Ortho Biotech Oncology Research

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Ortho Biotech Oncology Research

  1. 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 FOR Oncologic 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 Cancer NDA #22-447 AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION Issue/Report Date: 10 JUNE 2009 Document No.: EDMS-PSDB-9357037:3.0 1
  2. 2. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting TABLE OF CONTENTS LIST OF IN-TEXT TABLES ...................................................................................................... 4 LIST OF IN-TEXT FIGURES..................................................................................................... 6 ABBREVIATIONS..................................................................................................................... 7 EXECUTIVE SUMMARY........................................................................................................... 8 1. INDICATION AND DOSE REGIMEN......................................................................... 13 2. BACKGROUND ......................................................................................................... 13 2.1. Unmet Medical Need ..................................................................................................13 2.2. Current Management and Prognosis for Patients With Relapsed Ovarian Cancer ... 14 2.3. Overview of Trabectedin............................................................................................. 15 3. PRECLINICAL EFFICACY DATA ............................................................................. 16 4. CLINICAL PHARMACOLOGY .................................................................................. 16 4.1. Clinical Pharmacokinetics........................................................................................... 16 4.1.1. Pharmacokinetics of Trabectedin: Population Analyses............................ 17 4.1.2. Distribution of Trabectedin ......................................................................... 18 4.1.3. Metabolism of Trabectedin......................................................................... 18 4.1.4. Excretion and Clearance of Trabectedin.................................................... 18 4.1.5. Influence of Intrinsic Factors on the Pharmacokinetics of Trabectedin ..... 19 4.1.6. Effect of Co-administered Drugs on the Pharmacokinetics of Trabectedin ................................................................................................20 4.1.7. Influence of Trabectedin on the Pharmacokinetics of Other Co-Administered Drugs.............................................................................. 22 5. CLINICAL STUDIES IN OVARIAN CANCER ........................................................... 23 5.1. Phase 1 Study ET743-USA-11................................................................................... 23 5.2. Phase 2 Studies in Ovarian Cancer ........................................................................... 24 5.2.1. Study ET-B-026-03..................................................................................... 24 5.2.2. Study ET-B-009-99..................................................................................... 25 5.2.3. Study ET743-INT-11 .................................................................................. 25 5.2.4. Summary of Efficacy for Single Agent Trabectedin ................................... 26 5.3. Phase 3 Study ET743-OVA-301 ................................................................................ 26 5.3.1. Goal and Hypothesis.................................................................................. 26 5.3.2. Rationale for Treatment Regimen.............................................................. 26 5.3.3. Study Design.............................................................................................. 28 5.3.3.1. Efficacy Endpoints ..................................................................................29 5.3.4. Independent Review of Efficacy Endpoints................................................ 30 5.3.5. Statistical Methodology .............................................................................. 30 5.3.5.1. Randomization ........................................................................................ 30 5.3.5.2. Sample Size Determination .................................................................... 31 5.3.5.3. Analyses of Primary Efficacy Endpoint: Progression-Free Survival ....... 31 5.3.6. Subject Disposition..................................................................................... 31 5.3.7. Demographics and Disease Characteristics .............................................. 32 5.3.8. Extent of Exposure..................................................................................... 37 5.3.8.1. Duration of Exposure, Dose Intensity and Relative Dose Intensity ........ 37 5.3.9. Efficacy Results.......................................................................................... 38 5.3.9.1. Primary Efficacy Endpoint: Progression-Free Survival........................... 39 5.3.9.1.1. Supportive Analysis of Progression-Free Survival.................................. 43 5.3.9.1.1.1. Stratified Log-Rank Test...................................................................... 43 5.3.9.1.1.2. Multivariate Analysis............................................................................ 44 2
  3. 3. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting 5.3.9.2. Secondary Efficacy Endpoints ................................................................ 45 5.3.9.2.1. Overall Survival....................................................................................... 45 5.3.9.2.2. Objective Response Rate ....................................................................... 48 5.3.9.2.3. Duration of Response ............................................................................. 49 5.3.9.3. Supportive Efficacy Analyses.................................................................. 50 5.3.9.3.1. CA-125 Overall Response Rate and CA-125 Progression-Free Survival ................................................................................................50 5.3.9.3.2. Efficacy Assessment by Platinum Sensitivity.......................................... 51 5.3.9.3.3. Subsequent Therapy............................................................................... 54 5.4. Efficacy Conclusions ..................................................................................................55 5.5. Patient Reported Outcomes ....................................................................................... 56 5.6. Hospitalizations .......................................................................................................... 56 6. SUMMARY OF SAFETY............................................................................................ 57 6.1. Safety Population ....................................................................................................... 57 6.2. Ovarian Cancer .......................................................................................................... 59 6.2.1. Integrated Phase 2 Ovarian Studies- Safety Profile .................................. 59 6.2.2. Phase 3 Study ET743-OVA-301-Safety Profile ......................................... 60 6.2.2.1. Dose Modifications and Cycle Delay ...................................................... 62 6.2.2.2. Reasons For Dose Delays and Dose Adjustments................................. 64 6.2.2.3. Discontinuations Due to Adverse Events................................................ 65 6.3. All Tumor Types - Integrated Phase 2 Single-Agent Studies - Safety Profile............ 68 6.4. Summary of Toxicities Associated With Trabectedin as Single-Agent or in Combination With DOXIL ........................................................................................... 69 6.4.1. Deaths on Study......................................................................................... 69 6.4.2. Selected Adverse Events ........................................................................... 70 6.4.2.1. Liver Function..........................................................................................70 6.4.2.1.1. Liver Biopsy Results in Study ET743-USA-11........................................ 75 6.4.2.2. HematologicToxicity................................................................................ 76 6.4.2.2.1. Neutrophil Count Abnormalities and Infection ........................................ 76 6.4.2.2.1.1. Infection-Related Adverse Events ....................................................... 79 6.4.2.2.2. Thrombocytopenia and Bleeding Events ................................................ 80 6.4.2.3. Other Adverse Events.............................................................................80 6.4.2.3.1. Neurotoxicity ........................................................................................... 80 6.4.2.3.2. Ototoxicity ............................................................................................... 80 6.4.2.3.3. Alopecia ..................................................................................................80 6.4.2.3.4. Hand-Foot Syndrome.............................................................................. 81 6.4.2.3.5. Creatine Phosphokinase Increase and Rhabdomyolysis ....................... 81 6.4.2.4. Cardiac Events........................................................................................ 82 6.4.2.5. Hypersensitivity....................................................................................... 83 6.5. Safety Conclusions..................................................................................................... 83 7. BENEFIT-RISK ASSESSMENT................................................................................. 83 8. CONCLUSION............................................................................................................85 REFERENCES ........................................................................................................................ 86 3
  4. 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)................................................................................ 11 Table 2: Basic Population Pharmacokinetic Parameters of Trabectedin in Subjects With Cancer (Population Pharmacokinetics Report) ........................................... 18 Table 3: Median Pharmacokinetic Parameters of Trabectedin in Subjects With and Without Concomitant Administration of Pegylated Liposomal Doxorubicin (Population Pharmacokinetics Report) ................................................................ 22 Table 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) ................................................................ 23 Table 5: Key Efficacy Results for Subjects Treated With Single Agent Trabectedin......... 26 Table 6: Subject Disposition............................................................................................... 32 Table 7: Demographic Data (Study ET743-OVA-301: All Randomized Subjects Analysis Set) ........................................................................................................ 33 Table 8: Baseline Disease Characteristics (Study ET743-OVA-301: All Randomized Subjects Analysis Set) ......................................................................................... 35 Table 9: Summary of Previous Ovarian Cancer Therapy (Study ET743-OVA-301: All Randomized Subjects Analysis Set)............................................................... 36 Table 10: Exposure to Treatment ........................................................................................ 37 Table 11: Explanation of Discrepancy in PFS Events Between Independent Radiologist and Investigator.................................................................................................... 39 Table 12: Progression-Free Survival: Independent Radiologist Review (All Measurable) (Study ET743-OVA-301: All Measurable Subjects Analysis Set) ........................ 39 Table 13: Progression-Free Survival: Multivariate Analysis, Independent Radiologist Review Data, All Measurable Subjects (Study ET743-OVA-301) ....................... 44 Table 14: Progression-Free Survival: Multivariate Analysis, Independent Oncologist Review Data, All Randomized Subjects (Study ET743-OVA-301)...................... 45 Table 15: Progression-Free Survival: Multivariate Analysis, Investigators Data, All Randomized Subjects (Study ET743-OVA-301)............................................. 45 Table 16: Overall Survival (All Randomized) (Study ET743-OVA-301: All Randomized Subjects Analysis Set) ......................................................................................... 46 Table 17: Overall Survival: Multivariate Analysis, All Randomized Subjects (Study ET743-OVA-301)...................................................................................... 47 Table 18: Objective Response Rate (ORR) - Independent Radiologist Review Data (Study ET743-OVA-301: All Randomized Subjects Analysis Set)....................... 48 Table 19: Objective Response Rate (ORR) - Independent Oncologist Review Data (Study ET743-OVA-301: All Randomized Subjects Analysis Set)....................... 49 Table 20: Duration of Response: Independent Radiologist Review Data (Study ET743-OVA-301: All Responders (CR/PR) Analysis Set)........................ 50 Table 21: Best Overall CA-125 Response (Study ET743-OVA-301: All Randomized Subjects Analysis Set) ......................................................................................... 51 Table 22: CA-125 Progression-Free Survival (Study ET743-OVA-301: All Randomized Subjects Analysis Set) ......................................................................................... 51 4
  5. 5. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting Table 23: Efficacy Summary: Platinum-Sensitive and Platinum-Resistant – Independent Radiologist Review............................................................................................... 54 Table 24: Subsequent Ovarian Cancer Therapy in at Least 2% of Subjects (Study ET743-OVA-301: All Randomized Subjects Analysis Set)....................... 55 Table 25: Efficacy Summary for Study ET743-OVA-301..................................................... 56 Table 26: Reason for Hospitalization (Study ET743-OVA-301: All Randomized Subjects Analysis Set) ........................................................................................................ 56 Table 27: Safety Profile (Trabectedin - Integrated Phase 2 Ovarian Studies: All Treated Subjects Analysis Set) ......................................................................................... 59 Table 28: Drug-Related Grade 3/4 Adverse Event (>=5% of Subjects; Integrated Analysis-Phase 2 Studies in Ovarian Cancer)..................................................... 60 Table 29: Safety Profile (Study ET743-OVA-301: All Treated Subjects Analysis Set)........ 61 Table 30: Treatment-Emergent Grade 3 or 4 Adverse Events in at Least 5% of Subjects (Study ET743-OVA-301: All Treated Subjects Analysis Set)................ 62 Table 31: Cycle Delays, Dose Reductions – Overall (Study ET743-OVA-301: All Treated Subjects Analysis Set)............................................................................ 63 Table 32: Reasons For Cycle Delays, Dose Reductions – Overall (Study ET743-OVA-301: All Treated Subjects Analysis Set) .............................. 64 Table 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)....................................................................... 65 Table 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........................................................................ 66 Table 35: Treatment-Emergent Drug-Related Adverse Events Leading to Treatment Termination (Study ET743-OVA-301: All Treated Subjects Analysis Set) .......... 67 Table 36: Safety Profile (Trabectedin – Integrated Phase 2 Studies: All Treated Subjects Analysis Set) ......................................................................................... 69 Table 37: Deaths During Study (Study ET743-OVA-301: All-Treated Subjects Analysis Set).......................................................................................................................70 Table 38: Laboratory Tests -- Worst Toxicity Grade During Study by Chemistry (Study ET743-OVA-301: All-Treated Subjects Analysis Set) .............................. 73 5
  6. 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)..................... 17 Figure 2: Influence of Dexamethasone Pretreatment on the Plasma Clearance of Trabectedin ..........................................................................................................21 Figure 3: Kaplan-Meier Plot of Progression-Free Survival: Independent Radiologist Review (Study ET743-OVA-301: All Measurable Subject Analysis Set)............. 40 Figure 4: Kaplan-Meier Plot for Progression-Free Survival: Independent Oncologist Review (Study ET743-OVA-301: All-Randomized Subjects Analysis Set).......... 41 Figure 5: Kaplan-Meier Plot for Progression-Free Survival: Investigator Review (Study ET743-OVA-301: All-Randomized Subjects Analysis Set) ...................... 42 Figure 6: Progression-Free Survival for Independent Reviewers and Investigators (Study ET743-OVA-301, By Analysis Set)........................................................... 43 Figure 7: Progression-Free Survival for Independent Reviewers and Investigators Stratified by Platinum Sensitivity (Study ET743-OVA-301, by Analysis Set)....... 43 Figure 8: Kaplan-Meier Estimate of Overall Survival (Study ET743-OVA-301: All Randomized Subjects Analysis Set)............................................................... 47 Figure 9: Kaplan-Meier Plot of Progression-Free Survival by Platinum Sensitivity (Sensitive) Independent Radiologist Review (Study ET743-OVA-301: All Measurable Analysis Set) ............................................................................... 52 Figure 10: Kaplan-Meier Plot of Progression-Free Survival by Platinum Sensitivity (Resistant) Independent Radiologist Review (Study ET743-OVA-301: All Measurable Analysis Set) ............................................................................... 53 Figure 11: Kaplan-Meier Plot of Overall Survival by Platinum Sensitivity (Sensitive) (Study ET743-OVA-301: All Randomized Subjects Analysis Set)....................... 53 Figure 12: Kaplan-Meier Plot of Overall Survival by Platinum Sensitivity (Resistant) (Study ET743-OVA-301: All Randomized Subjects Analysis Set)....................... 54 Figure 13: Grouping of Studies Contributing Safety Data to the Summary of Clinical Safety ...................................................................................................................58 Figure 14: Median Values for ALT – Cycles With a Grade 3-4 Event (Study ET743-OVA-301: All-Treated Subjects Analysis Set) .............................. 74 Figure 15: Median Values for ALT Peak - Subjects Who Received >=6 Cycles of Treatment (Study ET743-OVA-301: All-Treated Subjects Analysis Set)............. 75 Figure 16: Median Values for Neutrophils - Cycles With a Grade 3 or 4 Event (Study ET743-OVA-301: All Treated Subjects Analysis Set) .............................. 77 Figure 17: Median Values for Neutrophil Nadir - Subjects Who Received =>6 Cycles of Treatment (Study ET743-OVA-301: All-Treated Subjects Analysis Set)............. 78 Figure 18: Median Values for Neutrophil Nadir - Subjects With >=6 Cycles of Treatment (Trabectedin - Integrated Phase 2 Ovarian Studies: All-Treated Subjects Analysis Set) ........................................................................................................ 79 6
  7. 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. 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. 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 trabectedin–guanine 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. 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. 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. 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 <1% of subjects treated with trabectedin + DOXIL. Myelosuppression was managed with dose delays, dose reductions, and when indicated, the administration of colony-stimulating growth factors. The incidence of Grade 3-4 neutropenia observed in Study ET743-OVA-301 was similar to the rate reported in the literature for some other cytotoxic agents commonly utilized for the treatment of ovarian cancer when used alone or in combination, such as topotecan (77%) (Gordon 2001) or gemcitabine in combination with carboplatin (70%) (Pfisterer 2006). The lower dose of DOXIL in the combination arm compared with that used in the monotherapy arm, resulted in a lower incidence of DOXIL-related toxicities. Hand-foot syndrome (palmar-plantar-erythrodysesthesia, [PPE]) occurred in 54% of subjects in the DOXIL monotherapy arm compared with 24% of subjects in the trabectedin + DOXIL arm. Similarly, the rate of stomatitis was lower in the combination arm (20%) than in the DOXIL monotherapy arm (33%). Other toxicities commonly associated with standard chemotherapy in ovarian cancer were relatively uncommon with trabectedin in combination with DOXIL. For example, alopecia (Grade 2 or higher), 2% compared with 86% for paclitaxel and a platinum (Parmar 2003); Grade 2-4 peripheral neuropathy, 1.8% compared with 20% for paclitaxel and a platinum (Parmar 2003); and hypersensitivity reactions, 1% compared with 10% to 15% for platinum agents (Markman 2009). Neuropathy or hypersensitivity may prevent the continued use of platinum or paclitaxel containing regimens. 12
  13. 13. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting In Study ET743-OVA-301 there were similar rates of decreases in left ventricular ejection fraction (LVEF) for the trabectedin + DOXIL (28 subjects, 14%) and DOXIL monotherapy (22 subjects, 13%) arms. Congestive heart failure was reported for 1 subject (<1%) in the DOXIL monotherapy arm and 6 subjects (2%) in the trabectedin + DOXIL arm. Summary and Conclusions The addition of trabectedin to DOXIL offers patients with relapsed ovarian cancer a new treatment regimen that has a unique mechanism of action, that may be administered to those who cannot receive platinum- or taxane-based treatment because of hypersensitivity, or neuropathy, and that prolongs PFS compared with single-agent therapy. Study ET743-OVA-301 is a randomized, controlled study that included rigorous, unbiased assessment of the primary PFS endpoint by Independent Radiologist review. The magnitude of the PFS effect among platinum-sensitive subjects is comparable to that observed when other combination regimens were studied. In addition, the primary analysis is supported by relevant sensitivity analyses, significant improvement in response rates, and a trend in OS, all of which consistently favor the combination. The observed safety profile is consistent with what is observed when trabectedin and DOXIL are given as single-agents. Although elevation of liver transaminases and myelosuppression are common laboratory abnormalities associated with the combination, they are rarely associated with serious clinical sequelae. Thus, the benefit to risk profile is favorable, especially for women with relapsed ovarian cancer who cannot or prefer not to be treated with platinum-based regimens. 1. INDICATION AND DOSE REGIMEN The company is seeking approval for the proposed indication: Trabectedin is an antineoplastic indicated in combination with DOXIL for treatment of patients with relapsed ovarian cancer. The recommended dose regimen is DOXIL 30 mg/m2 , as a 90-minute/60-minute (European territory) intravenous (i.v.) infusion followed by trabectedin administered at 1.1 mg/m2 as a 3-hour i.v. infusion once every 3 weeks (q3wk). 2. BACKGROUND 2.1. Unmet Medical Need Ovarian cancer is the most common cause of death from gynecological cancer in the US. It is the fifth most common cause of cancer-related mortality in women. For 2009 it was estimated that there would be approximately 21,550 newly diagnosed patients and 14,600 deaths from this disease. There is a 5-year OS rate of approximately 46% (American Cancer Society 2009). 13
  14. 14. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting Although advances have been made over the last 20 years in the management of patients with ovarian cancer, progress has been slow. The most significant medical improvement has been the use of platinum-based compounds in combination with taxanes, but beyond these combinations there are limited effective options for treating patients following failure of platinum-based therapies (Gordon 2003). There are unmet needs for patients who have relapsed, particularly for those who are no longer candidates for retreatment with platinum- and taxane-based combinations due to resistance, hypersensitivity, or residual symptomatic toxicities such as neuropathy. Therefore, there is a need for a non-platinum, non-taxane option for patients with relapsed ovarian cancer. 2.2. Current Management and Prognosis for Patients With Relapsed Ovarian Cancer Standard primary therapy for advanced ovarian cancer involves maximal tissue reductive surgery followed by systemic platinum chemotherapy often combined with a taxane (Fung 2007). The prognosis and current management of patients who relapse after initial surgery and chemotherapy is based on the initial response to a platinum-taxane regimen. Accordingly, patients whose disease recurs more than 6 months after platinum-based therapy are considered to have “platinum-sensitive” disease. In the absence of residual toxicities, patients may be retreated with first-line therapy (Pectasides 2006). Patients whose disease progresses on front-line treatment or recurs within 6 months of first-line therapy with a platinum-based regimen are considered to have “platinum-resistant” disease and have limited treatment choices (Gordon 2001; 2003). Aside from retreatment with platinum-based or taxane-based regimens, treatment options are limited for patients with recurrent disease. Residual toxicity, or the patient’s initial intolerance to platinum or taxane, further limit the options for retreatment (Pectasides 2006). The United Kingdom’s National Institute for Health and Clinical Excellence (NICE) issued guidance that identifies DOXIL as an option for the treatment of patients with partially platinum-sensitive, (i.e. those relapsing within 6 to 12 months after initial platinum-based therapy), platinum-resistant (i.e. those relapsing in less than 6 months after initial platinum-based therapy), or platinum-refractory (no response or progression during platinum-based therapy) advanced ovarian cancer or for patients who are allergic to platinum-based compounds. Paclitaxel in combination with a platinum-based compound is recommended as an option for treatment of patients with platinum-sensitive or partially platinum-sensitive disease. Topotecan is limited to the treatment of patients with platinum-refractory or platinum-sensitive disease, if DOXIL or paclitaxel are considered unsuitable (NICE 2005). For patients with recurrent ovarian cancer, docetaxel, topotecan, gemcitabine, oral etoposide, vinorelbine, and DOXIL have shown single-agent activity. While they are acceptable recurrence modalities, none of these have 14
  15. 15. N O O H3C AcO CH3 OCH3 HO OH S O O H NH H3CO HO N CH3 YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting been shown to be superior. The National Comprehensive Cancer Network (NCCN) panel could not recommend any of these chemotherapeutic agents as a treatment of choice for recurrent ovarian cancer (NCCN 2009). 2.3. Overview of Trabectedin The chemical name using CAS nomenclature is as follows: (1'R,6R,6aR,7R,13S,14S,16R)-5-(acetyloxy)-3',4',6,6a,7,13,14,16-octahydro-6',8,14­ trihydroxy-7',9-dimethoxy-4,10,23-trimethyl-spiro[6,16-(epithiopropanoxymethano)­ 7,13-imino-12H-1,3-dioxolo[7,8]isoquino[3,2-b][3]benzazocine-20,1'(2'H)-isoquinolin]­ 19-one. The chemical structure is as follows: Trabectedin, formerly known as ecteinascidin-743 (ET-743), is a tris tetrahydroisoquinoline alkaloid with a novel mechanism of action. Trabectedin was originally isolated from the marine tunicate, Ecteinascidia turbinata; today, a synthetic process is used in the manufacturing of trabectedin. Unlike platinum drugs, which bind to the N7 position of guanines in the major groove of DNA, trabectedin binds to the N2 position of guanine in the minor groove of DNA. This interaction bends the DNA towards the major groove where interactions occur between the C-ring of trabectedin and the transcription-coupled nuclear excision repair machinery (TC-NER). Trabectedin is more active in platinum-resistant cell lines that have an intact TC-NER pathway or express increased activity of the TC-NER complex (Stevens 2008). In contrast, other DNA-binding cytotoxic agents are more effective in cells containing defects in the transcription-coupled NER pathway. Following exposure to trabectedin, progression through the cell cycle is slowed by checkpoint proteins that respond to damaged DNA. The resultant G2-M arrest leads to apoptosis and cell death. In addition, trabectedin targets inducible transcription (von Mehren 2008). For example, trabectedin selectively inhibits transcriptional induction of several genes including MDR1 (Jin 2000), HSP70 (Minuzzo 2000), type I collagen (Louneva 2003), SP1 (Friedman 2002) and the orphan 15
  16. 16. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting receptor SxR (Synold 2001) through inhibition of nuclear factor-Y binding to the CCAAT box (Synold 2001) The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux (Synold 2001). DOXIL, a pegylated liposome that contains doxorubicin, acts primarily by targeting the activity of topoisomerase II alpha. When topoisomerase II alpha is poisoned by DOXIL, cells accumulate double-stranded DNA breaks, which leads to apoptosis. Thus, the regimen of DOXIL and trabectedin combines 2 drugs with different mechanisms of action. 3. PRECLINICAL EFFICACY DATA Trabectedin has demonstrated in vitro or in vivo activity against a wide array of solid and hematopoietic tumor cell lines. These include ovarian cancer, STS, breast, and non-small cell lung cancers (Valoti 1998, Hendricks 1999, Morioka 2003, Faircloth 2001, Donald 2003, and Takahashi 2002). The in vivo activity of trabectedin has been observed in ovarian cancer xenografts, including long-lasting complete regressions of tumors from human ovarian carcinoma (HOC) tumor cell lines, HOC-22 and HOC-18. Subsequent experiments that assessed the effects of trabectedin on the HOC-18 late-stage model demonstrated that its activity was equivalent to that of cisplatin, the standard control agent (Parma 2003). Synergistic antitumoral effects with doxorubicin and trabectedin were demonstrated in a fibrosarcoma model and in other experimental systems (Takahashi 2002; Meco 2003). In vitro cell lines made resistant to trabectedin do not demonstrate enhanced P-glycoprotein (P-gp) activity, and P-gp overexpression does not appear to confer cross-resistance to trabectedin (Scotto 2001). Furthermore, trabectedin treatment can down-regulate MDR1-mediated P-gp expression, thereby potentiating the activity of other chemotherapeutic agents that are P-gp substrates (Kanzaki 2002). In vivo xenograft studies revealed that the maximum antitumoral effects of trabectedin were obtained using an intermittent schedule at the maximum tolerated dose (MTD). This was later shown to be consistent with the clinical findings (Valoti 1998). 4. CLINICAL PHARMACOLOGY 4.1. Clinical Pharmacokinetics Following i.v. administration, maximum trabectedin plasma concentrations were typically observed either during or just before the end of the 3-hour infusion (Figure 1). Thereafter, the decline in the plasma concentrations of trabectedin was characterized by an initial distribution half-life of approximately 0.2 hours, followed by 2 elimination 16
  17. 17. 3-Hour Intravenous Infusion (Study ET743-INT-3) 6.0 5.6 ) 5.2 /mL 4.8 (ng Cycle 1 (n=9) 4.4 din Cycle 2 (n=9) 4.0 ecte 3.6 rab 3.2 ofT 2.8 ion 2.4 trat 2.0 Concen 1.6 1.2 ma 0.8 Plas 0.4 8 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Time After Dosing (hours) YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting phases with half-lives of approximately 6 hours and 175 hours. The long terminal half- life was associated with very low drug concentrations. Therefore, little or no accumulation of trabectedin in plasma was observed upon repeat administration at 3-week intervals. The pharmacokinetics of trabectedin are predictable. Parameters such as plasma clearance, distribution volume, and half-life are comparable when administered as a 1-, 3-, or 24-hour i.v. infusion. Dose-proportionality with respect to the maximum plasma drug concentration (Cmax) or area under the concentration-time curve (AUC) values of trabectedin was demonstrated in an analysis (power model) that included 314 subjects treated with trabectedin at doses of 0.024 to 1.8 mg/m2 administered as a 1-, 3-, or 24-hour infusion. The pharmacokinetics of trabectedin are time-independent as evidenced by the lack of a statistically significant or clinically meaningful difference in the plasma clearance or distribution volume when each parameter was compared across multiple cycles. Figure 1: Mean Concentrations of Trabectedin in Plasma Following Administration of 1.3 mg/m2 as a 4.1.1. Pharmacokinetics of Trabectedin: Population Analyses A population analysis was performed on the plasma concentration versus time data collected from 603 subjects who received trabectedin during 15 Phase 1 and 2 studies. The influence of select covariates on the trabectedin pharmacokinetic parameters was examined, including age, sex, body size measurements (total body weight, lean body weight, ideal body weight, and body surface area), creatinine clearance, performance status, liver metastases, and dexamethasone pretreatment. 17
  18. 18. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting A 4-compartment pharmacokinetic model with linear elimination best characterized the trabectedin concentration-time profiles (Table 2). Table 2: Basic Population Pharmacokinetic Parameters of Trabectedin in Subjects With Cancer (Population Pharmacokinetics Report) Population Mean Estimate Intersubject Variability Parameter (Male/Female) (%CV) CL (L/h) 31.5 / 31.5 51.0 Vc (L) 16.1 / 13.9 34.1 Plasma half-life (h) - Alpha phase 0.20 / 0.23 - -- Beta phase 6.0 / 6.4 181 / 168 - - Gamma phase CL=plasma clearance, CV= coefficient of variation, h=hour, L=Liter, Vc =central volume of distribution 4.1.2. Distribution of Trabectedin The population estimate of distribution volume at steady state (i.e., sum total of central and peripheral compartments) exceeded 5,000 L. These results indicate that trabectedin undergoes extensive distribution into peripheral tissues; this is consistent with the trabectedin tissue distribution observed during preclinical studies and with the drug’s high affinity for DNA. This phenomenon is probably the main determinant of the long terminal (gamma) half-life of trabectedin in plasma. Trabectedin is extensively bound to plasma proteins. The in vitro free (unbound) fraction averaged 2.5% and was independent of the trabectedin concentrations (10 ng/mL and 100 ng/mL) in plasma as tested by equilibrium dialysis. 4.1.3. Metabolism of Trabectedin Following dosing in humans, trabectedin undergoes extensive oxidative metabolism to numerous metabolites, most of which have not been identified. On the basis of in vitro experiments, CYP3A4 is the predominant cytochrome P450 (CYP) enzyme responsible for the hepatic metabolism of trabectedin. Direct glucuronidation is not an important route of trabectedin metabolism. 4.1.4. Excretion and Clearance of Trabectedin A clinical metabolism and excretion study with 14C-labelled trabectedin was conducted in 5 male and 3 female subjects. Feces and urine samples were collected over a period of 24 and 10 consecutive days, respectively. Fecal and urinary excretion accounted for approximately 58% and 6%, respectively, of the administered radioactivity. The lack of complete recovery is not uncommon for cytotoxic drugs such as platinum-analogues and alkylating agents, which bind irreversibly to DNA and other tissue components. Urinary 18
  19. 19. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting excretion of unchanged drug plays a minor role (<1% of the dose) in the elimination of trabectedin. Variability in renal function is not expected to influence the clearance of trabectedin or its metabolites. 4.1.5. Influence of Intrinsic Factors on the Pharmacokinetics of Trabectedin Demographics None of the subject covariates (including age [19 – 83 years], sex, various measures of body size, performance status, and liver metastases) examined during the population analyses explained between-subject variability in the plasma clearance of trabectedin to a statistically significant degree (Section 4.1.1). The potential effects of race/ethnicity on the pharmacokinetics of trabectedin were not formally investigated, because the majority of subjects enrolled in clinical studies were White. However, gross differences in trabectedin pharmacokinetics across various race or ethnic groups are not anticipated. Trabectedin is dosed on the basis of body surface area. This is a widely used strategy to decrease pharmacokinetic variability and is expected to account for race/ethnic-related variability in body size. Genetic polymorphisms in CYP3A4 (the predominant cytochrome P450 responsible for trabectedin metabolism) are unlikely to contribute to any race/ethnic-related differences. CYP3A4 polymorphisms exhibit low allelic frequencies and are reported to have only limited relevance in explaining pharmacokinetic variability observed in African-American, Asian, and White subjects. (Baker 2004, Eap 2004, Floyd 2003, He 2005, Lee 2007, Lepper 2005, and Wandel 2000). Hepatic Impairment Among subjects with hepatic impairment, the clearance of trabectedin may be decreased, resulting in higher concentrations of trabectedin in plasma. The proposed label includes specific criteria for use of trabectedin in this patient population. Prior to the initiation of trabectedin therapy, patients should have a serum bilirubin ≤ upper limit of normal (ULN) and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations ≤2.5 x ULN. Renal Impairment Small quantities of unchanged trabectedin (<1% of the dose) or derived metabolites (<10% of the dose) were recovered in urine. The population analyses demonstrated that creatinine clearance (range, 30.3 to 150 mL/min) did not influence the plasma pharmacokinetics of trabectedin. 19
  20. 20. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting 4.1.6. Effect of Co-administered Drugs on the Pharmacokinetics of Trabectedin Binding to Plasma Proteins No drugs studied affected the in vitro protein binding of trabectedin to a significant degree at clinically relevant concentrations including acetylsalicylic acid, ceftazidime, cloxacillin, diazepam, diclofenac, digitoxin, erythromycin, ethanol, ondansetron, paracetamol, phenytoin, propranolol, tamoxifen, valproic acid, and warfarin. (Beumer 2004, Beumer 2009). Inhibitors or Inducers of Cytochrome P450 Co-administration with potent inducers of CYP3A4 may reduce the plasma concentrations of trabectedin, whereas inhibitors of this enzyme may increase the plasma concentrations of trabectedin. As indicated in the proposed draft label, caution is warranted if trabectedin is administered to patients co-administered medications that influence CYP3A4 activity. Dexamethasone The potential effects of dexamethasone pretreatment on the pharmacokinetics of trabectedin were evaluated using population methods. In vitro studies with human hepatocytes (Lu 2001, Pascussi 2000) indicated that dexamethasone may increase the activity of CYP3A, the predominant cytochrome P450 enzyme responsible for the hepatic metabolism of trabectedin. The median clearance values of trabectedin were comparable [34.1 L/h (n=37) and 38.3 L/h (n=290)] among those subjects who received trabectedin without dexamethasone pretreatment compared with those who were given a single i.v. dose of 10 or 20 mg dexamethasone just before trabectedin administration (Figure 2). Subjects who received dexamethasone regimens of longer duration exhibited higher median clearance values (42.0 L/h, n=57). 20
  21. 21. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting Figure 2: Influence of Dexamethasone Pretreatment on the Plasma Clearance of Trabectedin 01020304050 CLs(L/h) No Dexamethasone Single Dose 4-Days of Dexamethasone Dexamethasone Prior to Trabectedin Starting Prior to Trabectedin Note 1: Population estimates of the plasma clearance of trabectedin for each group are presented as the median (horizontal line) and the 25th (lower horizontal border) and 75th (upper horizontal border) percentiles. The analyses included trabectedin concentration-time data during the first cycle from 10 clinical studies during which trabectedin was given as a single therapeutic agent. Note 2: Subjects received trabectedin without dexamethasone (left; n=37 subjects), a single 10- or 20-mg intravenous dose of dexamethasone immediately prior to trabectedin (middle; n=290 subjects), or a twice-daily regimen of dexamethasone for 4 consecutive days beginning 24 hours prior to trabectedin administration (right; n=57 subjects). DOXIL The population analysis was repeated with pharmacokinetic data from 2 clinical studies during which trabectedin was co-administered with DOXIL (Phase 1 Study ET743-USA-11 and Phase 3 Study ET743-OVA-301) in addition to the 15 Phase 1 and 2 single-agent studies included in the original analysis (Section 4.1.1). The median (range) values for trabectedin pharmacokinetic parameter values are provided in Table 3. 21
  22. 22. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting Table 3: Median Pharmacokinetic Parameters of Trabectedin in Subjects With and Without Concomitant Administration of Pegylated Liposomal Doxorubicin (Population Pharmacokinetics Report) Trabectedin + DOXIL* Trabectedin Alone* Parameter (n = 122) (n = 488) Trabectedin Plasma Clearance** 32.1 L/h 36.7 L/h Vc (L) 11.6 13.7 Plasma half-life (h) - Alpha phase 0.28 0.25 - Beta phase 8.36 7.65 - Gamma phase 121.2 152.0 * Pooled results from studies ET743-USA-11 and ET743- OVA-301 (Trabectedin + DOXIL) and 15 Phase 1 and 2 studies (Trabectedin Alone) ** Results are presented as the median of post hoc estimates from the final 4-compartment pharmacokinetic model for subjects who were pretreated with at least 1 dose of dexamethasone. h=hour, L=Liter, Vc =central volume of distribution A high degree of overlap in the clearance values of trabectedin was evident for the combination (25th , 22.1 L/h; 75th percentile, 40.7 L/h) and when trabectedin was given alone (25th , 29.0 L/h; 75th percentile, 46.2 L/h) indicating that this parameter was not affected by the co-administration of DOXIL. The pharmacokinetics of trabectedin were also compared in a subset of subjects who were included in the population analysis. The subjects were enrolled in global, multicenter studies during which a limited number of pharmacokinetic samples were collected from each subject after trabectedin administration with DOXIL (Study ET743-OVA-301) and as a single-agent (Study ET743-STS-201). The median clearance values were 27.8 L/h (86 subjects in Study ET743-OVA-301) and 37.5 L/h (211 subjects in ET743-STS-201). The apparent lower clearance observed in Study ET743-OVA-301 is not expected to be clinically relevant. Subjects with ovarian and breast cancer enrolled in other completed, single-agent, Phase 2 studies (Studies ET-B-009, ET-B-026, and ET743-INT-3) tolerated higher doses of trabectedin (range, 1.3 to 1.5 mg/m2 infused over 3 h) than those administered during Study ET743-OVA-301 (1.1 mg/m2 infused over 3 h). 4.1.7. Influence of Trabectedin on the Pharmacokinetics of Other Co-Administered Drugs Inhibition of Cytochrome P450 Trabectedin exhibited limited inhibitory activity on human hepatic microsomal CYP enzymes. Therefore it is not expected to interact with co-administered drugs that undergo CYP-mediated metabolism by the following enzymes: CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4. 22
  23. 23. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting Induction of Cytochrome P450 In nonclinical studies, trabectedin has limited induction potential for the following human CYP enzymes: CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4, and 3A5. DOXIL The population analysis of the Phase 3 data from Study ET743-OVA-301 (trabectedin dose, 1.1 mg/m2 ) demonstrated only small differences in the pharmacokinetics of DOXIL when given with or without trabectedin (Table 4). Table 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) Population Mean Estimate (DOXIL With Trabectedin / Intersubject Parameter DOXIL Alone) Variability (%CV) CL (L/h) a 0.022 / 0.026 29.4 V (L) a 2.7 / 2.7 12.0 Plasma Half-life (h) 84.9 / 72.0 - a Based on the median value for body surface area of subjects in ET743-OVA-301 (1.8 m2 ) CL=plasma clearance; CV=coefficient of variation; V=volume of distribution. The results of Phase 1 Study ET743-USA-11 also suggested that concomitant administration with trabectedin (dose range, 0.4 to 1.3 mg/m2 ) does not influence the plasma pharmacokinetics of DOXIL, based on comparisons made with previously published single-agent studies (Lyass 2000, Hubert 2000, Hamilton 2002, and Briasoulis 2004). 5. CLINICAL STUDIES IN OVARIAN CANCER 5.1. Phase 1 Study ET743-USA-11 Study ET743-USA-11 was an open-label, single-arm study to determine the maximum tolerated dose (MTD) of trabectedin and pharmacokinetics of administering trabectedin in combination with DOXIL to subjects (n=36) with a variety of solid tumor types, including ovarian cancer. Escalating doses of trabectedin were administered over 3 hours after DOXIL 30 mg/m2 was administered over 1 to 2 hours. The dose of DOXIL is lower than recommended for single-agent treatment, but has shown to be active in combination with other cytotoxic agents used to treat a variety of tumors (Braud 2001). This dose of DOXIL was chosen to allow for a higher trabectedin dose to be reached in this combination. The recommended dose of trabectedin was determined to be 1.1 mg/m2 (MTD, 1.3 mg/m2 ), administered as a 3-hour infusion q3wk (Cohen 2005). This was the dose and schedule used in the pivotal Study ET743-OVA-301. Of the 18 subjects treated at the 1.1 mg/m2 dose level, 1 subject with disseminated, moderately to poorly-differentiated adenocarcinoma had a CR and 1 with primary neuroectodermal 23
  24. 24. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting tumor had a PR. Three subjects treated at the 1.4 mg/m2 dose level had PRs (sarcoma, 1; papillary serous adenocarcinoma of primary peritoneal origin, 1; head and neck carcinoma, 1). One subject with sarcoma, treated at the 0.4 mg/m2 dose level had a PR. The median duration of response for the 6 responding subjects was 15.2 months (95% CI: 12.7;15.4 months) [range 11.1 to 15.4 months] and all 6 were administered trabectedin at a dose of either 0.4 mg/m2 (1 subject), 1.1 mg/m2 (2 subjects) or 1.3 mg/m2 (3 subjects). Of the 4 subjects with ovarian cancer, 2 with platinum-sensitive disease achieved stable disease as their best response, and the other 2 with platinum-resistant disease had disease progression. 5.2. Phase 2 Studies in Ovarian Cancer Trabectedin as a single-agent treatment in ovarian cancer was studied in 3 Phase 2 clinical studies; Studies ET-B-026-03, ET-B-009-99, and ET743-INT-11. Three regimens were used: 3-hour infusion q3wk, 24-hour infusion q3wk, and 3-hour infusion once weekly (qwk), at doses ranging from 0.58 mg/m2 to 1.65 mg/m2 . The primary efficacy endpoint in these studies was response rate. 5.2.1. Study ET-B-026-03 Study ET-B-026-03 was a multicenter, 2-arm, randomized, controlled, Phase 2 study evaluating 2 schedules of trabectedin administered to subjects with relapsed, platinum-sensitive ovarian cancer. The primary objective was to explore the optimal infusion time of trabectedin, 24-hours or 3-hours q3wk. One hundred seven subjects were randomly assigned and treated with either a q3wk 24-hour regimen at 1.5 mg/m2 (Arm A, n=54) or a q3wk 3-hour regimen at 1.3 mg/m2 (Arm B, n=53). The lower dose used in Arm B was based on Phase 2 studies indicating that higher doses infused over shorter times were less well tolerated. In the intent-to-treat primary analysis, which included all randomized subjects, the ORR was 38.9% (95% CI: 25.9;53.1) in Arm A and 35.8% (95% CI: 23.1;50.2) in Arm B. While the study was not designed to compare arms, an exploratory analysis revealed no statistically significant differences between treatment arms with respect to ORR (p=0.8422). Twelve subjects (6 in each treatment arm) achieved a CR and 28 subjects (15 subjects in Arm A and 13 subjects in Arm B) achieved a PR. In the exploratory analysis, no statistically significant differences were seen between treatment arms for any of the secondary time-to-event endpoints, which included duration of response, time to progression, and PFS. The 24-hour infusion regimen had a higher rate of myelosuppression (55% compared with 37% of Grade 3-4 neutropenia, for Arm A and B respectively). 24
  25. 25. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting 5.2.2. Study ET-B-009-99 Study ET-B009-99 was a multicenter, open-label, single arm, Phase 2 study among subjects with ovarian cancer, persistent or recurrent after 1 platinum + taxane-containing regimen. The dose for the study was 1.65 mg/m2 administered over 3 hours and decreased to 1.3 mg/m2 and subsequently 1.1 mg/m2 in case of severe toxicity. The primary objective was to determine the antitumor activity, in terms of ORR of trabectedin administered as a 3-hour i.v. infusion, q3wk, as a salvage therapy. Fifty-nine subjects were enrolled: 29 in the relapsed group (subjects who had an objective response and then relapsed after 6 months from discontinuation of chemotherapy) and 30 in the refractory group (subjects who continued to progress or had stable disease while on therapy; or who relapsed following objective response while on therapy or within 6 months after discontinuation of chemotherapy. Fifty-one were evaluable for efficacy. The first 6 subjects received a higher initial trabectedin dose of 1.65 mg/m2 . Due to severity of increased transaminases observed at this dose, the study was amended to use a lower starting dose. The remaining 53 subjects received trabectedin doses of 1.3 and 1.5mg/m2 q3wk. The ORR was 43.5% (95% CI: 23.3;65.5) for the relapsed group (1 CR and 9 PR) and 7.1% (95% CI: 0.9;23.5) for the refractory subject group ( 2 PR). The median time to progression for the relapsed group was 6.7 months (95% CI: 5.0;7.9). 5.2.3. Study ET743-INT-11 Study ET743-INT-11 was a multicenter, single-arm, open-label, Phase 2 study. Trabectedin was administered to subjects with platinum-sensitive and platinum-resistant advanced ovarian cancer. The primary objective was to determine the ORR. Subjects with platinum-resistant ovarian cancer were defined as those with disease progression during treatment or those with disease relapse at ≤6 months after cessation of platinum-based chemotherapy. Trabectedin 0.58 mg/m2 was administered as a 3-hour infusion qwk for the first 3 weeks of a 4-week cycle. One hundred forty-one of the 147 treated subjects were included in the evaluable for efficacy analysis set. Of these, 51 subjects with platinum-sensitive disease, 62 subjects with platinum-resistant disease, and 28 subjects in the third cohort of subjects (28 subjects treated with nonplatinum-based chemotherapy prior to the third protocol amendment) were included in the primary efficacy analysis of ORR. No postbaseline tumor assessments were available for the remaining 6 subjects. Of the 147 subjects, 102 had 1 line of prior platinum-based chemotherapy administered and 45 had 2 lines of prior platinum-based chemotherapy. 25
  26. 26. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting For the platinum-sensitive cohort, the ORR was 29.4% (95% CI: 17.5;43.8). For the platinum-resistant cohort, the ORR was 4.8% (95% CI: 1.0;13.5). Median PFS and OS for the platinum-sensitive cohort were 5.3 months (95% CI: 3.1;6.4) and 21.3 months (95% CI: 14.8;upper level not reached), respectively. Median PFS and OS in the platinum-resistant cohort were 2.0 months (95% CI: 1.7;3.5) and 11.2 months (95% CI: 7.9;13.5), respectively. 5.2.4. Summary of Efficacy for Single Agent Trabectedin Table 5 summarizes the key efficacy results of the individual and integrated Phase 2 ovarian cancer studies. Table 5: Key Efficacy Results for Subjects Treated With Single Agent Trabectedin Median (95% CI) Months Objective Individual Studies (N) Progression-Free Survival Overall Survival Response Rate (%) (CR + PR) Population Phase 2: Ovarian Cancer Studies ET-B-026-03 (N=107) 6.1 (5.3; 7.2) 18.1 (16.1; 24.2) 37.4 Intent-to-Treat ET-B-009-99 (N=41) 5.0 (2.9; 6.7) 6.7 (5.1; 7.9) 2.2 (1.4; 4.6) (--) 22.9 43.8 5.3 All-Evaluable Platinum-Sensitive Platinum-Resistant ET743-INT-11 (N=147) 5.3 (3.1; 6.4) 2.0 (1.7; 3.5) 21.3 (14.8; --) 11.2 (7.9; 13.5) 29.4 4.8 Platinum-Sensitive Platinum-Resistant Integrated Ovarian Cancer Phase 2 Studies 4.6 (3.6; 5.3) 17.1 (14.9; 20.4) 26 All-Treated (N=295) 6.0 (5.3; 6.6) 20.4 (16.9; 24.2) 37 Platinum-Sensitive 2.0 (1.7; 2.8) 11.1 (8.9; 13.0) 7 Platinum-Resistant CR=complete response, PR=partial response, CI=confidence interval 5.3. Phase 3 Study ET743-OVA-301 5.3.1. Goal and Hypothesis The goal of the study was to define a safe and effective regimen that does not contain platinum or a taxane, to treat patients with relapsed ovarian cancer. The study was designed to test the hypothesis that trabectedin in combination with DOXIL would improve PFS, compared with DOXIL monotherapy, among subjects with relapsed ovarian cancer. 5.3.2. Rationale for Treatment Regimen The decision to combine trabectedin with DOXIL to treat subjects with relapsed ovarian cancer was based on their single-agent activity, different mechanisms of action, non-cross resistance, and non-overlapping toxicities, such as elevated transaminases and hand-foot syndrome. The dose and schedule chosen for the combination arm of the pivotal study, 26
  27. 27. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting ET743-OVA-301, was based on experience across a range of doses and schedules in Phase 1 and 2 studies described Sections 5.1 and 5.2. The results of the integrated Phase 2 studies showed a trend toward improved activity against ovarian cancer with the q3wk schedule compared with the qwk schedule. Studies ET-B-009-99 and ET-B-026-03 examined 2 different infusion times given q3wk. The 3-hour and 24-hour infusions were similar with respect to efficacy and safety, except for a higher rate of myelosuppression in the 24-hour infusion. For these reasons and for the patient’s and caregiver’s convenience, the q3wk, 3-h schedule was chosen for Study ET743-OVA-301. The Phase 1 Study ET743-USA-11, examined escalating doses of trabectedin using the chosen q3wk, 3-h schedule when combined with DOXIL dose fixed at 30mg/m2 . This dose and schedule of DOXIL has been used in combination with routinely-used doses of several other cytotoxic agents, including carboplatin (Braud 2001), paclitaxel, (Israel 1997, Modiano 1999), and docetaxel (Wasserheit 1999). This study concluded that the MTD for trabectedin was 1.3 mg/m2 when administered concomitantly with DOXIL dose fixed at 30mg/m2 q3wk. The preceding dose level of 1.1mg/m2 was determined to be the recommended dose for this combination and was used in Study, ET743-OVA-301 (von Mehren 2008). DOXIL was chosen as the comparator for several reasons. First, this pegylated liposome encapsulated formulation of doxorubicin is approved in 76 countries for relapsed ovarian cancer and is recommended as an acceptable treatment for relapsed ovarian cancer by NCCN and secondly, recommended by NICE as an option for the treatment of patients with partially platinum-sensitive, platinum-resistant, or platinum-refractory advanced ovarian cancer or for patients who are allergic to platinum-based compounds (Section 2.2). The basis for these treatment recommendations include the results of a study conducted by Gordon et al (Gordon 2004) comparing DOXIL as a single-agent with topotecan for the treatment of recurrent or refractory ovarian cancer. This study demonstrated that subjects treated with DOXIL had a longer median survival (14.4 months) compared with topotecan (13.7 months; p=0.050). Among subjects with platinum-sensitive disease, the median survival for the DOXIL group was 24.8 months compared with 16.1 months for the subjects who received topotecan. Among subjects who had platinum-refractory disease, survival was similar between treatment groups. (Gordon 2004). Based on these results, DOXIL was approved by the US FDA for the treatment of patients with relapsed ovarian cancer. 27
  28. 28. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting The 50 mg/m2 starting dose of DOXIL in the control arm of the pivotal ET743-OVA-301 study was selected because it is the approved monotherapy dose for treatment of relapsed ovarian cancer. The DOXIL dose intensity was 12.5mg/m2 weekly in the DOXIL monotherapy arm and 10mg/m2 weekly in the trabectedin + DOXIL combination arm. 5.3.3. Study Design 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, q3wk (Treatment Arm A). The efficacy and safety 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 (Treatment Arm B). Women with advanced ovarian cancer for whom a first-line platinum-based chemotherapy regimen had failed were eligible. Additionally, subjects had to have histologically proven epithelial ovarian, epithelial fallopian tube, or primary peritoneal carcinoma previously treated with only 1 platinum-based chemotherapy regimen. Subjects must have had radiologically confirmed measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. [nb: Subjects enrolled before Protocol Amendment 3 were not required to have measureable disease]. Subjects with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of ≤2; recurrence, or progression after a complete (6 cycles) initial regimen or more than 6 months after the beginning of the initial line of platinum-based chemotherapy were eligible, which would include subjects with both platinum-sensitive disease (platinum-free interval [PFI] ≥6 months) and platinum-resistant disease (PFI <6 months). Subjects with platinum-sensitive disease who were not expected to benefit from, or were ineligible for or were not willing to receive retreatment with platinum-based therapy, were included. Subjects with refractory disease (i.e., disease progression within 6 months from the first dose of the initial platinum-based therapy) were excluded. Other eligibility criteria included: Adequate organ function as evidenced by the following peripheral blood counts or serum chemistry values within 7 days before randomization: • hemoglobin ≥9 g/dL • absolute neutrophil count ≥1,500/µL • platelet count ≥100,000/µL 28
  29. 29. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting • serum creatinine ≤1.5 mg/dl (≤132.6 µmol/L) or creatinine clearance ≥60 mL/min • creatine phosphokinase (CPK) ≤upper limit of normal (ULN); • hepatic function : – total bilirubin ≤1.5 xULN, direct bilirubin ≤ULN – total alkaline phosphatase (ALP) ≤1.5 ULN, or if >1.5 ULN, then ALP liver fraction or 5’ nucleotidase must be ≤ULN – AST and ALT must have been ≤2.5 × ULN; and • Left ventricular ejection fraction by baseline multigated acquisition scan or 2-dimensional echocardiogram within normal limits for the institution. If subjects met any of the following additional exclusion criteria, they were not allowed to participate in this study: isolated rise in CA-125 without documented radiological evidence of disease progression; less than 4 weeks from radiation or experimental therapy; less than 2 weeks from the last dose of hormonal therapy, or less than 3 weeks from prior chemotherapy or biological therapy; and myocardial infarct within 6 months of enrollment, New York Heart Association Class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormalities. Accrual was monitored to ensure that the number of subjects enrolled in the group with platinum-resistant disease did not exceed 50% of the study population. 5.3.3.1. Efficacy Endpoints The primary efficacy endpoint for Study ET743-OVA-301 was OS in the original protocol. In April 2006, an FDA-ASCO-AACR Public Workshop on the Clinical Trial Endpoints in Ovarian Cancer was held (Bast 2007). The consensus conference conclusion was that PFS might be an acceptable endpoint for studies of relapsed ovarian cancer. In July 2006, gemcitabine, in combination with carboplatin, was approved by the FDA for the treatment of platinum-sensitive ovarian cancer based on PFS data. Therefore, in October 2006, after Study ET743-OVA-301 had started, an inquiry was made to the FDA as to whether the primary efficacy endpoint could be changed to PFS, with OS as a secondary endpoint. The Agency indicated that PFS could be an acceptable primary endpoint, depending on the magnitude of the benefit, the risk to benefit ratio, the proportion of subjects with nonmeasurable disease, and provided there was no decrement in survival. There were several reasons to adopt PFS as the primary endpoint for this study. PFS offers a direct measure of drug activity unaffected by subsequent therapies. 29
  30. 30. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting Progression-free survival has the intrinsic advantage of assessing the time of tumor control and may be an appropriate indicator of clinical benefit and an appropriate surrogate of OS in ovarian cancer (Bast 2007; Burzykowski 2006; Buyse 2007). 5.3.4. Independent Review of Efficacy Endpoints The validity of PFS as a surrogate for clinical benefit relies heavily on the rigor by which it is assessed (Biotechnology Law Report 2007). In accordance with recommendations by the FDA, the independent assessment of tumor response was performed and date of progression was assigned by an independent central radiology review panel according to a pre-specified charter, based on imaging of measurable disease only. In Study ET743-OVA-301, the date of progression was determined by independent radiologists who used the RECIST criteria. Only imaging data were used in the assessment. Therefore, only subjects with measureable disease could be included. The central review process was detailed in a charter that was finalized prior to the start of the independent assessments. The 2 primary Independent Radiologists were blinded to treatment designation, and the Investigator’s, and each other’s results for PFS. The results of determination of progression by the radiologists were combined with data on death. In addition to PFS measured by Independent Radiologist review, the charter also specified that an independent, blinded central oncology review assess the results of the radiology review together with clinical data, where liver function tests were removed to ensure blinding. The date of progression or censoring and an assessment of best overall response was provided by the Independent Oncologist. A third analysis of PFS was made using Investigator determination of progression. In Study ET743-OVA-301 radiological assessments were symmetrical between the 2 treatment arms, as recommended by the Biotechnology Law Report 2007 and Committee For Medicinal Products For Human Use (CHMP 2008). Despite different cycle lengths for the two treatments, complete tumor assessments were required every 8 weeks. 5.3.5. Statistical Methodology 5.3.5.1. Randomization Subjects were stratified according to platinum sensitivity (sensitive versus resistant) and baseline ECOG performance status score (0 and 1 versus 2) and then assigned randomly 1:1 to the treatment groups. Platinum-sensitive disease was defined as disease that progressed or relapsed at or after a treatment-free interval of 6 months after the last dose of initial chemotherapy. Platinum-resistant disease was defined as disease progression or relapse less than 6 months after the last dose of initial chemotherapy. 30
  31. 31. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting 5.3.5.2. Sample Size Determination Approximately 650 subjects were to be randomized over 2 years. The primary analysis (PFS) was to be conducted after at least 415 events (progression or death) were observed. Assuming that DOXIL has a median PFS of 16 weeks and that the combination of trabectedin + DOXIL has a targeted median PFS of 22 weeks, this design would allow the demonstration of a statistically significant difference in PFS at a 2-sided 5% significance level with at least 90% power. An OS analysis was performed in conjunction with this PFS analysis. An additional OS is planned for when there are 520 deaths. Assuming that DOXIL has a median OS of 14.4 months and that the combination of trabectedin + DOXIL has a targeted median OS of 19.2 months, this study design would allow for the demonstration of the statistically significant difference in OS at a 2-sided 5% significance level with at least 90% power. It was anticipated that the second OS analysis would be performed approximately 2 years after the first analysis. 5.3.5.3. Analyses of Primary Efficacy Endpoint: Progression-Free Survival 5.3.6. Subject Disposition Six hundred seventy-two subjects were enrolled in this study from 124 centers in 21 countries, and were randomly assigned to treatment between April 2005 and May 2007. Within the United States, 121(18%) subjects were enrolled from 24 centers. Nine subjects were randomized but did not receive study drug (6 subjects in the DOXIL monotherapy arm and 3 in the trabectedin + DOXIL arm) (Table 6). The remaining 663 randomized subjects received at least 1 dose of study medication (trabectedin + DOXIL, n=334; DOXIL alone, n=329) and comprise the “All Treated Subjects” and “Safety Analysis” populations. One subject was randomly assigned to trabectedin + DOXIL but received only 1 dose of DOXIL and opted to discontinue treatment without receiving trabectedin. This subject was included in the DOXIL monotherapy arm for the safety analysis only. Less than 1% of subjects were lost to follow up. The most common cause for discontinuation of treatment was disease progression. Three hundred seventeen subjects in the DOXIL arm and 328 in the trabectedin combination arm had measurable disease at baseline, and were included in the primary analysis of PFS. 31
  32. 32. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting Table 6: Subject Disposition Randomly Assigned (n=672) Lost to follow-up (n=0) Lost to follow-up (n=2) DOXIL (n=335 Treated (n=329) Discontinued (n=322) • Disease progression (n=178) • Patient choice (n=50) • Adverse event (n=39) • Other (n=33) • CR(confirmed) (n=14) • Death (n=8) Trabectedin + DOXIL (n=337) Treated (n=334) Discontinued (n=325) • Disease progression (n=139) • Patient choice (n=57) • Adverse event (n=69) • Other (n=28) • CR(confirmed) (n=24) • Death (n=8) Measurable Disease (n=317) Measurable Disease (n=328) 5.3.7. Demographics and Disease Characteristics Demographic characteristics (Table 7) for subjects were similar between the 2 treatment arms and consistent with what was expected for the planned study population. The median age of the study population was 57 years (range, 26-87 years); 78% were white. The study arms were stratified by ECOG performance status score (0/1, vs 2) and platinum sensitivity (sensitive vs resistant) assuring balance between the study arms for these factors. Within the strata of ECOG performance status scores 0/1, there were 57% of subjects with a 0 ECOG PS in the DOXIL arm and 68% in the combination arm. Sixty-four percent of subjects had platinum-sensitive disease (i.e. with platinum free interval (PFI) ≥6 months; PFI=time from end of initial platinum therapy to disease progression) (Table 7). Mean PFI for the trabectedin + DOXIL arm was 10.6 months compared with 13.3 months for DOXIL arm (Table 8). 32
  33. 33. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting Table 7: Demographic Data (Study ET743-OVA-301: All Randomized Subjects Analysis Set) DOXIL Trabectedin + DOXIL Total (N=335) (N=337) (N=672) Race, n (%) N 335 337 672 White 259 (77) 265 (79) 524 (78) Asian 71 (21) 66 (20) 137 (20) Black 3 (1) 2 (1) 5 (1) Other 2 (1) 4 (1) 6 (1) Age, Years N 335 337 672 Category, n (%) <65 229 (68) 257 (76) 486 (72) ≥65 106 (32) 80 (24) 186 (28) Mean (SD) 58.2 (10.75) 56.8 (10.48) 57.5 (10.63) Median 58.0 56.0 57.0 Range (27; 87) (26; 82) (26; 87) Age ≥75, Years N 16 20 36 Mean (SD) 79.1 (3.48) 77.8 (2.27) 78.4 (2.91) Median 78.5 77.5 78.0 Range (75; 87) (75; 82) (75; 87) Baseline Weight, kg N 335 337 672 Mean (SD) 68.9 (14.29) 69.5 (16.64) 69.2 (15.51) Median 68.0 65.9 66.1 Range (42; 111) (36; 140) (36; 140) Height, cm N 330 334 664 Mean (SD) 159.9 (7.01) 160.3 (6.53) 160.1 (6.77) Median 160.0 160.0 160.0 Range (140; 188) (144; 175) (140; 188) Baseline ECOG Performance Status, n (%) N 335 337 672 0 192 (57) 230 (68) 422 (63) 1 132 (39) 98 (29) 230 (34) 2 11 (3) 9 (3) 20 (3) Platinum Sensitivity, n (%) N 335 337 672 Platinum-Sensitive 212 (63) 218 (65) 430 (64) Platinum-Resistant 123 (37) 119 (35) 242 (36) (continued) 33
  34. 34. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting Table 7: Demographic Data (Continued) (Study ET743-OVA-301: All Randomized Subjects Analysis Set) DOXIL Trabectedin + DOXIL Total (N=335) (N=337) (N=672) Baseline BMI, kg/m2 N 330 334 664 Category, n (%) < 20 16 (5) 21 (6) 37 (6) 20 - < 25 118 (36) 129 (39) 247 (37) 25 - < 30 110 (33) 98 (29) 208 (31) ≥ 30 86 (26) 86 (26) 172 (26) Mean (SD) 26.9 (5.23) 26.9 (5.83) 26.9 (5.54) Median 26.2 25.5 25.9 Range (16; 43) (14; 47) (14; 47) Baseline BSA, m2 N 335 336 671 Mean (SD) 1.719 (0.1834) 1.725 (0.1936) 1.722 (0.1885) Median 1.700 1.700 1.700 Range (1.29; 2.23) (1.30; 2.42) (1.29; 2.42) Investigator Measurability*, n (%) N 335 337 672 Measurable 305 (91) 317 (94) 622 (93) Unmeasurable 30 (9) 20 (6) 50 (7) *Note: the subject’s lesions were able to be measured by the Investigator ECOG = Eastern Cooperative Oncology Group; BMI=body mass index; BSA=body surface area Baseline disease characteristics are presented in Table 8. Papillary/serous histology (68%) was the most prevalent subtype. Fifty-two percent of subjects had Grade 3 tumors. Sites of involvement at baseline (median of 2 sites) for all subjects included abdomen (74%), pelvis (69%), liver (29%), and lungs (18%). 34
  35. 35. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting Table 8: Baseline Disease Characteristics (Study ET743-OVA-301: All Randomized Subjects Analysis Set) ----- DOXIL ----- Trabectedin+DOXIL ----- Total ----­ (N=335) (N=337) (N=672) Histology, n (%) N 335 336 671 Mucinous 4 ( 1) 5 ( 1) 9 ( 1) Endometrioid 17 ( 5) 23 ( 7) 40 ( 6) Clear Cell Carcinoma 16 ( 5) 13 ( 4) 29 ( 4) Mixed Epithelial Tumor 5 ( 1) 4 ( 1) 9 ( 1) Papillary/Serous 230 ( 69) 225 ( 67) 455 ( 68) Peritoneal Carcinoma 9 ( 3) 11 ( 3) 20 ( 3) Fallopian Tube Carcinoma 3 ( 1) 3 ( 1) 6 ( 1) Transitional Carcinoma (Brenner) 2 ( 1) 2 ( 1) 4 ( 1) Other 49 ( 15) 50 ( 15) 99 ( 15) Histology Grade, n (%) N 334 336 670 Grade 1 10 ( 3) 18 ( 5) 28 ( 4) Grade 2 59 ( 18) 58 ( 17) 117 ( 17) Grade 3 174 ( 52) 175 ( 52) 349 ( 52) Unknown 91 ( 27) 85 ( 25) 176 ( 26) Time from End of Last Plat. Rx to PD, mo N 335 336 671 Category, n (%) <6 124 ( 37) 118 ( 35) 242 ( 36) 6 - <12 90 ( 27) 123 ( 37) 213 ( 32) 12 - <24 76 ( 23) 70 ( 21) 146 ( 22) ≥24 45 ( 13) 25 ( 7) 70 ( 10) Mean (SD) 13.3 (16.56) 10.6 (10.87) 11.9 (14.06) Median 8.3 7.6 7.8 Range (0;159) (0;107) (0;159) Number of Sites Involved at Baseline N 335 337 672 Category, n (%) 0 3 ( 1) 6 ( 2) 9 ( 1) 1 – 3 295 ( 88) 278 ( 82) 573 ( 85) >3 37 ( 11) 53 ( 16) 90 ( 13) Mean (SD) 2.3 (1.04) 2.3 (1.19) 2.3 (1.12) Median 2.0 2.0 2.0 Range (0;7) (0;6) (0;7) Sites Involved at Baseline, n (%) N 332 331 663 Pelvis 239 ( 71) 228 ( 68) 467 ( 69) Abdomen 255 ( 76) 243 ( 72) 498 ( 74) Liver 92 ( 27) 100 ( 30) 192 ( 29) Spleen 26 ( 8) 28 ( 8) 54 ( 8) Lungs 50 ( 15) 69 ( 20) 119 ( 18) Mediastin 42 ( 13) 47 ( 14) 89 ( 13) Others 57 ( 17) 62 ( 18) 119 ( 18) Plat = platinum; Rx = treatment; PD = progressive disease; SD = standard deviation; mo = months. 35
  36. 36. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting Table 9 summarizes prior therapies for cancer. Consistent with the eligibility requirements, all subjects had previously received at least 1 course of platinum-based chemotherapy. The median number of agents used for prior chemotherapy was 2 (range, 1 to 7). Approximately 80% of subjects had received a taxane. Ninety-nine percent of subjects had previously undergone surgery for ovarian cancer. Two percent had received prior radiotherapy. Table 9: Summary of Previous Ovarian Cancer Therapy (Study ET743-OVA-301: All Randomized Subjects Analysis Set) ---- DOXIL ---- Trabectedin+DOXIL ----- Total ----­ (N=335) (N=337) (N=672) Had Previous Chemotherapy for Ovarian Cancer, n (%) N 335 337 672 Yes 335 (100) 337 (100) 672 (100) No. Agents of Previous Chemotherapy for Ovarian Cancer N 335 337 672 Mean (SD) 2.2 (0.59) 2.2 (0.63) 2.2 (0.61) Median 2.0 2.0 2.0 Range (1; 7) (1; 5) (1; 7) Therapeutic Phase of Previous Chemotherapy, n (%) N 335 337 672 Adjuvant 245 (73) 231 (69) 476 (71) Neo-adjuvant 91 (27) 82 (24) 173 (26) Advanced/metastatic 60 (18) 72 (21) 132 (20) Best Response to First Line Platinum Therapy, n (%) N 335 337 672 Complete Response 182 (54) 165 (49) 347 (52) Partial Response 65 (19) 72 (21) 137 (20) No Change (Stable Disease) 19 (6) 32 (9) 51 (8) Progression of Disease 5 (1) 5 (1) 10 (1) Not Applicable 50 (15) 48 (14) 98 (15) Unknown 14 (4) 14 (4) 28 (4) Prior Taxane (Yes Versus No), n (%) N 335 337 672 Yes 271 (81) 269 (80) 540 (80) No 64 (19) 68 (20) 132 (20) Had Previous Ovarian Cancer Surgery, n (%) N 335 337 672 Yes 334 (>99) 333 (99) 667 (99) No 1 (<1) 4 (1) 5 (1) Had Previous Radiotherapy for Ovarian Cancer, n (%) N 335 337 672 Yes 11 (3) 5 (1) 16 (2) No 324 (97) 332 (99) 656 (98) 36
  37. 37. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting 5.3.8. Extent of Exposure The exposure to treatment comparing the two arms of the pivotal study, ET743-OVA-301 is shown in Table 10. Table 10: Exposure to Treatment Study ET743-OVA-301 DOXIL Trabectedin + DOXIL (n=330) (n=333) Total treatment duration (weeks) Mean (SD) 22.5 (16.5) 22.1 (15.3) Median (range) 20.4 (4.0-97.1) 18.7 (3.0-81.3) Number of cycles Category, n (%) 1 cycle 31 (9) 24 (7) 2 cycles 66 (20) 35 (11) 3 cycles 21 (6) 43 (13) 4 cycles 36 (11) 23 (7) 5 cycles 29 (9) 35 (11) 6 cycles 68 (21) 48 (14) 7 cycles 17 (5) 20 (6) 8 cycles 15 (5) 31 (9) 9 cycles 12 (4) 11 (3) ≥10 cycles 35 (11) 63 (19) Mean (SD) 5.3 (3.7) 6.2 (4.0) Median (range) 5.0 (1-22) 6.0 (1-21) DOXIL Trabectedin DOXIL Cumulative dose (mg/m2 ) Mean (SD) 238.6 (158.5) 6.3 (3.98) 172.1 (108.9 Median (range) Dose intensity (mg/m2 per 216.0 (3-1061) 5.6 (1-23) 154.4 (15-630) cycle) Mean (SD) 44.29 (6.96) 0.91 (0.14) 24.84 (3.96) Median (range) Dose intensity (mg/m2 per 46.73 (2.76-51.60) 0.91 (0.54 -1.14) 24.77 (14.40- 31.27) week) Mean (SD) 11.07 (1.74) 0.30 (0.05)) 8.28 (1.32) Median (range) 11.68 (0.69-12.90) 0.30 (0.18-0.38) 8.26 (4.80-10.42) Relative dose intensity (%) Mean (SD) 88.6 (13.9) 82.4 (13.1) 82.8 (13.2) Median (range) 93.5 (6-103) 82.5 (49-104) 82.6 (48-104) 5.3.8.1. Duration of Exposure, Dose Intensity and Relative Dose Intensity The target dose of trabectedin was 1.1 mg/m2 administered as a 3-hour infusion q3wk. The median dose intensity for trabectedin was 0.91 mg/m2 per cycle. The median cumulative trabectedin dose was 5.6 mg/m2 (range, 1 to 23 mg/m2 ) (Table 10). The median dose intensity for DOXIL in the combination arm was 24.8 mg/m2 per cycle, (approximately 83% of the specified dose of 30 mg/m2 ) and the cumulative dose was 154.4 mg/m2 (range, 15 to 630 mg/m2 ) (Table 10). 37
  38. 38. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting In the DOXIL monotherapy arm, the median number of cycles was 5.0 (range, 1 to 22). The median duration of treatment was 20.4 weeks. In the trabectedin + DOXIL arm, the median total number of cycles was 6.0 (range, 1 to 21). The median duration of treatment was of 18.7 weeks. A higher percentage of subjects in the combination treatment arm received 7 or more cycles of therapy (24% in the DOXIL monotherapy arm compared with 37.5% in the trabectedin + DOXIL arm). Fewer than 10% of subjects in either treatment arm received only 1 cycle of treatment (Table 10). 5.3.9. Efficacy Results At the predetermined 15 May 2008 clinical cutoff date, 389 subjects had disease progression assessed by Independent Radiology or had died, 194 in the DOXIL monotherapy arm and 195 in the trabectedin + DOXIL arm; 432 subjects had disease progression assessed by the Independent Oncologist review or died, and 520 had disease progression assessed by the Investigator or died. Progression-free survival events as determined by the Investigators were confirmed by Independent Radiologists for 72% of subjects in each arm, and 75% percent by Independent Oncologists (76% in the DOXIL monotherapy arm and 75% in the trabectedin + DOXIL arm). Twenty eight percent of the subjects in both treatment arms were censored by Independent Radiologists. The majority of those subjects (58 of 65 in DOXIL arm and 55 of 62 in trabectedin + DOXIL arm) were censored due to receipt of subsequent therapy. These were subjects who had not progressed in the opinion of the Independent Radiologist, and were started on subsequent therapy based on Investigator’s assessment of progression. There were 520 progression events by Investigator and 389 by Independent Radiologist. The difference in the number of events between the Independent Radiologist and Investigator can be explained. Twenty-one subjects who had events by Investigator assessment were excluded from the primary analysis because of non-measurable disease (Table 11). The difference between the Independent Radiologist and Investigator assessments, in most cases, was with regard to non-target lesions, This accounted for 86 subjects, where progression was declared by Investigator, but not the Independent Radiologist. The likely reason is that non-target progression is based on subjective criteria (“unequivocal progression of existing non-target lesion”). There was also a discordance in 66 subjects for other reasons, such as progression of disease based on target lesion, new lesion, clinical deterioration. In contrast, progression was declared by Independent Radiologist, but not Investigator, in a few events, 42. If these are subtracted from the 173 subject total, the final difference of events is 131. The reason for 38
  39. 39. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting discrepancy in number of events between independent Radiologist and Investigator was well balanced between both treatment arms (Table 11). Table 11: Explanation of Discrepancy in PFS Events Between Independent Radiologist and Investigator Subjects with Discrepancy Reasons for Discrepancy DOXIL Trabectedin + DOXIL Total Non-measurable 14 7 21 Discordance on non-target lesion 46 40 86 Other 34 32 66 Total 94 79 173 PD by IR but not Inv. -16 -26 -42 Difference in events 78 53 131 PD= disease progression; IR= Independent Radiologist; Inv=Investigator 5.3.9.1. Primary Efficacy Endpoint: Progression-Free Survival The study met its primary endpoint (PFS by Independent Radiologist review) as shown in Table 12 and Figure 3. Treatment with trabectedin + DOXIL resulted in a 21% reduction of risk for disease progression or death compared with DOXIL monotherapy [HR=0.79; (95% CI: 0.65;0.96; p=0.0190]. The median PFS was 7.3 months (95% CI: 5.9;7.9) for trabectedin + DOXIL and 5.8 months (95% CI:, 5.5;7.1) for DOXIL monotherapy. The PFS rate favoring the combination arm was maintained at 4, 6, and 12 months. Table 12: Progression-Free Survival: Independent Radiologist Review (All Measurable) (Study ET743-OVA-301: All Measurable Subjects Analysis Set) Descriptivea DOXIL Trabectedin+DOXIL Progression-free survival (months) Number Assessed 317 328 Number Censored (%) 123 (38.8) 133 (40.5) Number of Events (%) 194 (61.2) 195 (59.5) 25% Quantile (95% CI) 2.4 (1.9; 3.6) 2.6 (1.9; 3.7) Median (95% CI) 5.8 (5.5; 7.1) 7.3 (5.9; 7.9) 75% Quantile (95% CI) 10.1 (8.9; 11.6) 12.7 (11.1; 14.8) 4-Month PFS Rate, % (95% CI) 58.9 (52.7; 64.5) 67.6 (61.9; 72.6) 6-Month PFS Rate, % (95% CI) 48.9 (42.5; 55.0) 54.6 (48.5; 60.4) 12-Month PFS Rate, % (95% CI) 18.5 (12.9; 24.9) 25.8 (19.7; 32.3) Overall p valueb 0.0190 Hazard Ratio (95% CI) (over DOXIL) 0.79 (0.65; 0.96) a Based on Kaplan-Meier product limit estimates. b Log rank test. The hazard ratio is calculated as the hazard in the trabectedin+DOXIL dosage group, divided by the hazard in the DOXIL dosage group. PFS=progression-free survival; CI = confidence interval 39
  40. 40. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting Figure 3: Kaplan-Meier Plot of Progression-Free Survival: Independent Radiologist Review (Study ET743-OVA-301: All Measurable Subject Analysis Set) Independent Oncologist Review Further analysis of All-Randomized Subjects assessed by the Independent Oncologists indicated that treatment with trabectedin + DOXIL resulted in a 28% risk reduction in disease progression or death compared with DOXIL monotherapy (HR=0.72; 95% CI: 0.60;0.88; p=0.0008). The proportion of subjects who were progression free at 6 months in the DOXIL monotherapy arm was 46.2% (95% CI: 40.2;52.0) compared with 57.3% (95% CI: 51.3;62.8) in the trabectedin + DOXIL arm. The proportion of subjects progression-free at 12 months in the DOXIL monotherapy arm was 16.2% (95% CI: 11.3;21.9) compared with 26.0% (95% CI: 20.2;32.1) in the trabectedin + DOXIL arm (Figure 4). 40
  41. 41. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting Figure 4: Kaplan-Meier Plot for Progression-Free Survival: Independent Oncologist Review (Study ET743-OVA-301: All-Randomized Subjects Analysis Set) Investigator Review The analysis of All-Randomized Subjects assessed by the Investigators showed that treatment with trabectedin + DOXIL resulted in a 28% risk reduction in disease progression or death compared with DOXIL monotherapy (HR=0.72; 95% CI: 0.61;0.86; p = 0.0002). The proportion of subjects who were progression-free at 6 months in the DOXIL monotherapy arm was 43.7% (95% CI: 38.0;49.2) compared with 55.8% (95% CI: 49.9;61.2) in the trabectedin + DOXIL arm. The proportion of subjects who were progression-free at 12 months in the DOXIL monotherapy arm was 15.1% (95% CI: 11.1;19.7) compared with 24.2% (95% CI: 19.2;29.5) in the trabectedin + DOXIL arm (Figure 5) 41
  42. 42. YONDELIS® (trabectedin): Briefing Document for 15 July 2009 ODAC Meeting Figure 5: Kaplan-Meier Plot for Progression-Free Survival: Investigator Review (Study ET743-OVA-301: All-Randomized Subjects Analysis Set) Summary of PFS Analyses The combination of trabectedin + DOXIL improves PFS compared with DOXIL monotherapy. The results of the PFS analysis by the Independent Oncologist review were consistent with that of the Independent Radiologist review in favor of the combination arm. In both cases, reviewers were blinded to treatment arm. The Independent Oncologist review took into account clinical and imaging data, as well as the Investigator assessment to determine progression. The Independent Oncologist and Investigator determinations of PFS were similar with hazard ratios indicating slightly larger treatment effects than the Independent Radiologist review. The robustness of the PFS endpoint is demonstrated by results that were consistent across the 3 analyses, Independent Radiologist, Independent Oncologist, and Investigator assessment. Figure 6 summarizes the results of the PFS analyses. 42

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