1. Ortho Biotech Oncology Research & Development, Unit of Johnson & Johnson Pharmaceutical Research & Development, L.L.C. On behalf of the NDA holder, Centocor Ortho Biotech Products, L.P.BACKGROUND INFORMATION FOROncologic Drugs Advisory Committee Meeting July 15, 2009 YONDELIS (trabectedin) in Combination With DOXIL /CAELYX (doxorubicin HCL liposome injection) for the Treatment of Patients With Relapsed Ovarian CancerNDA #22-447 AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION Issue/Report Date: 10 JUNE 2009 Document No.: EDMS-PSDB-9357037:3.0 1

2. YONDELIS (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting TABLE OF CONTENTS LIST OF IN-TEXT TABLES ...................................................................................................... 4LIST OF IN-TEXT FIGURES..................................................................................................... 6ABBREVIATIONS..................................................................................................................... 7EXECUTIVE SUMMARY........................................................................................................... 81. INDICATION AND DOSE REGIMEN......................................................................... 132. BACKGROUND ......................................................................................................... 132.1. Unmet Medical Need ..................................................................................................132.2. Current Management and Prognosis for Patients With Relapsed Ovarian Cancer ... 142.3. Overview of Trabectedin............................................................................................. 153. PRECLINICAL EFFICACY DATA ............................................................................. 164. CLINICAL PHARMACOLOGY .................................................................................. 164.1. Clinical Pharmacokinetics........................................................................................... 164.1.1. Pharmacokinetics of Trabectedin: Population Analyses............................ 174.1.2. Distribution of Trabectedin ......................................................................... 184.1.3. Metabolism of Trabectedin......................................................................... 184.1.4. Excretion and Clearance of Trabectedin.................................................... 184.1.5. Influence of Intrinsic Factors on the Pharmacokinetics of Trabectedin ..... 194.1.6. Effect of Co-administered Drugs on the Pharmacokinetics ofTrabectedin ................................................................................................204.1.7. Influence of Trabectedin on the Pharmacokinetics of OtherCo-Administered Drugs.............................................................................. 225. CLINICAL STUDIES IN OVARIAN CANCER ........................................................... 235.1. Phase 1 Study ET743-USA-11................................................................................... 235.2. Phase 2 Studies in Ovarian Cancer ........................................................................... 245.2.1. Study ET-B-026-03..................................................................................... 245.2.2. Study ET-B-009-99..................................................................................... 255.2.3. Study ET743-INT-11 .................................................................................. 255.2.4. Summary of Efficacy for Single Agent Trabectedin ................................... 265.3. Phase 3 Study ET743-OVA-301 ................................................................................ 265.3.1. Goal and Hypothesis.................................................................................. 265.3.2. Rationale for Treatment Regimen.............................................................. 265.3.3. Study Design.............................................................................................. 285.3.3.1. Efficacy Endpoints ..................................................................................295.3.4. Independent Review of Efficacy Endpoints................................................ 305.3.5. Statistical Methodology .............................................................................. 305.3.5.1. Randomization ........................................................................................ 305.3.5.2. Sample Size Determination .................................................................... 315.3.5.3. Analyses of Primary Efficacy Endpoint: Progression-Free Survival ....... 315.3.6. Subject Disposition..................................................................................... 315.3.7. Demographics and Disease Characteristics .............................................. 325.3.8. Extent of Exposure..................................................................................... 375.3.8.1. Duration of Exposure, Dose Intensity and Relative Dose Intensity ........ 375.3.9. Efficacy Results.......................................................................................... 385.3.9.1. Primary Efficacy Endpoint: Progression-Free Survival........................... 395.3.9.1.1. Supportive Analysis of Progression-Free Survival.................................. 435.3.9.1.1.1. Stratified Log-Rank Test...................................................................... 435.3.9.1.1.2. Multivariate Analysis............................................................................ 442 3. YONDELIS (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting 5.3.9.2. Secondary Efficacy Endpoints ................................................................ 455.3.9.2.1. Overall Survival....................................................................................... 455.3.9.2.2. Objective Response Rate ....................................................................... 485.3.9.2.3. Duration of Response ............................................................................. 495.3.9.3. Supportive Efficacy Analyses.................................................................. 505.3.9.3.1. CA-125 Overall Response Rate and CA-125 Progression-Free Survival ................................................................................................505.3.9.3.2. Efficacy Assessment by Platinum Sensitivity.......................................... 515.3.9.3.3. Subsequent Therapy............................................................................... 545.4. Efficacy Conclusions ..................................................................................................555.5. Patient Reported Outcomes ....................................................................................... 565.6. Hospitalizations .......................................................................................................... 566. SUMMARY OF SAFETY............................................................................................ 576.1. Safety Population ....................................................................................................... 576.2. Ovarian Cancer .......................................................................................................... 596.2.1. Integrated Phase 2 Ovarian Studies- Safety Profile .................................. 596.2.2. Phase 3 Study ET743-OVA-301-Safety Profile ......................................... 606.2.2.1. Dose Modifications and Cycle Delay ...................................................... 626.2.2.2. Reasons For Dose Delays and Dose Adjustments................................. 646.2.2.3. Discontinuations Due to Adverse Events................................................ 656.3. All Tumor Types - Integrated Phase 2 Single-Agent Studies - Safety Profile............ 686.4. Summary of Toxicities Associated With Trabectedin as Single-Agent or in Combination With DOXIL ........................................................................................... 696.4.1. Deaths on Study......................................................................................... 696.4.2. Selected Adverse Events ........................................................................... 706.4.2.1. Liver Function..........................................................................................706.4.2.1.1. Liver Biopsy Results in Study ET743-USA-11........................................ 756.4.2.2. HematologicToxicity................................................................................ 766.4.2.2.1. Neutrophil Count Abnormalities and Infection ........................................ 766.4.2.2.1.1. Infection-Related Adverse Events ....................................................... 796.4.2.2.2. Thrombocytopenia and Bleeding Events ................................................ 806.4.2.3. Other Adverse Events.............................................................................806.4.2.3.1. Neurotoxicity ........................................................................................... 806.4.2.3.2. Ototoxicity ............................................................................................... 806.4.2.3.3. Alopecia ..................................................................................................806.4.2.3.4. Hand-Foot Syndrome.............................................................................. 816.4.2.3.5. Creatine Phosphokinase Increase and Rhabdomyolysis ....................... 816.4.2.4. Cardiac Events........................................................................................ 826.4.2.5. Hypersensitivity....................................................................................... 836.5. Safety Conclusions..................................................................................................... 837. BENEFIT-RISK ASSESSMENT................................................................................. 838. CONCLUSION............................................................................................................85REFERENCES ........................................................................................................................ 863 4. YONDELIS (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting LIST OF IN-TEXT TABLES Table 1: Phase 3 Ovarian Study Comparisons of RR, PFS, and OS (Subjects With Platinum-Sensitive Disease)................................................................................ 11Table 2: Basic Population Pharmacokinetic Parameters of Trabectedin in SubjectsWith Cancer (Population Pharmacokinetics Report) ........................................... 18Table 3: Median Pharmacokinetic Parameters of Trabectedin in Subjects With and Without Concomitant Administration of Pegylated Liposomal Doxorubicin (Population Pharmacokinetics Report) ................................................................ 22Table 4: Population Pharmacokinetic Parameters of Total (Liposomal Encapsulated and Free) Doxorubicin in Subjects With Ovarian Cancer Who Received Pegylated Liposomal Doxorubicin With and Without Trabectedin(Population Pharmacokinetics Report) ................................................................ 23Table 5: Key Efficacy Results for Subjects Treated With Single Agent Trabectedin......... 26Table 6: Subject Disposition............................................................................................... 32Table 7: Demographic Data (Study ET743-OVA-301: All Randomized SubjectsAnalysis Set) ........................................................................................................ 33Table 8: Baseline Disease Characteristics (Study ET743-OVA-301: All Randomized Subjects Analysis Set) ......................................................................................... 35Table 9: Summary of Previous Ovarian Cancer Therapy (Study ET743-OVA-301: All Randomized Subjects Analysis Set)............................................................... 36Table 10: Exposure to Treatment ........................................................................................ 37Table 11: Explanation of Discrepancy in PFS Events Between Independent Radiologist and Investigator.................................................................................................... 39Table 12: Progression-Free Survival: Independent Radiologist Review (All Measurable)(Study ET743-OVA-301: All Measurable Subjects Analysis Set) ........................ 39Table 13: Progression-Free Survival: Multivariate Analysis, Independent Radiologist Review Data, All Measurable Subjects (Study ET743-OVA-301) ....................... 44Table 14: Progression-Free Survival: Multivariate Analysis, Independent OncologistReview Data, All Randomized Subjects (Study ET743-OVA-301)...................... 45Table 15: Progression-Free Survival: Multivariate Analysis, Investigators Data, All Randomized Subjects (Study ET743-OVA-301)............................................. 45Table 16: Overall Survival (All Randomized) (Study ET743-OVA-301: All Randomized Subjects Analysis Set) ......................................................................................... 46Table 17: Overall Survival: Multivariate Analysis, All Randomized Subjects(Study ET743-OVA-301)...................................................................................... 47Table 18: Objective Response Rate (ORR) - Independent Radiologist Review Data (Study ET743-OVA-301: All Randomized Subjects Analysis Set)....................... 48Table 19: Objective Response Rate (ORR) - Independent Oncologist Review Data (Study ET743-OVA-301: All Randomized Subjects Analysis Set)....................... 49Table 20: Duration of Response: Independent Radiologist Review Data(Study ET743-OVA-301: All Responders (CR/PR) Analysis Set)........................ 50Table 21: Best Overall CA-125 Response (Study ET743-OVA-301: All Randomized Subjects Analysis Set) ......................................................................................... 51Table 22: CA-125 Progression-Free Survival (Study ET743-OVA-301: All RandomizedSubjects Analysis Set) ......................................................................................... 514 5. YONDELIS (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting Table 23: Efficacy Summary: Platinum-Sensitive and Platinum-Resistant Independent Radiologist Review............................................................................................... 54Table 24: Subsequent Ovarian Cancer Therapy in at Least 2% of Subjects(Study ET743-OVA-301: All Randomized Subjects Analysis Set)....................... 55Table 25: Efficacy Summary for Study ET743-OVA-301..................................................... 56Table 26: Reason for Hospitalization (Study ET743-OVA-301: All Randomized SubjectsAnalysis Set) ........................................................................................................ 56Table 27: Safety Profile (Trabectedin - Integrated Phase 2 Ovarian Studies: All Treated Subjects Analysis Set) ......................................................................................... 59Table 28: Drug-Related Grade 3/4 Adverse Event (>=5% of Subjects; IntegratedAnalysis-Phase 2 Studies in Ovarian Cancer)..................................................... 60Table 29: Safety Profile (Study ET743-OVA-301: All Treated Subjects Analysis Set)........ 61Table 30: Treatment-Emergent Grade 3 or 4 Adverse Events in at Least 5% ofSubjects (Study ET743-OVA-301: All Treated Subjects Analysis Set)................ 62Table 31: Cycle Delays, Dose Reductions Overall (Study ET743-OVA-301: All Treated Subjects Analysis Set)............................................................................ 63Table 32: Reasons For Cycle Delays, Dose Reductions Overall(Study ET743-OVA-301: All Treated Subjects Analysis Set) .............................. 64Table 33: Treatment-Emergent Adverse Events Leading to Dose Adjustment or Cycle Delay in >=2% of Subjects in Either Treatment Arm (Study ET743-OVA-301: All Treated Subjects Analysis Set)....................................................................... 65Table 34: Treatment-Emergent Adverse Events Leading to Treatment Termination in>= 2% of Subjects in Either Treatment Group (Study ET743-OVA-301: All-Treated Subjects Analysis Set........................................................................ 66Table 35: Treatment-Emergent Drug-Related Adverse Events Leading to Treatment Termination (Study ET743-OVA-301: All Treated Subjects Analysis Set) .......... 67Table 36: Safety Profile (Trabectedin Integrated Phase 2 Studies: All Treated Subjects Analysis Set) ......................................................................................... 69Table 37: Deaths During Study (Study ET743-OVA-301: All-Treated Subjects AnalysisSet).......................................................................................................................70Table 38: Laboratory Tests -- Worst Toxicity Grade During Study by Chemistry(Study ET743-OVA-301: All-Treated Subjects Analysis Set) .............................. 735 6. YONDELIS (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting LIST OF IN-TEXT FIGURES Figure 1: Mean Concentrations of Trabectedin in Plasma Following Administration of 1.3 mg/m 2 as a 3-Hour Intravenous Infusion (Study ET743-INT-3)..................... 17Figure 2: Influence of Dexamethasone Pretreatment on the Plasma Clearance ofTrabectedin ..........................................................................................................21Figure 3: Kaplan-Meier Plot of Progression-Free Survival: Independent Radiologist Review (Study ET743-OVA-301: All Measurable Subject Analysis Set)............. 40Figure 4: Kaplan-Meier Plot for Progression-Free Survival: Independent OncologistReview (Study ET743-OVA-301: All-Randomized Subjects Analysis Set).......... 41Figure 5: Kaplan-Meier Plot for Progression-Free Survival: Investigator Review(Study ET743-OVA-301: All-Randomized Subjects Analysis Set) ...................... 42Figure 6: Progression-Free Survival for Independent Reviewers and Investigators(Study ET743-OVA-301, By Analysis Set)........................................................... 43Figure 7: Progression-Free Survival for Independent Reviewers and InvestigatorsStratified by Platinum Sensitivity (Study ET743-OVA-301, by Analysis Set)....... 43Figure 8: Kaplan-Meier Estimate of Overall Survival (Study ET743-OVA-301: All Randomized Subjects Analysis Set)............................................................... 47Figure 9: Kaplan-Meier Plot of Progression-Free Survival by Platinum Sensitivity(Sensitive) Independent Radiologist Review (Study ET743-OVA-301: All Measurable Analysis Set) ............................................................................... 52Figure 10: Kaplan-Meier Plot of Progression-Free Survival by Platinum Sensitivity(Resistant) Independent Radiologist Review (Study ET743-OVA-301: All Measurable Analysis Set) ............................................................................... 53Figure 11: Kaplan-Meier Plot of Overall Survival by Platinum Sensitivity (Sensitive)(Study ET743-OVA-301: All Randomized Subjects Analysis Set)....................... 53Figure 12: Kaplan-Meier Plot of Overall Survival by Platinum Sensitivity (Resistant)(Study ET743-OVA-301: All Randomized Subjects Analysis Set)....................... 54Figure 13: Grouping of Studies Contributing Safety Data to the Summary of ClinicalSafety ...................................................................................................................58Figure 14: Median Values for ALT Cycles With a Grade 3-4 Event (Study ET743-OVA-301: All-Treated Subjects Analysis Set) .............................. 74Figure 15: Median Values for ALT Peak - Subjects Who Received >=6 Cycles ofTreatment (Study ET743-OVA-301: All-Treated Subjects Analysis Set)............. 75Figure 16: Median Values for Neutrophils - Cycles With a Grade 3 or 4 Event(Study ET743-OVA-301: All Treated Subjects Analysis Set) .............................. 77Figure 17: Median Values for Neutrophil Nadir - Subjects Who Received =>6 Cycles ofTreatment (Study ET743-OVA-301: All-Treated Subjects Analysis Set)............. 78Figure 18: Median Values for Neutrophil Nadir - Subjects With >=6 Cycles of Treatment (Trabectedin - Integrated Phase 2 Ovarian Studies: All-Treated SubjectsAnalysis Set) ........................................................................................................ 796 7. YONDELIS (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting ABBREVIATIONS AACR American Association for Cancer Research ALP alkaline phosphatase ALT alanine aminotransferase ASCO American Society for Clinical Oncology AST aspartate aminotransferase AUC area under the concentration-time curve CHMP Committee for Medicinal Products for Human Use CI confidence interval Cmax maximum drug concentration CPK creatine phosphokinase CR complete response CYP cytochrome P450 ECOG Eastern Cooperative Oncology Group EMEA European Agency for the Evaluation of Medicinal Products EORTC European Organization for Research and Treatment of Cancer FDA (United States) Food and Drug Administration HOC human ovarian cancer HR hazard ratio LVEF left ventricular ejection fraction MTD maximum tolerated dose NASH nonalcoholic steatohepatitis NCCN National Comprehensive Cancer Network NER nucleotide excision repair NICE National Institute for Health and Clinical Excellence ORR objective response rate OS overall survival P-gp P-glycoprotein PLD pegylated liposomal doxorubicin PFI platinum-free interval PFS progression-free survival PR partial response PRO patient reported outcomes PS performance status QLQ Quality Life Questionnaire qwk once every week q3wk once every 3 weeks RECIST Response Evaluation Criteria in Solid Tumors STS soft tissue sarcoma ULN upper limit of normal US United States 7 8. YONDELIS (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting EXECUTIVE SUMMARY Overview Study ET743-OVA-301 evaluated the combination of trabectedin and DOXIL (doxorubicin HCl liposome injection) for the treatment of subjects with relapsed ovarian cancer. The positive results of this study serve as the basis for the New Drug Application submitted by Ortho Biotech Oncology Research & Development, unit of Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Study ET743-OVA-301 was conducted at 124 sites in 21 countries, including 24 sites (121 subjects) in the United States (US). This large, international, randomized, controlled study of 672 subjects with relapsed ovarian cancer confirms the favorable benefit to risk profile of trabectedin for the treatment of a disease with high unmet medical need. The addition of trabectedin to DOXIL in Study ET743-OVA-301 resulted in improvement in the predefined primary endpoint of progression-free survival (PFS) as determined by Independent Radiologist review. The results demonstrated a 21% decrease in the risk of disease progression or death (hazard ratio [HR]=0.79; 95% confidence interval [CI]: 0.65;0.96; p=0.0190). Significant improvements in objective response rates (ORR) and a trend in overall survival (OS) that favored the combination further support the clinical significance of the primary analysis (ORR = 28% in trabectedin + DOXIL compared with 19% in DOXIL monotherapy; median OS for trabectedin + DOXIL 20.5 months compared with 19.4 months for DOXIL monotherapy [HR=0.85; 95% CI: 0.67;1.06]). The safety profile of trabectedin and DOXIL was consistent with the known side effects of each drug. The lower dose of DOXIL (30 mg/m2 ) administered in the combination resulted in less frequent DOXIL-related side effects, such as stomatitis and hand-foot syndrome, compared with monotherapy. As reported in studies of single-agent trabectedin, frequent, reversible elevations of liver function tests and neutropenia, in most cases without clinical sequelae, were also observed in Study ET743-OVA-301. The addition of trabectedin to DOXIL resulted in a benefit to risk profile consistent with other doublets currently used to treat patient with relapsed ovarian cancer. Importantly, the approval of this trabectedin-based regimen will provide a clinically useful, platinum-free treatment option for women with relapsed ovarian cancer. The use of PFS as a primary endpoint for the approval of drugs to treat ovarian cancer was established in 2006. Given the improvement in PFS observed with the addition of trabectedin to DOXIL and the trend in survival that favors the combination in Study ET743-OVA-301, Ortho Biotech Oncology Research & Development, unit of Johnson & Johnson Pharmaceutical Research & Development, L.L.C. proposes that 8 9. YONDELIS (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting trabectedin receive regulatory approval for the treatment of patients with relapsed ovarian cancer. Trabectedin Trabectedin, formerly known as ecteinascidin-743 (ET-743), is a tris tetrahydroisoquinolone alkaloid with a unique mechanism of action. Trabectedin alkylates the N2 position of guanine in the minor groove of DNA, unlike most agents that target DNA by binding in the major groove. The trabectedinguanine N2 adduct traps nuclear excision repair (NER) proteins, rendering them ineffective. Checkpoint proteins that respond to damaged DNA, slow progression through the cell cycle. The resultant G2-M arrest leads to apoptosis and cell death. The combination of trabectedin and DOXIL includes drugs with mechanisms of action that are not affected by upregulation of the NER proteins. An additional benefit of the combination is that it may be administered to approximately 10% of patients who develop hypersensitivity to platinum or taxanes and the approximately 20% of patients who cannot receive a taxane-platinum-based regimen because of persistent neuropathy after front-line treatment. Trabectedin is approved for the treatment of soft tissue sarcoma (STS) in 37 countries, including the countries that participate in the European Agency for the Evaluation of Medicinal Products (EMEA) since 2007. The application for the ovarian cancer indication has been submitted to the EMEA and is under review by the Committee for Medicinal Products for Human Use (CHMP). Indication On November 19, 2008, the company submitted data to the US Food and Drug Administration (FDA) in a New Drug Application to support the following indication: Trabectedin is an antineoplastic indicated in combination with DOXIL for treatment of patients with relapsed ovarian cancer. Trabectedin Studies of Subjects with Relapsed Ovarian Cancer The efficacy and safety data supporting the use of trabectedin for the treatment of relapsed ovarian cancer were obtained from 4 completed studies of subjects with ovarian cancer: Studies ET743-INT-11, ET-B-026-03, ET-B-009-99, and the pivotal study, ET743-OVA-301. In addition to data from Study ET743-OVA-301, safety data from the following studies are included in the submission: 16 completed Phase 2 studies of trabectedin as a single-agent in various tumor types and 18 completed Phase 1 studies, one of which is a dose escalation study supporting the dose and schedule for the 9 10. YONDELIS (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting trabectedin + DOXIL combination (Study ET743-USA-11). Across the 38 completed clinical studies included in this submission, 2,322 subjects have been treated with trabectedin. Efficacy Study ET743-OVA-301 was a Phase 3, open-label, multicenter, randomized study of adult women with relapsed ovarian cancer. This study was designed to investigate the efficacy and safety of the combination of DOXIL 30 mg/m2 administered as a 90-minute i.v infusion (60-minutes for subjects in Europe per the European Summary of Product Characteristics) followed by trabectedin 1.1 mg/m2 as a 3-hour i.v. infusion, every 3 weeks. The outcomes for this combined treatment were compared with those of DOXIL 50 mg/m2 administered as a 90-minute i.v. infusion every 4 weeks. Despite the difference in cycle length in the 2 arms, tumor assessments were mandated every 8 weeks for both arms. The results of Study ET743-OVA-301, the pivotal study in this dossier, demonstrate that subjects with relapsed ovarian cancer (n=672) who are treated with trabectedin + DOXIL have better outcomes than those who are treated with DOXIL monotherapy. DOXIL is approved in 76 countries for the treatment of relapsed ovarian cancer and thus is an appropriate active comparator in this setting. The addition of trabectedin to DOXIL resulted in a 21% decrease in the risk of disease progression or death (PFS) compared with DOXIL monotherapy. The PFS endpoint was assessed among all subjects with measurable disease by Independent Radiologists using imaging only. The median PFS for the trabectedin + DOXIL combination arm was 7.3 months compared with 5.8 months for the DOXIL monotherapy arm (HR=0.79; 95% CI: 0.65;0.96; p=0.0190). Additional analyses of PFS among all randomized subjects included clinical and imaging data in the assessment of disease progression, by Independent Oncologists, (HR=0.72; 95% CI: 0.60;0.88; p=0.0008), and by the Study Investigators (HR=0.72; 95% CI: 0.61;0.86; p=0.0002), demonstrate consistent results independent of the method of assessment. The ORR was 28% in the trabectedin + DOXIL arm compared with 19% in the DOXIL monotherapy arm. Overall survival data were not mature at the time of the clinical cutoff date (55% censored). However, the planned analysis of OS at the time of final PFS analysis demonstrated a 15% reduction in the risk of death for subjects in the trabectedin + DOXIL arm (median OS for the trabectedin + DOXIL arm was 20.5 months compared wth 19.4 months for the DOXIL monotherapy arm; HR=0.85; 95% CI: 0.67;1.06). Sensitivity analyses support the robustness of the efficacy endpoints. An analyses of patient-reported outcomes (PRO), such as the EORTC quality life questionnaire (QLQ) 10 11. YONDELIS (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting C30, Global Health Status Score, showed no significant change when trabectedin and DOXIL were administered in combination relative to DOXIL monotherapy. Table 1 summarizes the reduction in the risk of disease progression and death observed in Study ET743-OVA-301, as well as that observed in a study of paclitaxel added to a platinum-based compound, and a study of gemcitabine added to carboplatin. The latter studies include only platinum-sensitive subjects; and the date of progression was determined by the Investigators rather than Independent Radiologists review. Therefore, the results for Study ET743-OVA-301 shown in Table 1, are only for the platinum- sensitive subgroup assessed by Independent Radiologists review (primary endpoint), and the Investigators. As is shown in Table 1, the proportion of poorer prognosis subjects, that is, those who progressed after prior taxane therapy and who had partially sensitive disease, is highest in Study ET743-OVA-301. Despite this, the addition of trabectedin to DOXIL results in a reduction in the risk of progression that is comparable to what is observed when other approved drugs were tested in doublets. Also, the trend in reduction in the risk of death is comparable to that observed when paclitaxel is added to a platinum-based regimen. Recognizing the limitations of cross-study comparisons, this summary of the active combination regimens for the treatment of relapsed ovarian cancer demonstrates that when similar patient populations are considered, the magnitude of the clinical effect of adding trabectedin to DOXIL is similar to that observed with platinum-containing doublets. Table 1: Phase 3 Ovarian Study Comparisons of RR, PFS, and OS (Subjects With Platinum-Sensitive Disease) Carboplatin Carboplatin Paclitaxel Gemcitabine Parmar et al. Pfisterer et al. Trabectedin + DOXIL N 802 356 430 10 Endpoint OS PFS PFS Prior Taxane 40% 71% 77% 6-12 months PFI 25% 43% 50% PFS Assessment Investigator Investigator Ind. Radiologist/Investigator Risk of Progression 24% 28% 27%/38% Risk of Death 18% No 18% Added Toxicity Myelo, Neuro Myelo Myelo, LFTs Myelo= myelosuppression, Neuro= neurotoxicity, LFTs= liver function tests, PFI=platinum free interval; PFS=progression-free survival; OS=overall survival Source: (Pfisterer 2006; Parmar 2003) 11 12. YONDELIS (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting Safety As was seen with the administration of trabectedin alone, the combination of trabectedin and DOXIL commonly results in transient, reversible elevations of liver transaminases. Grade 3-4 elevations in transaminases were more frequent in the trabectedin + DOXIL arm (ALT 31%, AST 7%, n=333) compared with the DOXIL monotherapy arm (AST 1%, ALT 1%, n=330). The elevations generally occur after the first administration, return to normal before the next cycle, but decrease in severity with continued cycles of treatment. This decrease in severity occurs with or without dose reduction. Early experience with trabectedin showed that dexamethasone premedication decreased the frequency and severity of transaminase elevations. Premedication with dexamethasone is now administered routinely. In Study ET743-OVA-301, Grade 3-4 neutropenia was more frequent in the trabectedin + DOXIL arm (63%, n=333) compared with the DOXIL monotherapy arm (22%, n=330). Febrile neutropenia was reported for 8% of subjects in the trabectedin + DOXIL arm, and 2% of subjects receiving DOXIL alone. Sepsis, septic shock, or sepsis syndrome were reported for