Evaluation of optimal treatment combination of bevacizumab in combination with gemcitabine/carboplatin or pegylated liposomal doxorubicin/carboplatin in patients with platin-sensitive recurrent ovarian cancer.

Conditions: 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.
MedDRA version: 18.1Level: PTClassification code 10016180Term: Fallopian tube cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 18.1Level: PTClassification code 10066697Term: Ovarian cancer recurrentSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2012-004125-24-BE

Lead Sponsor: AGO Research GmbH

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: Female

Target Recruitment: 654

Inclusion Criteria

1. Signed written informed consent obtained prior to initiation of any trial-specific procedures and treatment as confirmation of the patients awareness and willingness to comply with the trial requirements.
2. Females aged >= 18 years
3. Histologically confirmed diagnosis of epithelial ovarian carcinoma or fallopian tube carcinoma or primary peritoneal carcinoma. All FIGO stages, histologically grades and types are allowed.
4. First disease recurrence > 6 months after first-line platinum-based chemotherapy, no prior chemotherapy in the recurrent setting is allowed. Patients must have stopped any 1st line maintenance treatment with any type of anticancer treatment including Bevacizumab at least 30 days prior randomization.
5. Patients with measurable or non-measurable disease (according to RECIST v1.1) or CA 125 assessable disease (according to GCIG criteria) or histological proven diagnosis of relapse.
6. In case of cytoreductive surgery for recurrence, patients must be able to commence cytotoxic chemotherapy within 8 weeks of cytoreductive surgery. The first dose of Bevacizumab can be omitted in both arms if the investigator decides to start chemotherapy within 4 weeks of debulking surgery for recurrent disease.
7. ECOG performance status (PS) 0-2
8. Life expectancy > 3 months
9. Adequate bone marrow function (within 28 days prior to randomization)
• Absolute Neutrophil Count (ANC) >= 1.5 x 109/L
• Platelets (PLT) >= 100 x 109/L
• Hemoglobin (Hb) >= 9.5 g/dL (hemoglobin may be supported by transfusion or erythropoietin or other approved hematopoietic growth factors)
10. Adequate coagulation parameters1 (within 28 days prior to randomization)
• Patients not receiving anticoagulant medication who have an International Normalised Ratio (INR) <= 1.5 and an Activated ProThrombin Time (aPTT) <= 1.5 x ULN
(The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to institution medical standard) and the patient has been on a stable dose of anticoagulants for at least two weeks at the time of randomization.)
11. Adequate liver function (within 28 days prior to randomization)
• Serum bilirubin (BR) <= 2 x ULN
• Serum transaminases <= 2.5 x ULN (<= 5 x ULN in the presence of liver metastasis)
12. Adequate renal function (within 28 days prior to randomization)
• Serum creatinin < 1.6 mg/dL or creatinin clearance = 60 mL/min
• postoperative glomerular filtration rate > 40 ml/min (estimates based on the Cockroft-Gault or Jelliffe formula are sufficient)
• Urine dipstick for proteinuria < 2+. If urine dipstick is >= 2+, 24 hour urine collection must demonstrate <= 1 g of protein in 24 hours.
13. Normal blood pressure or adequately treated and controlled hypertension (either systolic BP = 140 mmHg and/or diastolic BP = 90 mmHg) .

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 435
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 219

Exclusion Criteria

1. Non-epithelial origin of the ovary, the fallopian tube or the peritoneum (i.e. germ cell tu-mors).
2. Ovarian tumors of low malignant potential (e.g. borderline tumors).
3. Malignancies other than ovarian cancer within 5 years prior to randomization, except for adequately treated
- carcinoma in situ of the cervix
- and/or basal cell skin cancer
- and/or non-melanomatous skin cancer
- and/or carcinoma in situ of the breast
- and/or endometrial carcinoma (FIGO stage = IA).
Patients may have received previous adjuvant chemotherapy for other malignancies (e.g. breast or colorectal carcinoma) if diagnosed over 5 years ago before randomization with no evidence of subsequent recurrence.
4. Administration of other simultaneous chemotherapy drugs, any other anticancer therapy or anti-neoplastic hormonal therapy, or simultaneous radiotherapy during the trial treat-ment period (hormonal replacement therapy is permitted as are steroidal antiemetics).
5. Any previous radiotherapy to the abdomen or pelvis.
6. Treatment with any other investigational agent, or participation in another clinical trial testing a drug within the past 30 days before randomization.
7. 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.
8. Current or recent (within 10 days prior to randomization) chronic use of aspirin
> 325 mg/day.
9. Surgery (including open biopsy) within 4 weeks prior to anticipated first dose of bevaci-zumab (allowing for the fact that bevacizumab can be omitted from the first cycle of chemotherapy). It is strongly recommended that an interval of 7 days is left between the insertion of any central venous access devices (CVADs) and the onset of bevacizumab treatment.
10. Any planned surgery during the trial treatment period plus 4 additional weeks to allow for bevacizumab clearance.
11. History of VEGF therapy related abdominal fistula or gastrointestinal perforation.
12. Current, clinically relevant bowel obstruction, including sub-occlusive disease, related to underlying disease.
13. Patients with evidence of abdominal free air not explained by paracentesis or recent sur-gical procedure.
14. Previous Cerebro-Vascular Accident (CVA), Transient Ischaemic Attack (TIA) or Sub-Arachnoid Hemorrhage (SAH) within 6 months prior to randomization.
15. Prior history of hypertensive crisis or hypertensive encephalopathy. Uncontrolled hypertension (sustained elevation of either systolic blood pressure >140 mmHg and/or diastolic >90 mmHg despite antihypertensive therapy).
16. Clinically significant (e.g. active) cardiovascular disease, including:
• myocardial infarction or unstable angina within = 6 months of randomization
• New York Heart Association (NYHA) >= grade 2 congestive heart failure (CHF)
• poorly controlled cardiac arrhythmia despite medication (patients with rate-controlled atrial fibrillation are eligible)
• peripheral vascular disease grade = 3 (e.g. symptomatic and interfering with activities of daily living [ADL] requiring repair or revision)
17. Left ventricular ejection fraction (LVEF) defined by ECHO/MUGA below the institutional lower limit of normal.
18. Significant traumatic injury during 4 weeks prior to randomization.
19. History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI of the brain is mandatory (within 4 weeks prior to randomization) in case of suspected brain

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The primary efficacy outcome measure is investigator-determined progression-free survival (PFS);Secondary Objective: •Overall Survival (OS) <br>• Biological Progression-free Survial (PFSBIO) by serum CA 125 assessed according to the GCIG criteria<br>• Quality of Life (QoL) assessed by EORTC QLQ-C30 and QLQ-OV28<br>• Safety and Tolerability<br>;Primary end point(s): progression-free survival (PFS);Timepoint(s) of evaluation of this end point: At least 564 PFS events have been observed.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): • Overall Survival (OS)<br>• Biological Progression-free Survial (PFSBIO) by serum CA 125 assessed according to the GCIG criteria<br>• Quality of Life (QoL) assessed by EORTC QLQ-C30 and QLQ-OV28<br>• Safety and Tolerability<br>;Timepoint(s) of evaluation of this end point: Overall Survival (OS): appr. 33.3 months

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