A Study Comparing the Combination of Trabectedin (YONDELIS) and DOXIL/CAELYX With DOXIL/CAELYX for the Treatment of Advanced-Relapsed Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

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

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

Official Title
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A Randomized, Open-Label Study Comparing the Combination of YONDELIS and DOXIL/CAELYX With DOXIL/CAELYX Monotherapy for the Treatment of Advanced-Relapsed Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

Conditions
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Ovarian Neoplasms, Peritoneal Neoplasms, Fallopian Tube Neoplasms

Intervention / Treatment
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* Drug: Trabectedin
* Drug: DOXIL
* Drug: Dexamethasone
* Drug: DOXIL


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven advanced-relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer Eastern Cooperative Oncology Group (ECOG) performance status grade of 0 or 1 Received first-line treatment with a platinum-based regimen and had no evidence of disease progression for >= 6 months after the last dose Received second-line treatment with a platinum-based regimen, with progression of disease after attaining a response Progression of disease based on imaging after the second-line platinum-based regimen (individuals treated with a pegylated liposomal doxorubicin-containing regimen as a second-line therapy are eligible if subsequent disease progression occurs >=9 months from the first dose) Evidence of measurable disease at screening as evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) (Version 1.1) Participants no longer need to be able to receive intravenous (IV) dexamethasone or an equivalent IV corticosteroid Have a known BRCA 1/2 mutation status (for participants who do not have a known BRCA 1/2 status at screening, a blood sample will be collected to determine the status with the results available prior to randomization Laboratory values within protocol -defined parameters Have left ventricular ejection fraction by multigated acquisition scan (MUGA) scan or 2D-ECHO within normal limits for the institution Have side effects (except alopecia) of prior treatment resolved to at least Grade 1 according to the National Cancer Institute - Common Terminology Criteria of Adverse Events (NCICTCAE) (Version 4.0) Have a negative urine or serum pregnancy test at screening Agrees to protocol-defined use of effective contraception Exclusion Criteria: Diagnosis of ovarian carcinoma with mucinous histology Had more than 2 prior lines of systemic therapy. Maintenance therapies and hormonal therapies are not considered additional lines of therapy Participants who had a prior exposure to trabectedin or hypersensitivity to any of the excipients will not be excluded from receiving single-agent Doxil Prior treatment with doxorubicin or other anthracycline at cumulative doses greater than 300 mg/m2 (calculated using doxorubicin equivalent doses: 1 mg doxorubicin = 1 mg Doxil/Caelyx = 1.8 mg epirubicin = 0.3 mg mitoxantrone = 0.25 mg idarubicin) Participants unwilling or unable to have a central venous catheter placed will not be excluded from receiving single-agent Doxil Pregnant or breast-feeding Would receive study treatment within 3 weeks from radiation therapy, experimental therapy, hormonal therapy, prior chemotherapy, or biological therapy; use an invasive investigational device; or is currently enrolled in an investigational study History of another invasive malignancy (except non-metastatic basal cell carcinoma or squamous cell carcinoma of the skin or cervical carcinoma in situ adequately treated) unless in remission for >=5 years, or a non - invasive malignancy requiring ongoing therapy Known allergies, hypersensitivity, or intolerance to Doxil, dexamethasone, or their excipients Known history of central nervous system metastasis Known significant chronic liver disease, such as cirrhosis or active hepatitis (potential participants who test positive for hepatitis B surface antigen or hepatitis C antibodies are allowed provided they do not have active disease requiring antiviral therapy) Had a myocardial infarct within 6 months before enrollment, New York Heart Association (NYHA) 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 Has any of the following medical conditions: uncontrolled diabetes, psychiatric disorder (including dementia) that prevents compliance with protocol, uncontrolled seizures, newly diagnosed deep vein thrombosis, active systemic infection that is likely to interfere with study procedure or results Has any condition that, in the opinion of the investigator, would compromise the well-being of the participant or the study or prevent the participant from meeting or performing study requirements

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time between the date of randomization and the date of death. Participants who died, regardless of the cause of death, were considered to have had an event. | Up to 4.3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS is defined as the time between the date of randomization and the date of disease progression or death. PFS was assessed using the response evaluation criteria in solid tumors (RECIST) Version 1.1. As per criteria progressive disease in case of target lesions means at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeter (mm). Progressive disease in case of non-target lesions means unequivocal progression of existing non-target lesions. In both cases the appearance of one or more new lesions is also considered progression. | Up to 4.3 years | 
| Objective Response Rate (ORR) | ORR is defined as the percentage of participants with measurable disease achieving a best overall response of either complete response (CR) or partial response (PR) based on RECIST. CR: disappearance of all target and non-target lesions and normalization of tumor marker levels in non-target lesions. PR: at least a 30 percent (%) decrease in the sum of longest diameter (LD) of target lesions or persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits. | Up to 4.3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Trabectedin, Ovarian neoplasms, Peritoneal neoplasms, Fallopian tube neoplasms, Advanced-relapsed epithelial ovarian cancer, Advanced-relapsed primary peritoneal cancer, Advanced-relapsed fallopian tube cancer, Yondelis, Doxil, Caelyx, Platinum sensitive, Tthird-line, BRCA, Patient related outcome