E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
BRCA Mutated Advanced (FIGO Stage III-IV) Ovarian Cancer |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 18.0 |
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) |
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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 (PFS) using blinded independent central review (BICR) according to modified Response Evaluation Criteria in Solid Tumours (RECIST 1.1) of olaparib maintenance monotherapy compared to placebo in BRCA mutated high risk advanced ovarian cancer patients who are in clinical complete response or partial response following first line platinum based chemotherapy. |
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E.2.2 | Secondary objectives of the trial |
All apply to BRCA mutated high risk advanced ovarian cancer patients who are in clinical complete or partial response following first line platinum based chemotherapy
1) To determine the efficacy of olaparib maintenance monotherapy compared to placebo patients by assessment of
a) overall survival (OS).
b) time to earliest progression by RECIST or Cancer Antigen-125 (CA-125) or death.
c) time from randomisation up to study completion at the latest.
2) Compare the effects of olaparib maintenance monotherapy compared to placebo on the rate of deterioration of HRQoL as assessed by the TOI of the FACT-O.
3) Assess efficacy of olaparib in patients identified as having a deleterious or uspected deleterious variant in either of the BRCA genes using variants identified with current and potential future BRCA mutation assays (gene sequencing and large rearrangement analysis).
4) To assess the safety and tolerability of olaparib maintenance monotherapy. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Female patients with newly diagnosed, histologically confirmed, high risk advanced (FIGO stage III – IV) BRCA mutated high grade serous or high grade endometriod ovarian cancer, primary peritoneal cancer and / or fallopian-tube cancer who have completed first line platinum based chemotherapy (intravenous or intraperitoneal).
• Stage III patients must have had one attempt at optimal debulking surgery (upfront or interval debulking). Stage IV patients must have had either a biopsy and/or upfront or interval debulking surgery.
• Documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function).
• Patients who have completed first line platinum (carboplatin or cisplatin), containing therapy (intravenous or intraperitoneal) prior to randomisation:
• Patients must have, in the opinion of the investigator, clinical complete response or partial response and have no clinical evidence of disease progression on the post treatment scan or rising CA-125 level, following
completion of this chemotherapy course. Patients with stable disease on the post-treatment scan at completion of first line platinum-containing therapy are not eligible for the study. |
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E.4 | Principal exclusion criteria |
•BRCA1 and/or BRCA2 mutations that are considered to be non detrimental (e.g. “Variants of uncertain clinical significance” or “Variant of unknown significance” or “Variant, favor polymorphism” or “benign polymorphism” etc).
• Patients with early stage disease (FIGO Stage I, IIA, IIB or IIC)
•Stable disease or progressive disease on the post-treatment scan or clinical evidence of progression at the end of the patient's first line chemotherapy treatment.
• Patients where more than one debulking surgery has been peformed before randomisation to the study. (Patients who, at the time of diagnosis, are deemed to be unresectable and undergo only a biopsy or oorphorectomy but then go on to receive chemotherapy and interval debulking surgery are eligible).
• Patients who have previously been diagnosed and treated for earlier stage ovarian, fallopian tube or primary peritoneal cancer.
• Patients who have previously received chemotherapy for any abdominal or pelvic tumour, including treatment for prior diagnosis at an earlier stage for their ovarian, fallopian tube or primary peritoneal cancer. (Patients who have received prior adjuvant chemotherapy for localised breast cancer may be eligible, provided that it was completed more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease).
• Patients with synchronous primary endometrial cancer, or a past history of primary endometrial cancer, unless all of the following conditions are met: Stage not greater than I-A; no more than superficial myometrial invasion, without vascular or lymphatic invasion; no poorly differentiated subtypes, including papillary serous, clear cell or other FIGO Grade 3 lesions. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression Free Survival (PFS) by central review of RECIST data |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Radiologic scans performed at baseline then every ~12 weeks for ~2 years, then every ~24 weeks thereafter until objective radiological disease progression. Study data collection expected to last for ~7 years. |
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E.5.2 | Secondary end point(s) |
1) Efficacy in patients following First Line Platinum Based Chemotherapy by assessment of
a)overall survival.
b)time to earliest progression by RECIST or Cancer Antigen-125 (CA-125).
c)time from randomisation to second progression.
2) Time to deterioration of Health-Related Quality of Life (HRQoL) as assessed by OI and FACT-O.
3) Efficacy in patients with a deleterious or suspected deleterious variant in either of the BRCA genes by assessment of
4) Safety and tolerability of olaparib.
progression free survival |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1a)Survival 4 weekly until discontinuation or 2 years whichever is earlier, then every 12 weeks.
1b)CA125 4 weekly for ~2 years, then every 12 weeks. Radiologic scans every ~12 weeks for ~2 years, then every ~24 weeks until progression.
1c)Radiologic scans at baseline then every ~12 weeks for ~2 years, then every ~24 weeks until first progression. Then as local clinical practice until 2nd progression.
2)Paper questionnaires at baseline, Day 29 and then in line with RECIST, until progression.
3)Radiologic scans at baseline then every ~12 weeksfor ~2 years, then every ~24 weeks, until progression.
4)AEs collected from IC until post treatment 30-day follow-up period. Lab parameters collected until treatment discontinued.
Study data collection expected to last for ~7 years for all |
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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 | No |
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 | Yes |
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 | 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) | 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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 38 |
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 |
Brazil |
Canada |
China |
France |
Germany |
Italy |
Japan |
Korea, Republic of |
Netherlands |
Poland |
Russian Federation |
Spain |
Sweden |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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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LVLS (last visit last subject) undergoing the study |
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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 | 9 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 9 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |