| 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 epithelial ovarian, fallopian tube, or peritoneal cancer treated with standard first-line treatment |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with advanced epithelial ovarian, fallopian tube, or peritoneal cancer treated with standard first-line treatment |
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| 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 | 20.1 |
| 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) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| 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) |
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| 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 platinum-taxane based chemotherapy plus bevacizumab, and planned to receive bevacizumab in the maintenance phase. |
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| 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.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1. To explore pre planned subgroups analyses of efficacy (including PFS1 and OS) based on relevant potential prognostic factors, including, but not limited to stratification factors, clinical characteristics and tumour HR deficiency Status (BRCAm, mutations in other HR genes and Myriad HRD scar status).
2. To explore the time to next severe toxicity (grade 4 neutropenia lasting > 7 days, grade ≥ 3 febrile neutropenia, grade 4 thrombocytopenia with bleeding or platelet transfusion, grade ≥ 3 non-hematological toxicity) in both arms
3. To explore the correlation between geriatric assessment and efficacy and tolerance of olaparib versus placebo for patients > 70 years old.
4. To explore the efficacy of olaparib by assessment of overall survival (OS) adjusting for the impact of spontaneous switching (outside of study design) to Polyadenosine 5’diphosphoribose [poly (ADP ribose)] polymerization (PARP) inhibitors or other potentially active investigational agents.
5. Biological biomarkers analysis: to determine the frequency of somatic BRCA mutation (sBRCAm) in tumor samples and to compare this with germline BRCA mutation (gBRCAm) status. To determine a HR deficiency signature correlated with olaparib efficacy combined with bevacizumab.
6. To explore whether resistance mechanisms to olaparib can be identified through analysis of tumor and blood samples – archival tumor and blood sample at baseline (mandatory), tumor biopsy and blood sample on progression (optional).
7. Future exploratory research into factors that may influence response to study treatment (where response is defined broadly to include efficacy, tolerability or safety) and may be performed on the collected and stored archival tumor samples that were mandatory for entry onto the study or on optional tumor biopsy samples collected during the course of the study.
8. To collect and store DNA (according to each country’s local and ethical procedures) for future exploratory research into genes/genetic variation that may influence response (i.e., distribution, safety, tolerability and efficacy) to study treatments and or susceptibility to disease (optional).
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| E.3 | Principal inclusion criteria |
I-1. Female Patients 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 (see appendix 1).
I-4. Patients who have 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.), patients 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. Patients must have received prior to randomization a minimum of 3 cycles of bevacizumab in combination with the 3 last cycles of platinum-based chemotherapy. Only in case of interval debulking surgery, it is allowed to realize only 2 cycles of bevacizumab in combination with the last 3 cycles of platinium-based chemotherapy. Bevacizumab treatment should be planned for maintenance phase.
I-6. Patients must be prior to randomization without evidence of disease (NED) or in complete response (CR) or partial response (PR) from their first line treatment. There should be no clinical evidence of disease progression (physical exam, imagery, CA 125) throughout their first line treatment and prior to study randomization.
I-7. Patients must be randomized at least 3 weeks and no more than 9 weeks after their 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 peripherical neuropathy).
I-8. Patients must have normal organ and bone marrow function:
a. Haemoglobin ≥ 10.0 g/dL, with no red blood cells transfusion in the past 28 days
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,
g. Patients not receiving anticoagulant medication who have 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). If the patient is on oral anticoagulants, dose has to be stable for at least two weeks at the time 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 (see appendix 3)
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.
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| E.4 | Principal exclusion criteria |
-Non-epithelial origin of the ovary, the fallopian tube or the peritoneum (i.e. germ cell tumors).
-Ovarian tumors of low malignant potential (e.g. borderline tumors), or mucinous carcinoma.
-Patients with synchronous primary endometrial cancer unless both of the following criteria are met:
-stage < II,
-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 endometrial carcinoma
OR ≥ 60 years old at the time of diagnosis of endometrial cancer with stage IA grade 1 or 2 endometrioid adenocarcinoma.
-Patients with serous or clear cell adenocarcinoma or carcinosarcoma of the endometrium are not eligible.
-Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer curatively treated in situ cancer of the cervix, ductal carcinoma in situ .
Patients with history of primary triple negative breast cancer may be eligible provided they completed their definitive anticancer treatment more than 3 years ago and they remain breast cancer disease free prior to start of study treatment.
-Patients with myelodysplastic syndrome/acute myeloid leukemia history.
-Patients having experienced a delay > 2 weeks in the chemotherapy course administration due to prolonged hematological recovery.
-Patients receiving radiotherapy within 6 weeks prior to study treatment.
-Major surgery within 4 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
-Previous allogenic bone marrow transplant.
-Any previous treatment with PARP inhibitor, including olaparib.
-Administration of other simultaneous chemotherapy drugs, any other anticancer therapy or anti-neoplastic hormonal therapy, or simultaneous radiotherapy during the trial treatment period
-Current or recent (within 10 days prior to randomization) chronic use of aspirin > 325 mg/day.
-Concomitant use of known potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir.
-Prior history of hypertensive crisis (CTC-AE grade 4) or hypertensive encephalopathy.
-Clinically significant cardiovascular disease, including:
-Myocardial infarction or unstable angina within ≤ 6 months of randomization,
-NYH ≥ grade 2 congestive heart failure (CHF),
-Poorly controlled cardiac arrhythmia despite medication (patients with rate controlled atrial fibrillation are eligible), or any clinically significant abnormal finding on resting ECG,
-Peripheral vascular disease grade ≥ 3 (e.g. symptomatic and interfering with activities of daily living [ADL] requiring repair or revision).
-Previous Cerebro-Vascular Accident, Transient Ischemic Attack or Sub- Arachnoids Hemorrhage within 6 months prior to randomization.
-History or evidence of hemorrhagic disorders within 6 months prior to randomization.
-Evidence of bleeding diathesis or significant coagulopathy
-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 disease, unless adequately treated with standard medical therapy .
-Significant traumatic injury during 4 weeks prior to randomization.
-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 of VEGF therapy related abdominal fistula or gastrointestinal perforation or active gastrointestinal bleeding within 6 months prior to the first study treatment.
-Current, clinically relevant bowel obstruction, including sub-occlusive disease, related to underlying disease.
-Patients with evidence of abdominal free air not explained by paracentesis or recent surgical procedure.
-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.
-Pregnant or lactating women.
--Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
-Patients with a known hypersensitivity to olaparib or any of the recipients of the product.
-Immunocompromised patients, e.g., with known active hepatitis due to risk of transmitting the infection through blood or other body fluids or patients who are known to be serologically positive for human immunodeficiency virus
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| E.5 End points |
| E.5.1 | Primary end point(s) |
PFS1 is defined as the time from randomization until the date of the first objective radiological disease progression according to investigator assessment of RECIST version 1.1 or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomized study treatment or receives another anti-cancer therapy prior to progression. Patients who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment from their last evaluable RECIST assessment. However, if the patient progresses or dies after two or more missed visits, the patient will be censored at the time of the latest evaluable RECIST assessment. If the patient has no evaluable visits or does not have a baseline assessment they will be censored at day 1 unless they die within two visits of baseline.
The PFS time will always be derived based on imagery assessment dates not visit dates. RECIST assessments contributing towards a particular visit may be performed on different dates. The following rules will be applied:
• Date of progression will be determined based on the earliest date of the RECIST assessment fulfilling criteria of disease progression.
• When censoring a patient for PFS the patient will be censored at the latest of the RECIST assessment dates contributing to a particular overall visit assessment.
The primary analysis will be based on investigator-recorded assessments. An independent central review (ICR) of the radiological scans may be carried out. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| PFS1 is defined as the time from randomization until the date of the first objective radiological disease progression according to investigator assessment of RECIST version 1.1 or death |
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| E.5.2 | Secondary end point(s) |
Overall Survival (OS)
Overall survival is defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive.
Time to earliest progression by RECIST or CA-125
Time to earliest progression by RECIST v. 1.1 or CA-125 or death is defined as the time from randomization to the earliest date of RECIST or CA-125 progression or death by any cause. Progression according to CA-125 will be assessed according to GCIG (see appendix 8).
Patients without a CA-125 progression or a RECIST progression who are still alive at the time of analysis will be censored at their last evaluable RECIST assessment or their last available CA-125 measurement, whichever is the most recent at the time of the analysis. If a patient progresses or dies after two or more missed RECIST and
CA-125 assessments, then the patient will be censored at the time of their last evaluable assessment. If only one assessment is missing during this period, no censoring is required.
Second Progression Free Survival (PFS2)
Time from randomization to second progression is defined as the time from the date of randomization to the earliest of the progression event subsequent to that used for the primary variable PFS, or date of death. The date of second progression will be recorded by the investigator and defined according to local standard clinical practice and may involve any of; objective radiological, CA-125 or symptomatic progression or death. Second progression status will be reviewed regularly following the progression event used for the primary variable PFS (PFS1) and recorded. Patients alive and for whom a second disease progression has not been observed should be censored at the last time known to be alive and without a second disease progression, i.e. censored at the latest of the tumor assessment date if the patient has not had a second progression or death).
Time to start of first subsequent therapy or death (TFST) will be assessed. TFST is defined as the time from the date of randomization to the earliest of the date of anti-cancer therapy start date following study treatment discontinuation, or death. Subsequent therapies intended to control ovarian cancer will be reported. Any patient not known to have died at the time of the analysis and not known to have had a further intervention of this type will be censored at the last known time to have not received subsequent therapy, i.e. the last follow-up visit where this was confirmed.
Safety and Tolerability
Safety and tolerability will be assessed in terms of AEs, deaths, laboratory data, vital signs and ECG. AE will be described according to MedDRA terms (version 17.0) and graded according to CTCAE version 4.03. These will be collected for all patients. Appropriate summaries of these data will be presented
Patient reported outcome variables
Patient-reported health-related quality of life (HRQoL) will be assessed using the FACT-O questionnaire 24(Basen-Engquist K et al 2001). The FACT-O is composed of the following subscales: physical, social/family, emotional, and functional well-being as well as the additional concerns scales consisting of specific ovarian cancer symptoms.
The total FACT-O score will be calculated which is made up of the sum of the individual subscale scores: physical well being (PWB), social well being (SWB), emotional well being (EWB) and functional well being (FWB).
Geriatric assessment
Geriatric assessment will be assessed using the Geriatric Vulnerability Score (GVS). Further details of the analysis based on the geriatric assessment will be outlined in the SAP.
Pharmacoeconomy
frequency and estimates of resource use, including length of stay and number of hospital admissions, will be derived from the resource use information.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
Quality of life
Geriatric assessment
Biomarkers
genomic and genetic |
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| 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 | 43 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 154 |
| 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 |
| Italy |
| Japan |
| Monaco |
| Spain |
| Sweden |
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| 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
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The end of the study is defined as ‘the last visit of the last patient undergoing the study’.
The study is expected to start in Quarter 1 2015 and to end by Quarter 2 2022. The study may be terminated at individual centers if the study procedures are not being performed according to GCP, or if recruitment is slow. ARCAGYResearch may also terminate the entire study prematurely if concerns for safety arise within this study or in any other study with olaparib. |
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| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
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