| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with platinum-sensitive recurrent ovarian cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with recurrent ovarian cancer which has returned more than six months after treatment with a platinum containing chemotherapy |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016180 |
| E.1.2 | Term | Fallopian tube cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033128 |
| E.1.2 | Term | Ovarian cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary efficacy outcome measure for this clinical trial is investigator-determined progression-free survival |
|
| E.2.2 | Secondary objectives of the trial |
(1) Overall survival
(2) Biological Progression-free Survival (PFSbio) by serum CA125 assessed according to GCIG criteria
(3) Quality of Life (QoL) assessed by EORTC QLQ-C30 and QLQ-OV28
(4) Safety and tolerability |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
(1) Written informed consent
(2) Females >= 18 years
(3) Histologically confirmed diagnosis of:
- epithelial ovarian carcinoma (including mixed Mullerian tumours) or
- fallopian tube carcinoma or
- primary peritoneal carcinoma
All FIGO stages, histological 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.
(5) Patient with measurable or non-measurable disease (according to RECIST v1.1) or CA125 assessable disease (according to GCIG criteria) or histological proven diagnosis or relapse
(6) In case of cytoreductive surgery for recurrent, patients must be able to commence cytotoxic chemotherapy within 8 weeks after cytoreductive surgery. The first dose of bevacizumab can be omitted in both arms if the investigator decides to start chemotherapy within 4 weeks after 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 randomisation):
- ANC >= 1.5 x 109
- Platelets >= 100 x 109
- Haemoglobin >= 9.5 g/dL
(10) Adequate coagulation parameters (within 28 days prior to randomisation:
- Patients not receiving anticoagulant medication who have an INR <=1.5 and an aPTT <= 1.5 x ULN
(11) Adequate liver function (within 28 days prior to randomisation):
- 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 randomisation):
- serum creatinine < 1.6 mg/dL or creatiine clearance >= 40 mL/min
- Glomerular filtration rate > 40 ml/min based on the Cockcroft-Gault or Jelliffe formula are sufficient)
- Urine dipstick for proteinuria < 2+
(13) Normal blood pressure or adequately treatment and controlled hypertension (systolic BP <= 140mmHg and/or diastolic BP <= 90mmHg)
Please see protocol for full details on inclusion criteria. |
|
| E.4 | Principal exclusion criteria |
(1) Non-epithelial origin of the ovary, the fallopian tube or the peritoneum (i.e. germ cell tumors).
(2) Ovarian tumors of low malignant potential (i.e. borderline tumors)
(3) Malignancies other than ovarian cancer within 5 years prior to randomisation, 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 <= 1A)
Patients may have received previous adjuvant chemotherapy for other malignancies e.g. breast or colorectal carcinoma if diagnosed over 5 years ago before randomisation 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 treatment period (hormone 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 randomisation
(7) Known hypersensitivity to used chemotherapeutic agents in this trial and bevacizumab and its excipients, chinese hamster ovary cell products or other recombinant hum or humanised antibodies
(8) Current or recent (within 10 days prior to randomisation) chronic use of aspirin >325 mg/day
(9) Surgery (including open biopsy) within 4 weeks prior to anticipated first dose of bevacizumab (allowed for the fact that bevacizumab can be omitted for 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 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 surgical procedure
(14) Previous Cerebro-Vascular Accident (CVA), Transient Ischaemic Attack (TIA) or Sub-Arachnoid Haemorrhage (SAH) within 6 months prior to randomisation
(15) Prior history of hypertensive crisis or hypertensive encephalopathy. Uncontrolled hypertension (sustained elevation of systolic blood pressure > 140 mmHg and/or diastolic >90 mmHg despite antihypertensive therapy).
(16) Clinically significant (i.e. active) cardiovascular disease, including:
- myocardial infarction or unstable anginal within <= 6 months of randomisation
- 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 (i.e. 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 randomisation
(19) Current brain metastases or spinal cord compression. CT/MRI of the brain is mandatory (within 4 weeks prior to randomisation) in case of suspected brain metastases. Spinal MRI is mandatory (within 4 weeks prior to randomisation) in case of suspected spinal cord compression
(20) History or evidence upon neurological examination of central nervous system (CNS) disease, unless adequately treated with standard medical therapy, e.g. uncontrolled seizures
(21) 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.
(22) History or evidence of thrombotic or haemorrhagic disorders within 6 months prior to randomisation
(23) Evidence of bleeding diathesis or significant coagulatopathy (in the absence of therapeutic coagulation)
(24) 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
(25) Pregnant or lactating women
(26) 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.
(27) Requirements of therapeutic coagulation using marcumar, warfarin or PTT-prolonging heparin. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome measure is Progression-free survival (PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Tumor assessments will include gynecological examination and cross sectional imaging (by CT, or MRI in case of contrast allergy) of the pelvis and abdomen and (by X-ray or CT scan,) of the chest every 12 weeks. Evaluation will be based on RECIST v. |
|
| E.5.2 | Secondary end point(s) |
(1)Overall Survival (OS)
(2)Biological Progression-free survival (PFSBIO) by serum CA125 assessed according to the GCIG criteria
(3)Quality of Life (QoL) assessed by EORTC QLQ-C30 and QLQ-OV28
(4)Safety and Tolerability |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Overall survival (OS) is defined as the time from the date of randomization to the date of death.
CA 125 will be measured at baseline, day 1 of each cycle (i.e. every 3 or 4 weeks depending on treatment arm) during study treatment, and every 3 months until a minimum of 30 months or disease progression or occurrence of unacceptable toxicity.
Toxicity: The National Cancer Institute’s Cancer Toxicity Criteria for Adverse Events (NCI-CTCAE) version 4.03 will be used to evaluate the clinical safety of the treatment.
Quality of Life (EORTC QLQ-C30 and QLQ-OV28 questionnaires will be assessed every 12 weeks starting on day 1 of cycle 1 until
disease progression or the occurrence of an unacceptable toxicity (whichever occurs first) and at the safety follow up visit. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 177 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| France |
| Germany |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The definition of the end of the trial will be last vist of the last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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