| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with advanced FIGO stage IIIB – IV high grade serous or endometrioid ovarian, fallopian tube, or peritoneal cancer treated with standard first-line treatment, combining platinum-taxane chemotherapy and bevacizumab concurrent with chemotherapy and in maintenance |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with advanced ovarian, fallopian tube, or peritoneal cancer after standard first-line treatment |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10070908 |
| E.1.2 | Term | Ovarian cancer stage IV |
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10070907 |
| E.1.2 | Term | Ovarian cancer stage III |
| 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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016187 |
| E.1.2 | Term | Fallopian tube cancer stage IV |
| 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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016186 |
| E.1.2 | Term | Fallopian tube cancer stage III |
| 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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016182 |
| E.1.2 | Term | Fallopian tube cancer metastatic |
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10057529 |
| E.1.2 | Term | Ovarian cancer metastatic |
| 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 | 20.0 |
| 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 | 20.0 |
| 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 |
| To determine the efficacy by progression free survival (PFS1) investigator based according to modified Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) of olaparib maintenance compared to placebo in high grade epithelial ovarian, fallopian tube, or peritoneal cancer that are in clinical complete response or partial response following first line platinumtaxane based chemotherapy plus bevacizumab, and planned to pursue bevacizumab in the maintenance phase up to a total of 15 months. |
|
| E.2.2 | Secondary objectives of the trial |
1. To determine :
· time to earliest progression by RECIST or Cancer Antigen-125 (CA-125) or death
· time from randomization to first subsequent therapy or death (TFST)
· time from randomization to second progression (PFS2)
· time from randomization to second subsequent therapy or death (TSST)
· overall survival (OS)
2. To assess the safety and tolerability of olaparib maintenance compared to placebo.
3. To compare the effects of olaparib maintenance compared to placebo on
Health-Related Quality of Life (HRQoL) and patient reported outcomes (PROs), with consideration of patient preference.
4. To evaluate the impact of treatment and disease on resource use. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
I-1. Female Patient must be ≥18 years of age.
I-2. Signed informed consent and ability to comply with treatment and follow-up.
I-3. Patient with newly diagnosed
I-3-1 Ovarian cancer, primary peritoneal cancer and/or fallopian-tube cancer,
I-3-2 Histologically confirmed (based on local histopathological findings):
· high grade serous (see appendix 2) or
· high grade endometrioid (see appendix 2) or
· other epithelial non mucinous ovarian cancer in a patient with germline BRCA 1 or 2 deleterious mutation
I-3-3 at an advanced stage: FIGO stage IIIB, IIIC, or IV of the 1988 FIGO classification
I-4. Patient who has completed prior to randomization first line platinum-taxane
chemotherapy:
a. Platinum-taxane based regimen must have consisted of a minimum of 6 treatment cycles and a maximum of 9. However if platinum based therapy must be discontinued early as a result of non hematological toxicity specifically related to the platinum regimen, (i.e. neurotoxicity, hypersensitivity etc.), patient must have received a minimum of 4 cycles of the platinum regimen.
b. Intravenous, intraperitoneal, or neoadjuvant platinum based chemotherapy is allowed; for weekly therapy, three weeks are considered one cycle. Interval debulking is allowed.
I-5. Patient must have received prior to randomization a minimum of 3 cycles of
bevacizumab in combination with the 3 last cycles of platinum-based chemotherapy. Bevacizumab treatment should be administered at a dose 15mg/kg q3 weeks up to a total of 15 months.
I-6. Patient must be prior to randomization without evidence of disease (NED) or in complete response (CR) or partial response (PR) from her first line treatment. There should be no clinical evidence of disease progression (physical exam, imagery, CA 125) throughout her first line treatment and prior to study randomization.
I-7. Patient must be randomized at least 3 weeks and no more than 9 weeks after her last dose of chemotherapy (last dose is the day of the last infusion) and all major toxicities from the previous chemotherapy must have resolved to CTC AE grade 1 or better (except alopecia and peripheral neuropathy).
I-8. Patient must have normal organ and bone marrow function:
a. Hemoglobin ≥ 10.0 g/dL.
b. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
c. Platelet count ≥ 100 x 109/L.
d. Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).
e. Aspartate aminotransferase /Serum Glutamic Oxaloacetic Transaminase
(ASAT/SGOT)) and Alanine aminotransferase /Serum Glutamic Pyruvate Transaminase (ALAT/SGPT)) ≤ 2.5 x ULN, unless liver metastases are present in
which case they must be ≤ 5 x ULN.
f. Serum creatinine ≤ 1.25 x institutional ULN and creatinine clearance > 50 mL/min.
g. Patient not receiving anticoagulant medication who has an International
Normalized 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 site medical standard) and if the patient is on a stable dose of anticoagulants for at least two weeks at thetime of randomization.
h. Urine dipstick for proteinuria < 2+. If urine dipstick is ≥2+, 24-hour urine must demonstrate <1 g of protein in 24 hours.
i. Normal blood pressure or adequately treated and controlled hypertension
(systolic BP ≤ 140 mmHg and/or diastolic BP ≤ 90 mmHg).
I-9. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
I-10. Formalin fixed, paraffin embedded (FFPE) tumor sample from the primary cancer must be available for central BRCA testing and test result must be available for stratification.
I-11. Postmenopausal or evidence of non-childbearing status for women of childbearing potential prior to the first dose of study treatment.
I-12. For France only: In France, a subject will be eligible for randomization in this study only if either affiliated to, or a beneficiary of, a social security category. |
|
| E.4 | Principal exclusion criteria |
E-1. Non-epithelial origin of the ovary, the fallopian tube or the peritoneum (i.e. germ cell tumors).
E-2. Ovarian tumors of low malignant potential (e.g. borderline tumors), or mucinous carcinoma.
E-3. Patient with synchronous primary endometrial cancer unless both of the following criteria are met:
a. stage < II,
b. Less than 60 years old at the time of diagnosis of endometrial cancer with stage IA or IB grade 1 or 2, or stage IA grade III endometrioid adenocarcinoma
OR ≥ 60 years old at the time of diagnosis of endometrial cancer with stage IA
grade 1 or 2 endometrioid adenocarcinoma.
Patient with serous or clear cell adenocarcinoma or carcinosarcoma of the endometrium is not eligible.
E-4. Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer curatively treated in situ cancer of the cervix, DCIS.
E-5. Patient with myelodysplastic syndrome/acute myeloid leukemia history.
E-6. Patient having experienced for at least one cycle, a delay > 2 weeks due to prolonged hematological recovery during the first line chemotherapy.
E-7. Patient receiving radiotherapy within 6 weeks prior to study treatment.
E-8. Major surgery within 4 weeks of starting study treatment and patient must have recovered from any effects of any major surgery.
E-9. Previous allergenic bone marrow transplant.
E-10. Any previous treatment with PARP inhibitor, including olaparib.
E-11. Administration of other simultaneous chemotherapy drugs, any other anticancer therapy or anti-neoplastic hormonal therapy, or simultaneous radiotherapy during the trial treatment period (hormonal replacement therapy is permitted as are steroidal antiemetics).
E-12. Current or recent (within 10 days prior to randomization) chronic use of aspirin > 325 mg/day.
E-13. Concomitant use of known potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir.
E-14. Prior history of hypertensive crisis (CTC-AE grade 4) or hypertensive encephalopathy.
E-15. Clinically significant (e.g. active) cardiovascular disease, including:
a. Myocardial infarction or unstable angina within ≤ 6 months of randomization,
b. NYHA ≥ grade 2 congestive heart failure.
c. Poorly controlled cardiac arrhythmia despite medication (patient with rate
controlled atrial fibrillation are eligible), or any clinically significant abnormal
finding on resting ECG,
d. Peripheral vascular disease grade ≥ 3 (e.g. symptomatic and interfering with
ADL requiring repair or revision).
E-16. Previous Cerebro-Vascular Accident, Transient Ischemic Attack or Sub-
Arachnoids Hemorrhage within 6 months prior to randomization.
E-17. History or evidence of hemorrhagic disorders within 6 months prior to randomization.
E-18. Evidence of bleeding diathesis or significant coagulopathy (in the absence of coagulation).
E-19. History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI of the brain is mandatory in case of suspected brain
metastases. Spinal MRI is mandatory in case of suspected spinal cord compression.
E-20. History or evidence upon neurological examination of central nervous system disease, unless adequately treated with standard medical therapy (e.g. uncontrolled seizures).
E-21. Significant traumatic injury during 4 weeks prior to randomization.
E-22. Non-healing wound, active ulcer or bone fracture. Patient with granulating incisions healing by secondary intention with no evidence of facial dehiscence or infection is eligible but require 3 weekly wound examinations.
E-23. History of VEGF therapy related abdominal fistula or gastrointestinal perforation or active gastrointestinal bleeding within 6 months prior to the first study treatment.
E-24. Current, clinically relevant bowel obstruction, including sub-occlusive disease, related to underlying disease.
E-25. Patient with evidence of abdominal free air not explained by paracentesis or recent surgical procedure.
E-26. Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment related complications.
E-27. Pregnant or lactating women.
E-28. Participation in another clinical study with an investigational product during her chemotherapy course immediately prior to randomization.
E-29. Patient unable to swallow orally administered medication and patient with
gastrointestinal disorders likely to interfere with absorption of the study medication.
E-30. Patient with a known hypersensitivity to olaparib or any of the recipients of the product.
E-31. Immunocompromised patient, e.g., with known active hepatitis (i.e. Hepatitis B or C) due to risk of transmitting the infection through blood or other body fluids or patient who is known to be serologically positive for HIV. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is progression-free survival (PFS1) defined as the time from the date of randomization to the first documented disease progression (according to RECIST v1.1) or death from any cause, whichever occurs first. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
An interim analysis of PFS1 will be performed when approximately 50% (187 events) of the final number of PFS1 events has been reached.
Final analysis will be performed when 372 PFS1 events have occurred |
|
| E.5.2 | Secondary end point(s) |
1 Time from randomization to second progression (PFS2) and overall survival
2 Time to earliest progression or death, TFST, TSST
3 Patient reported outcome (QoL)
4 Pharmaco-economic analysis
5 Safety; The assessment of safety will be based mainly on the frequency of adverse events (AE). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 An interim analysis of PFS2 and OS will be performed at the time of the final PFS1 analysis. A further analysis of PFS2 and OS will be performed when the PFS2 data are approximately 54% mature (approximately 329 events); A final update of overall survival results will be performed when the OS data are approximately 60% mature.
2-4 same as for primary endpoint
5 continously; The period of safety analysis will be defined from the first dose of any study treatment to 30 days after end of last study treatment. |
|
| 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 | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 200 |
| 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 |
| Austria |
| Belgium |
| Denmark |
| Finland |
| France |
| Germany |
| Japan |
| Spain |
| Sweden |
|
| 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
|
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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