Evaluation of Optimal Treatment With Bevacizumab in Patients With Platinum-sensitive Recurrent Ovarian Cancer

Study Overview
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Brief Summary
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Evaluation of the best therapeutic index for patients with platinum-sensitive ovarian cancer when treatment with bevacizumab and gemcitabine/carboplatin or with bevacizumab and PLD/carboplatin.

Official Title
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A Prospective Randomized Phase III Trial of Carboplatin/Gemcitabine/Bevacizumab vs. Carboplatin/Pegylated Liposomal Doxorubicin/Bevacizumab in Patients With Platinum-sensitive Recurrent Ovarian Cancer

Conditions
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Recurrent Platinum-sensitive Ovarian Cancer

Intervention / Treatment
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* Drug: Carboplatin
* Drug: PLD
* Biological: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diagnosis of epithelial ovarian carcinoma or fallopian tube carcinoma or primary peritoneal carcinoma First disease recurrence >6 months after first-line platinum-based chemotherapy Patients with measurable or non-measurable disease (RECIST v1.1) or CA 125 assessable disease (GCIG criteria) or histological proven diagnosis of relapse In case of cytoreductive surgery for recurrence, patients must be able to commence cytotoxic chemo-therapy within 8 weeks after cytoreductive surgery ECOG PS 0-2 Absolute Neutrophil Count >= 1.5 x 10^9/L; Platelets >= 100 x 10^9/L; Hemoglobin >= 9.5 g/dL Patients not receiving anticoagulant medication who have an International Normalized Ratio <= 1.5 and an Activated ProThrombin Time <= 1.5 x ULN Serum bilirubin <= 2 x ULN; Serum transaminases <= 2.5 x ULN (<= 5 x ULN in the presence of liver metastasis) Serum creatinine < 1.6 mg/dL or creatinine clearance >= 40 mL/min; Glomerular filtration rate > 40 ml/min (estimates based on the Cockroft-Gault or Jelliffe formula); Urine dipstick for proteinuria < 2+. If urine dipstick is >= 2+, 24 hour urine collection must demonstrate <= 1 g of protein in 24 hours Normal blood pressure or adequately treated and controlled hypertension (either systolic BP ≤ 140 mmHg and/or diastolic BP ≤ 90 mmHg) Exclusion Criteria: Ovarian tumors of low malignant potential Malignancies other than ovarian cancer within 5 years prior to randomization Administration of other simultaneous chemotherapy drugs, any other anticancer therapy or anti-neoplastic hormonal therapy, or simultaneous radiotherapy during the trial treatment period Any previous radiotherapy to the abdomen or pelvis Known hypersensitivity to used chemotherapeutic agents in this trial and bevacizumab and its excipients, chinese hamster ovary cell products or other recombinant human or humanised antibodies Current or recent chronic use of aspirin > 325 mg/day Surgery (including open biopsy) within 4 weeks prior to anticipated first dose of Bevacizumab History of VEGF therapy related abdominal fistula or gastrointestinal perforation Current, clinically relevant bowel obstruction, including sub-occlusive disease, related to underlying disease Patients with evidence of abdominal free air not explained by paracentesis or recent surgical procedure Previous Cerebro-Vascular Accident , Transient Ischaemic Attack or Sub-Arachnoid Haemorrhage Prior history of hypertensive crisis or hypertensive encephalopathy Clinically significant disease, including: myocardial infarction or unstable angina within ≤ 6 months of randomization; New York Heart Association (NYHA) >= grade 2 Congestive Heart Failure; poorly controlled cardiac arrhythmia despite medication; peripheral vascular disease grade >= 3 LVEF defined by ECHO/MUGA below the institutional lower limit of normal Significant traumatic injury during 4 weeks prior to randomization Current brain metastases or spinal cord compression History or evidence upon neurological examination of central nervous system disease Non-healing wound, active ulcer or bone fracture History or evidence of thrombotic or hemorrhagic disorders within 6 months prior to randomization Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic coagulation) Fertile woman of childbearing potential not willing to use adequate contraception (oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) for the duration of the trial and at least 6 months afterwards Pregnant or lactating women Requirement of therapeutic anticoagulation using marcumar, warfarin or PTT-prolonging heparin

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 |
| --- | --- |
| No Intervention: Control Arm<br>Patients receive bevacizumab 15 mg/kg iv on day 1 followed by gemcitabine 1000mg/m² iv on day 1 & 8 and carboplatin AUC4 iv on day 1 every 3 weeks for up to 6 cycles in the absence of progression disease or unacceptable toxicities. Patients then continue to receive bevacizumab 15 mg/kg iv every 3 weeks until progression disease or unacceptable toxicities. | |
| Experimental: Research Arm<br>Patients receive bevacizumab 10 mg/kg iv on day 1 & 15 followed by PLD 30mg/m² iv on day 1 carboplatin AUC4 iv on day 1 every 4 weeks for up to 6 cycles in the absence of progression disease or unacceptable toxicities. Patients then continue to receive bevacizumab 15 mg/kg iv every 3 weeks until progression disease or unacceptable toxicities. | Drug: Carboplatin<br> <br> Drug: PLD<br> <br> Biological: Bevacizumab<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| investigator-determined progression-free survival |  | every 12 weeks until progression or up to 30 months (whichever occurs first) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| biological progression-free survival by serum CA 125 |  | every 3 weeks until progression or up to 30 months (whichever occurs first) | 
| Health related Quality of Life (QoL) |  | Baseline and then every 12 weeks until investigator-determined progresssion-free survival and thereafter at every visit for th 5-years follow-up or death (whichever occurs first) | 
| Safety and Tolerability, i.e. type, frequency, severity and duration o adverse reactions |  | every 3 weeks, 30 months after start of treatment or if applicable 4 weeks after last dose of bevacizumab (whichever occurs later) | 
| Overall Survival |  | every 3 weeks during treatment with bevacizumab, thereafter every 6 months; for up 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ovarian Carcinoma, Bevacizumab, Gemcitabine, PLD, pegylated liposomal doxorubicin, Carboplatin, best therapeutic index, progression-free survival