Bevacizumab and Trabectedin +/- Carboplatin in Advanced Ovarian Cancer

Study Overview
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Brief Summary
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This study is aimed at assessing the efficacy and the safety of the combination of bevacizumab and trabectedin with or without carboplatin in adult women with epithelial ovarian cancer at first recurrence occurred 6-12 months after the end of the last (first or second) platinum-containing regimen. According to the Bryant and Day design the primary endpoints will be the proportion of progression-free patients at 6 months for the efficacy, and the proportion of patients with severe toxicity for the safety at the same time-point.

Official Title
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Multicenter, Randomized, Non-comparative, Phase II Trial on the Efficacy and Safety of the Combination of Bevacizumab and Trabectedin With or Without Carboplatin in Adult Women With Platinum Partially Sensitive Recurring Ovarian Cancer.

Conditions
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Ovarian Epithelial Cancer Recurrent

Intervention / Treatment
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* Drug: bevacizumab and trabectedin
* Drug: bevacizumab, trabectedin and carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age≥18years Eastern Cooperative Oncology Group (ECOG)- performance status 0-2 Cytological/histological diagnosis of epithelial ovarian cancer Progression free interval between 6-12 months (calculated from the first day of the last cycle of the previous last platinum-based chemotherapy until the date of progression confirmation through radiologic imaging) One or two previous platinum-based chemotherapy lines Measurable disease according to RECIST version 1.1 Life expectancy ≥ 12 weeks Patients must be able to receive dexamethasone or its equivalent, as a premedication for trabectedin Written informed consents given before the enrolment according to International Conference on Harmonization/ Good Clinical Practice (ICH/GCP). Exclusion Criteria: Prior treatment with trabectedin Prior progression while on therapy containing bevacizumab or other vascular endothelial growth factor (VEGF) pathway-target therapy Pre-existing grade > 1 sensitive/motor neurologic disorder Current or recent (within 30 days of first study dosing) treatment with another investigational drug Surgery (including open biopsy) within 4 weeks prior to the first planned dose of bevacizumab Current or recent (within 10 days prior to the first study drug dose) use of full-dose oral or parenteral anticoagulant or thrombolytic agent for therapeutic purposes (except for line patency, in which case international normalized ratio (INR) must be maintained below 1.5). Post operative prophylaxis with low molecular weight heparin sc is allowed Inadequate bone marrow function: absolute neutrophil count (ANC): <1.5 x 109/l, or platelet count <100 x 109/l or haemoglobin <9 g/dl. Patients may be transfused to maintain haemoglobin values ≥9 g/dl Inadequate coagulation parameters: activated partial thromboplastin time (APTT) >1.5 x upper limit of normal (ULN) or INR >1.5 Inadequate liver function, defined as: serum (total) bilirubin > ULN for the institution AST/serum glutamic-oxaloacetic transaminase (SGOT) or ALT/ serum glutamic-pyruvic transaminase (SGPT) >2.5 x ULN Inadequate renal function: serum creatinine >1.5 mg/dL or >132 micromol/L and urine dipstick for proteinuria > or = 2+ and >1g of protein in their 24-hour urine collection History or evidence of brain metastases or spinal cord compression Pregnant, breastfeeding women and women of child bearing potential, who do not agree to use a medically acceptable method of contraception through the treatment period and for 6 months after discontinuation of treatment History or evidence of thrombotic or hemorrhagic disorders; including cerebrovascular accident, stroke or transient ischemic attack or sub-arachnoid haemorrhage within 6 months prior to the first study treatment Uncontrolled hypertension (sustained systolic >150 mmHg and/or diastolic >100 mmHg despite antihypertensive therapy) or clinically significant (i.e. active) cardiovascular disease, including: myocardial infarction or unstable angina within 6 months prior to the first study treatment, New York Heart Association grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication History of bowel obstruction, including subocclusive disease, related to the underlying disease and history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess. Evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction Non-healing wound, ulcer or bone fracture hepatitis C virus (HCV) positivity Other malignancy within the last 5 years, except for adequately treated carcinoma in situ of the cervix or squamous carcinoma of the skin, or adequately controlled limited basal cell skin cancer.

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
Interventional Model Description: This is a multicentre, randomized, non-comparative phase II study aimed at assessing efficacy and safety of two regimens according to a Bryant and Day two-stage design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: bevacizumab and trabectedin<br>Arm A: bevacizumab (15 mg/kg) given as 1 hour infusion will be followed by trabectedin (1.1 mg/sqm) 3 hour iv infusion; to be repeated every 21 days until progression, unacceptable toxicity, patient or physician decision to discontinue, or death patients | Drug: bevacizumab and trabectedin<br>* Arm A: bevacizumab (15 mg/kg) given as 1 hour infusion will be followed by trabectedin (1.1 mg/sqm) 3 hour iv infusion; to be repeated every 21 days until progression, unacceptable toxicity, patient or physician decision to discontinue, or death patients<br>* Other names: Yondelis;|
| Experimental: bevacizumab, trabectedin and carboplatin<br>Arm B: cycle 1-6, bevacizumab given as 1 hour infusion will be followed by carboplatin area under curve 4 (AUC 4) and trabectedin 3 hour iv infusion. Cycle 7- end of treatment, bevacizumab given as 1 hour infusion will be followed by trabectedin 3 hour iv infusion. Patient enrolled in arm B will receive (cycle 1-6): trabectedin 0.8 mg/m2 ,carboplatin AUC 4 day 1 every 28 days and bevacizumab 10 mg/kg iv on day 1 and day 15. From cycle 7 to disease progression, unacceptable toxicity, patient or physician decision to discontinue, or death patients will receive bevacizumab 15 mg/kg iv and trabectedin 1.1 mg/m2 day 1 every 21 days | Drug: bevacizumab, trabectedin and carboplatin<br>* Arm B: cycle 1- 6, bevacizumab given as 1 hour infusion will be followed by carboplatin AUC 4 and trabectedin 3 hour iv infusion. Cycle 7- end of treatment, bevacizumab given as 1 hour infusion will be followed by trabectedin 3 hour iv infusion. Patient enrolled in arm B will receive (cycle 1-6): trabectedin 0.8 mg/m2 ,carboplatin AUC 4 day 1 every 28 days and bevacizumab 10 mg/kg iv on day 1 and day 15. From cycle 7 to disease progression, unacceptable toxicity, patient or physician decision to discontinue, or death patients will receive bevacizumab 15 mg/kg iv and trabectedin 1.1 mg/m2 day 1 every 21 days<br>* Other names: Carboplatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival at 6 months (PFS-6) | The PFS-6, defined as the percentage of patients who are alive and progression free at 6 months after the randomization. | from randomization up to 6 months | 
| Proportion of patients with severe toxicity within 6 months from randomization. | The following conditions will be considered as severe toxicity: absolute neutrophil count (ANC) < 0.5x109/L lasting > 7 days and/or with fever platelets < 25x109/L any other grade 3-4 (evaluated by the National Cancer Institute-Common Terminology Criteria for Adverse Events [NCI-CTCAE] version 4.0) non-hematological toxicities except for reversible nausea/vomiting, diarrhea, hypersensitivity reactions, and alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation reversible to grade 1 by day 28 any toxicity causing a delay of >14 days in the following cycle | from randomization up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | Defined for each patient as the time from the date of randomization to the date of first progression, second primary malignancy or death for any cause, whichever comes first. Subjects not progressed or died at the time of the analysis will be censored at the last disease assessment date. | from randomization up to 30 months | 
| Overall survival at 12 months (OS-12) | Defined as the percentage of patients who are alive at 12 months after the randomization. | one year | 
| Clinical Benefit (CB) | clinical benefit, defined as the percentage of patients who are judged by the Investigators to have a complete response (CR), or partial response (PR) or stable disease (SD) according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria, version 1.1 after 12 weeks from the date of randomization. | from randomization up to 30 months | 
| Incidence of Adverse Events (AEs) | Incidence of AEs, according to NCI-CTCAE, version 4.0 | from randomization up to 30 months | 
| Maximum toxicity grade | Maximum toxicity grade experienced by each patient for each specific toxicity | from randomization up to 30 months | 
| Percentage of patients experiencing grade 3-4 toxicity for each specific toxicity | Percentage of patients experiencing grade 3-4 toxicity for each specific toxicity during the study | from randomization up to 30 months | 
| Patients with at least a Serious Adverse Drug Reaction (SADR) | Patients with at least a SADR during the study | from randomization up to 30 months | 
| Patients with at least a Suspect Unexpected Serious Adverse Reaction (SUSAR). | Patients with at least a suspect unexpected serious adverse reaction during the study | from randomization up to 30 months | 
| Percentage of patients with dose and/or time modifications | Percentage of patients with dose and/or time modifications of the study drugs | from randomization up to 30 months | 
| Percentage of premature withdrawals | Percentage of premature withdrawals of the enrolled patients | from randomization up to 30 months | 
| Patients with at least a Serious Adverse Event (SAE) | Patients with at least a SAE during the study | from randomization up to 30 months | 
| Nature of AEs | Nature of AEs, according to NCI-CTCAE, version 4.0 | from randomization up to 30 months | 
| Severity of AEs | Severity of AEs, according to NCI-CTCAE, version 4.0 | from randomization up to 30 months | 
| Seriousness of AEs | Seriousness of AEs according to NCI-CTCAE, version 4.0 | from randomization up to 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ovarian cancer, bevacizumab, trabectedin, carboplatin, randomized trial, phase II