Multicenter Phase III Randomized Study With Second Line Chemotherapy Plus or Minus Bevacizumab in Patients With Platinum Sensitive Epithelial Ovarian Cancer Recurrence After a Bevacizumab/Chemotherapy First Line
- Female patients ≥18 years of age.
- Patients with histologically confirmed epithelial ovarian or fallopian tube carcinoma
or primary peritoneal carcinoma, including mixed Mullerian Tumours
- Recurrence or progression at least 6 months after the last chemotherapy cycle of a
first line carboplatin + paclitaxel chemotherapy including bevacizumab (recurrence or
progression might occur either during or after bevacizumab as maintenance)
- Patients can be included if they have a RECIST progression, with either measurable or
- ECOG (Eastern Cooperative Oncology Group Performance) Status of 0-2.
- Life expectancy of at least 12 weeks.
- Signed informed consent obtained prior to initiation of any study-specific procedures
and treatment as confirmation of the patient's awareness and willingness to comply
with the study requirements including blood samples for molecular analyses.
- Availability of tumour samples for molecular analyses from primary surgery
(mandatory) and secondary surgery (when available)
- Ovarian tumours with low malignant potential (i.e. borderline tumours)
- History or evidence of synchronous primary endometrial carcinoma, unless all of the
following criteria related to the endometrial carcinoma are met:
- stage ≤Ia
- no more than superficial myometrial invasion
- no lymphovascular invasion
- not poorly differentiated (grade 3 or papillary serous or clear cell carcinoma).
- 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.
Prior current or planned treatment:
- More than one previous chemotherapy line
- Previous therapy with other anti-angiogenetic agents different from bevacizumab.
- Any prior radiotherapy to the pelvis or abdomen.
- Surgery (including open biopsy) within 4 weeks prior to the first bevacizumab
dose.Current or recent (within 10 days prior to the first study drug dose) use of
full-dose oral or parenteral anticoagulants or thrombolytic agents 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.
- Current or recent (within 30 days of first study dosing) treatment with any other
- Inadequate bone marrow function: ANC (absolute neutrophil count): <1500/mm3, or
platelet count <100,000/mm3 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)
- INR (international normalized ratio) >1.5
- Inadequate liver function, defined as:
- serum (total) bilirubin >1.5 x ULN for the institution
- AST/SGOT or ALT/SGPT > 2.5 x ULN.
- Inadequate renal function, defined as:
- serum creatinine >2.0 mg/dl or >177 micromol/l
- urine dipstick for proteinuria >2+. Patients with ≥ 1+ proteinuria at baseline
dipstick analysis should undergo a 24-hour urine collection and must demonstrate
≤1g of protein in their 24-hour urine collection.
Prior or concomitant conditions or procedures:
- History or evidence of brain metastases or spinal cord compression.
- Pregnant or lactating females.
- History or evidence of thrombotic or haemorrhagic disorders; including
cerebrovascular accident (CVA) / stroke or transient ischemic attack (TIA) or
sub-arachnoid haemorrhage within ≤6 months prior to the first study treatment).
- Uncontrolled hypertension (sustained systolic >150 mm Hg and/or diastolic >100 mm Hg
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
- New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF)
- serious cardiac arrhythmia requiring medication (with the exception of atrial
fibrillation or paroxysmal supraventricular tachycardia)
- peripheral vascular disease ≥grade 3 (i.e. symptomatic and interfering with
activities of daily living requiring repair or revision).
- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess, or with signs of impending bowel obstruction within 6 months prior to the
first study treatment.
- Non-healing wound, ulcer or bone fracture. Patients with granulating incisions
healing by secondary intention with no evidence of facial dehiscence or infection are
eligible but require three weekly wound examinations.
- Evidence of any other medical conditions (such as psychiatric illness, peptic ulcer,
etc.), physical examination or laboratory findings that may interfere with the
planned treatment, affect patient compliance or place the patient at high risk from