INOVATYON STUDY -International, Randomized Study in Patients With Ovarian Cancer

Study Overview
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Brief Summary
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The objective of this multicentric, randomised, Phase III study is to demonstrate superiority, in terms of survival, of trabectedin and Pegylated Liposomal Doxorubicin (PLD) versus carboplatin and PLD in partially-platinum sensitive ovarian cancer patients.

Detailed Description
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Patients will be randomised to: Arm A: PLD 30 mg/m2 and carboplatin AUC 5; Arm B: PLD 30 mg/m2 and trabectedin 1.1 mg/m2. Patients' characteristics: patients over 18 years of age with advanced, progressive ovarian cancer 6-12 months after completion of first line or second line treatment with platinum-based chemotherapy.

Official Title
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Phase III International, Randomized Study of Trabectedin Plus Pegylated Liposomal Doxorubicin (PLD) Versus Carboplatin Plus PLD in Patients With Ovarian Cancer Progressing Within 6-12 Months of Last Platinum

Conditions
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Ovarian Cancer

Intervention / Treatment
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* Drug: Carboplatin
* Drug: Pegylated Lipoxomal Doxorubicin (PLD)
* Drug: Trabectedin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female, aged ≥ 18 years Histologically and/or cytologically proven epithelial ovarian, epithelial fallopian tube cancer or primary peritoneal cancer Progression free interval between six and twelve (6-12) months (calculated from the first day of the last cycle of the last platinum-based chemotherapy until the date of progression confirmation through radiologic imagery). Patients may have received up to two platinum-based chemotherapy lines, of which at least one must have contained a taxane Measurable or evaluable disease confirmed by radiological imaging, such as magnetic resonance imaging (MRI), computed tomography (CT) scan, or PET/CT scan at study entry (CA-125 rise not supported by radiological evidence of disease is not accepted as criteria for defining progression) or histological proven recurrent ovarian cancer even in the absence of postoperatively measurable or evaluable lesions. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2 Estimated life expectancy ≥ 12 weeks Patients must be accessible for treatment and follow-up Adequate organ function within 14 days prior to first cycle as evidenced Patients must be able to receive dexamethasone or its equivalent, which is required if randomly assigned to treatment with trabectedin plus PLD Informed consent of the patient Exclusion Criteria: Non epithelial ovarian or mixed epithelial/non epithelial tumors (e.g., Mullerian tumors) Patients who did not respond to last platinum-based therapy or in whom last relapse occurred < 6 months or > 12 months from the last dose of platinum Bowel obstruction, sub-occlusive disease or the presence of symptomatic brain metastases Pre-existing grade > 1 motor or sensory neuropathy according to the National Cancer Institute Common Toxicity Criteria Adverse Event (NCI-CTCAE) version 4.0 Myocardial infarct within six months before enrolment, New York Association (NYHA) Class II or worse heart failure (Appendix 1. The New York Heart Association), uncontrolled angina, severe uncontrolled ventricular arrythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormalities History of liver disease Concurrent severe medical problems or any unstable medical condition unrelated to malignancy, which would significantly limit full compliance with the study or expose the patient to extreme risk or decreased life expectancy Breastfeeding women and women of child bearing potential must use effective contraception during treatment and 3 months thereafter, which may include prescription contraceptives (oral, injection, or patch), intrauterine device, double-barrier method or male partner sterilization (not applicable to patients that are surgically sterile) Prior exposure to trabectedin Prior resistance to anthracyclines or PLD defined as a progression during anthracycline-based chemotherapy or a recurrence within 6 months from its ending Prior severe PLD related toxicity Prior exposure to cumulative doses of doxorubicin >400mg/m2 or epirubicin >720mg/m2 Treatment with any investigational product within 30 days prior to inclusion in the study

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 |
| --- | --- |
| Active Comparator: Carboplatin plus PLD<br>Pegylated Lipoxomal Doxorubicin (PLD) 30 mg/ m2 followed by carboplatin AUC 5. | Drug: Carboplatin<br>* Carboplatin AUC 5<br>* Other names: Carboplatin generic;Drug: Pegylated Lipoxomal Doxorubicin (PLD)<br>* PLD 30 mg/m² i.v.<br>* Other names: Caelyx;|
| Experimental: Trabectedin plus PLD<br>Pegylated Lipoxomal Doxorubicin (PLD) 30 mg/m2 infusion followed by trabectedin 1.1 mg/m2 infusion. | Drug: Pegylated Lipoxomal Doxorubicin (PLD)<br>* PLD 30 mg/m² i.v.<br>* Other names: Caelyx;Drug: Trabectedin<br>* trabectedin 1.1 mg/m2 3-hour i.v. infusion on Day 1 every 3 weeks. The use of central venous access is strongly recommended.<br>* Other names: Yondelis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | This is an event driven study. The study will continue until 442 events have occurred. | This outcome measure will be assess approximately 4.5-5 years after the last patient enrolled | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS will be measured from the date of randomization to the date of documented PD or death (regardless of cause of death). | This outcome measure will be assess approximately 4.5-5 years after the last patient enrolled, at the same time points of the Primary Endpoint | 
| Objective RR | Objective RR will be the best response obtained in any evaluation according to RECIST 1.1 | This outcome measure will be assess approximately 4.5-5 years after the last patient enrolled, at the same time points of the Primary Endpoint | 
| CA-125 serological response | CA-125 serological response will be the best response obtained in each arm | This outcome measure will be assess approximately 4.5-5 years after the last patient enrolled, at the same time points of the Primary Endpoint | 
| Duration of Response | Duration of response: will be calculated from the date of first documentation of response (CR or partial response [PR], whichever occurs first) to the date of documented PD or death. | This outcome measure will be assess approximately 4.5-5 years after the last patient enrolled, at the same time points of the Primary Endpoint | 
| Time to subsequent chemotherapy administration | The time from randomization to subsequent chemotherapy counted from the administration of subsequent chemotherapy will be evaluated as an exploratory analysis. | This outcome measure will be assess approximately 4.5-5 years after the last patient enrolled, at the same time points of the Primary Endpoint | 
| OS for Subsequent chemotherapies | the overall survival counted from the administration of subsequent chemotherapy until death | This outcome measure will be assess approximately 4.5-5 years after the last patient enrolled, at the same time points of the Primary Endpoint | 
| PFS for the Subsequent Chemotherapies | the progression free survival counted from the administration of subsequent chemotherapy untill disease progression or death whichever occurs first | This outcome measure will be assess approximately 4.5-5 years after the last patient enrolled, at the same time points of the Primary Endpoint | 
| Frequency of serious adverse events (SAEs) | Number of SAEs for each randomization arm | This outcome measure will be assess approximately 4.5-5 years after the last patient enrolled, at the same time points of the Primary Endpoint | 
| QoL according to the EORTC QLQ-C30 and QLQ-OV28 | Two PRO instruments will be administered in this study: the EORTC QLQ-C30 and QLQ-OV28.PRO instruments will be completed by the patient at screening (before randomization) and within four weeks after the 6th cycle or at the time of progression, whichever occurs first. | This outcome measure will be assess approximately 4.5-5 years after the last patient enrolled, at the same time points of the Primary Endpoint | 
| Best response to each Subsequent chemotherapy line | The best response obtained to each Subsequent chemotherapy line calculated as frequency of patients with CR, PR, SD or PD. | This outcome measure will be assess approximately 4.5-5 years after the last patient enrolled, at the same time points of the Primary Endpoint | 
| Frequency of toxicities, graded according to the NCI-CTAE version 4.0 | Clinical and laboratory toxicities | This outcome measure will be assess approximately 4.5-5 years after the last patient enrolled, at the same time points of the Primary Endpoint | 
| Frequency of toxicities leading to dose delays | Clinical and laboratory toxicities | This outcome measure will be assess approximately 4.5-5 years after the last patient enrolled, at the same time points of the Primary Endpoint | 
| Frequency of toxicities leading to dose modifications | Clinical and laboratory toxicities | This outcome measure will be assess approximately 4.5-5 years after the last patient enrolled, at the same time points of the Primary Endpoint | 
| Frequency of toxicities leading to treatment discontinuation | Clinical and laboratory toxicities | This outcome measure will be assess approximately 4.5-5 years after the last patient enrolled, at the same time points of the Primary Endpoint |