Evaluation of Optimal Treatment Duration of Bevacizumab Combination With Standard Chemotherapy in Patients With Ovarian Cancer

A Prospective Randomised Phase III Trial to Evaluate Optimal Treatment Duration of First-line Bevacizumab in Combination With Carboplatin and Paclitaxel in Patients With Primary Epithelial Ovarian, Fallopian Tube or Peritoneal Cancer

The purpose of this study is to determine whether the early and continuous addition of bevacizumab for up to 30 months to the standard chemotherapy is more effective than the early and continuous addition of bevacizumab for up to 15 months.

Determination whether the early and continuous addition of bevacizumab for up to 30 months to the standard chemotherapy is more effective than the early and continuous addition of bevacizumab for up to 15 months

Inclusion Criteria:

• Signed written informed consent obtained prior to initiation of any study specific procedures and treatment as confirmation of the patients awareness and willingness to comply with the study requirements

• Primary diagnosis is confirmed by specialized pathology review (Germany only)

• Females aged ≥ 18 years

• Histologically confirmed, newly diagnosed

  • Epithelial ovarian carcinoma
  • Fallopian tube carcinoma
  • Primary peritoneal carcinoma AND FIGO stage IIb - IV (all grades and all histological types)

• Patients should have already undergone surgical debulking, by a surgeon experienced in the management of ovarian cancer, with the aim of maximal surgical cytoreduction according to the GCIG Conference Consensus Statement. There must be no planned surgical debulking prior to disease progression. Patients with stage III and IV disease in whom initial surgical debulking was not appropriate or possible will still be eligible providing

  • the patient has a histological diagnosis and
  • debulking surgery prior to disease progression is not foreseen

• 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 surgery.

• ECOG 0-2

• Life expectancy > 3 months

• Adequate bone marrow function (within 14 days prior to randomization)

  • ANC ≥ 1.5 x 10^9/L
  • PLT ≥ 100 x 10^9/L
  • Hb ≥ 9 g/dL (can be post-transfusion)

• Adequate coagulation parameters (within 14 days prior to randomization)

  • Patients not receiving anticoagulant medication who have an INR ≤ 1.5 and an aPTT ≤ 1.5 x ULN
  • The use of full-dose oral or par-enteral 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.

• Adequate liver function (within 14 days prior to randomization)

  • Serum bilirubin ≤ 1.5 x ULN
  • Serum transaminases ≤ 2.5 x ULN

• Urine dipstick for proteinuria < 2+. If urine dipstick is ≥ 2+, 24 hour urine must demonstrate ≤ 1 g of protein in 24 hours

• Adequate postoperative GFR > 40 ml/min (estimates based on the Cockroft-Gault or Jelliffe formula are sufficient)

Exclusion Criteria:

• Non-epithelial origin of the ovary, the fallopian tube or the peritoneum

• Borderline tumours (tumours of low malignant potential) and FIGO stage Ia - IIa tumours

• Planned intraperitoneal cytotoxic chemotherapy

• Prior systemic anti-cancer therapy for ovarian cancer (for example chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy or hormonal therapy)

• Surgery (including open biopsy) within 4 weeks prior to anticipated first dose of bevacizumab (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.

• Any planned surgery during the study treatment period plus 4 additional weeks to allow for bevacizumab clearance

• Uncontrolled hypertension (sustained elevation of BP systolic > 150mmHg and/or diastolic > 100mmHg despite antihypertensive therapy)

• Any previous radiotherapy to the abdomen or pelvis

• Significant traumatic injury during 4 weeks preceding the potential first dose of bevacizumab

• 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 metastases. Spinal MRI is mandatory (within 4 weeks prior to randomization) in case of suspected spinal cord compression.

• History or evidence upon neurological examination of central nervous system (CNS) disease, unless adequately treated with standard medical therapy e.g. uncontrolled seizures

• Previous Cerebro-Vascular Accident (CVA), Transient Ischaemic Attack (TIA) or Sub-Arachnoid Haemorrhage (SAH) within 6 months prior to randomization

• 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 study duration and at least 6 months afterwards

• Pregnant or lactating women

• Treatment with other investigational agents, or participation in another clinical trial testing a drug within the past 4 weeks before start of therapy concomitantly with this trial

• 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
  • carcinoma in situ of the breast
  • and/or early endometrial carcinoma as specified below. Patients may have received previous adjuvant chemotherapy for other malignancies e.g. breast or colorectal carcinoma if diagnosed over 5 years ago with no evidence of subsequent recurrence.

• Patients with synchronous primary endometrial carcinoma, or a past history of primary endometrial carcinoma, are excluded unless ALL of the following criteria for describing the endometrial carcinoma are met

  • Disease stage FIGO stage ≤ IA (tumour invades less than one half of the myometrium)

• Known hypersensitivity to bevacizumab and its excipients, Chinese hamster ovary cell products or other recombinant human or humanised antibodies

• Non healing wound, active ulcer or bone fracture. Patients with granulating incisions healing by secondary intention with no evidence of facial dehiscence or infection are eligible but require 3 weekly wound examinations

• History or evidence of thrombotic or hemorrhagic disorders within 6 months prior to randomization

• Clinically significant cardiovascular disease, including

  • Myocardial infarction or unstable angina within 6 months of randomization
  • NYHA ≥ Grade 2 Congestive Heart Failure (CHF)
  • Poorly controlled cardiac arrhythmia despite medication (patients with rate-controlled atrial fibrillation are eligible)
  • Grade ≥ 3 peripheral vascular disease (i.e. symptomatic and interfering with activities of daily living requiring repair or revision)

• Current or recent (within 10 days prior to randomization) chronic use of aspirin > 325 mg/day

• Pre-existing sensory or motor neuropathy ≥ Grade 2

• Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contra-indicates the use of an investigational drug or puts the patient at high risk for treatment-related complications