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 | 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) |
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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) investigator assessment 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 pateints 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 endometrioid 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 (eg. 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, favour 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 performed before randomisation to the study. (Patients who, at the time of diagnosis, are deemed to be unresectable and undergo only a biopsy or oophorectomy 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 unless both of the following criteria are met: 1) stage <2 2) 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 3 endometrioid adenocarcinoma 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression Free Survival (PFS) by investigator 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 a maximum of 3 years, then every ~24 weeks thereafter until objective radiological disease progression. Study data collection expected to last for ~10 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 suspecteddeleterious variant in either of the BRCA genes by assessment of progression free survival.
4) Safety and tolerability of olaparib.
5) Efficacy of olaparib by time to first subsequent therapy or death (TFST).
6) Efficacy of olaparib by time to second subsequent therapy or death (TSST).
7) Efficacy of olaparib by time from randomisation to study treatment discontinuation or death (TDT). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1a)Survival 4 wkly until discontin or 3 yrs whichever is earlier, then 12 wkly 1b)CA125 4 wkly for ~2 yrs, then 12 wkly. Radiologic scans ~12 wkly for ~3 yrs, then every ~24 wks until prog 1c)Radiologic scans baseline, ~12 wkly for ~2 yrs, then every ~24 wks until 1st prog. Then as local clinical practice until 2nd prog 2)Questionnaires baseline, Day 29 and as per RECIST, until date of 1ary analysis 3)Radiologic scans baseline, ~12 wkly for ~3 yrs, then every ~24 wks, until prog 4)AEs collected from IC until post treatment 30-day follow-up period. Labs collected until treatment discontin.
Data collection expected to last for ~10 years for all. Randomisation to:5)1st therapy or death6)2nd therapy or death7)discont or death. Assessed at 1ary PFS and final OS, data collect for ~10 years |
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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 | No |
E.6.11 | Pharmacogenomic | Yes |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 |
Israel |
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 | 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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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 | 0 |
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 |