| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Platinum Sensitive Relapsed Ovarian Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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) |
|
| 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 of Olaparib vs. physician’s choice single agent chemotherapy by assessment of Objective Response Rate (ORR) using blinded independent central review. |
|
| E.2.2 | Secondary objectives of the trial |
To compare the efficacy of olaparib vs physician’s choice chemotherapy by
PFS by BICR using RECIST 1.1 criteria;
Time from randomisation to PFS2 by investigator assessment of radiological, clinical or CA-125 progression;
Overall survival (OS);
Time to earliest progression by RECIST 1.1 or CA-125 or death;
Time to first subsequent therapy or death (TFST);
Time to 2nd subsequent therapy or death (TSST);
Time to study treatment discontinuation or death (TDT);
Duration of response (DoR) by BICR using RECIST 1.1 criteria for
evaluable patients;
Time to response (TTR) by BICR using RECIST 1.1 criteria for evaluable patients.
2.Compare the efficacy of olaparib vs physician's choice chemotherapy on the HrQoL measured by TOI of the FACT-O.
3.To assess efficacy of olaparib in patients who have a deleterious or suspected deleterious variant in either of the BRCA genes by: ORR (by
BICR), PFS (by BICR), PFS2, OS, TDT, TFST and TSST.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Patients must be ≥ 18 years of age during randomisation
- Female patients with histologically diagnosed relapsed high grade serous ovarian cancer (including primary peritoneal and/or fallopian tube cancer) or high grade endometrioid cancer
- Documented germline mutation in BRCA1 and/or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function)
- At least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline by CT/MRI and is suitable for repeated assessment.
- Patients must have received at least 2 prior platinum based previous lines of chemotherapy for ovarian cancer prior randomisation
- Patients must be partially platinum sensitive (defined as progression 6 -12 months after the end of the last platinum based chemotherapy) or platinum sensitive (defined as progression > 12 months after the end of the last platinum based chemotherapy).
- Patients must be suitable to start treatment with single agent chemotherapy based on physician’s choice of weekly paclitaxel or topotecan or pegylated liposomal doxorubicin or gemcitabine.
- Patients must have normal organ and bone marrow function measured within 28 days of randomisation,
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- Patients must have a life expectancy ≥ 16 weeks
- Postmenopausal or evidence of non-childbearing status for women of childbearing potential
- Formalin fixed, paraffin embedded tumour sample from the primary or recurrent cancer must be available for central testing. |
|
| E.4 | Principal exclusion criteria |
BRCA 1 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.)
- Previous randomisation in the present study
- Exposure to any investigational product within 30 days or 5 half lives (whichever is longer) prior to randomisation
- Any previous treatment with a PARP inhibitor, including olaparib.
- Patients who have platinum resistant or refractory disease
- 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 (DCIS), Stage 1, grade 1 endometrial carcinoma, or other solid tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for ≥5 years. Patients with history of primary 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 randomisation
- Clinical significant abnormality on resting ECG
- Patients receiving any systemic chemotherapy within 3 weeks prior to first randomisation (or a longer period depending on the defined characteristics of the agents used) or radiotherapy within 2 weeks prior to randomisation.
- Previous single agent exposure to the selected chemotherapy regimen for randomisation
- Concomitant use of known potent CYP3A4/5 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir.
- Persistent toxicities (> Common Terminology Criteria for Adverse Event grade 2) caused by previous cancer therapy, excluding alopecia and CTCAE grade 2 peripheral neuropathy.
- Patients with myelodysplastic syndrome/treatment related acute myeloid leukaemia (t-AML)
- Patients with symptomatic uncontrolled brain metastases.
- Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
- Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection.
- Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
- Breastfeeding women.
- Patients with a known hypersensitivity to olaparib or any of the excipients of the product.
- Patients with known active hepatitis B or C or HIV.
- Previous allogeneic bone marrow transplant or double umbilical cord blood transplantation
- Whole blood transfusions in the last 120 days prior to randomisation |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression Objective Response Rate (ORR) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Primary endpoint will be assessed at the time of the primary analysis: 6 months after LSI or January 2019, whichever is sooner. |
|
| E.5.2 | Secondary end point(s) |
1) Time from randomisation to first progression (PFS)
2) Time from randomisation to second progression (PFS2)
3) Overall Survival
3) Time to earliest progression by RECIST or CA-125 or death
4) Duration of response (DoR)
5) Time to Response (TTR)
6) GCIG CA-125 response
7)Time from randomisation to first subsequent therapy or death (TFST)
8)Time from randomisation to second subsequent therapy or death (TSST)
9)Time from randomisation to study treatment discontinuation or death (TDT)
10) Patient Reported Outcome (HQoL): FACT-O, TOI
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints will be assessed at the time of the primary analysis: 6 months after LSI or January 2019, whichever is sooner.
An additional PFS2 and OS analysis will only be conducted with further follow up (~60% OS events) if both ORR and PFS are statistically significant based on the primary analysis and the null hypotheses for PFS2 and/or OS are not rejected at the time of the primary analysis.
|
|
| 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 | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| single agent standard chemotherapy |
|
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Canada |
| China |
| Israel |
| Japan |
| Russian Federation |
| United States |
| Vietnam |
| Belgium |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Sweden |
| United Kingdom |
| Czechia |
|
| 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
|
| the date of the last visit of the last patient undergoing the study |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 2 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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