| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| 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. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Evaluation of best chemotherapy with bevacizumab for patients with platinum-sensitive recurrent ovarian cancer. |
|
| 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 | 18.0 |
| 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 | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066697 |
| E.1.2 | Term | Ovarian cancer recurrent |
| 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 is investigator-determined progression-free survival (PFS) |
|
| E.2.2 | Secondary objectives of the trial |
•Overall Survival (OS)
• Biological Progression-free Survial (PFSBIO) by serum CA 125 assessed according to the GCIG criteria
• Quality of Life (QoL) assessed by EORTC QLQ-C30 and QLQ-OV28
• Safety and Tolerability
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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) .
|
|
| E.4 | Principal 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 metastases. Spinal MRI is mandatory (within 4 weeks prior to randomization) in case of suspected spinal cord compression.
20. History or evidence upon neurological examination of central nervous system (CNS) dis-ease, unless adequately treated with standard medical therapy (e.g. uncontrolled sei-zures).
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 hemorrhagic disorders within 6 months prior to randomization.
23. Evidence of bleeding diasthesis or significant coagulopathy (in the absence of 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 duration of the clinical 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. Requirement of therapeutic anticoagulation using marcumar, warfarin or PTT-prolonging heparin.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| progression-free survival (PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At least 564 PFS events have been observed. |
|
| E.5.2 | Secondary end point(s) |
• Overall Survival (OS)
• Biological Progression-free Survial (PFSBIO) by serum CA 125 assessed according to the GCIG criteria
• Quality of Life (QoL) assessed by EORTC QLQ-C30 and QLQ-OV28
• Safety and Tolerability
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Overall Survival (OS): appr. 33.3 months |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | Yes |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 190 |
| 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 |
| Belgium |
| Canada |
| 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
|
| disease progression or occurrence of unacceptable toxicities |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
