- 1. Ortho Biotech Oncology Research & Development, Unit of
Johnson & Johnson Pharmaceutical Research & Development,
L.L.C. On behalf of the NDA holder, Centocor Ortho Biotech
Products, L.P.BACKGROUND INFORMATION FOROncologic Drugs Advisory
Committee Meeting July 15, 2009 YONDELIS (trabectedin) in
Combination With DOXIL /CAELYX (doxorubicin HCL liposome injection)
for the Treatment of Patients With Relapsed Ovarian CancerNDA
#22-447 AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION
Issue/Report Date: 10 JUNE 2009 Document No.: EDMS-PSDB-9357037:3.0
1
2. YONDELIS (trabectedin): Briefing Document for 15 July 2009
ODAC Meeting TABLE OF CONTENTS LIST OF IN-TEXT TABLES
......................................................................................................
4LIST OF IN-TEXT
FIGURES.....................................................................................................
6ABBREVIATIONS.....................................................................................................................
7EXECUTIVE
SUMMARY...........................................................................................................
81. INDICATION AND DOSE
REGIMEN.........................................................................
132. BACKGROUND
.........................................................................................................
132.1. Unmet Medical Need
..................................................................................................132.2.
Current Management and Prognosis for Patients With Relapsed Ovarian
Cancer ... 142.3. Overview of
Trabectedin.............................................................................................
153. PRECLINICAL EFFICACY DATA
.............................................................................
164. CLINICAL PHARMACOLOGY
..................................................................................
164.1. Clinical
Pharmacokinetics...........................................................................................
164.1.1. Pharmacokinetics of Trabectedin: Population
Analyses............................ 174.1.2. Distribution of
Trabectedin
.........................................................................
184.1.3. Metabolism of
Trabectedin.........................................................................
184.1.4. Excretion and Clearance of
Trabectedin....................................................
184.1.5. Influence of Intrinsic Factors on the Pharmacokinetics of
Trabectedin ..... 194.1.6. Effect of Co-administered Drugs on the
Pharmacokinetics ofTrabectedin
................................................................................................204.1.7.
Influence of Trabectedin on the Pharmacokinetics of
OtherCo-Administered
Drugs..............................................................................
225. CLINICAL STUDIES IN OVARIAN CANCER
........................................................... 235.1.
Phase 1 Study
ET743-USA-11...................................................................................
235.2. Phase 2 Studies in Ovarian Cancer
...........................................................................
245.2.1. Study
ET-B-026-03.....................................................................................
245.2.2. Study
ET-B-009-99.....................................................................................
255.2.3. Study ET743-INT-11
..................................................................................
255.2.4. Summary of Efficacy for Single Agent Trabectedin
................................... 265.3. Phase 3 Study
ET743-OVA-301
................................................................................
265.3.1. Goal and
Hypothesis..................................................................................
265.3.2. Rationale for Treatment
Regimen..............................................................
265.3.3. Study
Design..............................................................................................
285.3.3.1. Efficacy Endpoints
..................................................................................295.3.4.
Independent Review of Efficacy
Endpoints................................................ 305.3.5.
Statistical Methodology
..............................................................................
305.3.5.1. Randomization
........................................................................................
305.3.5.2. Sample Size Determination
....................................................................
315.3.5.3. Analyses of Primary Efficacy Endpoint: Progression-Free
Survival ....... 315.3.6. Subject
Disposition.....................................................................................
315.3.7. Demographics and Disease Characteristics
.............................................. 325.3.8. Extent of
Exposure.....................................................................................
375.3.8.1. Duration of Exposure, Dose Intensity and Relative Dose
Intensity ........ 375.3.9. Efficacy
Results..........................................................................................
385.3.9.1. Primary Efficacy Endpoint: Progression-Free
Survival........................... 395.3.9.1.1. Supportive
Analysis of Progression-Free
Survival.................................. 435.3.9.1.1.1.
Stratified Log-Rank
Test......................................................................
435.3.9.1.1.2. Multivariate
Analysis............................................................................
442 3. YONDELIS (trabectedin): Briefing Document for 15 July 2009
ODAC Meeting 5.3.9.2. Secondary Efficacy Endpoints
................................................................
455.3.9.2.1. Overall
Survival.......................................................................................
455.3.9.2.2. Objective Response Rate
.......................................................................
485.3.9.2.3. Duration of Response
.............................................................................
495.3.9.3. Supportive Efficacy
Analyses..................................................................
505.3.9.3.1. CA-125 Overall Response Rate and CA-125
Progression-Free Survival
................................................................................................505.3.9.3.2.
Efficacy Assessment by Platinum
Sensitivity.......................................... 515.3.9.3.3.
Subsequent
Therapy...............................................................................
545.4. Efficacy Conclusions
..................................................................................................555.5.
Patient Reported Outcomes
.......................................................................................
565.6. Hospitalizations
..........................................................................................................
566. SUMMARY OF
SAFETY............................................................................................
576.1. Safety Population
.......................................................................................................
576.2. Ovarian Cancer
..........................................................................................................
596.2.1. Integrated Phase 2 Ovarian Studies- Safety Profile
.................................. 596.2.2. Phase 3 Study
ET743-OVA-301-Safety Profile
......................................... 606.2.2.1. Dose
Modifications and Cycle Delay
...................................................... 626.2.2.2.
Reasons For Dose Delays and Dose
Adjustments................................. 646.2.2.3.
Discontinuations Due to Adverse
Events................................................ 656.3. All
Tumor Types - Integrated Phase 2 Single-Agent Studies - Safety
Profile............ 686.4. Summary of Toxicities Associated With
Trabectedin as Single-Agent or in Combination With DOXIL
...........................................................................................
696.4.1. Deaths on
Study.........................................................................................
696.4.2. Selected Adverse Events
...........................................................................
706.4.2.1. Liver
Function..........................................................................................706.4.2.1.1.
Liver Biopsy Results in Study
ET743-USA-11........................................ 756.4.2.2.
HematologicToxicity................................................................................
766.4.2.2.1. Neutrophil Count Abnormalities and Infection
........................................ 766.4.2.2.1.1.
Infection-Related Adverse Events
.......................................................
796.4.2.2.2. Thrombocytopenia and Bleeding Events
................................................ 806.4.2.3. Other
Adverse
Events.............................................................................806.4.2.3.1.
Neurotoxicity
...........................................................................................
806.4.2.3.2. Ototoxicity
...............................................................................................
806.4.2.3.3. Alopecia
..................................................................................................806.4.2.3.4.
Hand-Foot
Syndrome..............................................................................
816.4.2.3.5. Creatine Phosphokinase Increase and Rhabdomyolysis
....................... 816.4.2.4. Cardiac
Events........................................................................................
826.4.2.5.
Hypersensitivity.......................................................................................
836.5. Safety
Conclusions.....................................................................................................
837. BENEFIT-RISK
ASSESSMENT.................................................................................
838.
CONCLUSION............................................................................................................85REFERENCES
........................................................................................................................
863 4. YONDELIS (trabectedin): Briefing Document for 15 July 2009
ODAC Meeting LIST OF IN-TEXT TABLES Table 1: Phase 3 Ovarian Study
Comparisons of RR, PFS, and OS (Subjects With Platinum-Sensitive
Disease)................................................................................
11Table 2: Basic Population Pharmacokinetic Parameters of
Trabectedin in SubjectsWith Cancer (Population Pharmacokinetics
Report) ........................................... 18Table 3:
Median Pharmacokinetic Parameters of Trabectedin in Subjects With
and Without Concomitant Administration of Pegylated Liposomal
Doxorubicin (Population Pharmacokinetics Report)
................................................................
22Table 4: Population Pharmacokinetic Parameters of Total
(Liposomal Encapsulated and Free) Doxorubicin in Subjects With
Ovarian Cancer Who Received Pegylated Liposomal Doxorubicin With
and Without Trabectedin(Population Pharmacokinetics Report)
................................................................
23Table 5: Key Efficacy Results for Subjects Treated With Single
Agent Trabectedin......... 26Table 6: Subject
Disposition...............................................................................................
32Table 7: Demographic Data (Study ET743-OVA-301: All Randomized
SubjectsAnalysis Set)
........................................................................................................
33Table 8: Baseline Disease Characteristics (Study ET743-OVA-301:
All Randomized Subjects Analysis Set)
.........................................................................................
35Table 9: Summary of Previous Ovarian Cancer Therapy (Study
ET743-OVA-301: All Randomized Subjects Analysis
Set)...............................................................
36Table 10: Exposure to Treatment
........................................................................................
37Table 11: Explanation of Discrepancy in PFS Events Between
Independent Radiologist and
Investigator....................................................................................................
39Table 12: Progression-Free Survival: Independent Radiologist
Review (All Measurable)(Study ET743-OVA-301: All Measurable
Subjects Analysis Set) ........................ 39Table 13:
Progression-Free Survival: Multivariate Analysis, Independent
Radiologist Review Data, All Measurable Subjects (Study
ET743-OVA-301) ....................... 44Table 14: Progression-Free
Survival: Multivariate Analysis, Independent OncologistReview Data,
All Randomized Subjects (Study ET743-OVA-301)......................
45Table 15: Progression-Free Survival: Multivariate Analysis,
Investigators Data, All Randomized Subjects (Study
ET743-OVA-301)............................................. 45Table
16: Overall Survival (All Randomized) (Study ET743-OVA-301: All
Randomized Subjects Analysis Set)
.........................................................................................
46Table 17: Overall Survival: Multivariate Analysis, All Randomized
Subjects(Study
ET743-OVA-301)......................................................................................
47Table 18: Objective Response Rate (ORR) - Independent Radiologist
Review Data (Study ET743-OVA-301: All Randomized Subjects Analysis
Set)....................... 48Table 19: Objective Response Rate
(ORR) - Independent Oncologist Review Data (Study ET743-OVA-301:
All Randomized Subjects Analysis Set).......................
49Table 20: Duration of Response: Independent Radiologist Review
Data(Study ET743-OVA-301: All Responders (CR/PR) Analysis
Set)........................ 50Table 21: Best Overall CA-125
Response (Study ET743-OVA-301: All Randomized Subjects Analysis
Set)
.........................................................................................
51Table 22: CA-125 Progression-Free Survival (Study ET743-OVA-301:
All RandomizedSubjects Analysis Set)
.........................................................................................
514 5. YONDELIS (trabectedin): Briefing Document for 15 July 2009
ODAC Meeting Table 23: Efficacy Summary: Platinum-Sensitive and
Platinum-Resistant Independent Radiologist
Review...............................................................................................
54Table 24: Subsequent Ovarian Cancer Therapy in at Least 2% of
Subjects(Study ET743-OVA-301: All Randomized Subjects Analysis
Set)....................... 55Table 25: Efficacy Summary for Study
ET743-OVA-301.....................................................
56Table 26: Reason for Hospitalization (Study ET743-OVA-301: All
Randomized SubjectsAnalysis Set)
........................................................................................................
56Table 27: Safety Profile (Trabectedin - Integrated Phase 2
Ovarian Studies: All Treated Subjects Analysis Set)
.........................................................................................
59Table 28: Drug-Related Grade 3/4 Adverse Event (>=5% of
Subjects; IntegratedAnalysis-Phase 2 Studies in Ovarian
Cancer).....................................................
60Table 29: Safety Profile (Study ET743-OVA-301: All Treated
Subjects Analysis Set)........ 61Table 30: Treatment-Emergent Grade
3 or 4 Adverse Events in at Least 5% ofSubjects (Study
ET743-OVA-301: All Treated Subjects Analysis Set)................
62Table 31: Cycle Delays, Dose Reductions Overall (Study
ET743-OVA-301: All Treated Subjects Analysis
Set)............................................................................
63Table 32: Reasons For Cycle Delays, Dose Reductions Overall(Study
ET743-OVA-301: All Treated Subjects Analysis Set)
.............................. 64Table 33: Treatment-Emergent
Adverse Events Leading to Dose Adjustment or Cycle Delay in >=2%
of Subjects in Either Treatment Arm (Study ET743-OVA-301: All
Treated Subjects Analysis
Set).......................................................................
65Table 34: Treatment-Emergent Adverse Events Leading to Treatment
Termination in>= 2% of Subjects in Either Treatment Group (Study
ET743-OVA-301: All-Treated Subjects Analysis
Set........................................................................
66Table 35: Treatment-Emergent Drug-Related Adverse Events Leading
to Treatment Termination (Study ET743-OVA-301: All Treated Subjects
Analysis Set) .......... 67Table 36: Safety Profile (Trabectedin
Integrated Phase 2 Studies: All Treated Subjects Analysis Set)
.........................................................................................
69Table 37: Deaths During Study (Study ET743-OVA-301: All-Treated
Subjects
AnalysisSet).......................................................................................................................70Table
38: Laboratory Tests -- Worst Toxicity Grade During Study by
Chemistry(Study ET743-OVA-301: All-Treated Subjects Analysis Set)
.............................. 735 6. YONDELIS (trabectedin):
Briefing Document for 15 July 2009 ODAC Meeting LIST OF IN-TEXT
FIGURES Figure 1: Mean Concentrations of Trabectedin in Plasma
Following Administration of 1.3 mg/m 2 as a 3-Hour Intravenous
Infusion (Study ET743-INT-3)..................... 17Figure 2:
Influence of Dexamethasone Pretreatment on the Plasma Clearance
ofTrabectedin
..........................................................................................................21Figure
3: Kaplan-Meier Plot of Progression-Free Survival: Independent
Radiologist Review (Study ET743-OVA-301: All Measurable Subject
Analysis Set)............. 40Figure 4: Kaplan-Meier Plot for
Progression-Free Survival: Independent OncologistReview (Study
ET743-OVA-301: All-Randomized Subjects Analysis Set)..........
41Figure 5: Kaplan-Meier Plot for Progression-Free Survival:
Investigator Review(Study ET743-OVA-301: All-Randomized Subjects
Analysis Set) ...................... 42Figure 6: Progression-Free
Survival for Independent Reviewers and Investigators(Study
ET743-OVA-301, By Analysis
Set)...........................................................
43Figure 7: Progression-Free Survival for Independent Reviewers and
InvestigatorsStratified by Platinum Sensitivity (Study
ET743-OVA-301, by Analysis Set)....... 43Figure 8: Kaplan-Meier
Estimate of Overall Survival (Study ET743-OVA-301: All Randomized
Subjects Analysis
Set)...............................................................
47Figure 9: Kaplan-Meier Plot of Progression-Free Survival by
Platinum Sensitivity(Sensitive) Independent Radiologist Review
(Study ET743-OVA-301: All Measurable Analysis Set)
...............................................................................
52Figure 10: Kaplan-Meier Plot of Progression-Free Survival by
Platinum Sensitivity(Resistant) Independent Radiologist Review
(Study ET743-OVA-301: All Measurable Analysis Set)
...............................................................................
53Figure 11: Kaplan-Meier Plot of Overall Survival by Platinum
Sensitivity (Sensitive)(Study ET743-OVA-301: All Randomized
Subjects Analysis Set)....................... 53Figure 12:
Kaplan-Meier Plot of Overall Survival by Platinum Sensitivity
(Resistant)(Study ET743-OVA-301: All Randomized Subjects Analysis
Set)....................... 54Figure 13: Grouping of Studies
Contributing Safety Data to the Summary of ClinicalSafety
...................................................................................................................58Figure
14: Median Values for ALT Cycles With a Grade 3-4 Event (Study
ET743-OVA-301: All-Treated Subjects Analysis Set)
.............................. 74Figure 15: Median Values for ALT
Peak - Subjects Who Received >=6 Cycles ofTreatment (Study
ET743-OVA-301: All-Treated Subjects Analysis Set).............
75Figure 16: Median Values for Neutrophils - Cycles With a Grade 3
or 4 Event(Study ET743-OVA-301: All Treated Subjects Analysis Set)
.............................. 77Figure 17: Median Values for
Neutrophil Nadir - Subjects Who Received =>6 Cycles ofTreatment
(Study ET743-OVA-301: All-Treated Subjects Analysis
Set)............. 78Figure 18: Median Values for Neutrophil Nadir -
Subjects With >=6 Cycles of Treatment (Trabectedin - Integrated
Phase 2 Ovarian Studies: All-Treated SubjectsAnalysis Set)
........................................................................................................
796 7. YONDELIS (trabectedin): Briefing Document for 15 July 2009
ODAC Meeting ABBREVIATIONS AACR American Association for Cancer
Research ALP alkaline phosphatase ALT alanine aminotransferase ASCO
American Society for Clinical Oncology AST aspartate
aminotransferase AUC area under the concentration-time curve CHMP
Committee for Medicinal Products for Human Use CI confidence
interval Cmax maximum drug concentration CPK creatine phosphokinase
CR complete response CYP cytochrome P450 ECOG Eastern Cooperative
Oncology Group EMEA European Agency for the Evaluation of Medicinal
Products EORTC European Organization for Research and Treatment of
Cancer FDA (United States) Food and Drug Administration HOC human
ovarian cancer HR hazard ratio LVEF left ventricular ejection
fraction MTD maximum tolerated dose NASH nonalcoholic
steatohepatitis NCCN National Comprehensive Cancer Network NER
nucleotide excision repair NICE National Institute for Health and
Clinical Excellence ORR objective response rate OS overall survival
P-gp P-glycoprotein PLD pegylated liposomal doxorubicin PFI
platinum-free interval PFS progression-free survival PR partial
response PRO patient reported outcomes PS performance status QLQ
Quality Life Questionnaire qwk once every week q3wk once every 3
weeks RECIST Response Evaluation Criteria in Solid Tumors STS soft
tissue sarcoma ULN upper limit of normal US United States 7 8.
YONDELIS (trabectedin): Briefing Document for 15 July 2009 ODAC
Meeting EXECUTIVE SUMMARY Overview Study ET743-OVA-301 evaluated
the combination of trabectedin and DOXIL (doxorubicin HCl liposome
injection) for the treatment of subjects with relapsed ovarian
cancer. The positive results of this study serve as the basis for
the New Drug Application submitted by Ortho Biotech Oncology
Research & Development, unit of Johnson & Johnson
Pharmaceutical Research & Development, L.L.C. Study
ET743-OVA-301 was conducted at 124 sites in 21 countries, including
24 sites (121 subjects) in the United States (US). This large,
international, randomized, controlled study of 672 subjects with
relapsed ovarian cancer confirms the favorable benefit to risk
profile of trabectedin for the treatment of a disease with high
unmet medical need. The addition of trabectedin to DOXIL in Study
ET743-OVA-301 resulted in improvement in the predefined primary
endpoint of progression-free survival (PFS) as determined by
Independent Radiologist review. The results demonstrated a 21%
decrease in the risk of disease progression or death (hazard ratio
[HR]=0.79; 95% confidence interval [CI]: 0.65;0.96; p=0.0190).
Significant improvements in objective response rates (ORR) and a
trend in overall survival (OS) that favored the combination further
support the clinical significance of the primary analysis (ORR =
28% in trabectedin + DOXIL compared with 19% in DOXIL monotherapy;
median OS for trabectedin + DOXIL 20.5 months compared with 19.4
months for DOXIL monotherapy [HR=0.85; 95% CI: 0.67;1.06]). The
safety profile of trabectedin and DOXIL was consistent with the
known side effects of each drug. The lower dose of DOXIL (30 mg/m2
) administered in the combination resulted in less frequent
DOXIL-related side effects, such as stomatitis and hand-foot
syndrome, compared with monotherapy. As reported in studies of
single-agent trabectedin, frequent, reversible elevations of liver
function tests and neutropenia, in most cases without clinical
sequelae, were also observed in Study ET743-OVA-301. The addition
of trabectedin to DOXIL resulted in a benefit to risk profile
consistent with other doublets currently used to treat patient with
relapsed ovarian cancer. Importantly, the approval of this
trabectedin-based regimen will provide a clinically useful,
platinum-free treatment option for women with relapsed ovarian
cancer. The use of PFS as a primary endpoint for the approval of
drugs to treat ovarian cancer was established in 2006. Given the
improvement in PFS observed with the addition of trabectedin to
DOXIL and the trend in survival that favors the combination in
Study ET743-OVA-301, Ortho Biotech Oncology Research &
Development, unit of Johnson & Johnson Pharmaceutical Research
& Development, L.L.C. proposes that 8 9. YONDELIS
(trabectedin): Briefing Document for 15 July 2009 ODAC Meeting
trabectedin receive regulatory approval for the treatment of
patients with relapsed ovarian cancer. Trabectedin Trabectedin,
formerly known as ecteinascidin-743 (ET-743), is a tris
tetrahydroisoquinolone alkaloid with a unique mechanism of action.
Trabectedin alkylates the N2 position of guanine in the minor
groove of DNA, unlike most agents that target DNA by binding in the
major groove. The trabectedinguanine N2 adduct traps nuclear
excision repair (NER) proteins, rendering them ineffective.
Checkpoint proteins that respond to damaged DNA, slow progression
through the cell cycle. The resultant G2-M arrest leads to
apoptosis and cell death. The combination of trabectedin and DOXIL
includes drugs with mechanisms of action that are not affected by
upregulation of the NER proteins. An additional benefit of the
combination is that it may be administered to approximately 10% of
patients who develop hypersensitivity to platinum or taxanes and
the approximately 20% of patients who cannot receive a
taxane-platinum-based regimen because of persistent neuropathy
after front-line treatment. Trabectedin is approved for the
treatment of soft tissue sarcoma (STS) in 37 countries, including
the countries that participate in the European Agency for the
Evaluation of Medicinal Products (EMEA) since 2007. The application
for the ovarian cancer indication has been submitted to the EMEA
and is under review by the Committee for Medicinal Products for
Human Use (CHMP). Indication On November 19, 2008, the company
submitted data to the US Food and Drug Administration (FDA) in a
New Drug Application to support the following indication:
Trabectedin is an antineoplastic indicated in combination with
DOXIL for treatment of patients with relapsed ovarian cancer.
Trabectedin Studies of Subjects with Relapsed Ovarian Cancer The
efficacy and safety data supporting the use of trabectedin for the
treatment of relapsed ovarian cancer were obtained from 4 completed
studies of subjects with ovarian cancer: Studies ET743-INT-11,
ET-B-026-03, ET-B-009-99, and the pivotal study, ET743-OVA-301. In
addition to data from Study ET743-OVA-301, safety data from the
following studies are included in the submission: 16 completed
Phase 2 studies of trabectedin as a single-agent in various tumor
types and 18 completed Phase 1 studies, one of which is a dose
escalation study supporting the dose and schedule for the 9 10.
YONDELIS (trabectedin): Briefing Document for 15 July 2009 ODAC
Meeting trabectedin + DOXIL combination (Study ET743-USA-11).
Across the 38 completed clinical studies included in this
submission, 2,322 subjects have been treated with trabectedin.
Efficacy Study ET743-OVA-301 was a Phase 3, open-label,
multicenter, randomized study of adult women with relapsed ovarian
cancer. This study was designed to investigate the efficacy and
safety of the combination of DOXIL 30 mg/m2 administered as a
90-minute i.v infusion (60-minutes for subjects in Europe per the
European Summary of Product Characteristics) followed by
trabectedin 1.1 mg/m2 as a 3-hour i.v. infusion, every 3 weeks. The
outcomes for this combined treatment were compared with those of
DOXIL 50 mg/m2 administered as a 90-minute i.v. infusion every 4
weeks. Despite the difference in cycle length in the 2 arms, tumor
assessments were mandated every 8 weeks for both arms. The results
of Study ET743-OVA-301, the pivotal study in this dossier,
demonstrate that subjects with relapsed ovarian cancer (n=672) who
are treated with trabectedin + DOXIL have better outcomes than
those who are treated with DOXIL monotherapy. DOXIL is approved in
76 countries for the treatment of relapsed ovarian cancer and thus
is an appropriate active comparator in this setting. The addition
of trabectedin to DOXIL resulted in a 21% decrease in the risk of
disease progression or death (PFS) compared with DOXIL monotherapy.
The PFS endpoint was assessed among all subjects with measurable
disease by Independent Radiologists using imaging only. The median
PFS for the trabectedin + DOXIL combination arm was 7.3 months
compared with 5.8 months for the DOXIL monotherapy arm (HR=0.79;
95% CI: 0.65;0.96; p=0.0190). Additional analyses of PFS among all
randomized subjects included clinical and imaging data in the
assessment of disease progression, by Independent Oncologists,
(HR=0.72; 95% CI: 0.60;0.88; p=0.0008), and by the Study
Investigators (HR=0.72; 95% CI: 0.61;0.86; p=0.0002), demonstrate
consistent results independent of the method of assessment. The ORR
was 28% in the trabectedin + DOXIL arm compared with 19% in the
DOXIL monotherapy arm. Overall survival data were not mature at the
time of the clinical cutoff date (55% censored). However, the
planned analysis of OS at the time of final PFS analysis
demonstrated a 15% reduction in the risk of death for subjects in
the trabectedin + DOXIL arm (median OS for the trabectedin + DOXIL
arm was 20.5 months compared wth 19.4 months for the DOXIL
monotherapy arm; HR=0.85; 95% CI: 0.67;1.06). Sensitivity analyses
support the robustness of the efficacy endpoints. An analyses of
patient-reported outcomes (PRO), such as the EORTC quality life
questionnaire (QLQ) 10 11. YONDELIS (trabectedin): Briefing
Document for 15 July 2009 ODAC Meeting C30, Global Health Status
Score, showed no significant change when trabectedin and DOXIL were
administered in combination relative to DOXIL monotherapy. Table 1
summarizes the reduction in the risk of disease progression and
death observed in Study ET743-OVA-301, as well as that observed in
a study of paclitaxel added to a platinum-based compound, and a
study of gemcitabine added to carboplatin. The latter studies
include only platinum-sensitive subjects; and the date of
progression was determined by the Investigators rather than
Independent Radiologists review. Therefore, the results for Study
ET743-OVA-301 shown in Table 1, are only for the platinum-
sensitive subgroup assessed by Independent Radiologists review
(primary endpoint), and the Investigators. As is shown in Table 1,
the proportion of poorer prognosis subjects, that is, those who
progressed after prior taxane therapy and who had partially
sensitive disease, is highest in Study ET743-OVA-301. Despite this,
the addition of trabectedin to DOXIL results in a reduction in the
risk of progression that is comparable to what is observed when
other approved drugs were tested in doublets. Also, the trend in
reduction in the risk of death is comparable to that observed when
paclitaxel is added to a platinum-based regimen. Recognizing the
limitations of cross-study comparisons, this summary of the active
combination regimens for the treatment of relapsed ovarian cancer
demonstrates that when similar patient populations are considered,
the magnitude of the clinical effect of adding trabectedin to DOXIL
is similar to that observed with platinum-containing doublets.
Table 1: Phase 3 Ovarian Study Comparisons of RR, PFS, and OS
(Subjects With Platinum-Sensitive Disease) Carboplatin Carboplatin
Paclitaxel Gemcitabine Parmar et al. Pfisterer et al. Trabectedin +
DOXIL N 802 356 430 10 Endpoint OS PFS PFS Prior Taxane 40% 71% 77%
6-12 months PFI 25% 43% 50% PFS Assessment Investigator
Investigator Ind. Radiologist/Investigator Risk of Progression 24%
28% 27%/38% Risk of Death 18% No 18% Added Toxicity Myelo, Neuro
Myelo Myelo, LFTs Myelo= myelosuppression, Neuro= neurotoxicity,
LFTs= liver function tests, PFI=platinum free interval;
PFS=progression-free survival; OS=overall survival Source:
(Pfisterer 2006; Parmar 2003) 11 12. YONDELIS (trabectedin):
Briefing Document for 15 July 2009 ODAC Meeting Safety As was seen
with the administration of trabectedin alone, the combination of
trabectedin and DOXIL commonly results in transient, reversible
elevations of liver transaminases. Grade 3-4 elevations in
transaminases were more frequent in the trabectedin + DOXIL arm
(ALT 31%, AST 7%, n=333) compared with the DOXIL monotherapy arm
(AST 1%, ALT 1%, n=330). The elevations generally occur after the
first administration, return to normal before the next cycle, but
decrease in severity with continued cycles of treatment. This
decrease in severity occurs with or without dose reduction. Early
experience with trabectedin showed that dexamethasone premedication
decreased the frequency and severity of transaminase elevations.
Premedication with dexamethasone is now administered routinely. In
Study ET743-OVA-301, Grade 3-4 neutropenia was more frequent in the
trabectedin + DOXIL arm (63%, n=333) compared with the DOXIL
monotherapy arm (22%, n=330). Febrile neutropenia was reported for
8% of subjects in the trabectedin + DOXIL arm, and 2% of subjects
receiving DOXIL alone. Sepsis, septic shock, or sepsis syndrome
were reported for