Drug Administration
USP
United States Pharmacopeia
WBC
white blood cell
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YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
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Approved, 9 January 2018
1.
INTRODUCTION
Trabectedin (YONDELIS) is a tris tetrahydroisoquinoline alkaloid originally isolated from the 
marine ascidian ecteinascidin turbinate, Ecteinascidia turbinata. It exerts its action by binding to 
the N2 position of guanine in the minor groove of deoxyribonucleic acid (DNA), unlike other 
DNA-binding agents that bind to the major groove. This bends the DNA towards the major 
groove, a property unique to this class of DNA-binding agents, thereby inhibiting inducible 
transcription.12 In contrast to other DNA-binding cytotoxic agents, which are either equally or 
more effective in cells containing defects of the transcription-coupled nucleotide excision repair 
(NER) pathway, trabectedin is more effective in cells with an intact NER pathway.6,18
Additionally, trabectedin has been proposed to have unique modulatory effects on the tumor
micro-environment that has been attributed to its effect on tumor-associated macrophages and 
histiocytes. 1,5,7
Trabectedin is approved in the European Union (EU) and in other countries outside the United 
States of America (USA) for the treatment of soft tissue sarcoma (STS,) and relapsed platinum-
sensitive ovarian cancer. The requirement for platinum-sensitivity for the indication of ovarian 
cancer varies by country. In the USA, trabectedin is approved for the treatment of unresectable 
or metastatic liposarcoma or leiomyosarcoma in patients who received a prior anthracycline-
containing regimen.
DOXIL/CAELYXis doxorubicin hydrochloride (HCl) encapsulated in STEALTHliposomes 
for IV administration. Doxorubicin belongs to the anthracycline class and has a broad spectrum 
of antineoplastic activity. DOXIL(also known as doxorubicin HCl liposome injection) is 
approved by the United States Food and Drug Administration (US FDA) and CAELYX(also 
known as pegylated liposomal doxorubicin [PLD]) is approved by the European Medicines 
Agency (EMA) and other countries for the treatment of ovarian cancer. Generic doxorubicin HCl
liposome injection was recently approved by the US FDA. Hereafter, in this document,
DOXIL/doxorubicin HCl liposome injection (USA only) and CAELYX/PLD (non-USA) will 
collectively be referred to as DOXIL.
Trabectedin and DOXIL, 2 agents with different mechanisms of action, have shown efficacy in 
treating women with advanced ovarian cancer. The combination of trabectedin and DOXIL has 
previously been demonstrated in the ET743-OVA-301 Phase 3 study to improve progression-free 
survival (PFS), as compared with DOXIL monotherapy, in the second-line treatment of 
refractory ovarian cancer. Median overall survival (OS) was also increased by 3.3 months in the 
combined trabectedin+DOXIL treatment arm, but this result did not reach statistical significance 
(p=0.0835)4. Retrospective analysis suggested that the efficacy of the trabectedin+DOXIL 
combination was greatest in subjects with platinum-sensitive disease (subjects with a platinum-
free interval [PFI] 6 months), and that the lack of statistical significance for OS may have 
resulted from an imbalance in prognostic factors. Thus, limiting treatment to patients with 
platinum-sensitive disease is expected to result in improved demonstrated efficacy, as well as an 
improved risk-benefit ratio.
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Clinical Protocol ET743-OVC-3006 – Amendment 6
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Study ET743-OVC-3006 is designed to investigate the activity of trabectedin+DOXIL for the 
treatment of subjects with platinum-sensitive advanced-relapsed epithelial ovarian, primary 
peritoneal, or fallopian tube cancer. As second-line therapy with a platinum-based combination 
regimen is now considered superior to a single-agent in this patient population,15 this study will 
compare the activity of trabectedin+DOXIL to that of DOXIL monotherapy in the third-line 
setting in subjects who have received 2 previous lines of platinum-based chemotherapy.
For the most comprehensive nonclinical and clinical information regarding the efficacy and 
safety of trabectedin, refer to the latest version of the Investigator's Brochure and Addenda for 
YONDELIS (trabectedin).21
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
1.1.
Trabectedin
Trabectedin is the first agent identified in a new cytotoxic class having a unique mechanism of 
action. Trabectedin binds to the minor groove of DNA. In contrast to other DNA-interacting 
chemotherapeutic agents, which are most active in the S phase and have an enhanced activity in 
NER-deficient cells, trabectedin is most active in the G1 phase and requires a functional 
transcription-coupled NER system to demonstrate activity. In vitro activity was observed at 
concentrations in the nanomolar range prompting studies in animal models and eventually 
evaluation in subjects with ovarian cancer.
1.1.1.
Human Pharmacokinetics of Trabectedin
The pharmacokinetics (PK) of trabectedin were evaluated after administration of a 1.3 mg/m2
3-h IV infusion to subjects with advanced breast cancer (Study ET743-INT-3).20 Maximum 
plasma concentrations were generally observed at 1.5 h to 3 h after the start of the 3-h IV 
infusion. After the first dose in Cycle 1 (1.3 mg/m2), mean maximum plasma concentrations 
were approximately 6.3 ng/mL. When the infusion was stopped, an initial rapid decline in 
plasma concentrations was observed, which was followed by a much slower decrease in 
concentrations. Mean systemic clearance rates of trabectedin ranged from 17 L/h to 69 L/h. The 
volume of distribution (mean: 4,860 L) was greater than total body water, indicating that 
trabectedin distributes extensively into peripheral tissues. The mean terminal half-life of this 
compound was 148 h. The range of values observed for the various PK parameters were 
comparable for the first 2 cycles of therapy.21
1.1.2.
Metabolism of Trabectedin
Following dosing in humans, trabectedin undergoes extensive oxidative metabolism to numerous 
metabolites, most of which have not been identified. There is no evidence that trabectedin 
undergoes direct glucuronidation. On the basis of in vitro experiments, CYP3A4 is considered the 
predominant cytochrome P450 enzyme responsible for the hepatic metabolism of trabectedin.21
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YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
40
Approved, 9 January 2018
1.2.
Combination Therapy - Trabectedin + DOXIL
1.2.1.
Pivotal Efficacy Study
Study ET743-OVA-301 was a Phase 3, randomized, open-label, active-control, parallel-group, 
multicenter study designed to assess the efficacy and safety of the trabectedin+DOXIL 
combination therapy when used to treat subjects with advanced-relapsed epithelial ovarian 
cancer.4 The study was designed to determine whether or not the non-platinum, non-taxane 
combination of trabectedin+DOXIL would provide an option for patients who may not be able to 
receive further platinum-
or taxane-based therapies. 
Subjects received either the 
trabectedin+DOXIL combination therapy every 3 weeks (DOXIL 30 mg/m 2 as a 90 minute 
infusion followed by 1.1 mg/m2 of trabectedin as a 3h infusion) or DOXIL as a monotherapy 
every 4 weeks (DOXIL 50 mg/m2 as a 90 minute infusion). Subjects in the combination therapy 
arm were pretreated with IV dexamethasone (or an equivalent IV corticosteroid). 
When compared with DOXIL monotherapy, the combination therapy of DOXIL and trabectedin 
prolonged PFS for women with advanced-relapsed epithelial ovarian cancer after failure of first-
line platinum-based chemotherapy. The median PFS was 7.3 months (95% confidence interval 
[CI]: 5.9 to 7.9) for the trabectedin+DOXIL arm and 5.8 months (95% CI: 5.5 to 7.1) for the 
DOXIL monotherapy arm. The hazard ratio (HR) was 0.79 (95% CI: 0.65 to 0.96, p=0.0190) 
which represented a 21% risk reduction in disease progression or death in the combination arm 
compared with DOXIL monotherapy (Figure 1).
Figure 1:
Kaplan-Meier Plot of Progression-Free Survival 
(Study ET743-OVA-301: Independent Radiologist Review)
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YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
41
Approved, 9 January 2018
Median survival was 22.2 months for the trabectedin+DOXIL arm and 18.9 months for the 
DOXIL arm, a 3.3 month improvement with the combination treatment. The HR was 0.86 with 
95% CI: 0.72 to 1.02, and a p-value of 0.0835 (un-stratified log-rank test) (Figure 2). An 
unexpected but significant imbalance in PFI favoring the DOXIL arm (mean PFI: 
DOXIL=13.3 months; trabectedin+DOXIL=10.6 months) was identified. On the basis of this 
finding, a retrospective analysis adjusting for the PFI imbalance and other prognostic factors 
suggested an improvement in OS associated with the trabectedin+DOXIL arm (HR=0.82; 95% 
CI: 0.69 to 0.98; p=0.0285).
Figure 2:
Kaplan-Meier Plot of Overall Survival
(Study ET743-OVA-301: All Randomized Subjects)
Subgroups by Platinum-Free Interval
A subgroup analysis of OS by PFI (0 to 6 months, 6 to 12 months, and >12 months) was 
conducted for Study ET743-OVA-301 (Figure 3). Subjects with a PFI <6 months received no 
benefit 
from 
trabectedin+DOXIL
second-line, 
combination 
chemotherapy
in
Study ET743-OVA-301. The benefit of the combination therapy (trabectedin+DOXIL) was 
evident in the subject population that was platinum sensitive (ie, patients with a PFI of 6 to 
12 months and >12 months); the subset of subjects with a PFI of 6 to 12 months had the largest 
difference in OS (HR: 0.64; 95% CI: 0.47 to 0.86; p=0.0027).
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YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
42
Approved, 9 January 2018
Figure 3:
Overall Survival by Platinum-Free Interval
(Study ET743-OVA-301: All Randomized Subjects Analysis Set)
CI=confidence interval; Combo=combination therapy (trabectedin+DOXIL); HR=hazard ratio; Mono=monotherapy 
(DOXIL); PFI=platinum-free interval 
1.2.2.
Pivotal Safety Study
In Study ET743-OVA-301, the safety profile of the trabectedin+DOXIL combination therapy 
was consistent with the well-characterized toxicities seen with each agent alone.4 The incidence 
of Grade 3 or 4 adverse events, drug-related serious adverse events, and adverse events leading 
to treatment termination were higher for the trabectedin+DOXIL combination arm than for the 
DOXIL monotherapy arm. Death due to adverse events was infrequent, occurring in 2 (1%) 
subjects in the DOXIL monotherapy arm and in 5 (2%) subjects in the trabectedin+DOXIL arm. 
No subjects developed myelodysplasias or acute myeloid leukemia during the study. Treatment 
with the combination of trabectedin+DOXIL primarily resulted in additional myelosuppression 
and liver enzyme abnormalities, both of which did not usually result in serious clinical sequelae. 
The incidence of Grades 3 and 4 adverse events for neutropenia was higher in the 
trabectedin+DOXIL arm (63%) compared with DOXIL monotherapy (23%). In the 
trabectedin+DOXIL arm 8% of subjects developed Grade 3 or 4 neutropenic fever compared 
with 2% in DOXIL monotherapy arm. Neutropenia was managed by dose delays and reductions, 
as well as the use of colony stimulating agents.
The incidence of Grade 3 or 4 alanine aminotransferase (ALT) was 1% in the DOXIL 
monotherapy arm and 32% in the trabectedin+DOXIL arm.4 This was not unexpected, because 
acute, transient elevations in both ALT and aspartate aminotransferase (AST) have been 
associated with single-agent trabectedin. Transaminase elevations were generally of short 
duration, usually returning to normal before the next cycle. In addition, in most cases, it 
decreased in incidence and magnitude in subsequent cycles, and did not result in severe liver 
toxicity or failure. Transaminase elevations were generally managed by dose reductions and 
delays.4,21
The overall incidence of increased blood creatine phosphokinase (CPK) adverse events was 
11 (3%) subjects in the DOXIL monotherapy arm and 24 (7%) subjects in the 
trabectedin+DOXIL arm. The incidence of rhabdomyolysis, a potential complication of 
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Clinical Protocol ET743-OVC-3006 – Amendment 6
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Approved, 9 January 2018
increased CPK, was 0% and <1% in the DOXIL monotherapy and trabectedin + DOXIL arms, 
respectively. The overall incidence of renal and urinary disorder adverse events was 8% of 
subjects in the DOXIL monotherapy arm and 10% of subjects in the trabectedin+DOXIL arm.
The incidence of cardiac dysfunction, measured as a decrease in left ventricular ejection fraction 
(LVEF) 
from 
baseline 
to 
treatment 
termination, 
were 
comparable 
between 
the 
trabectedin+DOXIL combination therapy arm and the DOXIL monotherapy arm (6% vs 8%, 
respectively). The incidence of hand and foot syndrome (HFS) (26% vs 54%), stomatitis
(20% vs 33%), mucosal inflammation (13% vs 20%), and abdominal pain (22% vs 24%) were all 
reduced, respectively, as might be expected with the lower dose of DOXIL (30 mg/m2) in the 
trabectedin+DOXIL arm compared with the DOXIL monotherapy arm (50 mg/m2).4
1.3.
Comparator DOXIL 
DOXIL is doxorubicin HCl encapsulated in STEALTH liposomes for IV administration. 
Doxorubicin belongs to the anthracycline class and has a broad spectrum of antineoplastic 
activity. The STEALTH liposome escapes instant recognition and uptake by the mononuclear 
phagocyte system resulting in a longer circulation time. These liposomes eventually extravasate 
through the abnormally permeable vessels characteristic of many tumors. Once concentrated in 
tumors, DOXIL can deliver high levels of doxorubicin to malignant cells. The safety profile is 
improved, with less cardiotoxicity, nausea and vomiting, and alopecia compared with standard 
doxorubicin. 
The major dose-limiting toxicity of DOXIL is bone marrow suppression. Other toxicities include 
HFS and irreversible cumulative cardiac toxicity that limits the total deliverable dose. Special 
attention must be given to the myocardial damage that may be associated with cumulative doses 
of doxorubicin and other anthracyclines. In addition, very rare cases of secondary oral cancer 
have been observed in patients with long-term exposure to DOXIL (>1 year or those receiving a 
cumulative dose of 720 mg/m2). Refer to the package insert for safety information.
DOXILis approved by the US FDA for the treatment of patients with ovarian cancer whose 
disease has progressed or recurred after platinum-based chemotherapy. It is approved by the 
EMA and other countries as CAELYXfor the treatment of advanced ovarian cancer in women 
after failure of first-line platinum-based chemotherapy regimen. Generic doxorubicin HCl 
liposome injection was recently approved by the US FDA. For the treatment of ovarian 
carcinoma, DOXIL, as a single agent, is administered at a dose or 50 mg/m2 every 4 weeks.
1.4.
Overall Rationale for the Study
Single-agent activity of trabectedin has been studied in several Phase 1 and 2 clinical studies. 
Trabectedin had a favorable safety profile and promising activity in recurrent ovarian cancer 
patients.10,17 Pooled analysis of 3 Phase 2 studies showed a response rate of 34% and time-to-
progression (TTP) of 5.8 months in subjects who had a PFI of 6 months or more after the last 
platinum-based therapy.11 No efficacy difference was seen between the patients with 2 prior lines 
of platinum-based therapy and patients with only 1 prior platinum-based therapy.
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YONDELIS(trabectedin)
Clinical Protocol ET743-OVC-3006 – Amendment 6
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Approved, 9 January 2018
DOXIL has demonstrated efficacy for the treatment of metastatic ovarian carcinoma after failure 
of first-line chemotherapy. The long-term follow-up from a multicenter Phase 3 study comparing 
DOXIL with topotecan demonstrated an 18% reduction in the risk of death for subjects treated 
with DOXIL (median survival 62.7 weeks compared with 59.7 weeks for topotecan-treated 
subjects; HR: 1.216; 95% CI: 1.000 to 1.478; p=0.050). 8,9
In the Phase 1 Study ET743-USA-11, the trabectedin+DOXIL combination therapy was 
administered to subjects with a variety of tumor types. The recommended dose level was 
trabectedin 1.1 mg/m2 and DOXIL 30 mg/m2, administered once every 3 weeks (q3wk).19
In the Phase 3 Study ET743-OVA-301, the efficacy and safety of the trabectedin+DOXIL
combination therapy was assessed in subjects with first-relapsed ovarian cancer after 
platinum-based chemotherapy. In this study, 672 subjects were randomly assigned to receive 
DOXIL 30 mg/m2 followed by a 3-h infusion of trabectedin 1.1 mg/m2 every 3 weeks or DOXIL 
50 mg/m2 every 4 weeks as a monotherapy. The median PFS was 7.3 months with the 
trabectedin+DOXIL combination therapy vs 5.8 months with the DOXIL monotherapy 
(HR: 0.79; 95% CI: 0.65 to 0.96; p=0190). The median OS for trabectedin+DOXIL and DOXIL 
monotherapy arms was 22.2 months and 18.9 months, respectively (HR: 0.86; 95% CI: 0.72 to 
1.02; p=0.0835 [un-stratified log-rank test]).4,13 In an unplanned subset analysis, an unexpected 
but significant imbalance in the PFI favoring the DOXIL monotherapy arm was identified (mean 
PFI: DOXIL arm=13.3 months; trabectedin+DOXIL arm=10.6 months). On the basis of this 
finding, a retrospective analysis adjusting for the PFI imbalance and other prognostic factors was 
performed, which suggested an improvement in OS associated with the trabectedin+DOXIL arm 
(HR: 0.82; 95% CI:0.69 to 0.98; p=0.0285).14 Within the trabectedin+DOXIL combination arm, 
neutropenia (78% vs 39%) and Grade 3 to 4 transaminase elevations (ie, ALT: 32% vs 1%) were 
more commonly observed, while HFS (26% vs 54%) and mucositis (13% vs 20%) were less 
frequently observed than within the DOXIL monotherapy arm.13
On the basis of prior clinical experience, the combination of non-platinum agents, trabectedin 
and DOXIL, is expected to provide improved efficacy compared with DOXIL monotherapy and 
an acceptable safety profile in subjects with platinum-sensitive advanced-relapsed epithelial 
ovarian, primary peritoneal, or fallopian tube cancer who have received 2 prior lines of 
platinum-based chemotherapy.
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objective
To compare the OS after treatment with trabectedin+DOXIL combination therapy to that 
observed after treatment with DOXIL monotherapy for subjects with platinum-sensitive 
advanced-relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer who have 
received 2 previous lines of platinum-based chemotherapy.
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Secondary Objectives

To evaluate PFS.

To evaluate the objective response rate (ORR).

To characterize the plasma PK of trabectedin using a sparse sampling scheme in the 
trabectedin+DOXIL treatment group.

To evaluate the safety of the trabectedin+DOXIL combination therapy and DOXIL 
monotherapy. 
Exploratory Objectives

To conduct pharmacogenomic evaluations of OS, PFS and other endpoints in subjects with 
and without mutations in BRCA1 or BRCA2.

To evaluate patient-reported outcomes (PROs).
2.2.
Hypothesis
Trabectedin in combination with DOXIL will improve OS compared with DOXIL monotherapy 
in the treatment of subjects with platinum-sensitive advanced-relapsed epithelial ovarian, 
primary peritoneal, or fallopian tube cancer who received 2 previous lines of platinum-based 
chemotherapy.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a randomized, open-label, active-controlled, multicenter study designed to assess the 
efficacy and safety of trabectedin+DOXIL as a third-line chemotherapy in subjects with 
platinum-sensitive advanced-relapsed epithelial ovarian, primary peritoneal, or fallopian tube 
cancer who received 2 previous lines of platinum-based chemotherapy. Approximately 670 adult 
subjects will be enrolled in this study, with 335 subjects per planned treatment group. At
randomization, subjects will be stratified by 4 criteria: 1) the time from the last dose of first-line 
platinum therapy to disease progression (6 months to 12 months vs >12 months to 24 months vs 
>24 months), 2) Eastern Cooperative Oncology Group (ECOG) performance status grade
(0 vs 1), 3) BRCA 1/2 status (mutation vs no mutation), and 4) prior DOXIL therapy (no vs yes).
Subjects will then be randomly assigned in a 1:1 ratio to the trabectedin+DOXIL combination 
therapy group (Arm A) or to the DOXIL monotherapy group (Arm B).
During the treatment phase, subjects will receive study drug by IV infusion on Day 1 of a 21-day 
cycle in Arm A and on Day 1 of a 28-day cycle in Arm B. Treatment will continue until the 
occurrence of disease progression or unacceptable treatment toxicity, or until 2 cycles after 
assessment of a complete response (CR). Subjects assigned to the trabectedin+DOXIL group
(Arm A) will be pretreated with 20 mg of dexamethasone IV, or an equivalent IV corticosteroid, 
approximately 30 minutes prior to initiation of infusion of DOXIL on Day 1 of each treatment 
cycle.
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Subjects will be followed for survival at least every 8 weeks for the first 2 years after the 
treatment termination visit and approximately every 12 weeks thereafter. This study will end 
2 months after the last subject has received the last dose of study drug, when 514 deaths have 
been observed, or until the clinical cutoff date.
The analysis of the primary endpoint, OS, will be conducted after at least 514 events (deaths) are 
observed or up to the clinical cutoff date. An interim analysis is planned for this study (after 
observing 60% [308 death events] of the total number of required [514] death events) to 
determine whether efficacy has been adequately demonstrated, allowing for early study 
termination and subject crossover from the monotherapy arm. Given the findings from Study 
ET743-OVA-301, which demonstrated superior PFS and a favorable survival trend for the 
trabectedin+DOXIL combination therapy, there are no plans to conduct a futility analysis at the 
interim analysis.
Secondary efficacy endpoints of PFS and ORR will be assessed using the Response Evaluation 
Criteria in Solid Tumors (RECIST, Version 1.1). Scheduled assessments of disease status will be
performed within 30 days before randomization, every 8 weeks (5 days) after randomization for 
the first 4 assessments, and then every 12 weeks (5 days) thereafter. Disease assessments, 
including assessments for subjects who discontinue treatment for reasons other than disease 
progression, will be performed until disease progression is radiographically confirmed, the start 
of subsequent anticancer therapy, withdrawal of subject consent, or the clinical cutoff date. For 
subjects who discontinue study treatment, documentation of all subsequent anticancer therapy,
survival status, and safety evaluations as outlined in the Time and Events Schedule will be
required. Survival status should be recorded at least every 8 weeks for the first 2 years after the 
treatment termination visit and approximately every 12 weeks thereafter. Collection of survival 
status will continue until at least 514 deaths have been observed or until the clinical cutoff date.
The primary efficacy endpoint is OS, defined as the time between randomization and death from 
any cause. Secondary endpoints are PFS (defined as the time between the date of randomization 
and the date of disease progression or death), and ORR (defined as the proportion of subjects 
who achieve CR or partial response [PR]).
Safety will be assessed using laboratory test results and the incidence and severity of adverse 
events. Left ventricular ejection fraction assessments (either multigated acquisition [MUGA]
scans or 2-dimensional echocardiograms [2D-ECHO]) and electrocardiograms (ECGs) will be 
used to monitor cardiac function.
An IDMC will assess safety and efficacy data (Section 11.9, Independent Data Monitoring 
Committee). Safety data will be reviewed approximately every 6 months. A final cardiac analysis 
will be conducted and a report will be provided. An interim analysis of OS will be performed 
after approximately 308 subjects have died. The final analysis of OS will occur when at least
514 deaths have been observed or until the clinical cutoff date. 
A Study Steering Committee will periodically review issues related to study conduct and offer 
advice as needed. The Steering Committee is composed of physicians who have extensive 
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experience with both trabectedin and the treatment of ovarian cancer. The Steering Committee 
will meet with the Study Team periodically to review the study status and make 
recommendations for actions to take with regard to study recruitment, data gathering, and data
review. The Steering Committee will not have access to unblinded data listings or summary 
analyses during the study.
Supportive care (eg, antibiotics, analgesics, transfusions) may be provided according to 
institutional standards. Appropriate prophylactic antiemetic regimens may be provided, as 
necessary.2 No concurrent investigational agents or antineoplastic agents will be permitted. 
It is anticipated that the volumes of blood drawn for each subject for routine laboratory 
evaluations throughout the study will be approximately 15 mL for screening serum chemistry 
and hematology tests; 10 mL for BRCA 1/2 testing at screening (for subjects who do not have a 
known BRCA 1/2 status); 4 mL for subjects consenting to the optional pharmacogenomics 
component of the study (where local regulations permit); 45 mL and 60 mL for treatment 
Arms A and B, respectively, per cycle for serum biochemistry and hematology tests; 4 mL per 
scheduled CA-125 sample; and 24 mL from those subjects who provide PK samples.
All subjects who discontinue study treatment will be monitored for survival. The subject will 
have completed the study when the study is terminated or the subject has died or has withdrawn 
consent for follow-up.
A diagram of the study design is provided below (Figure 4).
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Figure 4:
Study Design
Screening Phase
Inclusion/Exclusion Criteria Fulfilled?
No
Do not randomize
Yes
1:1 Randomization
Arm A
Trabectedin + DOXIL Group: n=335
Arm B
DOXIL: n=335
Pretreatment: 20 mg dexamethasone IV
(or the IV equivalent) approximately 
30 minutes before DOXIL study drug
DOXIL: 30 mg/m2 as an ≈90 min IV 
infusion followed by
Trabectedin: 1.1 mg/m2 as an ≈3-h IV 
infusion on Day 1 of each 21-day cycle
DOXIL: 50 mg/m2 as an ≈90 min IV 
infusion on Day 1 of each 28-day cycle
Assess disease status every 8 weeks for 
the first 4 assessments and then every 
12 weeks until disease progression is 
radiographically confirmed
Assess disease status every 8 weeks for 
the first 4 assessments and then every 
12 weeks until disease progression is 
radiographically confirmed
Disease 
progression
Disease 
progression
Treatment Termination Visit
Follow-up Phase
Overall survival
Note: On 26 June 2017, the IDMC requested a futility analysis of OS to be performed at the time 
of the next meeting 6 months later. In view of the IDMC request, study data up to 
20 September 2017 were evaluated for safety and OS (45% rather than 60% of the required death 
events at the planned interim analysis). Following the review of the study data by the IDMC on 
15 December 2017, the HR for OS was 0.962, crossing the previously agreed upon threshold for 
futility of 0.93. In view of this result and the observed and expected higher toxicity in Arm A as 
compared with Arm B, the IDMC recommended discontinuing the study. Therefore, as of 
Amendment 6, no new subjects will be randomized to study treatment, and treatment with 
trabectedin should be immediately discontinued for subjects
assigned to Arm A 
(trabectedin+DOXIL). All study subjects (Arm A or Arm B) currently on study who, in the 
opinion of the investigator, are deriving clinical benefit may continue treatment with single-agent 
DOXIL as per the local standard of care. Treatment for these subjects may continue as long as 
the subjects comply with protocol-specified prohibitions and restrictions for treatment 
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(Section 4.3) and as long as they experience clinical benefit in the opinion of the investigator. 
DOXIL will be provided by JR&D as needed until post-trial access to DOXIL is available or 
until disease progression, whichever occurs first.
Accordingly, the end of study data collection is defined as when all subjects on study treatment 
have completed treatment termination visit assessments as specified in the Time and Events 
Schedule for Amendment 6 or by 18 January 2018, whichever occurs first. For subjects 
continuing treatment with single-agent DOXIL, as per the local standard of care, only serious 
adverse events should be reported to JR&D as outlined in Section 12.3.2.
3.2.
Study Design Rationale
Most ovarian cancer patients are diagnosed with advanced disease, resulting in poor prognosis 
with inferior survival. Despite high rates of objective responses to the combination of 
cytoreductive surgery and platinum-based chemotherapy, disease often relapses. The results of 
second-line treatment depend largely on the PFI after the last dose of first-line therapy, with 
patients exhibiting a longer PFI having a better response to subsequent chemotherapy. 
Unfortunately, the response is of relatively short duration, and most patients require a third line 
of chemotherapy. There are very few published studies of chemotherapy administered after 
2 lines of platinum-containing regimens to inform the choice of chemotherapy in the third-line 
setting, even though relapse of epithelial ovarian cancer is common. Study ET743-OVC-3006 is 
designed to investigate the activity of trabectedin+DOXIL for the treatment of subjects with 
platinum-sensitive advanced-relapsed epithelial ovarian, primary peritoneal, or fallopian tube 
cancer who have received 2 previous lines of platinum-based chemotherapy.
Randomization
Randomization will be used to minimize bias in the assignment of subjects to treatment groups, 
to increase the likelihood that known and unknown subject attributes (eg, demographic and 
baseline characteristics) are evenly balanced across treatment groups, and to enhance the validity 
of statistical comparisons across treatment groups.
Following Amendment 6, subjects will not be randomized to study treatment, and no new 
subjects will be screened. Subjects currently in screening are be eligible to receive treatment with 
single-agent DOXIL, if the investigator confirms that such treatment would be a clinically 
appropriate therapeutic option.
Pharmacokinetic Sample Collection
A population PK model has been developed using data from 15 studies performed in patients 
with solid malignancies, including 3 studies (ET-743-INT-11, ET-B-009-9, and ET-OVA-301) 
in subjects with ovarian cancer. Blood samples for population PK analysis will be collected 
using a sparse sampling scheme from at least 40 subjects in the trabectedin+DOXIL combination 
treatment group. These data will be analyzed using a population PK model to characterize the PK 
of trabectedin in the patient population enrolled in the present study.
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BRCA 1 and BRCA 2 Mutations
The mechanisms of action of both trabectedin and DOXIL involve DNA damage. BRCA 1/2 is 
part of the homologous recombination repair (HRR) machinery responsible for DNA repair. This 
study will attempt to build on existing data by investigating the association of BRCA 1/2
mutation status with OS, PFS, and other endpoints by stratification based on BRCA 1/2 mutation 
status (mutation vs no mutation) prior to randomization. 
4.
SUBJECT POPULATION
Following Amendment 6, in those instances where the investigator confirms that single-agent 
treatment with DOXIL would be a clinically appropriate therapeutic option for subjects in 
screening, those subjects in screening would need to meet study inclusion and exclusion criteria
as specified in Sections 4.1 and 4.2.
The inclusion and exclusion criteria are described in the following 2 subsections. If there is a 
question about the inclusion or exclusion criteria below, the investigator should consult with the 
appropriate sponsor representative and resolve any issues before enrolling a subject in the study. 
Waivers are not allowed.
Prior to randomization, inclusion criteria #4 through #8 must be reviewed by sponsor’s medical 
monitor. Note: As of Amendment 6, subjects will not be randomized to study treatment.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study. Each 
subject must:
1.
Be a woman 18 years of age or older.
2.
Have histologically proven advanced-relapsed epithelial ovarian, primary peritoneal, or 
fallopian tube cancer.
3.
Have an ECOG performance status grade of 0 or 1.
4.
Have received first-line treatment with a platinum-based regimen and had no evidence of 
disease progression for 6 months after the last dose.
5.
Criterion modified per amendment
5.1
Have received second-line treatment with a platinum-based regimen, with progression 
of disease after attaining a response. A response could have been determined by 
imaging or by serum CA-125 levels.
6.
Criterion modified per amendment
6.1.
Have progression of disease based on imaging after the second-line platinum-based
regimen.
o
Subjects treated with a DOXIL-containing regimen as a second-line therapy are 
eligible if subsequent disease progression occurs 9 months from the first dose.
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7.
Criterion modified per amendment
7.1
Per Amendment 6, subjects no longer need to have disease response and disease 
progression events as noted in criteria #5 and #6 reviewed by the sponsor’s medical 
monitor prior to randomization.
8.
Have evidence of measurable disease at screening as evaluated by RECIST (Version 1.1) 
criteria (Attachment 2).
9.
Criterion modified per amendment
9.1
Per Amendment 6, subjects no longer need to be able to receive IV dexamethasone or 
an equivalent IV corticosteroid.
10. Have a known BRCA 1/2 mutation status. For subjects who do not have a known BRCA 1/2 
status at screening, a blood sample will be collected to determine the status with the results 
available prior to randomization.
11. Criterion modified per amendment
11.1
Criterion modified per amendment
11.2
Have all of the following:

hemoglobin 9 g/dL (without transfusion in the prior 7 days). Subjects may be enrolled 
into the study while receiving recombinant erythropoietin provided they have received
recombinant erythropoietin for at least 4 weeks before the first dose of study drug.

albumin 25 g/L

absolute neutrophil count (ANC) 1,500/μL

platelet count 100,000/µL (without transfusion in the prior 7 days)

either a serum creatinine 1.5 mg/dL or a calculated glomerular filtration rate 
60 mL/min/1.73 m2 (Cockcroft-Gault) (Attachment 6)

CPK 2.5 x upper limit of normal (ULN)
12. Have total bilirubin ULN. If total bilirubin is >ULN, measure direct and indirect bilirubin 
to evaluate for Gilbert’s syndrome (if direct bilirubin is within normal range, subject may be 
eligible).
13. Have alkaline phosphatase (ALP) 2.5xULN; if the ALP is >2.5xULN, then an ALP liver 
fraction or 5' nucleotidase must be ULN (as reported in absolute units of measure).
14. Have AST and ALT 2.5xULN.
15. Have LVEF by MUGA scan or 2D-ECHO within normal limits for the institution.
16. Have side effects (except alopecia) of prior treatment resolved to at least Grade 1 according 
to the National Cancer Institute – Common Terminology Criteria of Adverse Events 
(NCI-CTCAE) Version 4.0 (except for those laboratory criteria listed in eligibility criterion 
#11).
17. Have a negative pregnancy test (urinary or serum β-human chorionic gonadotropin [HCG]) 
at screening (applicable to women of child bearing potential).
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18. Criterion modified per amendment
18.1
Criterion modified per amendment
18.2
Be postmenopausal (>45 years of age with amenorrhea for at least 2 years or any 
age with amenorrhea for at least 6 months and a serum follicle stimulating hormone 
level >40 IU/L or mIU/mL), surgically sterile (have had a hysterectomy or bilateral 
oophorectomy, bilateral salpingectomy, bilateral tubal occlusion ligation [which 
includes tubal ligation procedures as consistent with local regulations], or otherwise 
be incapable of pregnancy), abstinent (acceptability of this method is at the 
discretion of the investigator who will ensure and document that the subject 
understands the definition of "abstinence", and who will periodically remind and 
counsel the subject on this topic), or if heterosexually active, be practicing two 
effective methods of birth control (eg, prescription hormonal contraceptive, 
intrauterine device, double-barrier method [eg, condoms, occlusive cap (diaphragm 
or cervical/vault caps) with spermicidal foam, cream, gel, film, or suppository]), 
before enrollment, and must agree to continue to use the same two methods of 
contraception throughout the study and for 6 months thereafter. Note: a female 
condom and a male condom should not be used together as friction between the two 
can result in either product failing.
Note: If the childbearing potential changes after the start of the study (eg, woman who is not 
heterosexually active becomes active), then the woman must begin two effective methods of 
birth control, as described above.
19. Be willing and able to adhere to the prohibitions and restrictions specified in this protocol. 
(Section 4.3, Prohibitions and Restrictions).
20. Each subject (or their legally acceptable representative) must sign an informed consent form 
(ICF) indicating that she understands the purpose of and procedures required for the study 
and is willing to participate in the study.
21. Each subject (or their legally acceptable representative) must sign a separate ICF if she 
agrees to provide an optional blood sample for pharmacogenomics research (where local 
regulations permit). Refusal to give consent for the optional research sample does not 
exclude a subject from participation in the study.
22. Must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study. A subject who:
1.
Has a diagnosis of ovarian carcinoma with mucinous histology.
2.
Criterion modified per amendment
2.1
Had more than 2 prior lines of systemic therapy. Maintenance therapies and hormonal 
therapies are not considered additional lines of therapy.
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Clinical Protocol ET743-OVC-3006 – Amendment 6
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3.
Criterion modified per amendment
3.1
Per Amendment 6, subjects who had a prior exposure to trabectedin or 
hypersensitivity to any of the excipients will not be excluded from receiving single-
agent DOXIL.
4.
Had prior treatment with doxorubicin or other anthracycline at cumulative doses greater 
than 300 mg/m2 (calculated using doxorubicin equivalent doses: 1 mg doxorubicin = 1 mg 
DOXIL = 1.8 mg epirubicin = 0.3 mg mitoxantrone = 0.25 mg idarubicin).
5.
Criterion modified per amendment:
5.1
Per Amendment 6, subjects unwilling or unable to have a central venous catheter 
placed will not be excluded from receiving single-agent DOXIL.
6.
Is pregnant or breast-feeding.
7.
Criterion modified per amendment
7.1
Would receive study treatment within 3 weeks from radiation therapy, experimental 
therapy, hormonal therapy, prior chemotherapy, or biological therapy; use an invasive 
investigational device; or is currently enrolled in an investigational study.
8.
Criterion modified per amendment
8.1 
Has a history of another invasive malignancy (except non-metastatic basal cell 
carcinoma or squamous cell carcinoma of the skin adequately treated) unless in 
remission for 5 years, or a non-invasive malignancy requiring ongoing therapy.
9.
Has known allergies, hypersensitivity, or intolerance to DOXIL, dexamethasone, or their 
excipients.
10. Has a known history of central nervous system metastasis.
11. Has known significant chronic liver disease, such as cirrhosis or active hepatitis (potential 
subjects who test positive for hepatitis B surface antigen or hepatitis C antibodies are 
allowed provided they do not have active disease requiring antiviral therapy). 
12. Had a myocardial infarct within 6 months before enrollment, New York Heart Association 
(NYHA) Class II or greater heart failure (Attachment 5), uncontrolled angina, severe 
uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or 
electrocardiographic evidence of acute ischemic or active conduction system abnormalities.
13. Has any of the following medical conditions:

Uncontrolled diabetes

Psychiatric disorder (including dementia) that prevents compliance with protocol

Uncontrolled seizures

Newly diagnosed deep vein thrombosis

Active systemic infection that is likely to interfere with study procedure or results
14. Has any condition that, in the opinion of the investigator, would compromise the well-being 
of the subject or the study or prevent the subject from meeting or performing study 
requirements.
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15. Is an employee of the investigator or study site, with direct involvement in the proposed 
study or other studies under the direction of that investigator or study site, as well as family 
members of the employees or the investigator.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
Section 17.4, Source Documentation, describes the required documentation to support meeting 
the enrollment criteria.
4.3.
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation:
1.
No concurrent investigational agents are permitted. 
2.
No concurrent antineoplastic therapy is permitted.
3.
No concurrent radiotherapy is permitted.
4.
No concurrent maintenance therapy for the disease being treated is permitted.
5.
Subjects may not receive dexrazoxane (Zinecard) during this study.
6.
Subjects may not receive yellow fever vaccine during this study.
The sponsor should be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
Investigators should take caution when administering inducers or inhibitors of cytochrome 
CYP3A4 (Section 8, Prestudy and Concomitant Therapy).
5.
TREATMENT ALLOCATION AND BLINDING
Following Amendment 6, subjects will not be randomized to study treatment. 
Treatment Allocation
Procedures for Stratification and Randomization
Prior to randomization, inclusion criteria #4 through #8 must be reviewed by sponsor’s medical 
monitor (Section 4.1, Inclusion Criteria). Following sponsor review, subjects will be stratified by 
the time from the last dose of first-line platinum therapy to disease progression (6 months to 
12 months vs >12 months to 24 months vs >24 months), ECOG performance status grade 
(0 vs 1), BRCA 1/2 status (mutation vs no mutation), and prior DOXIL therapy (no vs yes). 
Central randomization will be implemented in this study. Randomization of subjects should 
occur as close in time as possible before administration of the first dose of study drug(s) and 
must occur within 7 days of the subject receiving the first dose of study treatment. This 
maximum 7-day window is given to allow time for provision of central venous access for those 
subjects assigned to Treatment Arm A (Section 6, Dosage and Administration). Subjects will be 
randomly assigned, in a 1:1 ratio, to 1 of 2 treatment groups based on a computer-generated 
randomization schedule prepared before the study by or under the supervision of the sponsor. 
The interactive voice response system (IVRS) and/or interactive web response system (IWRS)
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Clinical Protocol ET743-OVC-3006 – Amendment 6
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Approved, 9 January 2018
will assign a unique treatment code, which will dictate the treatment assignment and matching 
study drug kit for the subject. The requestor must use his or her own user identification and 
personal identification number when contacting the IVRS/IWRS, and will then give the relevant 
subject details to uniquely identify the subject.
Blinding
The requirement of a central venous catheter, limited to the combination trabectedin+DOXIL 
arm, precludes blinded treatment in this study. This study will therefore be conducted as an 
open-label study.
6.
DOSAGE AND ADMINISTRATION
Janssen Research & Development (JR&D) will provide trabectedin and DOXIL as IV
formulations. The amount (in mg) of trabectedin and DOXIL to be administered will be 
determined by subject body surface area (BSA), which will be calculated according to the 
standard nomogram used at each center. Body surface area will be calculated either at Screening 
or on Day 1 of Cycle 1. It will not be necessary to recalculate BSA at each cycle unless the 
institution requires it or the subject has a significant weight change (approximately >10%). For 
those subjects with a body mass index (BMI) 30, the use of ideal body weight for dose 
calculation and capping of BSA utilized for dosing calculations will be left to the discretion of 
the investigator and to institutional guidelines. The calculated dose of DOXIL may be rounded to 
the nearest full mg that can be administered accurately. The dose of trabectedin may be rounded 
to the nearest second decimal place (eg, 1.721 can be rounded to 1.72) that can be administered 
accurately. The first dose of study drug may be administered at any time within 7 days of 
randomization. This period is to allow for the placement of central venous access, if a subject is 
assigned to the trabectedin+DOXIL arm of the study. 
Treatment Arm A: DOXIL 30 mg/m2 administered as an IV infusion over approximately
90 minutes (per package insert) followed by trabectedin 1.1 mg/m2 administered as an IV
infusion over approximately 3h, via central venous access, every 3 weeks. Central venous access 
is required for administration of trabectedin. If no infusion-related reaction is observed with 
DOXIL after the first infusion, DOXIL may be administered as a 60- to 90-minute infusion in 
subsequent cycles.
All subjects assigned to Treatment Arm A will be premedicated with 20 mg dexamethasone, 
administered IV approximately 30 minutes before the start of the DOXIL infusion, to reduce the 
incidence of transaminase elevation related to trabectedin. If dexamethasone is not available, an 
equivalent IV dose of another corticosteroid may be substituted. For subjects in Treatment Arm A, 
trabectedin will be administered as an IV infusion over approximately 3h immediately after the 
catheter is flushed well with 5% dextrose in water (D5W). Trabectedin should be diluted in normal 
saline or D5W to a volume of at least 500 mL and infused via a central venous catheter. Any 
calibrated infusion pump may be used to deliver the drug. The administration of both drugs will be 
repeated every 3 weeks. The prophylactic use of granulocyte-colony stimulating factor (G-CSF) is 
strongly recommended for those subjects assigned to Treatment Arm A.
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Treatment Arm B: DOXIL, 50 mg/m2 administered as an IV infusion over approximately 
90 minutes (per package insert) every 4 weeks. If no infusion-related reaction is observed with 
DOXIL after the first infusion, DOXIL may be administered as a 60- to 90-minute infusion in 
subsequent cycles. DOXIL may be administered through a central or peripheral venous catheter.
Treatment Arms A and B:
For both treatment arms, a scheduled dosing window of +2 days will be allowed for 
administrative purposes (eg, clinic scheduling, national holiday, patient's daughter is getting 
married). Administration of study drug within this window will not be considered a dosing delay 
and should not be recorded as such on the case report form (CRF) unless the delay is to allow for 
recovery from an adverse event. Detailed information on the requirements for storage, 
reconstitution and dilution, accountability, and disposal of trabectedin can be found in the 
Investigator Brochure.
Treatment Options – Amendment 6:
For subjects assigned to Arm A (trabectedin+DOXIL), treatment with trabectedin should be 
immediately discontinued. All study subjects (Arm A or Arm B) currently on study who, in the
opinion of the investigator, are deriving clinical benefit may continue treatment with single-agent 
DOXIL as per the local standard of care. Treatment for these subjects may continue as long as 
the subjects comply with protocol-specified prohibitions and restrictions for treatment 
(Section 4.3) and as long as they experience clinical benefit in the opinion of the investigator. 
DOXIL will be provided by the JR&D as needed until post-trial access to DOXIL is available or 
until disease progression, whichever occurs first.
6.1.
Criteria for Continuation of Treatment
On Day 1 of each subsequent treatment cycle (Cycle 2 and beyond), the criteria specified in Table 1
must be met in order for treatment to occur. If the criteria in Table 1 are not met on Day 1 of a new 
cycle, the subject must be evaluated at least weekly and the new cycle will start upon recovery to 
the Day 1 criteria specified in Table 1. Dosing may be delayed for a maximum of 3 weeks to allow 
for recovery of toxicity. If toxicity does not resolve after 3 weeks of delay, the subject must
discontinue treatment. If it is determined that a subject can continue treatment, it may be necessary 
to reduce the dose of study drug based on maximum toxicity or critical analytes or toxicities, that 
occurred since the previous dose as described in Section 6.2, Dose Modification. 
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Table 1:
Criteria for Continuation of Treatment
Variable
Day 1
Platelets
100,000/µL
ANC
1,500/µL
Hemoglobin
9 g/dL
Bilirubin
ULN
ALP
2.5 x ULN; unless ALP liver fraction or 
5' nucleotidase is normala
Albumin
25 g/L
Transaminases
2.5 x ULN
Creatine phosphokinase 
2.5 x ULN
Serum creatinine
1.5 mg/dL
LVEFb
≥LLN
Other nonhematologic, drug-related effects
Grade 2 or lower
ALP=alkaline phosphatase; ANC=absolute neutrophil count; LVEF=left ventricular ejection 
fraction; LLN=institutional lower limit of normal; ULN=upper limit of normal
a
If the results of the ALP liver fraction or 5’ nucleotidase are not yet available because of 
the length of time required to obtain these results, the subject may receive the study 
drugs to avoid a treatment delay only if on an earlier assessment, total ALP had a similar 
value and the ALP liver fraction or 5’ nucleotidase was ULN, confirming that the ALP 
elevation was of osseous origin. ALP liver fraction should be reported and evaluated in 
absolute units of measure.
b
As determined by the most recent LVEF assessment.
Treatment should be discontinued for subjects who experience liver abnormalities that include all 
of the following within the same cycle: 

bilirubin 2 x ULN,

transaminases (ALT or AST) 3 x ULN, and

ALP (liver fraction) <2 x ULN (as reported in absolute units of measure).
Subjects must discontinue DOXIL for clinical evidence of cardiac toxicity or if the LVEF is 
compromised (ie, any absolute decrease in LVEF 10% and an LVEF value below the 
institutional lower limit of normal [LLN]). However, dosing with trabectedin should continue if 
the criteria for continuation of treatment are met (Table 1) and at the same dose. For those 
subjects on treatment Arm A who continue with trabectedin as a monotherapy after a cumulative 
anthracycline dose of 300 mg/m2 has been exceeded or due to cardiotoxicity, regular monitoring 
of LVEF every 2 cycles of treatment should continue, regardless of the cumulative dose of 
anthracycline. All subjects in Arm A should undergo LVEF assessments after Cycle 3 of study 
treatment, even if DOXIL has been discontinued.
6.2.
Dose Modification
Dose reductions will be made on the basis of the worst drug-related toxicity. However, 
investigators may also reduce the dose of either or both study drugs for toxicity, as clinically 
warranted. Dose reductions will be made on the basis of the worst drug-related toxicity that 
occurred since the previous dose, except for reductions due to AST or ALT increases that should 
only be based on Day 15 toxicity; see Section 6.2.1, Dose Reductions Due to Hematologic 
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Toxicity, and Section 6.2.2, Dose Reductions Due to Nonhematologic Toxicity. Table 2 and 
Table 3 specify the dose levels that will be used when dose reductions are required for subjects 
in the trabectedin+DOXIL combination therapy group or DOXIL monotherapy group,
respectively. Subjects who experience toxicities that require more than 2 dose reductions of the 
same drug must discontinue treatment with that drug. If trabectedin is discontinued for a subject 
in Treatment Arm A, premedication with dexamethasone is no longer required. Dose escalations 
are not allowed following a dose reduction for toxicity.
Table 2:
Dose Level Reductions – Trabectedin + DOXIL Group
Dose Level
Trabectedin
DOXIL
Starting level
1.1 mg/m2
30 mg/m2
Level –1
0.9 mg/m2
25 mg/m2
Level –2
0.75 mg/m2
20 mg.m2
Table 3:
Dose Level Reductions – DOXIL Group
Dose Level
DOXIL
Starting level
50 mg/m2
Level –1
37.5 mg/m2
Level –2
28 mg/m2
6.2.1.
Dose Reductions Due to Hematologic Toxicity
Subjects in either treatment group who experience hematologic toxicity meeting either criteria 
cited in Table 4 will have a dose level reduction as specified in Table 2 (trabectedin+DOXIL
group) or Table 3 (DOXIL group). Investigators may also reduce the dose of either or both study 
drugs for any toxicity, as clinically warranted. Only 2 dose reductions will be allowed. Subjects 
who experience toxicities that require more than 2 dose reductions must discontinue study 
treatment.
Table 4:
Dose Reductions for Hematologic Toxicity
Nadir Toxicity
Nadir Value
Trabectedin
DOXIL
Neutrophil count
<500/L with fever (38.5C)/infection
Decrease 1 level
Decrease 1 level
<500/L lasting more than 5 days
Decrease 1 level
Decrease 1 level
Platelet count
<25,000/L 
Decrease 1 level
Decrease 1 level
The prophylactic use of G-CSF is strongly recommended for those subjects randomized to 
treatment Arm A (Section 8, Prestudy and Concomitant Therapy).3
6.2.2.
Dose Reductions Due to Nonhematologic Toxicity
Subjects in either treatment group who experience non-hematologic toxicity meeting any of the 
criteria cited in Table 5 will have a dose level reduction as specified in Table 2
(trabectedin+DOXIL group) or Table 3 (DOXIL group). Investigators may also reduce the dose 
of either or both study drugs for any toxicity, as clinically warranted. Only 2 dose reductions of 
each study drug will be allowed. Subjects who experience toxicities that require more than 
2 dose reductions of the same drug must discontinue study treatment with that drug.
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Table 5:
Dose Reductions for Nonhematologic Toxicity
Toxicitya
Worst CTC 
Grade
Trabectedin
DOXIL
Nausea or vomiting despite adequate treatment
3
Decrease 1 level
Decrease 1 level
Stomatitis
3
No reduction
Decrease 1 level
Hand and foot syndrome (HFS)

First occurrence
3
No reduction
Decrease 1 level

Any occurrence after first occurrence of Grade 3/4 HFS
1
No reduction
Decrease 1 level
Bilirubin ULN at any time
1
Decrease 1 level
No reduction
Transaminase elevation (Day 15 of each cycle)

Recovery to Grade 1 by Day 1 of the next cycle or up to 
3 weeks after this date
3b
Decrease 1 level
Decrease 1 level

No recovery to Grade 1 by Day 1 of the next cycle or up 
to 3 weeks after this date
3b
Treatment
termination
Treatment 
termination
Alkaline phosphatase (ALP) 
2c
Decrease 1 level
No reduction
Creatine phosphokinase
≥3
Decrease 1 level
No reduction
Liver abnormalities within the same treatment cycle

Bilirubin 2 x ULN, transaminases (ALT or AST) 3 x 
ULN, and ALP <2 x ULN
Treatment
termination
Treatment 
termination
LVEF decline 10% and <LLN or clinical evidence of cardiomyopathy

First occurrence
No change
Treatment 
termination

Subsequent occurrence
Decrease 1 level
Not applicable
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CTC=common terminology 
criteria; HFS=hand and foot syndrome; LLN=institutional lower limit of normal; ULN=upper limit of normal
a
Dose reductions for any other severe toxicity not listed in this table should be discussed with the sponsor.
b
Worst CTC grade refers to measurements on Day 15 only.
c
Unless non-hepatic source can be documented by ALP liver fraction ≤ULN or by 5’-nucleotidase ≤ULN.
For subjects in Treatment Arm A who are required to discontinue treatment with either 
trabectedin or DOXIL, treatment with the other agent may continue if the subject is benefiting 
from therapy. Subjects in Treatment Arm A who receive 2 dose reductions of trabectedin 
because of toxicity or can no longer receive dexamethasone or use a central line, may receive 
DOXIL as a single agent. For subjects in Treatment Arm A who receive 2 dose reductions of 
DOXIL or can no longer receive DOXIL because of cardiac or other toxicity, may receive 
trabectedin as a single agent. If the dose has not been previously reduced for related toxicity, the 
dose of the continued single-agent drug may be increased as monotherapy to 1.3 mg/m2 for 
trabectedin every 3 weeks or 35 mg/m2 for DOXIL every 3 weeks. The new dose will be subject 
to the same rules for adjustment as described above in this section. If DOXIL is discontinued due 
to cardiac toxicity, then refer to Table 5 for treatment guidelines for trabectedin monotherapy.
Any significant decrease in LVEF (defined as absolute decrease 15%, or less than LLN and 
absolute decrease 5%) should be captured as an adverse event regardless of assessed clinical 
significance or action taken. The supplemental cardiac adverse events form should also be 
completed for these adverse events.
7.
TREATMENT COMPLIANCE
Study drugs will be administered as IV infusions by qualified staff at the study sites and the 
details of each administration will be recorded in the CRF (including date, start and stop times of 
the IV infusion, and volume infused). Treatment compliance (administration of the correct dose 
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according to the assigned schedule) will be documented in the hospital charts or notes and 
assessed on the basis of the completed treatment page of the CRF.
8.
PRESTUDY AND CONCOMITANT THERAPY
Prestudy therapies administered up to 30 days before first dose of study drug must be recorded at 
screening.
Concomitant therapies must be recorded throughout the study beginning from the time the ICF is 
signed to 30 days after the last dose of study drug or until 18 January 2018, whichever occurs 
first. Concomitant therapies should be recorded beyond 30 days after the last dose of study drug 
only in conjunction with serious adverse events that meet the criteria outlined in Section 12.3.2, 
Serious Adverse Events.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, exercise regimens) different from the study drug must be recorded in the CRF. Recorded 
information will include a description of the type of the drug, treatment period, dosing regimen, 
route of administration, and its indication. Modification of an effective preexisting therapy 
should not be made for the explicit purpose of entering a subject into the study.
Premedication with IV dexamethasone (or an equivalent IV corticosteroid) is required for 
subjects in the trabectedin group. The use of IV dexamethasone (or an equivalent IV 
corticosteroid) for this purpose is not considered concomitant therapy and will be documented as 
a required pretreatment medication on the study drug administration section of the CRF. 
Additional corticosteroid administration is allowed for antiemetic purposes. The use of IV 
dexamethasone (or an equivalent IV corticosteroid) for reasons other than the required 
pretreatment of subjects in the trabectedin group should be documented in the concomitant 
therapy section of the CRF, and the associated indication should be recorded as an adverse event, 
if appropriate. 
Any new condition or a worsening of an existing condition that requires the use of new or altered 
doses of concomitant therapies must be documented on the adverse events section of the CRF. 
Subjects may receive supportive care while receiving study drug, including transfusions, 
hematopoietic growth factors, antibiotics, analgesics, and antidiarrheal agents. Megestrol acetate 
may be used only for appetite stimulation.
Concomitant medications or therapies should be documented in the CRF. This includes:

Antiinfective medications (eg, antibiotics, antifungals, antivirals)

Hematopoietic cytokines

Any medications the subject was receiving when a serious adverse event started and 
medications administered to treat the serious adverse event.

Blood product transfusions received (the events that lead to the need for blood product 
transfusion should be recorded as adverse events, but not the transfusions themselves).
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
Analgesics, antiemetics, antidiarrheal agents

All inhibitors or inducers of cytochrome CYP3A4 (see below)
The metabolism of trabectedin may be modified by concomitant administration of compounds 
that induce or inhibit CYP3A4. Caution should be exercised if administration of such agents 
becomes necessary. Inhibitors of CYP3A4 include but are not limited to the following: 
aprepitant, clarithromycin, clotrimazole, diltiazem, erythromycin, fluconazole, grapefruit juice, 
indinavir, 
itraconazole, 
ketoconazole, 
nefazodone, 
nelfinavir, 
ritonavir, 
saquinavir, 
telithromycin, troleandomycin, and verapamil. Inducers of CYP3A4 include but are not limited 
to the following: barbiturates, phenytoin, carbamazepine, rifabutin, rifampin, and St. John’s wort.
Supportive Care Measures

Prophylactic use of G-CSF is strongly recommended for subjects assigned to the 
combination arm (Arm A).

Subjects may be enrolled into the study while receiving recombinant erythropoietin provided 
they have received recombinant erythropoietin for at least 4 weeks before the first dose of 
study drug.

Subjects may continue receiving hormone replacement therapy while on study.

Subjects may receive pyridoxine (vitamin B6) at 200 mg by mouth daily to help prevent 
HFS due to DOXIL. If given, treatment should begin before Day 1, Cycle 1.

All subjects receiving DOXIL should be cautioned to avoid vigorous activity, pressure on 
the skin, and exposure to extreme heat, hot water, and sun to reduce HFS-related symptoms.
For any concomitant therapy administered as a treatment for a new condition or a worsening of 
an existing condition, the condition must be documented on the adverse events page in the CRF.
9.
STUDY EVALUATIONS
Following Amendment 6, study data collection will cease when all subjects on study treatment 
have completed the treatment termination visit assessments as specified in the Time and Events 
Schedule for Amendment 6 or by 18 January 2018, whichever occurs first. For subjects 
continuing treatment with single-agent DOXIL, as per the local standard of care, only serious 
adverse events should be reported to JR&D as outlined in Section 12.3.2.
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule for Amendment 6 summarizes the treatment termination visit 
assessments.
All visit-specific PRO assessments during a visit should be conducted before any tests, 
procedures, or other consultations for that visit to prevent influencing subject perceptions.
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Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the subject's participation in the study.
The blood volumes collected from each subject for laboratory evaluations throughout this study 
are approximately 15 mL for screening serum chemistry and hematology tests; 10 mL for 
BRCA 1/2 testing at screening (for subjects who do not have a known BRCA 1/2 status); 4 mL 
for subjects consenting to the optional pharmacogenomics component of the study (where local 
regulations permit); 45 mL and 60 mL for treatment Arms A and B, respectively, per cycle for 
serum biochemistry and hematology tests; 4 mL per scheduled CA-125 sample; and 24 mL from 
those subjects who provide PK samples. Repeat or unscheduled samples may be taken for safety 
reasons.
9.1.2.
Screening Phase
Informed consent must be obtained before the conduct of any protocol-specific procedure. All 
screening procedures must be completed and results obtained, where applicable, before random 
assignment to treatment. It should be noted, however, that clinical assessments performed as part 
of the subject’s routine clinical evaluation and not specifically for this study need not be repeated 
after signed informed consent has been obtained, provided that these assessments fulfill the 
study’s requirements.
The Screening Phase begins with the signing of the informed consent and should not last longer 
than 30 days. During the Screening Phase, the medical monitors will confirm subject eligibility 
based on previous therapy history, according to inclusion criteria #4 through #8 [Section 4.1, 
Inclusion Criteria]). Response to second-line platinum-based therapy will be confirmed either 
based on imaging demonstrating at least a 30% decline in tumor burden or a 50% reduction of 
elevated baseline serum CA-125 levels (2 x ULN, measured within approximately 4 weeks 
prior to the first dose of second-line platinum-based therapy that is maintained after at least 
28 days as modified from Gynecologic Cancer Intergroup [GCIG] criteria [Attachment 1]).
A complete medical history and review of systems will be taken, including concomitant 
medications, prior therapy, and a description of key features of the disease including disease 
histology. Each subject must have an ECG and LVEF assessment (MUGA scan or 2D-ECHO) to 
document the LVEF is within normal range according to the institutional guidelines. A physical 
examination (including vital signs, weight, and height) will be performed, and BSA will be 
calculated either during screening or on Day 1 of Cycle 1. Laboratory evaluations (CA-125 
measurement at a local laboratory, hematology and serum chemistry) will be done, and a urine or 
serum pregnancy test will be done for women of childbearing potential. Eastern Cooperative 
Oncology Group performance status will be assessed. BRCA 1/2 status will be collected on the 
CRF for subjects who have previously been tested for BRCA 1/2 mutations. For subjects who do 
not have a known BRCA 1/2 status, a blood sample will be collected to determine BRCA 1/2
status during the screening phase. It is expected that BRCA 1/2 analysis will require 
approximately 10 to 14 days. In the case of delayed BRCA 1/2 mutation reporting, the screening 
period may be extended for up to 14 days (with medical monitor approval). In such cases, only 
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screening clinical laboratory assessments (hematology, clinical chemistry, and liver panel) will 
need to be repeated. On Day 1 of Cycle 1, subjects will also be offered the option of providing a 
whole blood sample for pharmacogenomics analysis.
Subject participation in the 
pharmacogenomic research component of the study is voluntary and refusal to participate will 
not result in ineligibility for the main part of the study. Consent for this is independent of the 
subject’s consent for the main body of the study. Either consent or refusal to participate in the 
pharmacogenomic analysis must be documented within the pharmacogenomics consent form.
Screening procedures to be completed within 30 days before randomization include:

Signed informed consent (including the optional pharmacogenomics informed consent, 
where applicable).

Review of eligibility criteria

Review of medical history and demographics

Review of prestudy therapy

Review of preplanned surgery/procedures(s)

LVEF assessment (MUGA or 2D-ECHO) and ECG

Tumor assessments, including radiographic imaging of the chest (with lung views), 
abdomen, and pelvis.

BRCA 1/2 status (In case of delayed BRCA 1/2 mutation reporting, the screening period 
may be extended for up to 14 days, with medical monitor approval.)

Pregnancy testing

Physical examination

Vital signs

ECOG performance status

Laboratory tests including CA-125, hematology, and clinical chemistry

Review of concomitant therapy

Review of adverse events

Submission of redacted source documents supporting subject eligibility relevant to inclusion 
criteria #4 through #8.

On or prior to Day 1 of Cycle 1, all subjects will be provided with a “wallet (study) card”
and instructed to carry this card with them for the duration of the study.
9.1.3.
Open-Label Treatment Phase
Following Amendment 6, study data collection including laboratory tests, cardiovascular 
monitoring, physical examinations, tumor assessments, PROs, and ECOG status will cease when 
all subjects on study treatment have completed the treatment termination visit assessments as 
specified in the Time and Events Schedule for Amendment 6 or by 18 January 2018, whichever 
occurs first. For subjects continuing treatment with single-agent DOXIL, as per the local 
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standard of care, only serious adverse events should be reported to JR&D as outlined in 
Section 12.3.2.
9.1.3.1.
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology may be obtained from a central venous 
catheter or a peripheral vein. Blood samples will be obtained on Days 1, 8, and 15 for subjects 
assigned to Arm A and on Days 1, 8, 15, and 22 for subjects assigned to Arm B. Day 1 blood 
samples should be obtained before administration of the study drugs. For both treatment arms, 
CA-125 samples will be collected at screening, approximately every 8 weeks after randomization 
for the first 4 evaluations, then approximately every 12 weeks until disease progression is 
radiographically confirmed, and at the treatment termination visit. For subjects who terminate 
treatment prior to disease progression, CA-125 samples will be collected during the follow-up 
phase according to schedule until disease progression is radiographically confirmed, the start of 
subsequent anticancer therapy, withdrawal of subject consent, or the clinical cutoff date. All 
CA-125 sample collections should coincide (5 days) with the scheduled tumor assessments. All
blood samples are to be obtained within 2 days prior to drug administration on Day 1 and 
2 days on Days 8 and 15 (Treatment Arm A) or Days 8, 15, and 22 (Treatment Arm B) of each 
treatment cycle. If a subject has an ANC of 500/L, the ANC for this subject should be
repeated, at most 5 days later to document recovery to >500/µL, and the scheduled visit can 
occur up to 3 days earlier in order to obtain the blood sample to perform this assessment.
Laboratory reports will be maintained at the study sites as source documents. Any clinically 
significant changes occurring during the study must be recorded on the adverse event page in the 
CRF.
Serum Chemistry 
A sample of approximately 10 mL of venous blood will be collected for the following 
assessments: total protein, ALP, AST, ALT, CPK, total (direct and indirect) bilirubin, blood urea 
nitrogen (BUN), creatinine, sodium, potassium, glucose, and albumin.
Hematology
A sample of approximately 5 mL of venous blood will be collected for the following 
assessments: hemoglobin, ANC, white blood cell count (WBC), and platelet count.
9.1.3.2.
Cardiovascular Safety
Left ventricular ejection fraction assessments (MUGA scans or 2D-ECHOs) will be performed 
for all subjects at screening (baseline), after an approximately 100 mg/m2 cumulative dose of 
planned anthracycline treatment with DOXIL (ie, after Cycle 3 for treatment Arm A and after 
Cycle 2 for treatment Arm B) and as part of end-of-treatment assessments (ie, end-of-treatment 
termination visit). In addition, those subjects who receive a total cumulative dose of 
anthracycline exceeding 300 mg/m2 (including previous and on-study treatments) or have a 
clinically significant history of cardiomyopathy should have follow-up LVEF assessments after 
every 2 cycles of therapy, or as clinically warranted. The same methodology (MUGA scans or 
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2D-ECHOs) should be used to assess scheduled LVEF assessments throughout the study.
Additional LVEF assessments performed during the study should be reported as unscheduled 
LVEF assessments.
9.1.3.3.
Physical Examination
A physical exam is to be performed and the results recorded only once during screening.
9.1.3.4.
Tumor Assessment
Measurable disease and the response criteria used in this protocol are defined in the RECIST 
guidelines (Version 1.1) (Attachment 2) and will be based on radiologic assessment only.
Every effort should be made to ensure that the same radiographic method of disease assessment 
(computed tomography [CT] scans or magnetic resonance imaging [MRI]) be used throughout 
the study. Disease assessment procedures to evaluate objective response must be consistent with 
RECIST (Version 1.1) guidelines for radiologic assessment, as presented in Attachment 2, 
RECIST Guidelines. The disease assessments should include, at a minimum, imaging of the 
chest (with lung views) abdomen, and pelvis. All disease assessments, including CA-125 
measurements, will be performed within 30 days before randomization, every 8 weeks (5 days) 
from the date of randomization for the first 4 assessments, and then every 12 weeks (5 days) 
until disease progression is radiographically confirmed, the start of subsequent anticancer 
therapy, withdrawal of subject consent, or the clinical cutoff date. Disease assessments should be 
performed at the treatment termination visit and according to schedule thereafter if disease 
progression or follow-up therapy has not been documented. Every effort should be made to 
ensure that these assessments are done on the required date, although a window of 5 days will 
be accommodated.
In case of clinical progression, radiologic assessments should proceed according to the original 
Time and Events Schedule or as clinically indicated. The date of progression will be defined as 
the date of the first imaging study that documents progression. 
Elevated CA-125 in the absence of radiographic progression is not to be considered evidence of 
disease progression. Therefore, it should not trigger an unscheduled assessment of tumor status
nor result in treatment discontinuation. Other signs or symptoms deemed related to disease when 
suggestive of progression, including escalating pain not referable to another cause, increased 
ascites, protracted nausea and vomiting despite treatment, declining performance status, and 
examination findings consistent with disease progression, are valid reasons to consider an 
unscheduled assessment of tumor status. In this case, the assessment would include both imaging 
and CA-125. To the extent possible, it is important that all subjects have radiologic 
documentation of progression before study withdrawal or the initiation of follow-up therapy.
If a subject requests discontinuation of the study treatment but consents to continued evaluation, 
follow-up according to study procedure should be performed. In particular, tumor status 
assessment should be done according to the study timetable.
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9.1.3.5.
Patient Reported Outcomes Assessments
Health-related quality of life will be assessed using the quality of life questionnaire (QLQ) OV28 
(Attachment 3). An additional PRO instrument, EQ-5D-5L (Attachment 4), will also be administered 
to perform preference based utility analysis. These questionnaires will be collected before any other 
tests or procedures are conducted on Day 1 of each treatment cycle and at the end-of-treatment 
evaluations. In addition, the EQ-5D-5L questionnaire will be collected approximately every 8 weeks 
thereafter until start of subsequent anticancer therapy.
9.1.3.6.
Other Assessments
Eastern Cooperative Oncology Group performance status will be assessed during screening and 
at treatment discontinuation. Adverse events and changes in concomitant medications should be 
recorded at every visit.
9.1.4.
Posttreatment Phase (Follow-Up)
Termination of Treatment
As of Amendment 6, all subjects who are on study treatment should have treatment termination 
visit assessments as specified in the Time and Events Schedule for Amendment 6 (ie, within 30 
days of the last dose of study drug) or by 18 January 2018, whichever occurs first.
For subjects who discontinue treatment for reasons other than radiographic disease progression, 
tumor assessments (including CA-125) will continue on schedule until: 1) disease progression is 
radiographically confirmed, 2) the subject withdraws consent, 3) the subject begins subsequent 
anticancer therapy, or 4) the study is terminated (ie, clinical cutoff). For subjects who 
discontinue study treatment, documentation of all subsequent anticancer therapy, survival status, 
and safety evaluations as outlined in the Time and Events Schedule will be required. Survival 
status should be recorded at least every 8 weeks for the first 2 years after the treatment 
termination visit and approximately every 12 weeks thereafter. Collection of survival status will 
continue until at least 514 deaths have been observed or until the clinical cutoff date. The access 
to study treatment will remain available for subjects who are consenting and eligible for 
treatment continuation. Once the study has been terminated, reporting will be limited to 
unexpected, drug-related serious adverse events during treatment or within 30 days of last dose 
of the study treatment.
Assessments at Treatment Termination Visit 
When it has been determined that a subject should permanently discontinue study treatment, she 
will be asked to return for a treatment termination visit. This visit should occur 30 days (+3 days)
after the last dose of study drug. At this visit, the following assessments will be recorded: ECOG 
performance status, ECG, MUGA scan or 2D-ECHO, assessment of tumor status including 
CA-125 measurement, PRO assessments, and hematology and clinical chemistry assessments. 
Adverse events and concomitant therapies until 30 days after the last dose of study drug will be 
recorded.
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Follow-up Data Collection after Treatment Termination
As of Amendment 6, follow-up data will no longer be collected.
Follow-up assessments for survival status should occur at least every 8 weeks for the first 2 years 
after the treatment termination visit and then approximately every 12 weeks thereafter, until 
death or the clinical data cutoff date. Any clinically significant abnormalities persisting at 
30 days after the last dose of study drug will be followed by the investigator until resolution or 
until a clinically stable endpoint is reached. Drug-related Grade 3 or Grade 4 toxicities will be 
monitored until Grade 2 or less, or for a maximum of 6 months after the last dose of study drug, 
whichever, occurs first. Grade 2 to 4 liver or cardiac toxicities will be monitored until Grade 1 or 
less, or for a maximum of 6 months after the last dose of study drug, whichever occurs first.
Disease assessments (including CA-125) will be performed using the same radiographic 
technique (CT scans or MRI) approximately every 8 weeks after randomization for the first 
4 assessments and then approximately every 12 weeks until disease progression
is 
radiographically confirmed, the start of subsequent anticancer therapy, withdrawal of subject 
consent, or the clinical cutoff date. Subjects who have disease progression at treatment 
termination should continue to be followed for survival and the start of subsequent anticancer 
therapy. Every effort should be made to record all subsequent anticancer therapies, along with 
their dates of administration.
9.2.
Efficacy 
9.2.1.
Evaluations
Efficacy will be assessed by determination of the OS, PFS, and ORR end points (Attachment 2). 
Appropriate radiological disease assessments (CT scans or MRI) of the chest (with lung views), 
abdomen, and pelvis and will be performed within 30 days before randomization, approximately 
every 8 weeks (5 days) after randomization for the first 4 assessments, and then every 12 weeks 
(5 days) until disease progression is radiographically confirmed, the start of subsequent 
anticancer therapy, withdrawal of subject consent, or the clinical cutoff date (18 January 2018). 
Assessments must be done consistently (every 8 weeks [5 days] for the first 4 assessments and 
then every 12 weeks [5 days]) in both treatment arms to ensure an unbiased assessment of 
tumor response and progression. 
CA-125 analysis will be done at screening, approximately every 8 weeks after randomization for 
the first 4 evaluations and then approximately every 12 weeks until disease progression is 
radiographically confirmed, the start of subsequent anticancer therapy, withdrawal of subject 
consent, or the clinical cutoff date (18 January 2018). CA-125 sample collections should 
coincide (5 days) with the scheduled tumor assessments. Analyses of CA-125 will be done at a 
local laboratory. 
CA-125 shall not be used as a basis to assess disease response or progression during study 
treatment and should not guide treatment decisions.
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Survival follow up will continue for all enrolled subjects until at least 514 deaths are observed or 
until the clinical cutoff date.
9.2.2.
Endpoints 
Primary Endpoint

Overall survival (OS), is defined as the time between the date of randomization and the date 
of death.
Secondary Endpoints

Progression-free survival (PFS), is defined as the time between the date of randomization 
and the date of disease progression or death;

Objective response rate (ORR), defined as the total number of subjects with either a CR or 
PR

Population PK using a sparse sampling scheme

Safety will be described according to the frequency of adverse events that occur in the 
treatment arms.
Exploratory Endpoints

Pharmacogenomic evaluation of BRCA 1 or BRCA 2 mutation status (mutation vs no 
mutation).

Patient reported outcomes using the QLQ-OV28 and EQ-5D-5L questionnaires.
9.3.
Pharmacokinetics
9.3.1.
Evaluations
Sparse samples for measurement of trabectedin concentrations in plasma will be collected from 
at least 40 subjects in the trabectedin+DOXIL treatment group.
Venous blood samples of 4 mL each will be collected for determination of plasma concentrations 
of trabectedin within 1 h before the start of trabectedin infusion, at 1 h after start of infusion, at 
10 minutes before the end of infusion, and 0.5 h, 24 h, and 168 h after the end of infusion on
Cycle 1. The actual dates and times of sample collection must be recorded on the laboratory 
requisition form. Blood samples will be obtained through an indwelling peripheral venous 
catheter; therefore, an appropriate amount (1 mL) of serosanguineous fluid slightly greater than 
the dead space volume of the lock will be removed from the cannula and discarded before each 
blood sample is taken. Blood samples will be obtained directly from the lock in a slow manner 
into the Vacutainer tube. After blood sample collection, the cannula will be flushed with
0.9% sodium chloride, United States Pharmacopeia (USP) (or equivalent) and charged with a 
volume equal to the dead space volume of the lock. Instructions for blood collection, sample 
handling, and shipment are provided in the laboratory manual.
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Genetic analyses will not be performed on these plasma samples, and subject confidentiality will 
be maintained.
9.3.2.
Analytical Procedures
Pharmacokinetics
Plasma samples will be analyzed to determine concentrations of trabectedin using a validated, 
specific, 
and 
sensitive 
liquid 
chromatography/mass 
spectrometry/mass 
spectrometry
(LC-MS/MS) method by or under the supervision of the sponsor. 
9.3.3.
Pharmacokinetic Parameters
Pharmacokinetic analysis will be the responsibility of the sponsor in accordance with the current 
Clinical Pharmacokinetics Guideline. Clearance and volume of distribution will be the primary 
parameters of interest for the population PK analysis. Additional PK parameters will be 
calculated, if deemed appropriate.
9.4.
Pharmacogenomic Evaluations
9.4.1.
Mandatory BRCA 1 and BRCA 2 Mutation Analysis
Reporting of BRCA 1/2 status will be required prior to randomization and is to be collected on 
the CRF. For subjects who do not have a known BRCA 1/2 status, a blood sample will be 
collected, and BRCA 1/2 status determined within 30 days prior to randomization. It is expected 
that BRCA 1/2 analysis will require approximately 10 to 14 days. In the case of delayed 
BRCA 1/2 mutation reporting, the screening period may be extended for up to 14 days (with 
medical monitor approval). In such cases, only screening clinical laboratory assessments 
(hematology, clinical chemistry, and liver panel) will need to be repeated. Because there are 
multiple possible mutations for any one subject, stratification will be based on the presence of a 
BRCA 1/2 mutation (mutation vs no mutation).
For subjects with a known mutation status for either BRCA 1 or BRCA 2, but not for both genes, 
the result from the single gene tested will be captured in the CRF. If the status of the reported 
gene indicates a mutation, the status will be used for randomization. However, if the single gene 
tested indicates no mutation, then BRCA testing for the other gene is to be conducted and 
reported within 30 days prior to randomization.
9.4.2.
Optional Pharmacogenomic Analyses
Subjects will be given the opportunity to participate in the optional pharmacogenomic 
component of this study, where local regulations permit. Collection of pharmacogenomic 
samples will allow for genetic research to help understand trabectedin/DOXIL activity in 
advanced-relapsed epithelial ovarian, primary peritoneal, and fallopian tube cancers. Genetic 
analysis will be conducted if it is hypothesized that this may help resolve issues with the clinical 
data. DNA samples will be used for research related to trabectedin/DOXIL and 
advanced-relapsed epithelial ovarian, primary peritoneal, and fallopian tube cancers. They may 
also be used to develop tests/assays related to trabectedin/DOXIL and advanced-relapsed 
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epithelial ovarian, primary peritoneal, and fallopian tube cancers. Genetic research may consist 
of the analysis of one or more candidate genes or of the analysis of genetic markers throughout 
the genome (as appropriate) in relation to trabectedin/DOXIL and advanced-relapsed epithelial 
ovarian, primary peritoneal, and fallopian tube cancer clinical endpoints.
9.5.
Safety Evaluations
Details regarding the IDMC are provided in Section 11.9, Independent Data Monitoring 
Committee.
Any clinically significant abnormalities persisting 30 days after the last dose of study drug will 
be followed by the investigator until resolution, until a clinically stable endpoint is reached, or 
until the clinical cutoff date (18 January 2018). Drug-related Grade 3 or Grade 4 toxicities will 
be assessed until Grade 2 or less, for a maximum of 6 months after the last dose of study drug, or 
until the clinical cutoff date (18 January 2018), whichever occurs first. Grade 2 to 4 liver or 
cardiac toxicities will be monitored until the toxicity is Grade 1 or less, for a maximum of 
6 months after the last dose of study drug, or until the clinical cutoff date (18 January 2018), 
whichever occurs first.
In selected cases of cardiac adverse events, investigators may be asked to complete a 
supplemental CRF section in order to provide more detailed information relating to the event. 
Any additional LVEF assessments should be reported as unscheduled assessments.
Note: Following Amendment 6, study data collection for adverse events (except for serious 
adverse events), laboratory tests, cardiovascular monitoring, vital signs, and physical 
examinations will cease when all subjects on study treatment have completed the treatment 
termination visit assessments as specified in the Time and Events Schedule for Amendment 6 or 
by 18 January 2018, whichever occurs first. For subjects continuing treatment with single-agent 
DOXIL, as per the local standard of care, only serious adverse events should be reported to 
JR&D as outlined in Section 12.3.2.
Adverse Events
Adverse events will be reported by the subject or investigator (or, when appropriate, by a 
caregiver, surrogate, or the subject's legally-acceptable representative) for the duration of the 
study. Adverse events will be followed by the investigator as specified in Section 12, Adverse 
Event Reporting.
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Clinical Laboratory Tests
Blood samples for serum chemistry and hematology will be collected. The investigator must 
review the laboratory report, document this review, and record any clinically relevant changes 
occurring during the study in the adverse event section of the CRF. The following tests will be 
performed by the local laboratory and entered into the CRF:

Hematology Panel
-hemoglobin
-white blood cell (WBC) count 
-absolute neutrophil count (ANC)
-platelet count

Serum Chemistry Panel
-sodium
-alkaline phosphatase (ALP)
-potassium
-creatine phosphokinase (CPK)
-blood urea nitrogen (BUN)
-albumin
-creatinine
-total protein
-glucose
-aspartate aminotransferase (AST)
-alanine aminotransferase (ALT)
-total (direct and indirect) bilirubin

Serum or urine pregnancy testing for women of childbearing potential only.
Potential cases of hepatotoxicity will be thoroughly investigated. Investigators will complete a 
supplemental CRF section and provide additional supporting documentation for all subjects who 
experience all of the following within the same cycle: total bilirubin values 2 x ULN, elevated 
transaminase values (AST or ALT) 3 x ULN, and ALP values 2 x ULN.
Electrocardiogram and Left Ventricular Ejection Fraction Assessments
The study will include evaluations of ECGs and LVEF. The same procedure for the assessment 
of LVEF (MUGA scan or 2D-ECHO) should be used for all scheduled assessments throughout 
the study. The screening (baseline) LVEF assessment and ECG must be performed within 
30 days before randomization, and the LVEF must be within normal range according to the 
institutional guidelines. Left ventricular ejection fraction assessments will be performed after 
Cycle 3 for treatment Arm A and after Cycle 2 for treatment Arm B (ie, within the 21 day period 
after Cycle 3 Day 1 and the next scheduled dose and within the 28 day period after Cycle 2 
Day 1 and the next scheduled dose, respectively). In addition, subjects’ who have received a 
cumulative dose of anthracyclines that exceeds 300 mg/m2 (including previous and on-study 
treatments) or have a clinically significant history of cardiomyopathy, must have follow-up 
LVEF assessments after every 2 cycles of therapy. Each subject must also have a LVEF 
assessment at the treatment termination visit. Subsequent LVEF assessments may be indicated 
during the follow-up period if significant LVEF decline is noted (Section 9.1.4) at the time of 
end of treatment.
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During the collection of ECGs and LVEF assessments, subjects should be in a quiet setting 
without distractions (eg, television, cell phones). Subjects should rest in a supine position for at 
least 5 minutes before the ECG and LVEF assessments and should refrain from talking or 
moving arms or legs. If blood sampling or vital sign measurement is scheduled for the same time 
point as ECG recording, the procedures should be performed in the following order: ECGs, 
LVEF assessments, vital signs, blood draw.
Vital Signs (temperature, pulse/heart rate, respiration rate, and blood pressure)
Blood pressure and heart rate measurements will be assessed while the subject is in a seated 
position with a completely automated device. Manual techniques will be used only if an 
automated device is not available.
Blood pressure and heart rate measurements should be preceded by at least 5 minutes of rest in a 
quiet setting without distractions (eg, television, cell phones).
Physical Examination (including height and weight measurements)
9.6.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF or laboratory 
requisition form. For the pharmacokinetic samples, the actual dates and times of sample 
collection must be recorded on the laboratory requisition form. If blood samples are collected via 
an indwelling cannula, an appropriate amount (1 mL) of serosanguineous fluid slightly greater 
than the dead space volume of the lock will be removed from the cannula and discarded before 
each blood sample is taken. After blood sample collection, the cannula will be flushed with
0.9% sodium chloride, USP (or equivalent) and charged with a volume equal to the dead space 
volume of the lock. Refer to the Time and Events Schedule for the timing and frequency of all 
sample collections.
Instructions for the collection, handling, and shipment of samples are found in the laboratory 
manual that will be provided. Collection, handling, storage, and shipment of samples must be 
under the specified, and where applicable, controlled temperature conditions as indicated in the 
laboratory manual.
10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Completion
A subject will be considered to have completed the study if she has experienced a clinical 
endpoint that precludes further study (eg, mortality in a mortality endpoint study) or has 
withdrawn consent for follow-up. Following the completion of the treatment termination visit
assessments on or by 18 January 2018, per protocol Amendment 6, data collection will end. For 
subjects continuing treatment with single-agent DOXIL, as per the local standard of care, only 
serious adverse events should be reported to JR&D as outlined in Section 12.3.2.
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10.2.
Discontinuation of Treatment 
As of Amendment 6, treatment with trabectedin should be immediately discontinued for subjects 
assigned to Arm A (trabectedin+DOXIL). All study subjects (Arm A or Arm B) currently on 
study who, in the opinion of the investigator, are deriving clinical benefit may continue treatment 
with single-agent DOXIL as per the local standard of care. Treatment for these subjects may 
continue as long as the subjects comply with protocol-specified prohibitions and restrictions for
treatment (Section 4.3) and as long as they experience clinical benefit in the opinion of the 
investigator. DOXIL will be provided by JR&D as needed until post-trial access to DOXIL is 
available or until disease progression, whichever occurs first.
If a subject's study treatment must be discontinued before disease progression has been
documented, this will not result in automatic withdrawal of the subject from the study. 
A subject's study treatment should be discontinued if:

The subject has disease progression,

The subject meets protocol prescribed criteria for drug discontinuation due to toxicity after 
appropriate dose reductions (Section 6.2),

The subject does not meet the criteria for continuation of treatment (Section 6.1),

The subject develops a concurrent medical condition (adverse event) that precludes further 
participation,

The subject begins a subsequent anticancer therapy,

The subject completes 2 cycles of treatment after assessment of a CR,

The subject requests to stop receiving treatment, or

The subject becomes pregnant.
If a subject discontinues study treatment before disease progression has occurred, end-of-
treatment assessments should be obtained, and follow-up for scheduled assessments (eg, survival 
and radiographic disease assessments) should be continued.
10.3.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent (no further treatment and no further follow-up)
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal and survival 
status. The measures taken to follow up must be documented.
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When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the CRF and in the source document. Study drug assigned to the withdrawn 
subject may not be assigned to another subject. Subjects who withdraw will not be replaced.
A subject who withdraws from the study will have the following options regarding the optional
pharmacogenomic research sample:

The collected sample will be retained and used in accordance with the subject's original 
separate informed consent for optional research samples.

The subject may withdraw consent for optional research samples, in which case the sample 
will be destroyed and no further testing will take place. To initiate the sample destruction 
process, the investigator must notify the sponsor site contact of withdrawal of consent for 
the optional research samples and to request sample destruction. The sponsor study site 
contact will, in turn, contact the biomarker representative to execute sample destruction. If 
requested, the investigator will receive written confirmation from the sponsor that the 
sample has been destroyed.
Withdrawal From the Optional Research Samples While Remaining in the Main Study
The subject may withdraw consent for optional research samples while remaining in the study. In 
such a case, the optional research sample will be destroyed. The sample destruction process will 
proceed as described above. However, all samples will be made nonidentifiable after the Clinical 
Study Report is issued and thereafter cannot be identified for destruction. If the sample has 
already undergone conversion to the nonidentifiable format, the sponsor will notify the 
investigator in writing.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan.
11.1.
Subject Information
For all subjects who are randomly assigned to study drug descriptive statistics will be provided.
11.2.
Sample Size Determination
This study is designed to demonstrate a statistically significant difference in OS between subjects 
treated with the trabectedin+DOXIL combination therapy and those treated with the DOXIL 
monotherapy in the third-line setting. The OS endpoint will incorporate group sequential design 
by including 1 interim analysis and 1 final analysis using the O’Brien-Fleming boundaries as
implemented by Lan-DeMets α-spending method. It is assumed that failure will follow an 
exponential distribution with a constant hazard rate. Assuming a median OS of 16 months for the 
active control group (DOXIL monotherapy), a planned sample size of approximately 
670 subjects will provide 80% power to detect a HR of 0.78 (16 months vs 20.5 months) at a 
2-tailed significance level of 0.05 and an enrollment duration of approximately 52 months 
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(13 subjects/month enrollment) over a total study duration of 64 months to obtain the required 
514 events.
11.3.
Efficacy Analyses
All efficacy endpoints will be analyzed using the All Randomized set of the population. The 
Kaplan-Meier product limit method and un-stratified Cox proportional hazards model will be 
used to estimate the time-to-event variables and to obtain the HR and their 95% CI. The 
un-stratified log-rank test will be used as the primary analysis for treatment comparison. The 
response rate variables will be evaluated using Chi-square statistic (un-stratified).
Sensitivity analyses for the primary endpoint using the stratified log-rank test will also be 
performed. Subgroup analyses will be carried out to assess if the treatment effect is consistent 
across clinically relevant subgroups.
Primary Endpoint
Overall survival is defined as the time between the date of randomization and the date of death. 
Subjects who die, regardless of the cause of death, will be considered to have had an event. 
Subjects who are still being treated, who are lost to follow-up prior to the end of the study, or 
who have withdrawn consent from the study will be censored at the last available date where the 
subject is known to be alive. 
Overall survival will be compared between both treatment arms by the un-stratified, 2-sided, 
log-rank test. The analysis of the primary endpoint, OS, will be conducted after at least 
514 events (deaths) are observed or until the clinical cutoff date. An interim analysis is planned 
for this study; after observing 60% (308 death events) of the total number of required (514) death 
events. The Kaplan-Meier method will be used to estimate the distribution of functions of OS for 
each treatment arm. The number of events, subjects censored, the estimate of medians, and 95% 
CI for the medians will be presented. Survival rates will be calculated using the Kaplan-Meier 
method. The un-stratified Cox proportional hazards model will be used to obtain the HR and its
95% CI.
Overall survival will also be compared between the treatment arms by a 2-sided log-rank test, 
stratified for: the time from the last dose of first-line platinum therapy to disease progression 
(6 months to 12 months vs >12 months to 24 months vs >24 months), ECOG performance status 
grade (0 vs 1), BRCA 1/2 status (mutation vs no mutation), and prior DOXIL therapy (no vs 
yes).
In case an imbalance in baseline prognostic factors is observed, especially PFI, a Cox 
proportional hazards model will also be used to compare the 2 treatment arms. The following 
baseline information includes as covariates: baseline ECOG (0 vs 1), PFI (as continuous), BRCA 
1/2 status (mutation vs no mutation), prior DOXIL therapy (no vs yes), and any imbalanced 
factors. From the Cox proportional hazards regression, HR estimates and their 95% CIs will be 
estimated for treatment and for the prognostic factors.
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Secondary Endpoints
Progression-free survival is defined as the time between the date of randomization and the date 
of disease progression or death. Subjects who progressed or died will be considered to have had 
an event, except if the event occurs after the start of subsequent therapy for ovarian cancer, in 
which case the subject will be censored at the time of the last tumor assessment (prior to or on 
the first day of the first subsequent therapy for ovarian cancer). Subjects who do not progress or 
die (ie, lost to follow-up, or receiving treatment without documented disease progression, or 
started subsequent therapy for ovarian cancer and still alive) will be censored at the date of the 
last tumor assessment (prior to or on the first day of the first subsequent therapy for ovarian 
cancer).
Progression-free survival will be compared between both treatment arms using the un-stratified
log-rank test. The Kaplan-Meier method will be used to estimate the distribution function of PFS 
for each treatment arm. The number of events, subjects censored, the estimate of medians, and 
95% CIs for the medians will be presented. Six-month and 1-year progression-free rates will be 
calculated using the Kaplan-Meier product limit method.
Objective response rate is defined as the total number of subjects with either a CR or PR as 
defined by RECIST (Version 1.1). All other subjects will be considered non-responders in the 
analysis. The response rate will be evaluated using the Chi-square statistic (un-stratified).
The ECOG value at the end of treatment visit will be tabulated (not cross-tabulated against the 
baseline value). The listing will contain both ECOG values.
Hierarchical Testing
In the event that the primary endpoint of OS is significant, the Hochberg procedure will be used 
to hierarchically test the secondary endpoints at the overall (2-sided) significance level 0.05. 
11.4.
Pharmacokinetic Analyses
Sparse PK data will be listed in the population PK-report, for all subjects with available 
concentrations in the trabectedin+DOXIL treatment group. Subjects will be excluded from the 
PK analysis if their data do not allow for accurate assessment of the PK (eg, improper handling 
of PK samples, incomplete administration of the study agent; missing time or dosing 
information). All concentrations below the lowest quantifiable concentration or missing data will 
be labeled as such in the concentration data presentation. All subjects and samples excluded from 
the analysis will be retained in the dataset but will be flagged out and the criteria for exclusion 
documented. 
Population PK analysis of plasma concentration-time data of trabectedin will be performed using 
nonlinear mixed-effects modeling. Data may be combined with those of a selection of Phase 1, 2, 
and 3 studies to support a relevant structural model. Available subject characteristics 
(demographics, laboratory variables, genotypes, concurrent dexamethasone use, etc.) will be 
tested as potential covariates affecting PK parameters. Details will be given in a population PK 
analysis plan and the results of the population PK analysis will be presented in a separate report.
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11.5.
Patient Reported Outcomes
Patient reported outcome assessments based on the EQ-5D-5L and QLQ-OV28 questionnaires
will be analyzed to determine if therapeutic response and/or side effects of therapy are 
accompanied by measurable changes in the PROs. The analysis will be performed on summary 
scores as well as subscales, and individual symptoms, with specific analytical methods outlined 
in a formal Statistical Analysis Plan developed prior to database lock. 
Differences between the treatment arms will be evaluated using published methods. Specific 
interest centers on abdominal and gastrointestinal symptom scales of QLQ-OV28. The change in 
PRO scores between baseline and each postbaseline assessment will be described overall and 
according to the response to treatment. 
11.6.
Pharmacogenomic Analyses
BRCA 1/2 status will be evaluated for association with time-to-event endpoints (eg, OS and 
PFS) using the log-rank test. Response rate may also be evaluated using the appropriate 
categorical method. Analyses will be performed within and between each treatment group. The 
Kaplan-Meier method and Cox model will be used to obtain a HR and its 95% CI. Other clinical 
covariates, such as race, age, and tumor burden may also be included in the model.
11.7.
Safety Analyses
All subjects who have received at least part of 1 dose of study drug will be included in the safety 
analysis, according to the actual treatment received. The safety parameters to be evaluated are 
the incidence, intensity, and type of adverse events, ECGs, LVEF assessments (MUGA scans or 
2D-ECHOs), and clinical laboratory results. Exposure to the study drugs and reasons for 
discontinuation of study treatment will be tabulated.
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) and will be graded according 
to the NCI-CTCAE, Version 4.0. All reported adverse events with onset during the treatment 
phase (ie, those events that occur or worsen on or after the first dose of study drug up through 
30 days after the last dose of study drug) will be included in the analysis. Adverse events will be 
summarized by MedDRA system organ class and preferred term. For each adverse event, the 
percentage of subjects who experience at least 1 occurrence of the given event will be 
summarized overall and by treatment group. Serious adverse events and deaths will be listed. All 
adverse events resulting in discontinuation of study treatment, dose modification, the interruption 
of dosing, or a delay in treatment with the study drug will be listed and summarized by preferred 
term.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. The worst toxicity grade will be 
tabulated.
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Parameters with predefined NCI-CTCAE, Version 4.0, toxicity grades will be summarized. 
Change from baseline to the worst adverse event grade experienced by the subject during the 
study will be provided as shift tables.
Electrocardiogram and Multigated Acquisition Scans or 2-Dimensional Echocardiograms
The effects on cardiovascular variables will be evaluated by means of descriptive statistics and 
frequency tabulations. A separate report on cardiac safety will also be prepared.
11.8.
Interim Analysis
One interim analysis is planned for this study after observing 60% (308 events) of the total 
number of required (514) events (deaths). The spent will be 0.008 for the interim analysis. The 
O’Brien-Fleming boundaries as implemented by Lan-DeMets -spending functions are used for 
the boundary. The spent will be adjusted accordingly based on the actual number of events 
observed. Operating characteristics for the boundaries are presented in Table 6.
Table 6:
Statistical Operating Characteristics
Interim (60% of Total Events)
Final
Projected Observed Events
308
514
Efficacy Boundary (HR)
0.74
0.84
Cumulative α spent
0.008
0.05
HR=Hazard ratio
11.9.
Independent Data Monitoring Committee
An IDMC will be established to review the efficacy and safety data according to the prescribed 
statistical plan. The committee will meet periodically (approximately every 6 months) to review 
safety data. After the review, the IDMC will make recommendations regarding the continuation 
of the study. The details will be provided in a separate IDMC charter.
The committee will consist of members who are not employees of the sponsor and are not 
otherwise involved in the conduct of the study. The membership will include one or more
statisticians and medical oncologists with experience in treating subjects with ovarian cancer. 
Note: On 26 June 2017, the IDMC requested a futility analysis of OS to be performed at the time 
of the next meeting 6 months later. In view of the IDMC request, study data up to 
20 September 2017 were evaluated for safety and OS (45% rather than 60% of the required death 
events at the planned interim analysis). Following the review of the study data by the IDMC on 
15 December 2017, the HR for OS was 0.962, crossing the previously agreed upon threshold for 
futility of 0.93. In view of this result and the observed and expected higher toxicity in Arm A as 
compared with Arm B, the IDMC recommended discontinuing the study. Therefore, as of 
Amendment 6, no new subjects will be randomized to study treatment, and treatment with 
trabectedin should be immediately discontinued for subjects assigned to Arm A 
(trabectedin+DOXIL). All study subjects (Arm A or Arm B) currently on study who, in the 
opinion of the investigator, are deriving clinical benefit may continue treatment with single-agent 
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DOXIL as per the local standard of care. Treatment for these subjects may continue as long as 
the subjects comply with protocol-specified prohibitions and restrictions for treatment 
(Section 4.3) and as long as they experience clinical benefit in the opinion of the investigator. 
DOXIL will be provided by JR&D as needed until post-trial access to DOXIL is available or 
until disease progression, whichever occurs first.
12.
ADVERSE EVENT REPORTING
Following Amendment 6, only serious adverse events for subjects continuing to receive single-
agent DOXIL should be reported to JR&D as outlined in Section 12.3.2. 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not 
related to that medicinal (investigational or non-investigational) product. (Definition per 
International Conference for Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)
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
Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For trabectedin, the expectedness of an adverse 
event will be determined by whether or not it is listed in the Investigator's Brochure. For DOXIL, 
the expectedness of an adverse event will be determined by whether or not it is listed in the
package insert or the Committee for Medicinal Products for Human Use Summary of Product 
Characteristics.
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2, Attribution Definitions.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
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Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Inadvertent or accidental exposure to a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion)
Up to and including 18 January 2018, special reporting situations should be recorded in the CRF. 
After 18 January 2018, any special reporting situation that meets the criteria of a serious adverse 
event should be reported to JR&D using the Serious Adverse Event Form (Section 12.3.2).
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be 
reported from the time a signed and dated ICF is obtained until 30 days after the administration 
of the last dose of study drug or until the scheduled treatment termination visit on or prior to 
18 January 2018. Any drug-related Grade 3 or 4 toxicities will be followed by the investigator 
until Grade 2 or less, for a maximum of 6 months after the last dose of study drug, or until the 
scheduled treatment termination visit on or prior to 18 January 2018, whichever occurs first. 
Grade 2 to 4 liver or cardiac toxicities will be monitored until Grade 1 or less, for a maximum of 
6 months after the last dose of study drug, or until the scheduled treatment termination visit on or 
prior to 18 January 2018, whichever occurs first.
Serious adverse events, including those spontaneously reported to the investigator within 30 days 
after the last dose of study drug, must be reported using the Serious Adverse Event Form. The 
sponsor will evaluate any safety information that is spontaneously reported by an investigator 
beyond the time frame specified in the protocol. All events that meet the definition of a serious 
adverse event will be reported as serious adverse events, regardless of whether they are 
protocol-specific assessments.
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document and the CRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the CRF their opinion concerning the 
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relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The 
investigator (or sponsor where required) must report SUSARs to the appropriate Independent 
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless 
otherwise required and documented by the IEC/IRB.
Subjects (or their designees, if appropriate) must be provided with a "wallet (study) card" and 
instructed to carry this card with them for the duration of the study indicating the following: 

Study number

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Statement, in the local language(s), that the subject is participating in a clinical study.

Site number

Subject number
12.3.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, which must be completed and signed by a physician from the study site, 
and transmitted to the sponsor within 24 hours. The initial and follow-up reports of a serious 
adverse event should be made by facsimile (fax).
All serious adverse events that have not resolved upon discontinuation of the subject's 
participation in the study, must be followed until any of the following occurs:

The event resolves

The event stabilizes (as noted in Section 9.5).

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts)
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
The study ends (when post-trial access to DOXIL is available for subjects remaining on 
single-agent DOXIL or until disease progression, whichever occurs first).
Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the course of a subject's participation in a study must be reported as a serious 
adverse event, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons 
such as pending placement in long-term care facility).

Surgery or procedure planned before entry into the study (must be documented in the CRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not 
be considered serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event.

For reasons described in the protocol, eg, study drug administration, protocol-required 
testing.

For the administration of blood or platelet transfusion. Hospitalization or prolonged 
hospitalization for a complication of such transfusion remains a reportable serious adverse 
event.

As part of a procedure for protocol/disease related investigations (eg, surgery, scans, 
endoscopy, sampling for laboratory tests, bone marrow sampling). Hospitalization or 
prolonged hospitalization for a complication of such a procedure remains a reportable 
serious adverse event.
The cause of death of a subject in a study within 30 days of last dose of study drug, whether or 
not the event is expected or associated with the study drug, is considered a serious adverse event.
Disease progression should not be recorded as an adverse event or serious adverse event term; 
instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of 
efficacy will be reported if they fulfill the serious adverse event definition (see Section 12.1.1, 
Adverse Event Definitions and Classifications).
12.3.3.
Pregnancy 
All initial reports of pregnancy must be reported to the sponsor by the study-site personnel 
within 24 hours of their knowledge of the event using the Pregnancy Notification Form. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered serious adverse events and must be reported 
using the Serious Adverse Event Form. Any subject who becomes pregnant during the study 
must be promptly withdrawn from the study. Follow-up information regarding the outcome of 
the pregnancy and any postnatal sequelae in the infant will be required.
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12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. PQCs may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site staff within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be 
maintained for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
As of Amendment 6, subjects in treatment Arm A will discontinue treatment with trabectedin. 
All study subjects (Arm A or Arm B) currently on study treatment who, in the opinion of the 
investigator, are deriving clinical benefit may continue treatment with single-agent DOXIL as 
per the local standard of care. Treatment for these subjects may continue as long as the subjects 
comply with protocol-specified prohibitions and restrictions for treatment (Section 4.3) and as 
long as they experience clinical benefit in the opinion of the investigator. DOXIL will be 
provided by JR&D as needed until post-trial access to DOXIL is available or until disease 
progression, whichever occurs first. 
14.1.
Physical Description of Study Drug(s)
The trabectedin (YONDELISIV formulation) supplied for this study is a white to off-white 
powder for reconstitution, dilution, and IV infusion. Each vial of trabectedin for injection is a 
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single-use vial. It will be manufactured and provided under the responsibility of the sponsor. Refer 
to the Investigator's Brochure for a list of excipients. 
DOXIL will be supplied as a sterile, translucent, red liposomal dispersion. Refer to the 
Investigator's Brochure and package insert for a list of excipients.
14.2.
Packaging
The study drug will be packaged in individual kits. Each kit will consist of 1 vial of study drug
(trabectedin or DOXIL). Trabectedin is provided by the sponsor as a sterile lyophilized product 
in vials containing 1.0 mg of trabectedin. 
DOXIL is provided by the sponsor in glass, single-use vials. Each vial contains either 20 mg of 
DOXIL at a concentration of 2 mg/mL or 50 mg of DOXIL at a concentration of 2 mg/mL. See 
the package insert for more details.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage
Trabectedin
Refer to the Investigator's Brochure of YONDELIS (provided as a separate document) for 
instructions regarding drug inventory, handling, reconstitution, dilution, storage, accountability, 
and disposal.
Trabectedin is a cytotoxic anticancer medicinal product, and caution should be exercised during 
handling. 
No incompatibilities have been observed between YONDELIS and Type 1 glass vials, 
polyvinylchloride, 
polyethylene, 
polyethylene 
and 
polypropylene 
mixture 
bags, 
polyvinylchloride or polyethylene tubing, or titanium or plastic resin implantable vascular access 
systems.
Only calibrated infusion pumps with the above product contact surfaces should be used to deliver 
the drug. 
All trabectedin study drug must be stored at controlled temperatures ranging from 2ºC to 8ºC 
(36ºF to 46ºF) in a refrigerator.
DOXIL
The vials contain either 20 mg of doxorubicin HCl in 10 mL or 50 mg of doxorubicin HCl in 
25 mL (both at a concentration of 2 mg doxorubicin HCl/mL), unless specified otherwise on the 
label. Determine the volume of DOXIL to be administered (based on the dose specified in the 
protocol, see Section 6, Dosage and Administration).
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Take the appropriate volume of DOXIL up into a sterile syringe. Aseptic technique must be 
strictly observed since no preservative or bacteriostatic agent is present in DOXIL. Each vial is 
for single use only.
Dilute the DOXIL in D5W. For doses 12 mg and 90 mg, dilute in 250 mL of D5W. For doses 
90 mg, dilute in 500 mL of D5W. Once the DOXIL has been diluted, it must be kept 
refrigerated at 2°C to 8°C and administered within 24 hours of mixing. See Section 6, Dosage 
and Administration, for detailed instructions on administering DOXIL in this study. Infusion 
may be given through a peripheral vein or a central line.
DOXIL should not be mixed with other drugs until specific compatibility data are available. 
The presence of any bacteriostatic agent, such as benzyl alcohol, may cause precipitation of 
DOXIL.
Caution should be exercised in handling the DOXIL solution. The use of gloves is 
recommended. If DOXIL comes into contact with skin or mucosa, immediately wash thoroughly 
with soap and water.
DOXIL should be handled and disposed of in a manner consistent with other anticancer drugs.
All DOXIL study drug must be stored at controlled temperatures ranging 2C to 8C (36°F to 
46°F) in a refrigerator. Do not freeze.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The study drug administered to the subject must be 
documented on the drug accountability form. All study drug will be stored and disposed of 
according to the sponsor's instructions. Study-site personnel must not combine contents of the 
study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug must be available for verification by the sponsor's 
site monitor during on-site monitoring visits. The return to the sponsor of unused study drug, or 
used returned study drug for destruction, will be documented on the Drug Return Form. When 
the study site is an authorized destruction unit and study drug supplies are destroyed on site, this 
must also be documented on the Drug Return Form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. 
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
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to subjects participating in the study. Returned study drug must not be dispensed again, even to 
the same subject. Study drug may not be relabeled or reassigned for use by other subjects. The 
investigator agrees neither to dispense the study drug from, nor store it at, any site other than the 
study sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator's Brochure (trabectedin and DOXIL)

Case report forms 

Laboratory supplies to process samples that will be sent to the central laboratory, including 
study manuals

Package insert for DOXIL

NCI-CTCAE, Version 4.0

QLQ-OV28 and Euro EQ-5D-5L questionnaires

Investigator file binder to keep all documents concerning the trial.

RECIST guidelines Version 1.1

Patient Qualification Form

IVRS/IWRS Manual and codes. These are part of the Investigator file but are supplied in a 
separate binder.

An IDMC has been commissioned for this study. Details regarding objectives and 
procedures for this committee are contained in a separate Charter that will accompany the 
protocol in regions where this is required.

Electronic data capture (eDC) Manual
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
The current trial is a randomized, open-label study. As the experimental agent trabectedin is 
administered via a central catheter, for ethical reasons the comparator control is generally 
administered via a peripheral vein. The study is open label because blinding of the treatment 
arms is not possible due to the mode of administration and administration schedules of the study 
drugs. The single-agent arm (DOXIL) has a slightly higher dose of DOXIL (dose as per the 
product package insert) while the combination (trabectedin+DOXIL) combines the 2 agents at 
lower doses. Criteria for further dose adjustments are outlined for each study arm. The study 
population is well defined (subjects with platinum-sensitive advanced-relapsed epithelial 
ovarian, primary peritoneal, or fallopian tube cancer who have received 2 previous lines of 
platinum-based chemotherapy) and will receive the standard of care therapy in both arms of the 
trial. Subjects will be fully informed of the potential risks of treatment with the study drugs, and 
can withdraw consent at any time.
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The trabectedin+DOXIL combination therapy has shown better efficacy (prolonged PFS) than 
DOXIL monotherapy in the second-line treatment of refractory ovarian cancer
in 
Study ET743-OVA-301. Based on a retrospective analysis of OS in Study ET743-OVA-301, 
subjects with platinum-sensitive disease who receive the trabectedin+DOXIL combination 
therapy may also experience prolonged survival. Because trabectedin is added to DOXIL, the 
combination therapy is expected to result in a higher incidence of some adverse events when 
compared to the DOXIL monotherapy comparator arm.
The retrospective analysis of OS data in Study ET743-OVA-301 indicates that the lack of 
statistical significance for OS resulted from an imbalance in prognostic factors (PFI) at 
randomization. BRCA 1/2 mutation status is a key prognostic factor in ovarian cancer15,16. 
Therefore, subjects in this study will be stratified by BRCA 1/2 mutation status (mutation vs no 
mutation). The mutation status will only be used to stratify the subjects to treatment 
(trabectedin+DOXIL or DOXIL). Depending upon the region, it is expected that as many as 50% 
of potential subjects will have a known BRCA 1/2 status, as this testing is routinely used in 
standard medical practice to assess genetic risk to specific cancers15,16. For those subjects without 
a known BRCA 1/2 status, genetic analysis of BRCA 1/2 will be required and, therefore, 
performed as a study-related procedure. The results of this analysis will be reported to the 
investigator.
All participating subjects will receive full supportive care and will be followed closely for safety 
and efficacy throughout the trial. Efficacy assessments will occur according to the internationally 
accepted response criteria. Safety assessments will occur through regular clinic visits including 
laboratory analyses. It is anticipated that the volumes of blood drawn for each subject for routine 
laboratory evaluations throughout the study will be approximately 15 mL for screening serum 
chemistry and hematology tests; 10 mL for BRCA 1/2 testing at screening (for subjects who do 
not have a known BRCA 1/2 status); 4 mL for subjects consenting to the optional 
pharmacogenomics component of the study (where local regulations permit); 45 mL and 60 mL 
for treatment Arms A and B, respectively, per cycle for serum biochemistry and hematology 
tests; 4 mL per scheduled CA-125 sample; and 24 mL from those subjects who provide PK 
samples. Overall, the volume of blood to be drawn is deemed reasonable over the time frame of 
the study. An IDMC will follow safety and efficacy during the study at regular intervals 
(approximately every 6 months) and in the prespecified interim analysis, respectively.
Note: Following the review of the study data by the IDMC on 15 December 2017, the HR for OS 
was 0.962, crossing the previously agreed upon threshold for futility of 0.93. In view of this
result and the observed and expected higher toxicity in Arm A as compared with Arm B, the 
IDMC recommended discontinuing the study. Therefore, as of Amendment 6, no new subjects 
will be randomized to study treatment, and treatment with trabectedin should be immediately 
discontinued for subjects assigned to Arm A (trabectedin+DOXIL). All study subjects (Arm A or 
Arm B) currently on study treatment who, in the opinion of the investigator, are deriving clinical 
benefit may continue treatment with single-agent DOXIL as per the local standard of care. 
Treatment for these subjects may continue as long as the subjects comply with protocol-specified 
prohibitions and restrictions for treatment (Section 4.3) and as long as they experience clinical 
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benefit in the opinion of the investigator. DOXIL will be provided by JR&D as needed until 
post-trial access to DOXIL is available or until disease progression, whichever occurs first.
All subjects still on study treatment should be informed of the reasons for the discontinuation of 
the study, and the potential risks and benefits of continued treatment with single-agent DOXIL
should be discussed.
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled. 
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the clinical study is performed in accordance 
with the protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable 
regulatory and country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the clinical study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required,
as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects
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
Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data, or study conduct, unless required locally), the ICF, applicable 
recruiting materials, and subject compensation programs, and the sponsor has received a copy of 
this approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
Approval for the collection of optional samples for research and for the corresponding ICF must 
be obtained from the IEC/IRB. Approval for the protocol can be obtained independent of this 
optional research component. 
During the study, the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data, or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
study drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data, or trial conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
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At least once a year, the IEC/IRB will be asked to review and reapprove this study. The 
reapproval should be documented in writing (excluding the ones that are purely administrative, 
with no consequences for subjects, data, or study conduct).
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion.
16.2.3.
Informed Consent
Each subject (or a legally acceptable representative) must give written consent according to local 
requirements after the nature of the study has been fully explained. The ICF(s) must be signed 
before performance of any study-related activity. The ICF(s) that is/are used must be approved 
by both the sponsor and by the reviewing IEC/IRB and be in a language that the subject can read 
and understand. The informed consent should be in accordance with principles that originated in 
the Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory 
requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects or their legally acceptable representatives the aims, 
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail. Subjects will be informed that their participation is 
voluntary and that they may withdraw consent to participate at any time. They will be informed 
that choosing not to participate will not affect the care the subject will receive for the treatment 
of her disease. Subjects will be told that alternative treatments are available if they refuse to take 
part and that such refusal will not prejudice future treatment. Finally, they will be told that the 
investigator will maintain a subject identification register for the purposes of long-term follow up 
if needed and that their records may be accessed by health authorities and authorized sponsor 
personnel without violating the confidentiality of the subject, to the extent permitted by the 
applicable law(s) or regulations. By signing the ICF the subject or legally acceptable 
representative is authorizing such access, including permission to obtain information about her 
survival status, and agrees to allow her study physician to recontact the subject for the purpose of 
obtaining consent for additional safety evaluations, if needed, and subsequent disease-related 
treatments, or to obtain information about her survival status.
The subject or legally acceptable representative will be given sufficient time to read the ICF and 
the opportunity to ask questions. After this explanation and before entry into the study, consent 
should be appropriately recorded by means of either the subject's or her legally acceptable 
representative's personally dated signature. After having obtained the consent, a copy of the ICF
must be given to the subject.
Subjects will be asked to consent to provide optional samples for research (where local 
regulations permit). After informed consent for the clinical study is appropriately obtained, the 
subject or her legally acceptable representative will be asked to sign and personally date a 
separate ICF indicating agreement to participate in optional research component. Refusal to 
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participate in the optional research will not result in ineligibility for the study. A copy of this 
signed ICF will be given to the subject.
Where local regulations require, a separate ICF may be used for the required DNA component of 
the study.
If the subject or legally acceptable representative is unable to read or write, an impartial witness 
should be present for the entire informed consent process (which includes reading and explaining 
all written information) and should personally date and sign the ICF after the oral consent of the 
subject or legally acceptable representative is obtained.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of study subjects confidential.
The informed consent obtained from the subject (or her legally acceptable representative)
includes explicit consent for the processing of personal data and for the investigator/institution to 
allow direct access to his or her original medical records (source data/documents) for 
study-related monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also 
addresses the transfer of the data to other entities and to other countries.
The subject has the right to request through the investigator access to her personal data and the 
right to request rectification of any data that are not correct or complete. Reasonable steps will be 
taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory DNA research is not conducted under standards appropriate for the return of data to 
subjects. In addition, the sponsor cannot make decisions as to the significance of any findings 
resulting from exploratory research. Therefore, exploratory research data will not be returned to 
subjects or investigators, unless required by law or local regulations. Privacy and confidentiality 
of data generated in the future on stored samples will be protected by the same standards 
applicable to all other clinical data.
16.2.5.
Long-Term Storage of Samples for Future Research
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand trabectedin/DOXIL 
or advanced-relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer, to 
understand 
differential 
drug 
responders, 
and 
to 
develop 
tests/assays 
related 
to 
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trabectedin/DOXIL or advanced-relapsed epithelial ovarian, primary peritoneal, or fallopian tube 
cancer. The research may begin at any time during the study or the post-study storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (See Section 10.3, Withdrawal From the Study).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product, unless explicitly addressed as a specific ethical 
consideration in Section 16.1, Study-Specific Design Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IRB (and IEC where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative listed in the Contact Information page(s), which will be provided as a separate
document. Except in emergency situations, this contact should be made before implementing any 
departure from the protocol. In all cases, contact with the sponsor must be made as soon as 
possible to discuss the situation and agree on an appropriate course of action. The data recorded 
in the CRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
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17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all clinical sub-investigators

Documentation of sub-investigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable.
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
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reports and communications relating to the study will identify subjects by subject identification
and date of birth. In cases where the subject is not randomized into the study, the date seen and 
date of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the CRF: subject identification, eligibility, and study identification; study discussion 
and date of informed consent; dates of visits; results of safety and efficacy parameters as 
required by the protocol; record of all adverse events and follow-up of adverse events; 
concomitant medication; drug receipt/dispensing/return records; study drug administration 
information; and date of study completion and reason for early discontinuation of study drug or 
withdrawal from the study, if applicable. 
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document).
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents.
17.5.
Case Report Form Completion
Case report forms are provided for each subject in printed or electronic format. All CRF entries, 
corrections, and alterations must be made by the investigator or authorized study-site personnel. 
The investigator must verify that all data entries in the CRF are accurate and correct.
Electronic Data Capture (eDC) will be used for this study. The study data will be transcribed by 
study-site personnel from the source documents onto an electronic CRF, and transmitted in a 
secure manner to the sponsor within the timeframe agreed upon between the sponsor and the 
study site. The electronic file will be considered to be the CRF.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the subject's source documentation. All data relating to the 
study must be recorded in CRFs prepared by the sponsor. Data must be entered into CRFs in 
English. Study-site personnel must complete the CRF as soon as possible after a subject visit, 
and the forms should be available for review at the next scheduled monitoring visit.
The investigator must verify that all data entries in the CRFs are accurate and correct. All CRF 
entries, corrections, and alterations must be made by the investigator or other authorized 
study-site personnel. If necessary, queries will be generated in the eDC tool. If corrections to a 
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CRF are needed after the initial entry into the CRF, this can be done in either of the following 
ways:

Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and 
study-site personnel.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, and periodic monitoring visits by the sponsor. Written 
instructions will be provided for collection, preparation, and shipment of samples. 
Guidelines for CRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The sponsor will review CRFs for accuracy and completeness during 
on-site monitoring visits and after transmission to the sponsor; any discrepancies will be resolved 
with the investigator or designee, as appropriate. After the upload of the data into the study 
database, they will be verified for accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
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If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
17.8.
Monitoring
The sponsor will use a combination of monitoring techniques (central, remote, or on-site 
monitoring) to monitor the study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first 
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare the data entered into the CRFs with the source documents 
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the 
CRF are known to the sponsor and study-site personnel and are accessible for verification by the 
sponsor study-site contact. If electronic records are maintained at the study site, the method of 
verification must be discussed with the study-site personnel. 
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the CRF are consistent with the original source data. Findings 
from this review of CRFs and source documents will be discussed with the study-site personnel. 
The sponsor expects that, during monitoring visits, the relevant study-site personnel will be 
available, the source documentation will be accessible, and a suitable environment will be 
provided for review of study-related documents. The monitor will meet with the investigator on a 
regular basis during the study to provide feedback on the study conduct.
In addition, to on-site monitoring visits, remote contact can occur. It is expected that during these 
remote contacts, study-site personnel will be available to provide an update on the progress of 
the study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed with the last visit for the last subject participating in the 
study. The final data from the study site will be sent to the sponsor (or designee) after completion 
of the final subject visit at that study site, in the time frame specified in the Clinical Trial 
Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
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study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further drug development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection and comparison with the CRFs. Subject 
privacy must, however, be respected. The investigator and study-site personnel are responsible 
for being present and available for consultation during routinely scheduled study-site audit visits 
conducted by the sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding trabectedin and DOXIL or 
the sponsor's operations (eg, patent application, formulas, manufacturing processes, basic 
scientific data, prior clinical data, formulation information) supplied by the sponsor to the 
investigator and not previously published, and any data, including pharmacogenomic research 
data, generated as a result of this study, are considered confidential and remain the sole property 
of the sponsor. The investigator agrees to maintain this information in confidence and use this 
information only to accomplish this study, and will not use it for other purposes without the 
sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of trabectedin and DOXIL, and thus may 
be disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
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The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain CRF data from all study sites that participated in the study. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Results of pharmacogenomics 
analyses performed after the Clinical Study Report has been issued will be reported in a separate 
report and will not require a revision of the Clinical Study Report. Study subject identifiers will 
not be used in publication of results. Any work created in connection with performance of the 
study and contained in the data that can benefit from copyright protection (except any 
publication by the investigator as provided for below) shall be the property of the sponsor as 
author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. Subject to the publication terms under 
the Clinical Trial Agreement, the investigator has the right to publish study site-specific data 
after the primary data are published. If an investigator wishes to publish information from the 
study, a copy of the manuscript must be provided to the sponsor for review at least 60 days 
before submission for publication or presentation. Expedited reviews will be arranged for 
abstracts, poster presentations, or other materials. If requested by the sponsor in writing, the 
investigator will withhold such publication for up to an additional 60 days to allow for filing of a 
patent application. In the event that issues arise regarding scientific integrity or regulatory 
compliance, the sponsor will review these issues with the investigator. For multicenter study 
designs and substudy approaches, secondary results generally should not be published before the 
primary endpoints of a study have been published. Similarly, investigators will recognize the 
integrity of a multicenter study by not submitting for publication data derived from the individual 
study site until the combined results from the completed study have been submitted for 
publication, within 12 months of the availability of the final data (tables, listings, graphs), or the 
sponsor confirms there will be no multicenter study publication. Authorship of publications 
resulting from this study will be based on the guidelines on authorship, such as those described 
in the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, which state that 
the named authors must have made a significant contribution to the design of the study or 
analysis and interpretation of the data, provided critical review of the paper, and given final 
approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.
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McMeekin S (2007), Del Campo JM, Colombo N, et al. Trabectedin in relapsed ovarian cancer (ROC): a 
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Minuzzo M (2000), Marchini S, Broggini M, et al. Interference of transcriptional activation by the 
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Monk BJ (2010), Herzog TJ, Kaye SB, et al. Trabectedin plus pegylated doxorubicin in recurrent ovarian 
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Monk BJ (2012), Herzog TJ, Kaye SB, et al. Trabectedin plus pegylated liposomal doxorubicin (PLS) versus 
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NCCN Guidelines (2012). Genetic/Familial High-Risk Assessment: Breast and Ovarian Versioun1.2012. 
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Sessa C (2005), De Braud F, Perotti A, et al. Trabectedin for women with ovarian carcinoma after treatment 
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Von Mehren M (2008), Schilder RJ, Cheng JD, et al. A phase I study of the safety and pharmacokinetics of 
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& Development, LLC.
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Attachment 1: Evaluation of Response According to CA-125 (GCIG Criteria)
Definition of response. A response according to CA 125 has occurred if there is at least a 50% reduction 
in CA 125 levels from a pretreatment sample. The response must be confirmed and maintained for at least 
28 days. Patients can be evaluated according to CA 125 only if they have a pretreatment sample that is at 
least twice the upper limit of normal and within 2 weeks prior to starting treatment.
To calculate CA 125 responses accurately, the following rules apply:

intervening samples and the 28-day confirmatory sample must be less than or equal to (within an 
assay variability of 10%) the previous sample.

variations within the normal range of CA 125 levels will not interfere with the response definition.

For each patient, the same assay method must be used and the assay must be tested in a quality-
control scheme.

Patients are not evaluable by CA 125 if they have received mouse antibodies (unless the assay used 
has been shown not to be influenced by HAMA) or if there has been medical and/or surgical 
interference with their peritoneum or pleura during the previous 28 days. If assessing therapy that 
includes two treatment modalities for relapse (e.g., surgery and chemotherapy), any CA 125 response 
results from both treatments modalities. CA 125 cannot distinguish between the effects of the two 
treatments.
The date when the CA 125 level is first reduced by 50% is the date of the CA 125 response. To calculate 
response rates, an intent-to-treat analysis should be used that includes all patients with an initial CA 125 
level of at least twice the upper limit of normal as eligible and evaluable. In addition, as a separate 
analysis, those patients who have both a CA 125 response and whose CA 125 level falls to within the 
normal range, can be classified as CA 125 complete responders. Patients who have a fall of CA 125 to 
within the normal range but whose initial CA 125 was less than twice the upper limit of normal, have not 
had a CA 125 response and cannot therefore be classified as a CA 125 complete responder.
Evaluation of response according to CA 125 in patients receiving maintenance or consolidation 
therapy. Patients whose CA 125 is greater than twice the upper limit of normal when they start 
maintenance or consolidation therapy can be evaluated according to the GCIG CA 125 response 
definition. It should be noted that there is no data to validate response evaluation in this situation. To 
prevent the prior therapy interfering with the response assessment the following requirement is 
recommended. Two pre-treatment samples no more than 8 weeks apart are required if test treatment is 
given as part of maintenance or consolidation therapy. For the test treatment to be evaluable according to 
CA 125 there must be no more than a 10% fall in CA125 between the two pretreatment samples. The 
sample closest in time to the test therapy should be considered the pre-treatment sample
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Attachment 2: RECIST Guidelines 
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
The following information was extracted from Section 3, Section 4, and Appendix I of the New response 
evaluation criteria in solid tumours:  revised RECIST guideline (version 1.1) authored by Eisenhauer et al 
(2009). Refer to the European Journal of Cancer article (2009;45(2):228-247) for the complete 
publication. 
Measurability of tumor at baseline
Definitions
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as follows:
Measurable:
Tumor lesions:  Must be accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm)

10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with 
calipers should be recorded as non-measurable)

20 mm by chest X-ray 
Non-measurable:
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes with 
10 to <15 mm short axis) as well as truly non-measurable lesions. Lesions considered truly non-
measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified 
by physical exam that is not measurable by reproducible imaging techniques.
Specifications by methods of measurements
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up. Imaging based evaluation should always be done 
rather than clinical examination unless the lesion(s) being followed cannot be imaged but are assessable 
by clinical exam. 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial and 
10 mm diameter as assessed using calipers (e.g. skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is suggested. As 
noted above, when lesions can be evaluated by both clinical exam and imaging, imaging evaluation 
should be undertaken since it is more objective and may also be reviewed at the end of the study. 
Chest X-ray:  Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions 
on chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated lung. 
See Appendix II for more details. 
CT, MRI:  CT is the best currently available and reproducible method to measure lesions selected for 
response assessment. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. As is described in Appendix II, when CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
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thickness. MRI is also acceptable in certain situations (e.g. for body scans). More details concerning the 
use of both CT and MRI for assessment of objective tumor response evaluation are provided in 
Appendix II. 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at a 
later date and, because they are operator dependent, it cannot be guaranteed that the same technique and 
measurements will be taken from one assessment to the next. If new lesions are identified by ultrasound 
in the course of the study, confirmation by CT or MRI is advised. If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
Endoscopy, laparoscopy:  The utilization of these techniques for objective tumor evaluation is not 
advised. However, they can be useful to confirm complete pathological response when biopsies are 
obtained or to determine relapse in trials where recurrence following complete response or surgical 
resection is an endpoint. 
Tumor markers:  Tumor markers alone cannot be used to assess objective tumor response. If markers are 
initially above the upper normal limit, however, they must normalize for a patient to be considered in 
complete response (CR). 
Cytology, histology:  These techniques can be used to differentiate between PR and CR in rare cases if 
required by protocol (for example, residual lesions in tumor types such as germ cell tumors, where known 
residual benign tumors can remain). When effusions are known to be a potential adverse effect of 
treatment (e.g. with certain taxane compounds or angiogenesis inhibitors), the cytological confirmation of 
the neoplastic origin of any effusion that appears or worsens during treatment can be considered if the 
measurable tumor has met criteria for response or stable disease in order to differentiate between response 
(or stable disease) and progressive disease.
Tumor response evaluation
Assessment of overall tumor burden and measurable disease
To assess objective response or future progression, it is necessary to estimate the overall tumor burden at 
baseline and use this as a comparator for subsequent measurements. Measurable disease is defined by the 
presence of at least one measurable lesion 
Baseline documentation of ‘target’ and ‘non-target’ lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of five lesions 
total (and a maximum of two lesions per organ) representative of all involved organs should be identified 
as target lesions and will be recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to reproducible 
repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion, which can be measured 
reproducibly, should be selected. 
A sum of the diameters (longest for non-nodal lesions,) for all target lesions will be calculated and 
reported as the baseline sum diameters. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline. Measurements are not required and these lesions should be followed as ‘present’, 
‘absent’, or in rare cases ‘unequivocal progression. In addition, it is possible to record multiple nontarget 
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lesions involving the same organ as a single item on the case record form (e.g. ‘multiple enlarged pelvic 
lymph nodes’ or ‘multiple liver metastases’). 
Response criteria
This section provides the definitions of the criteria used to determine objective tumour response for target 
lesions.
Evaluation of target lesions
Complete Response (CR):  Disappearance of all target lesions. 
Partial Response (PR):  At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters.
Progressive Disease:  At least a 20% increase in the sum of diameters of target lesions, taking as reference 
the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to 
the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note:  
the appearance of one or more new lesions is also considered progression). 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
progressive disease, taking as reference the smallest sum diameters while on study.
Evaluation of non-target lesions
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor marker 
level. 
Non-CR/Non-progressive disease:  Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
Progressive Disease:  Unequivocal progression of existing non-target lesions. (Note:  the appearance of 
one or more new lesions is also considered progression).
Evaluation of best overall response
The best overall response is the best response recorded from the start of the study treatment until the end 
of treatment taking into account any requirement for confirmation. On occasion a response may not be 
documented until after the end of therapy so protocols should be clear if post-treatment assessments are to 
be considered in determination of best overall response. The patient’s best overall response assignment 
will depend on the findings of both target and non-target disease and will also take into consideration the 
appearance of new lesions. 
Timepoint response
It is assumed that at each protocol specified timepoint, a response assessment occurs. Table 1 on the next 
page provides a summary of the overall response status calculation at each timepoint for patients who 
have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be used. 
Best overall response:  all timepoints
The best overall response is determined once all the data for the patient is known. 
Best response determination in trials where confirmation of complete or partial response IS NOT 
required: Best response in these trials is defined as the best response across all timepoints (for example, a 
patient who has SD at first assessment, PR at second assessment, and progressive disease on last
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assessment has a best overall response of PR). When SD is believed to be best response, it must also meet 
the protocol specified minimum time from baseline. If the minimum time is not met when SD is 
otherwise the best timepoint response, the patient’s best response depends on the subsequent assessments. 
For example, a patient who has SD at first assessment, progressive disease at second and does not meet 
minimum duration for SD, will have a best response of progressive disease. The same patient lost to 
follow-up after the first SD assessment would be considered inevaluable.
Table 1 - Timepoint Response:  Patients With Target (+/- Non-Target) Disease
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease; 
NE=\inevaluable.
Table 2 - Timepoint Response:  Patients With Non-Target Disease only
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR=complete response; PD=progressive disease; NE=inevaluable.
a
Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as endpoint for assessment of efficacy in some trials so to assign this category 
when no lesions can be measured is not advised.
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as ‘symptomatic deterioration’. 
Every effort should be made to document objective progression even after discontinuation of treatment. 
Symptomatic deterioration is not a descriptor of an objective response:  it is a reason for stopping study 
therapy. The objective response status of such patients is to be determined by evaluation of target and 
non-target disease as shown in Tables 1–2.
Conditions that define ‘early progression, early death and inevaluability’ are study specific and should be 
clearly described in each protocol (depending on treatment duration, treatment periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When the 
evaluation of complete response depends upon this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before assigning a status of complete response. 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a 
residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this 
circumstance should be prospectively described in the protocol and supported by disease specific medical 
literature for the indication. However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/ sensitivity. 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes or 
necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at the next 
scheduled assessment, progression is confirmed, the date of progression should be the earlier date when 
progression was suspected.
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Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met for CR/PR 
(whichever is first recorded) until the first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest measurements recorded on study). 
The duration of overall complete response is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented. 
Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on study
(if the baseline sum is the smallest, this is the reference for calculation of progressive disease). 
The clinical relevance of the duration of stable disease varies in different studies and diseases. If the 
proportion of patients achieving stable disease for a minimum period of time is an endpoint of importance 
in a particular trial, the protocol should specify the minimal time interval required between two 
measurements for determination of stable disease. 
Summary of major changes RECIST 1.0 to RECIST 1.1a
RECIST 1.0
RECIST 1.1
Rationale
Minimum size 
measurable lesions
CT:  10 mm spiral; 20 
mm non-spiral
CT 10 mm; delete reference 
to spiral scan
Most scans used have 5 mm or 
less slice thickness Clearer to 
give instruction based on slice 
interval if it is greater than 5 
mm
Clinical: 20 mm
Clinical:  10 mm (must be 
measurable with calipers)
Caliper measurement will 
make this reliable.
Lymph node:  not 
mentioned
CT:
15 mm short axis for target
10 - <15 mm for non-target
<10 mm is non-pathological
Since nodes are normal 
structure need to define 
pathological enlargement. 
Short axis is most sensitive.
Special considerations 
on lesion measurability
-
Notes included on bone 
lesions, cystic lesions
Clarify frequently asked 
questions.
Overall tumour burden
10 lesions (5 per 
organ)
5 lesions (2 per organ)
Data warehouse analysis shows 
no loss of information if lesion 
number reduced from 10 to 5. 
A maximum of 2 lesions per 
organ yields sufficient 
representation per disease site.
Response criteria 
target disease
CR lymph node not 
mentioned
CR lymph nodes must be 
<10 mm short axis
In keeping with normal size of 
nodes.
PD 20% increase over 
smallest sum on study 
or new lesions
PD 20% increase over 
smallest sum on study 
(including baseline if that is 
smallest) and at least 5 mm 
increase or new lesions
Clarification that if baseline 
measurement is smaller than 
any on study measurement, it is 
reference against which PD is 
assessed 5 mm absolute 
increase to guard against over 
calling PD when total sum is 
very small and 20% increase is 
within measurement error.
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Summary of major changes RECIST 1.0 to RECIST 1.1a
RECIST 1.0
RECIST 1.1
Rationale
Response criteria 
non-target disease
‘unequivocal 
progression’ 
considered as PD
More detailed description of 
‘unequivocal progression’ to 
indicate that it should not 
normally trump target disease 
status. It must be 
representative of overall 
disease status change, not a 
single lesion increase
Confusion with RECIST 1.0 
where some were considering 
PD if ‘increase’ in any non-
target lesion, even when target 
disease is stable or responding.
New lesions
New section on New lesions
To provide guidance on when a 
lesion is considered new (and 
thus PD).
Overall response
Table integrated target 
and non-target lesions
Two tables:  one integrating 
target and non-target and the 
other of non-target only  
To account for the fact that 
RECIST criteria are now being 
used in trials where PFS is the 
endpoint and not all patients 
have measurable (target) 
disease at baseline.
Special notes:
How to assess and measure 
lymph nodes;
CR in face of residual tissue;
Discussion of ‘equivocal’ 
progression
Frequently asked questions on 
these topics.
Confirmatory measure
For CR and PR:  
criteria must be met 
again 4 weeks after 
initial documentation
Retain this requirement 
ONLY for non-randomised 
trials with primary endpoint 
of response
Data warehouse shows that 
response rates rise when 
confirmation is eliminated, but 
the only circumstance where 
this is important is in trials 
where there is no concurrent 
comparative control and where 
this measure is the primary 
endpoint.
Progression-free 
survival
General comments 
only
More specific comments on 
use of PFS (or proportion 
progression-free) as phase II 
endpoint. 
Greater detail on PFS 
assessment in phase III trials
Increasing use of PFS in phase 
III trials requires guidance on 
assessment of PD in patients 
with non-measurable disease
Reporting of response 
results
9 categories suggested 
for reporting phase II 
results
Divided into phase II and 
phase III;  
9 categories collapsed into 5;
In phase III, guidance given 
about reporting response
Simplifies reporting and 
clarifies how to report phase II 
and III data consistently. 
Response in phase III 
trials
More relaxed 
guidelines possible if 
protocol specified
This section removed and 
referenced in section above:  
no need to have different 
criteria for phase II and III
Simplification of response 
assessment by reducing 
number of lesions and 
eliminating need for 
confirmation in randomized 
studies where response is not 
the primary endpoint makes 
separate ‘rules’ unnecessary.
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Summary of major changes RECIST 1.0 to RECIST 1.1a
RECIST 1.0
RECIST 1.1
Rationale
Imaging appendix
Appendix I
Appendix II:  updated with 
detailed guidance on use of 
MRI, PET/CT. 
Other practical guidance 
included
Evolving use of newer 
modalities addressed. 
Enhanced guidance in response 
to frequent questions and from 
radiology review experience.
New appendices
Appendix I:  comparison of 
RECIST 1.0 and 1.1; 
Appendix III:  frequently 
asked questions
PD=progressive disease
a See publication for references applicable to this table.
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Attachment 3: EORTC QLQ – OV28 
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Attachment 4: EQ–5D-5L Health Questionnaire
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Attachment 5: New York Heart Association Classification
CLASS I: Subjects in whom angina is provoked by strenuous exertion.
Subjects with cardiac disease but without resulting limitations of physical activity. Ordinary 
physical activity does not cause undue fatigue, palpitations, dyspnea, or anginal pain.
CLASS II: Subjects with cardiac disease resulting in slight limitation of physical activity. They 
are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain.
CLASS III: Subjects with cardiac disease resulting in marked limitation of physical activity. 
They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, 
dyspnea, or anginal pain.
CLASS IV: Subjects with cardiac disease resulting in inability to carry on any physical activity 
without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be 
present even at rest.
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Attachment 6: Cockcroft-Gault Method
Creatinine clearance (CrCl) is to be estimated by using the following formula which is specific 
for females:
GFR =     (140-age) x (Weight measured in kg) x (0.85)
                (72 x serum creatinine measured in mg/deciliter)
GFR=glomerular filtration rate
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Attachment 7: Study Procedures as Outlined in Amendment 6
Independent Data Monitoring Committee
On 26 June 2017, the IDMC requested a futility analysis of OS to be performed at the time of the next 
meeting 6 months later. In view of the IDMC request, study data up to 20 September 2017 were evaluated 
for safety and OS (45% rather than 60% of the required death events at the planned interim analysis). 
Following the review of the study data by the IDMC on 15 December 2017, the HR for OS was 0.962, 
crossing the previously agreed upon threshold for futility of 0.93. In view of this result and the observed 
and expected higher toxicity in Arm A as compared with Arm B, the IDMC recommended discontinuing 
the study.
Subjects Assigned to Treatment Arm A and Treatment Arm B
As of Amendment 6, treatment with trabectedin should be immediately discontinued for subjects assigned 
to Arm A (trabectedin+DOXIL). All study subjects (Arm A or Arm B) currently on study who, in the 
opinion of the investigator, are deriving clinical benefit may continue treatment with single-agent DOXIL 
as per the local standard of care. Treatment for these subjects may continue as long as the subjects comply 
with protocol-specified prohibitions and restrictions for treatment (Section 4.3) and as long as they 
experience clinical benefit in the opinion of the investigator. DOXIL will be provided by JR&D as needed 
until post-trial access to DOXIL is available or until disease progression, whichever occurs first.
Accordingly, the end of study data collection is defined as when all subjects on study treatment have 
completed treatment termination visit assessments as specified in the Time and Events Schedule for 
Amendment 6 or by 18 January 2018, whichever occurs first. For subjects continuing treatment with 
single-agent DOXIL, as per the local standard of care, only serious adverse events should be reported to 
JR&D as outlined in Section 12.3.2.
Subjects in Screening
No new subjects will be screened. Subjects currently in screening are be eligible to receive treatment with 
single-agent DOXIL, if the investigator confirms that such treatment would be a clinically appropriate 
therapeutic option. These subjects will not be randomized to a treatment group, but must meet study
inclusion and exclusion criteria (per Amendment 6, Sections 4.1 and 4.2). As indicated above, for subjects 
in treatment Arms A and B who continue on single-agent DOXIL, subjects in screening who receive 
single-agent DOXIL will be allowed to continue treatment as long as the subjects comply with protocol-
specified prohibitions and restrictions for treatment (Section 4.3) and who, in the opinion of the 
investigator, are experiencing clinical benefit. DOXIL will be provided by JR&D as needed until post-
trial access to DOXIL is available or until disease progression, whichever occurs first.
Data Collection 
Following Amendment 6, study data collection will cease when all subjects on study treatment have 
completed the treatment termination visit assessments as specified in the Time and Events Schedule for 
Amendment 6 or by 18 January 2018, whichever occurs first. Data collection for adverse events or 
abnormal findings will be monitored until the study clinical cutoff date (18 January 2018).
For subjects continuing treatment with single-agent DOXIL, as per the local standard of care, only serious 
adverse events should be reported to JR&D as outlined in Section 12.3.2.
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INVESTIGATOR AGREEMENT
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SAP_001.pdf: 
1
Janssen Research & Development, LLC
Statistical Analysis Plan
A Randomized, Open-Label Study Comparing the Combination of YONDELIS® and 
DOXIL®/CAELYX® With DOXIL®/CAELYX® Monotherapy for the Treatment of 
Advanced-Relapsed Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer
Protocol ET743-OVC-3006: Phase 3
R279741 (trabectedin)
Original Issue Date:  May 21, 2012
Final Issue Date:       April 12, 2018
Document No.:           EDMS-ERI-43318524: version 6.0
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged 
or confidential.
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YONDELIS: Statistical Analysis Plan Study ET743-OVC-3006
1
TABLE OF CONTENTS
1.
INTRODUCTION.............................................................................................................................. 3
1.1.
Trial Objectives ................................................................................................................................ 3
1.2.
Trial Design ...................................................................................................................................... 3
1.3.
Sample Size Justification ................................................................................................................. 5
2.
ANALYSES PLANNED ................................................................................................................... 5
2.1.
General Analysis Definitions ............................................................................................................ 5
2.1.1.
Definition of Cycle, Treatment Phase, Baseline .............................................................. 5
2.1.2.
Pooling Strategy for Analysis Centers ............................................................................. 6
2.1.3.
Analysis Sets ................................................................................................................... 6
2.1.3.1.
Efficacy Analysis Sets .................................................................................................. 7
2.1.3.2.
Safety Analysis Set....................................................................................................... 7
2.1.3.3.
Definition of Subgroup.................................................................................................. 7
2.2.
Methods of Analysis......................................................................................................................... 7
2.2.1.
Statistical Hypotheses for Trial Objectives ...................................................................... 7
2.2.2.
Interim Analysis................................................................................................................ 7
2.2.2.1.
Futility Analysis............................................................................................................. 7
2.2.2.2.
Interim Analysis ............................................................................................................ 8
2.2.3.
Demographics and Baseline Characteristics................................................................... 8
2.2.4.
Discontinuation Information ............................................................................................. 9
2.2.5.
Extent of Exposure ........................................................................................................ 10
2.2.6.
Protocol Deviations........................................................................................................ 11
2.2.7.
Concomitant Medications .............................................................................................. 12
2.2.8.
Efficacy .......................................................................................................................... 12
2.2.8.1.
Analysis Specifications............................................................................................... 12
2.2.8.1.1
Level of Significance ............................................................................................ 12
2.2.8.2.
Primary Endpoint:  Overall Survival............................................................................ 13
2.2.8.3.
Tumor Assessment..................................................................................................... 14
2.2.8.3.1
Response Criteria (RECIST Version 1.1) ............................................................ 14
2.2.8.3.2
Evaluation of Overall Response for Each Assessment ....................................... 14
2.2.8.4.
Secondary Endpoint: Progression-Free survival........................................................ 16
2.2.8.4.1
Handling of Missing Assessments ....................................................................... 16
2.2.8.4.2
Analysis Methods................................................................................................. 16
2.2.8.5.
Other Secondary Efficacy Analyses ........................................................................... 17
2.2.8.5.1
Definition of Other Secondary Efficacy Variables................................................ 17
2.2.8.5.2
Analysis Methods................................................................................................. 17
2.2.8.6.
Supportive Analyses................................................................................................... 17
2.2.8.6.1
Symmetry of Tumor Assessment Schedules....................................................... 17
2.2.8.7.
ECOG ......................................................................................................................... 17
2.2.8.8.
Patient Reported Outcomes ....................................................................................... 17
2.2.8.9.
Subsequent treatment ................................................................................................ 18
2.2.9.
Safety............................................................................................................................. 18
2.2.9.1.
Adverse Events .......................................................................................................... 18
2.2.9.2.
Clinical Laboratory Tests............................................................................................ 19
2.2.9.2.1
Hematology.......................................................................................................... 19
2.2.9.2.2
Serum chemistry .................................................................................................. 19
2.2.9.2.3
Hy's Law2 Cases Analysis.................................................................................... 20
2.2.9.3.
Vital Signs and Physical Examination Findings ......................................................... 20
2.2.9.4.
Deaths ........................................................................................................................ 20
2.2.9.5.
ANALYSIS OF CARDIAC SAFETY............................................................................ 20
2.2.10.
Safety Narratives ........................................................................................................... 20
2.2.11.
Clinical Pharmacology Analyses.................................................................................... 20
3.
REFERENCES............................................................................................................................... 22
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4.
ATTACHMENTS............................................................................................................................ 23
4.1.
Imputation Rules for Incomplete Dates.......................................................................................... 23
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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis populations, derived 
variables, and statistical methods for the analysis of efficacy and safety.
1.1.
Trial Objectives
The primary objective of the study is to compare the overall survival (OS) after 
treatment with the trabectedin + DOXIL combination therapy to that observed after 
treatment with DOXIL monotherapy for subjects with advanced-relapsed epithelial 
ovarian, primary peritoneal, or fallopian tube cancer. 
Secondary Objectives are:
To evaluate PFS.
To evaluate the objective response rate (ORR).
To assess population pharmacokinetics (PK) of trabectedin using data from the
trabectedin + DOXIL treatment group.
To evaluate the safety of the trabectedin + DOXIL combination therapy and DOXIL 
monotherapy.
Exploratory Objectives are:
To conduct pharmacogenomic evaluations of OS, PFS and other endpoints in 
subjects with and without mutations in BRCA1 and BRCA2.
To evaluate patient-reported outcomes (PROs).
1.2.
Trial Design
This is a randomized, open-label, active-controlled, multicenter study designed to assess 
the efficacy and safety of trabectedin + DOXIL as a third-line chemotherapy in subjects 
with platinum-sensitive advanced-relapsed epithelial ovarian, primary peritoneal, or 
fallopian tube cancer who received 2 previous lines of platinum-based chemotherapy. 
Approximately 670 subjects will be enrolled in this study, with 335 subjects per planned 
treatment group. At randomization, subjects will be stratified by the time from the last 
dose of first-line platinum therapy to disease progression (6 months to 12 months vs 
>12 months to 24 months vs >24 months), Eastern Cooperative Oncology Group 
(ECOG) performance status score (0 vs 1), BRCA 1/2 status (mutation vs no mutation), 
and prior pegylated liposomal doxorubicin therapy (no vs yes). Then they will be
randomly assigned in a 1:1 ratio to the trabectedin + DOXIL combination therapy group
(Arm A) or to the DOXIL monotherapy group (Arm B). Study treatment will be 
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administered by IV infusion on Day 1 of a 21-day cycle in Arm A and on Day 1 of a 28-
day cycle in Arm B. 
Treatment Arm A: DOXIL 30 mg/m2 90-minute IV infusion (per DOXIL package 
insert) followed by trabectedin 1.1 mg/m2 3-h IV infusion, via central venous 
catheter, every 3 weeks. Central venous access is required for the administration of 
trabectedin.
Treatment Arm B: DOXIL 50 mg/m2 as a 90-minute IV infusion (per DOXIL 
package insert) every 4 weeks. If no infusion-related reaction is observed with 
DOXIL after the first infusion, DOXIL may be administered as a 30- to 90-minute 
infusion in subsequent cycles, as indicated in the product’s Package insert.
Subjects assigned to the trabectedin + DOXIL group (Arm A) will be pretreated with 
20 mg of dexamethasone (or an equivalent corticosteroid) 30 minutes prior to initiation 
of infusion of DOXIL IV, on Day 1 of each treatment cycle.
On 26 June 2017, the IDMC requested a futility analysis of OS to be performed at the 
time of the next meeting 6 months later. In view of the IDMC request, study data up to 
20 September 2017 were evaluated for safety and OS (45% rather than 60% of the 
required death events at the planned interim analysis). Following the review of the study 
data by the IDMC on 15 December 2017, the HR for OS was 0.962, crossing the 
previously agreed upon threshold for futility of 0.93. In view of this result and the 
observed and expected higher toxicity in Arm A as compared with Arm B, the IDMC
recommended discontinuing the study. Therefore, as of Amendment 6, no new subjects 
would be randomized to study treatment, and treatment with trabectedin should be 
immediately discontinued for subjects assigned to Arm A (trabectedin + DOXIL). All 
study subjects (Arm A or Arm B) currently on study treatment who, in the opinion of 
the investigator, were deriving clinical benefit may continue treatment with single-agent 
DOXIL as per the local standard of care. Treatment for these subjects may continue as
long as the subjects comply with protocol-specified prohibitions and restrictions for 
treatment (Protocol Section 4.3) and as long as they experience clinical benefit in the 
opinion of the investigator. DOXIL would be provided by JR&D as needed until post-
trial access to DOXIL is available or until disease progression, whichever occurs first.
Accordingly, the end of study data collection was defined as when all subjects on study 
treatment have completed treatment termination visit assessments as specified in the 
Time and Events Schedule for Amendment 6 or by 18 January 2018, whichever occurs 
first. For subjects continuing treatment with single-agent DOXIL, as per the local 
standard of care, only serious adverse events should be reported to JR&D.
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1.3.
Sample Size Justification
It is assumed that failure will follow an exponential distribution with a constant hazard 
rate. Assuming a median OS of 16 months for the active control group (DOXIL 
monotherapy), a planned sample size of approximately 670 subjects will provide 80% 
power to detect a HR of 0.78 (16 months versus 20.5 months; corresponding to a 28% 
improvement in median OS) at a 2-tailed significance level of 0.05 and a enrollment 
duration of approximately 52 months (13 subjects/month enrollment) over a total study 
duration of 64 months to obtained the required 514 events.
The OS endpoint will incorporate group sequential design by including 1 interim 
analysis and 1 final analysis using the O’Brien-Fleming boundaries as implemented by 
the Lan-DeMets alpha spending method. Subjects will be randomized in a 1:1 ratio to 
receive trabectedin + DOXIL combination therapy or DOXIL monotherapy.
2.
ANALYSES PLANNED
2.1.
General Analysis Definitions
2.1.1.
Definition of Cycle, Treatment Phase, Baseline
Cycle: The duration of cycles may not consistently be as the planned 21 days in the 
trabectedin + DOXIL Arm or 28 days in the DOXIL Arm, it will depend on the earliest 
date of the DOXIL/trabectedin doses given in the next cycle. If a subject experiences 
toxicity at the planned start of a cycle that leads to a delay in DOXIL/trabectedin 
administration, this new cycle will be delayed, and the previous cycle will be prolonged 
(without additional DOXIL or trabectedin treatment). 
The start of the cycle is the date of the first administration of DOXIL or trabectedin in a 
cycle. The end of a cycle is the day before the first infusion of the immediate 
subsequent cycle recorded on the case report form (CRF).  
The last cycle ends 3 weeks after the start of this cycle for the trabectedin + DOXIL
Arm, and 4 weeks for the DOXIL Arm. 
The assessments performed during the ‘End-of-treatment visit’ will be included in the 
last treated cycle for analysis. 
All lab samples taken after the last treatment and up to 30 days after the last 
DOXIL/trabectedin infusion will be captured in the last cycle.
End-of-treatment phase: The end of the treatment phase is the date the last cycle ends, 
i.e., 3 weeks after the first trabectedin or DOXIL dosing in the last cycle for Arm A, or 
4 weeks after the dose of DOXIL in the last cycle for Arm B.  
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Follow-up phase: Following termination of DOXIL/trabectedin treatment, subjects are 
followed every 8 weeks for survival for the first 2 years after randomization and every 
3 months thereafter until death or the clinical cut-off date defined at the time when 
514 deaths are observed, whichever is sooner. If disease progression has not occurred at 
treatment termination, then disease assessment should continue every 8 weeks until 
there is evidence of disease progression or death, or until the clinical data cut-off date, 
or until the start of first subsequent therapy for ovarian cancer, whichever is earlier. 
Disease assessment will also be done if necessary to confirm response or document 
disease progression. 
Relative day: Assessments will be presented chronologically by cycle day or study day, 
which are defined in the following:
Cycle day = assessment date - date of first DOXIL or trabectedin infusion for the cycle 
+ 1
Study day = assessment date - date of first DOXIL or trabectedin infusion in cycle 1 + 1
Baseline definition:
Baseline of each parameter is defined as the latest value on or prior to the first DOXIL
or trabectedin infusion in cycle 1. 
In addition to the cycle day and study day defined above, the laboratory assessments
completed on Day 1 of a cycle are considered to be baseline for that cycle as well as the 
last laboratory assessment for the previous cycle. 
2.1.2.
Pooling Strategy for Analysis Centers
Treatment-by-center interaction will not be formally tested. It can be assessed by 
graphics with regions/countries ordered according to their size.
2.1.3.
Analysis Sets
“All Randomized Subjects” analysis set is defined as all subjects who are randomized to 
this study, independent of whether they received study drug or not. 
“All Treated Subjects” analysis set is defined as all randomized subjects who receive at 
least 1 dose of DOXIL or trabectedin. Subjects who receive dexamethasone (or an 
equivalent corticosteroid) as pre-medication but who do not receive DOXIL or 
trabectedin will not be included in “All Treated Subject” analysis set.
The PK analysis set is defined as all subjects who received at least 1 dose of trabectedin 
and had at least 1 PK measurement.
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2.1.3.1.
Efficacy Analysis Sets
The “All Randomized Subjects” analysis set will be used.
2.1.3.2.
Safety Analysis Set
The safety analysis is based on the “All Treated Subject” analysis set, where the 
grouping into the different arms is based on the true treatment received during the first 
cycle.
2.1.3.3.
Definition of Subgroup
In addition to the main analysis, the efficacy analysis will be performed by the levels of 
stratification factors.
2.2.
Methods of Analysis
Final efficacy and safety analysis for the CSR will be using clinical cut-off date of 
January 18, 2018.
2.2.1.
Statistical Hypotheses for Trial Objectives
Overall Survival (OS) will be compared between treatment arms using an unstratified 
one-sided log-rank test. The trabectedin + DOXIL combination therapy will be declared 
better than DOXIL monotherapy if the OS is better with a p-value less than or equal to 
the significance level as specified by the alpha spending function. The overall 2-tailed
significance level of 0.05 will be spread over 1 interim and 1 final OS analyses, when 
approximately 308 and 514 events on OS (death) are seen. 
2.2.2.
Interim Analysis
2.2.2.1.
Futility Analysis
A non-binding futility analysis for OS will be implemented after observing 33% (170
events) of the total number of required 514 events.  The study may be considered futile if 
the estimated hazard ratio (HR) from Cox proportional-hazard model is equal to or 
greater than 0.95.  The probability of stopping under null hypothesis is approximately 
62%, and the probability of stopping under alternative hypothesis is approximately 10%.
After the futility analysis at 33% of the total number of OS events, on 26 June 2017, the
IDMC requested a futility analysis once again at 45% of the total number of OS events. 
So, a non-binding futility analysis for OS will also be implemented after observing 45% 
(232 events) of the total number of required 514 OS events.  The study may be 
considered futile if the estimated hazard ratio (HR) from Cox proportional-hazard model 
is equal to or greater than 0.93.  The probability of stopping under null hypothesis is 
approximately 71%, and the probability of stopping under alternative hypothesis is 
approximately 9%.
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2.2.2.2.
Interim Analysis
One interim analysis is planned for this study after observing 60% (308 events) of the 
total number of required (514) events. The alpha spend will be 0.008 for the interim 
analysis. The exact timing of the interim analysis will be determined according to the 
planned number of events. The O’Brien-Fleming boundaries, as implemented by 
Lan-DeMets alpha spending function will be used for the efficacy boundary. Operating 
characteristics for these boundaries are presented in the following table.  
Stopping Boundaries for OS
Variable 
Analyses
Interim
Final
Projected Observed OS Events 
308
514
Anticipated Time to Analysis (months) 
43
64
Anticipated Enrollment (n) 
563
669
Efficacy Boundary (HR) 
0.74
0.84
Boundary Crossing Prob. (H0)
0.008
0.048
Cumulative α spent
0.008
0.050
HR=Hazard ratio; Ho = 0% improvement; H1 = 28% improvement 
An Independent Data Monitoring Committee consisting of external members including 
clinicians and statistician will be formed. The committee will conduct periodic reviews 
of the safety data and will review the efficacy data according to the prescribed statistical 
plan. 
Following the review of the study data for the second utility analysis by the IDMC on 
15 December 2017, the HR for OS was 0.962, crossing the previously agreed upon 
threshold for futility of 0.93. In view of this result and the observed and expected higher 
toxicity in Arm A as compared with Arm B, the IDMC recommended discontinuing the 
study. The planned interim analysis will not be performed.
2.2.3.
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be summarized for all randomized 
subjects. 
Age, weight, height, and body surface area (BSA) recorded on the CRF will be 
summarized descriptively. Age is calculated based on the date of birth at the time date 
of randomization. Baseline body mass index (BMI) will be calculated, using the 
formula:
BMI = weight (kg) / length (m²).
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The BMI will be summarized, and the frequency counts of the different categories 
(<20, 20-<25, 25-<30, 30) will be displayed.
Age category (<65, 65), and race will be summarized with frequency counts.
For the ovarian cancer history, the histology and histological grade will be summarized. 
Time from initial diagnosis to the randomization, time from progression/recurrence 
during/after initial chemotherapy regimen to randomization, and time from end of first 
platinum-containing therapeutic line to disease progression will be calculated in months 
and summarized descriptively. Incomplete dates will be imputed by the methods 
specified in the attachment (Section 4.1).  
Baseline ECOG score and BRCA1 or BRCA2 mutation status will be summarized using 
frequency counts. A frequency tabulation of the number of subjects with and the 
different types of previous cancer surgery, radiotherapy, or systemic therapy will be 
given. A listing of all pre-planned surgeries will be generated. A summary of medical 
and surgical history will be presented per system (none, history, currently active). 
Baseline ECG and LVEF (Left Ventricular Ejection Fraction) will be summarized.  
2.2.4.
Discontinuation Information
The number of subjects enrolled per center and subject disposition will be summarized 
by randomization arm. Subject disposition includes the number of subjects in each of 
the following categories:

Randomized
o
Not Treated (subjects who are randomized but not treated with 
trabectedin or DOXIL
o
Treated (subjects who are treated with trabectedin or DOXIL)
An additional table will be created for all treated subjects, displaying for each treatment 
group the reason for treatment discontinuation by cycle.
A separate listing will be provided for subjects not treated. 
Reasons for treatment termination will be collected on the CRF and will be summarized 
for all randomized subjects with the following categories:

Overt progression of neoplastic disease

Subject Choice

Adverse Event
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
Death 

Subject completed 2 cycles of treatment after confirmed CR

Other

Lost to follow-up
The discontinuation reason due to an adverse event is further classified into drug-related 
and non-drug-related adverse events. 
2.2.5.
Extent of Exposure
Cycle duration:
Cycle duration (weeks) is defined as:
[(The earliest dosing date of trabectedin or DOXIL in the next cycle) - (the earliest 
dosing date of trabectedin or DOXIL in the current cycle)]/7
For the final cycle, cycle duration is equal to the pre-planned duration, ie, 3 weeks for 
the trabectedin + DOXIL arm and 4 weeks for the DOXIL arm. 
Treatment duration:
The treatment duration (weeks) is defined as: 
[(The last cycle end date) – (the first cycle start date) + 1]/7
Cumulative dose:
Cumulative will be calculated for DOXIL and trabectedin separately.
The cumulative dose during the treatment is defined as:
Sum of dose infused across at each cycle (mg) / the Body Surface Area (m2) at each 
cycle
Dose intensity: 
Dose intensity will be calculated for DOXIL and trabectedin separately.
Dose intensity during the treatment is defined as:
Cumulative dose/treatment duration.
The dose intensity is expressed in mg/m²/per 3 weeks for the trabectedin + DOXIL arm, 
and in mg/m²/per 4 weeks for the DOXIL arm.
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Relative Dose intensity: 
Relative dose intensity will be calculated for DOXIL and trabectedin separately.
Relative dose intensity is the dose intensity divided by the planned dose intensity. The 
planned dose intensity is 1.1 mg/m²/per 3 weeks for trabectedin in the trabectedin + 
DOXIL arm, 30mg/m²/per 3 weeks for DOXIL in the trabectedin + DOXIL arm, and 
50mg/m²/per 4 weeks for DOXIL in the DOXIL arm.
Number of Cycles: 
For each subject, total number of cycles received will be calculated. 
Descriptive statistics of treatment duration, cumulative dose, dose intensity, relative 
dose intensity, and the number of cycles received will be presented.
Cycle Delay, Dose Reduction:
The number of subjects with a cycle delay will be summarized by the number of delays. 
The number of subjects with a dose reduction will be summarized by the number of 
reductions. The reasons for cycle delay or dose reduction are further classified into 
drug-related adverse event (AE), non drug-related AE, or other reason. Only delays of at 
least 5 days will be used for the summary table. All delays will be provided on the 
listing.
A listing will be generated containing the data of those trabectedin and DOXIL
infusions that have been interrupted along with the reason.
Dosing information of dexamethasone will be listed. 
2.2.6.
Protocol Deviations
Protocol Deviations will be summarized for all randomized subjects.
A summary table with the number of inclusion/exclusion violators will be presented per 
criterion. These subjects will be listed with the criteria that are not met. 
Important protocol deviations will be documented during the trial execution based on 
pre-defined criteria. The detailed criteria will be documented in the data management 
plan and will be agreed to by the Janssen Research & Development, LLC (Janssen 
R&D) project physician. The classification of such protocol deviations will also be 
reviewed by the Janssen R&D project physician and finalized prior to the database lock. 
Once identified and recorded according to the rules, deviations will not be removed 
from the database. 
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Summary will be presented including the following categories:

Selection criteria not met

Subject not withdrawn as per protocol

Treatment deviation

Excluded concomitant medication

Efficacy assessment deviation

Other
2.2.7.
Concomitant Medications
Concomitant therapies will be categorized per coded term. The number of subjects 
receiving each type of therapy during the treatment phase will be tabulated in 2 separate 
tables: a frequency tabulation of the different therapies that started pre-trial, and a 
frequency tabulation of the different therapies that started during the trial. The 
accompanying listing will contain all concomitant therapies.
2.2.8.
Efficacy 
2.2.8.1.
Analysis Specifications
2.2.8.1.1
Level of Significance 
For the primary endpoint OS, the overall (two-sided) significance level is 0.05. This 
0.05 will be spread over 2 analyses by an O’Brien-Fleming boundaries as implemented 
by Lan-DeMets alpha spending function. The significance of efficacy will be claimed if 
the p-value is less than or equal to the significance level as calculated based on the 
above specified alpha spending function and the observed number of events.
Hierarchical Testing  
This following preplanned hierarchical testing will not be performed due to lack of 
efficacy per the futility analysis.
Only when OS is significant, the Hochberg procedure will be used to test the secondary 
endpoints at the overall (two-sided) significance level 0.05:  testing will begin with p
value P(m) with corresponding hypothesis H(m), where P(m) is the largest ordered p values 
amongst ‘m’ secondary endpoints and H(m) is the corresponding hypothesis. If P(m)α, 
then all hypotheses are rejected.  If not, then P(m-1), the (m-1)th largest p-value, is 
compared with α/(m-1).  If smaller, then all hypotheses from H(m-1) to H(1) are rejected.  
The testing procedure continues in this manner until no significant result is found  
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2.2.8.2.
Primary Endpoint:  Overall Survival
Overall survival (OS) is defined as the time between the randomization and death.
Subjects who die, regardless of the cause of death, will be considered to have had an 
event. All subjects who are lost to the follow-up prior to the end of the trial or who are 
withdrawn from the trial will be censored at the time of last contact. Subjects who are 
still being treated will be censored at the last available date where the subject is known 
to be alive.
OS will be compared between treatment arms using an unstratified two-sided log-rank 
test as primary analysis. The Kaplan-Meier method will be used to estimate the 
distribution functions of OS for each treatment arm. The number of events, subjects 
censored, the estimate of medians and 95% confidence interval for the medians will be 
presented. The plots of OS using the Kaplan-Meier method will be presented. 
Six-month and one-year survival rates will be calculated using the Kaplan-Meier 
method.  The unstratified Cox proportional hazards model will be used to obtain the HR 
and it’s 95% CI.
OS will also be compared between treatment arms by a two-sided log-rank test, 
stratified for the stratification factors: the time from the last dose of first-line platinum 
therapy to disease progression (6 to 12 months vs >12 to 24 months vs >24 months), 
Eastern Cooperative Oncology Group (ECOG) performance status score (0 vs 1), 
BRCA 1/2 status (mutation vs. no mutation) and prior pegylated liposomal doxorubicin 
therapy (no vs yes).
In case an imbalance in baseline prognostic factors is observed, especially PFI 
(platinum-free interval: the time from the last dose of first-line platinum therapy to 
disease progression), a Cox proportional hazards model will also be used to compare 2
treatment arms. The following baseline information includes as covariates: baseline 
ECOG (“0” vs. “1”), PFI (as continuous), BRCA1/2 status (mutation vs. no mutation), 
prior pegylated liposomal doxorubicin therapy (no vs yes), and any imbalanced factors. 
From the Cox proportional hazards regression, HR estimates and their 95% CIs will be 
estimated for treatment and for the prognostic factors. 
Subgroup analyses
The following preplanned subgroup analysis will not be performed due to lack of 
efficacy per the futility analysis.
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Subgroup analysis is planned for the primary endpoints OS to investigate whether 
treatment effects are consistent within subgroups. Each subgroup will be analyzed 
separately. The subgroups are as follows:

Age (<65, ≥65)

PFI (6 to 12 months vs >12 to 24 months vs >24 months), 

ECOG performance status score (0 vs 1), 

BRCA 1/2 status (mutation vs. no mutation) 

prior pegylated liposomal doxorubicin therapy (no vs yes)
2.2.8.3.
Tumor Assessment
Tumor response will be assessed by investigators, according to the RECIST 1.1 
response criteria.
Complete tumor assessments will be performed approximately every 8 weeks after 
randomization. Using RECIST 1.1 response criteria, tumor lesions are evaluated 
separately by target lesions and non-target lesions during each assessment. Then the 
combined results of target and non-target lesions will provide an overall tumor response 
for this assessment. 
2.2.8.3.1
Response Criteria (RECIST Version 1.1) 
Response evaluation for the target lesions and for the non-target lesions, and new 
lesions as assessed by the investigator, will be recorded on the CRF and included in the 
database. 
For details on the RECIST Version 1.1 criteria, see Attachment 2 of the PED.
2.2.8.3.2
Evaluation of Overall Response for Each Assessment
Overall response of the subject at an assessment cycle will be determined based on 
investigator’s assessments on target, non-target and new lesions according to the 
guidelines below: 
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Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated No
PR
SD
Non-PD or not all evaluated No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response; PR = partial response; SD = stable disease; PD = progressive 
disease; NE = Not evaluable.
For subjects with either target or non-target lesions only listed at baseline, the overall 
response will be evaluated by either the target or non-target lesions only (depending on 
which is missing), except in the case where a new lesion appears whereby the overall 
response would then become PD.
Subjects with a clinical deterioration of health status thought by the investigator to be 
related to disease progression and requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
Date of Progression
For the analysis based on the investigator’s tumor evaluations, the day of disease 
progression is determined by using the earliest time point from the following dates: the 
date of PD as evaluation of response on the CRF; the date of a new lesion on the CRF 
tumor measurements page.
For the analysis based on all investigator’s data, the day of disease progression is 
determined by using the earliest time point from the following dates: the date of PD as 
evaluation of response on the CRF; the date of a new lesion on the CRF tumor 
measurements page; the death date (if death is caused by PD);, the progression date as 
documented on the CRF treatment termination page, the progression date as 
documented on the CRF follow-up visit page.
Best Overall response
The best overall response is the best response recorded from the start of the treatment 
until disease progression or start of subsequent anticancer therapy. The best overall 
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response will be summarized per treatment group in a frequency table with categories: 
complete response (CR), partial response (PR), stable disease (SD), progressive disease 
(PD), not evaluable (NE).
2.2.8.4.
Secondary Endpoint: Progression-Free survival
The analysis of PFS will be based on the data received from the investigator, combined 
with information from the database on the subject’s death and on subsequent therapy for 
ovarian cancer.
Progression free survival (PFS) is defined as the time between the randomization and 
disease progression or death. Subjects who progressed or died will be considered to 
have had an event, except if this event occurs after the start of subsequent therapy for 
ovarian cancer, in which case the subject is censored at the time of last tumor 
assessment (prior to or on the first day of the first subsequent therapy for ovarian 
cancer). Subjects who did not progress nor died (lost to follow-up, or still being treated 
without documented disease progression, or started subsequent therapy for ovarian 
cancer and still alive) will be censored at the date of the last tumor assessment (prior to 
or on the first day of the first subsequent therapy for ovarian cancer).
2.2.8.4.1
Handling of Missing Assessments
Tumor scans are scheduled every 8 weeks for the first 4 assessments and then every 12 
weeks. Despite this, assessments are sometimes missing (not performed, not all lesions 
measured, lost, technically inadequate). If there is a time interval between the last non-
PD scan and the date of death or the date of progression, the following algorithm will be 
applied: 
if a subject has an interval of 18 weeks during the first 4 assessment or 26 weeks 
thereafter, this is an indication that more than one measurement is missing. Then the 
PFS is censored at the last disease assessment prior to the interval.
if a subject has an interval of <18 weeks prior to the fourth assessment or <26 weeks 
after the first 4 assessments, this is an indication that there is only 1 measurement 
missing, and then the subsequent information (PD date, death date) is used as event.
2.2.8.4.2
Analysis Methods
PFS will be compared between treatment arms using an unstratified two-sided log-rank 
test. The Kaplan-Meier method will be used to estimate the distribution functions of 
PFS for each treatment arm. The number of events, subjects censored, the estimate of 
medians and 95% confidence interval for the medians will be presented. The plots of 
PFS using the Kaplan-Meier method will be presented. Six-month and one-year 
progression-free rates will be calculated using the Kaplan-Meier method.  The 
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unstratified Cox proportional hazards model will be used to obtain the HR and it’s 95% 
CI.
2.2.8.5.
Other Secondary Efficacy Analyses
2.2.8.5.1
Definition of Other Secondary Efficacy Variables
Objective Response
Objective response is defined as having "CR" or "PR" as best overall response based on 
reconciled tumor assessment. Detail tumor response evaluation is described previously. 
The objective response rate is calculated as the number of objective responders divided 
by the number of subjects.
The response rate variable will be evaluated using the Chi-square statistic (unstratified).
2.2.8.5.2
Analysis Methods
The best overall response will be summarized per treatment arm in a frequency table 
with categories: complete response (CR), partial response (PR), stable disease (SD), 
progressive disease (PD), not evaluable (NE).
Subjects' overall response per cycle assessment will be determined and will be presented 
in a listing.
The response rate variable will be evaluated using the Chi-square statistic (unstratified).
2.2.8.6.
Supportive Analyses
2.2.8.6.1
Symmetry of Tumor Assessment Schedules
Tumor assessments were to be performed every 8 weeks. Timing of assessments in both 
treatment groups will be presented side by side with boxplots.
2.2.8.7.
ECOG
The ECOG value at the end of treatment visit will be tabulated (not cross-tabulated 
against the baseline value). The listing will contain both ECOG values.
2.2.8.8.
Patient Reported Outcomes
The following preplanned patient reported outcome analysis will not be performed due 
to lack of efficacy per the futility analysis.
The Patient Reported Outcomes will be measured by the OV28 and the EQ-5D 
questionnaires. Patients will be requested to fill these out at baseline, at the end of every 
cycle, at the treatment termination visit, and every 8 weeks till start of subsequent 
treatment. The analyses of these data will be performed on summary scores as well as 
subscales, and individual symptoms.
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Change from baseline at each time point and treatment termination will be analysed for 
selected scales of the OV28 items. In particular, Abdominal/Gastrointestinal Symptoms 
scales of OV28 will be tested based on the grouping criteria as specified in Greimel et 
al.1 Mean score changes from baseline at each time point and treatment termination will 
be compared between the treatment arms using T–test. The changes will also be 
analyzed using model for longitudinal data, taking the potential missing data and 
dropout into account. 
2.2.8.9.
Subsequent treatment
Frequency tabulation will be given, indicating how many subjects in each arm started 
subsequent therapy for ovarian cancer. 
The accompanying listing will contain details on the type of subsequent therapy for 
ovarian cancer as well as the start date.
2.2.9.
Safety
2.2.9.1.
Adverse Events 
Treatment emergent adverse events will be summarized by disease group and overall. A 
treatment-emergent adverse event is defined as any AE occurring or worsening on or 
after the first treatment of DOXIL/Trabectedin, and within 30 days after the last dose. 
For imputation rules for incomplete dates, see Attachment 4.1.
Adverse events are documented on the CRF together with their severity, according to 
the NCI CTC version 4.0, also referred to as NCI toxicity grading. For the 
categorization of the adverse events, the MedDRA dictionary will be used. Adverse 
events are considered drug related when the relation to trial medication is considered to 
be possible, probable, or very likely, according to the investigator's opinion.
Summary of overall adverse events will be done by body system and preferred term, by 
severity (worst toxicity grade), by relationship to the study drugs (trabectedin or 
DOXIL), and by AE outcome. Tables will be sorted by body system/preferred term and 
by the highest incidence. In the AE database, "neoplasm malignant aggravated", and 
"condition aggravated" are created terms to match the Global Medical Safety (GMS) 
death reporting database (in case of death due to disease progression). These will not be 
included in the AE summaries.
A listing will be prepared on all adverse events. If data is available, a listing for delayed 
adverse events (defined as new onset of AE occurring 30 days after last dose as judged 
by investigator to be related to trial medication) will be presented.
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First occurrence of grade 3 and 4 adverse events will be reported by cycle. The drug 
related grade 3 and 4 adverse events would be summarized.
A frequency table will be made for the AEs leading to cycle delay, dose reduction, 
skipped dose, or withdrawal of study medication. Adverse events leading to permanent 
stop and AE with outcome death will also be presented by drug relatedness.
For all serious adverse events (SAEs), the investigator has to send an SAE form to the
Janssen R&D GMS. The AEs that are indicated on the CRF as serious are used for the 
summary tables. A summary table by any grade SAEs will be presented. A similar table 
will be presented for the drug-related SAEs. 
2.2.9.2.
Clinical Laboratory Tests
2.2.9.2.1
Hematology
Laboratory results will be classified according to the NCI CTC version 4.0 as described 
in the attachment of the protocol. For absolute neutrophil count (ANC), platelet count 
and hemoglobin, the worst grade per subject will be tabulated overall during treatment 
and per cycle.  
Cross tabulation will be presented for the worst grade during treatment versus the 
baseline toxicity grading.
All data will be listed. In addition, a listing will present subjects' data by cycle and 
laboratory test for those whose laboratory values reach grade 4 anytime during the trial.
2.2.9.2.2
Serum chemistry
Similar to hematology analysis, the worst grade during treatment will be cross tabulated 
to the baseline grade for sodium, alanine aminotransferase [ALT], potassium, total 
bilirubin, direct bilirubin, blood urea nitrogen [BUN], alkaline phosphatase [ALP], 
creatinine, creatine phosphokinase [CPK], glucose, albumin, aspartate aminotransferase 
[AST], and total protein). 
Cross tabulation will be presented for the worst grade during treatment versus the 
baseline toxicity grading. 
All data will be listed. In addition, a listing will present subjects' data by cycle and 
laboratory test for those whose laboratory values reach grade 4 anytime during the trial.
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2.2.9.2.3
Hy's Law2 Cases Analysis
For subjects with any elevated AT (AST or ALT) of >3xULN, ALP <2xULN, and 
associated with an increase in bilirubin ≥2xULN, a listing for all subjects with all such 
records will be produced and a summary table of number of such subjects by treatment 
arm will also be generated.
2.2.9.3.
Vital Signs and Physical Examination Findings
Vital signs (pulse and blood pressure, as well as temperature) and body weight will be 
measured during the screening phase (within 14 days of randomization). Tabulation will 
be made summarizing the vital signs and the body weight.
A physical examination will be done during the screening phase (within 14 days of 
randomization).
2.2.9.4.
Deaths
Deaths during treatment or within 30 days from the last DOXIL/Trabectedin treatment 
administration will be tabulated, as well as their primary cause of death. A distinction 
will be made between drug related and non-drug related adverse events. 
An additional table will specify the number of subjects who are still alive, who died 
within 30 days after the last treatment (together with the reason), and who died more 
than 30 days after the last treatment (together with the reason).
2.2.9.5.
ANALYSIS OF CARDIAC SAFETY
For detailed cardiac safety analysis results please refer to post marketing request report 
for soft tissue sarcoma submission.
2.2.10.
Safety Narratives
Safety narratives will be written for the following 3 groups of subjects: 
1. Deaths for reasons other than disease progression that occurred within 30 days of the 
last dose of study medication;
2. Treatment-emergent serious adverse events;
3. Treatment-emergent adverse events that led to discontinuation of study medication
2.2.11.
Clinical Pharmacology Analyses
Sparse blood samples were collected to measure trabectedin plasma concentrations at 
the specified times as shown in the schedule of events of the protocol. Population PK
analysis will be based on PK-evaluable data set.
Population PK of trabectedin will be modelled from the data obtained in the phase III 
ET743-OVC-3006 study. Since PK characteristics of trabectedin have been extensively 
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studied in adult cancer population, the population PK model developed previously in 
adults (using data from phase I and phase II studies) will be utilized initially for 
describing trabectedin PK data from ET743-OVC-3006 study. A detailed analysis plan 
for population PK analysis will be developed separately, and a stand-alone report will 
be written to summarize the results of the population PK analysis.
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3.
REFERENCES
1.
Greimel E, et al., An international field study of the reliability and validity of a disease-specific 
questionnaire module (the QLQ-OV28) in assessing the quality of life of patients with ovarian 
cancer. European Journal of Cancer, Volume 39, Issue 10 , Page 1402
2.
Guidance for Industry, Drug-Induced Liver Injury: Premarketing Clinical Evaluation Oct 2007. 
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4.
ATTACHMENTS
4.1.
Imputation Rules for Incomplete Dates 
The following method is only for general reporting purpose. In the case of primary 
analysis, the imputation method has to be clearly and carefully specified in the 
Statistical Analysis Plan. 
The dates of certain historical or current clinical activities are key component for 
statistical analysis. Incomplete date appears when day, month or year is/are missing, and 
it could be imputed so that variables like time to and duration of certain event can be 
calculated. If none of day, month and year is available, then the date is missing, no 
imputation is necessary. 
The following dates are usually used for baseline characteristics and safety summaries.
1.
Date of initial diagnosis 
2.
Date of the first progression/recurrence
3.
Date of the last progression/recurrence 
4.
Date of chemotherapy 
5.
Date of radiation
6.
Date of surgery
7.
AE start date
8.
AE end date 
9.
Follow-up therapy start date
10. Date of death
Dates 1 to 6 will be mentioned as historic dates in the context. All above mentioned 
dates can be either start date or the end date in the calculation depending on the 
analysis, the imputation result could be different for the same date while used either as 
the start date or the end date. General rules for imputation will be specified for the start 
date and end date respectively.  
Historic Dates
For historic dates such as 1-6, the imputation will not distinguish between the usage of 
the start date or the end date, rules are as following: 
If day is unknown, the imputed date = 15th of the same month 
If day and month are missing, and the first visit started before July of the same year, 
the imputed date = 15th of the month prior to the month where the first visit started
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If day and month are missing, and the first visit started on or after last of July of the 
same year, the imputed date = 1st of July
If day and month are missing, and the recorded year is before the first visit year, the 
imputed date = 1st of July of the recorded year
See example below: 
First Visit Date
Recorded Date
Imputed Date
June 20, 2002
2002
May 15, 2002
July15, 2002
2002
July 1, 2002
July 15, 2002
1999
July 1, 1999
If year is missing, the imputed date is missing.
Adverse Event Dates
If incomplete dates exist after data cleaning and are used as the Start Date, the 
following imputation will be applied:
If month and year known, and if the study treatment started in the same month, the 
imputed date = the date of the first treatment. Otherwise, imputed date = 1st of that 
month
If day and month are missing, the imputed date = the first treatment date if the 
treatment started on the same year or Jan 1st if the treatment started before the 
recorded year. 
For example: 
Screen Visit Date
First treatment Date
Recorded Date
Imputed Date
May 20, 2002
June 6, 2002
June, 2002
June 6, 2002
May 20, 2002
June 1, 2002
2002
June 1, 2002
May 20, 2002
June 1, 2002
2003
Jan 1, 2003
If year is missing, the imputed date is missing.
If incomplete dates exist after data cleaning and are used as the End Date, the following 
imputation will be applied:
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If month and year known, and if the month is the same as the month of the last 
treatment date plus 30 days or the death, then the imputed date = the earlier date of 
these two dates in that month. Otherwise, the imputed date = last of the same month. 
For example: 
Last treatment Date
Death Date
Recorded Date
Imputed Date
May 20, 2002
June 6, 2002
June, 2002
June 6, 2002
May 20, 2002
Dec 6, 2002
June, 2002
June 19, 2002
Nov 20, 2002
Aug 6, 2003
June, 2002
June 30, 2002
If day and month are missing, and no death record in the same year, the imputed 
date = the last treatment date plus 30 days or the last date of the same year, 
whichever is earlier. If death did occur in the same year, the imputed date = the death 
date or the last treatment date plus 30 days, whichever is earlier. 
For example: 
Last treatment Date
Death Date
Recorded Date
Imputed Date
Dec 20, 2002
June 6, 2003
2002
Dec 31, 2002
August 1, 2002
Aug 15, 2002
2002
Aug 15, 2002
May 1, 2002
N/A
2002
May 31, 2002
If year is missing, the imputed date is missing.
If any date involved in the summary calculation is still missing after the imputation, 
then the calculation result (such as AE duration, time from first diagnosis, etc.) will be 
missing. For AEs, if both the start date and the end date are missing, it will still be 
considered as treatment emergent AE. For the analysis of time to and duration of certain 
AEs, if the end date is missing, the end date will be censored at the last treatment date 
plus 30 days. 
Follow-up therapy start date
In case the exact day of the start date of the follow-up therapy is missing, the following 
imputation rule will be applied: 
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The exact date is the latest of the following: Day 1 of that month, PD date during that 
month + 1 day, or study drug dosing date during that month + 1 day.
Date of death
In case the exact day of the date of death is missing, the following imputation rule will 
be applied: 
The exact date is the latest of the following: Day 1 of that month, or the date of last 
clinical data point during that month + 1 day.
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