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

• Progression Free Survival (PFS) [ Time Frame: 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 ] [ Designated as safety issue: No ]
  PFS will be measured from the date of randomization to the date of documented PD or death (regardless of cause of death).
• Objective RR [ Time Frame: 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 ] [ Designated as safety issue: No ]
  Objective RR will be the best response obtained in any evaluation according to RECIST 1.1
• CA-125 serological response [ Time Frame: 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 ] [ Designated as safety issue: No ]
  CA-125 serological response will be the best response obtained in each arm
• Duration of Response [ Time Frame: 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 ] [ Designated as safety issue: No ]
  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.
• Time to subsequent chemotherapy administration [ Time Frame: 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 ] [ Designated as safety issue: No ]
  The time from randomization to subsequent chemotherapy counted from the administration of subsequent chemotherapy will be evaluated as an exploratory analysis.
• OS for Subsequent chemotherapies [ Time Frame: 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 ] [ Designated as safety issue: No ]
• PFS for the Subsequent Chemotherapies [ Time Frame: 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 ] [ Designated as safety issue: No ]
• Frequency of serious adverse events (SAEs) [ Time Frame: 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 ] [ Designated as safety issue: Yes ]
• QoL according to the EORTC QLQ-C30 and QLQ-OV28 [ Time Frame: 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 ] [ Designated as safety issue: No ]
  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.
• Best response to every Subsequent chemotherapy [ Time Frame: 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 ] [ Designated as safety issue: No ]
• Frequency of toxicities, graded according to the NCI-CTAE version 4.0 [ Time Frame: 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 ] [ Designated as safety issue: Yes ]
• Frequency of toxicities leading to dose delays [ Time Frame: 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 ] [ Designated as safety issue: Yes ]
• Frequency of toxicities leading to dose modifications [ Time Frame: 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 ] [ Designated as safety issue: Yes ]
• Frequency of toxicities leading to treatment discontinuation [ Time Frame: 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 ] [ Designated as safety issue: Yes ]

The objective of this multicentric, randomised, Phase III study is to demonstrate superiority, in terms of prolonged survival, of trabectedin and Pegylated Liposomal Doxorubicin (PLD) versus carboplatin and PLD.

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'/subjects' characteristics: patients over 18 years of age with advanced, progressive ovarian cancer 6-12 months after completion of first line treatment with platinum-based chemotherapy.

• Drug: Carboplatin
  Carboplatin AUC 5
• Drug: Pegylated Lipoxomal Doxorubicin (PLD)
  PLD 30 mg/m² i.v.
• Drug: Trabectedin
  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.

• Active Comparator: Carboplatin plus PLD
  PLD 30 mg/ m2 followed by carboplatin AUC 5.
  Interventions:

  • Drug: Carboplatin
  • Drug: Pegylated Lipoxomal Doxorubicin (PLD)
• Experimental: Trabectedin plus PLD
  PLD 30 mg/m2 infusion followed by trabectedin 1.1 mg/m2 infusion.
  Interventions:

  • Drug: Pegylated Lipoxomal Doxorubicin (PLD)
  • Drug: Trabectedin

Inclusion Criteria:

1. Female, aged ≥ 18 years
2. Histologically and/or cytologically proven epithelial ovarian, epithelial fallopian tube cancer or primary peritoneal cancer
3. 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
4. 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.
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2
6. Estimated life expectancy ≥ 12 weeks
7. Patients must be accessible for treatment and follow-up
8. Adequate organ function within 14 days prior to first cycle as evidenced
9. Patients must be able to receive dexamethasone or its equivalent, which is required if randomly assigned to treatment with trabectedin plus PLD
10. Informed consent of the patient

Exclusion Criteria:

1. Non epithelial ovarian or mixed epithelial/non epithelial tumors (e.g., Mullerian tumors)
2. 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
3. Bowel obstruction, sub-occlusive disease or the presence of symptomatic brain metastases
4. Pre-existing grade > 1 motor or sensory neuropathy according to the National Cancer Institute Common Toxicity Criteria Adverse Event (NCI-CTCAE) version 4.0
5. 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
6. History of liver disease
7. 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
8. 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)
9. Prior exposure to trabectedin
10. Prior resistance to anthracyclines or PLD defined as a progression during anthracycline-based chemotherapy or a recurrence within 6 months from its ending
11. Prior severe PLD related toxicity
12. Prior exposure to cumulative doses of doxorubicin >400mg/m2 or epirubicin >720mg/m2
13. Treatment with any investigational product within 30 days prior to inclusion in the study

• PharmaMar
• Averion International Corporation