| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non Germline BRCA Mutated 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 by progression-free survival (PFS) (investigator-recorded assessments according to modified Response Evaluation Criteria In Solid Tumors [RECIST v1.1]) of olaparib maintenance monotherapy in non gBRCAm platinum sensitive relapsed (PSR) ovarian cancer |
|
| E.2.2 | Secondary objectives of the trial |
- Det. efficacy of olaparib maintenance monotherapy in non gBRCAm PSR ovarian cancer by assessment of time to first subsequent therapy or death (TFST)
- Det. efficacy of olaparib maintenance monotherapy in non gBRCAm PSR ovarian cancer by assessment of time to treatment discontinuation or death (TDT)
- Det. efficacy by PFS of olaparib maintenance in non gBRCAm PSR ovarian cancer according to tumour HRD status using the Myriad myChoice HRD test
- Det. efficacy of olaparib maintenance monotherapy in non gBRCAm PSR ovarian cancer by assessment of chemotherapy-free interval (CT-FI)
- Det. the OS of non-gBRCAm PSR ovarian cancer patients treated with olaparib maintenance monotherapy
- To investigate the HRQoL of non gBRCAm PSR ovarian cancer patients treated with olaparib maintenance monotherapy as assessed by the trial outcome index (TOI) of the FACT-O
- To assess the safety and tolerability of olaparib maintenance monotherapy in patients with non gBRCAm PSR ovarian cancer |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provision of informed consent prior to any study specific procedures
2. Patients must be ≥18 years of age
3. Female patients with histologically diagnosed relapsed HGSOC (including primary peritoneal and / or fallopian tube cancer) or high grade endometrioid ovarian cancer
4. Documented gBRCA1/2 mutation status Evidence that the patients do not have a gBRCA mutation that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental / lead to loss of function). gBRCA1 and/or gBRCA2 variants that are classified as
"Variants of uncertain clinical significance" or "Variant of unknown significance (VUS)" are eligible, as well as "Variant, favor polymorphism" or "benign polymorphism".
Evidence of the absence of a somatic BRCA mutation is not required.
Patients with a tumour BRCA test result only must undergo a gBRCA test to determine whether the BRCA aberration is germline or somatic in origin. If this analysis identifies the aberration as germline the patient is not eligible
5. Patients must have completed at least 2 previous courses of platinum containing therapy:
(a) For the penultimate chemotherapy course prior to enrolment on the study:
• Treatment must have contained a platinum agent (e.g. carboplatin, cisplatin or oxaliplatin per standard clinical practice; there are no other specific requirements)
• Patient was platinum sensitive after this treatment; defined as disease progression greater than 6 months after completion of their last dose of platinum chemotherapy
• Maintenance treatment is allowed at the end of the penultimate platinum regimen, including bevacizumab
(b) For the last chemotherapy course immediately prior to enrolment on the study
• Patients must be, in the opinion of the investigator, in response (partial or complete radiological response), or may have no evidence of disease (if optimal cytoreductive surgery was conducted prior to chemotherapy), and no evidence of a rising CA-125, as defined below, following completion of this chemotherapy course
• Patient must have received a platinum based chemotherapy regimen (carboplatin, cisplatin or oxaliplatin) and have received at least 4 cycles of treatment
• Patients must not have received bevacizumab during this course of treatment
• Patients must not have received any investigational agent during this course of treatment
• Patients must initiate treatment within 8 weeks of their last dose of chemotherapy (last dose is the day of the last infusion)
6. Pre-treatment CA-125 measurements must meet criterion specified below:
• If the first value is within upper limit of normal (ULN) the patient is eligible to be enrolled and a second sample is not required
• If the first value is greater than ULN a second assessment must be performed at least 7 days after the 1st. If the second assessment is ≥ 15% more than the first, the patient is not eligible
7. Patients must have normal organ and bone marrow function measured within 28 days of starting study treatment, as defined below. In the event of minor deviations from these values which would lead to screen failure, repeat testing within the 28-day screening period (limited to the tests listed below) is allowed before the patient is declared a screen failure.
8. ECOG performance status 0-1
9. Patients must have a life expectancy ≥16 weeks
10. Postmenopausal or evidence of non-childbearing status for women of childbearing potential :negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1
11. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
12. At least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline with computed tomography (CT) or magnetic resonance imaging (MRI) and is suitable for repeated assessment
OR
No evidence of disease following a complete response to chemotherapy (with or without cytoreductive surgery)
13. An appropriately prepared tumour sample from the cancer, of sufficient quantity and quality (as specified in the Central Laboratory Services Manual) must be available for future central testing of tumour genetic status. If a recent biopsied sample is provided, the biopsied tumour should not be assessed as target lesions as part of the RECIST assessments if there are other lesions available, and the biopsy should be taken after the baseline scan has been performed. Archival tissue samples may be from the primary tumour or metastatic tumour deposits. Archival bone metastases are not acceptable. Provision of blocks is usually preferred. Any exceptions to these conditions should be discussed with the Sponsor before enrollment of the patient. |
|
| E.4 | Principal exclusion criteria |
Patients should not enter the study if any of the following exclusion criteria are fulfilled.
Those asterisked* should be excluded before a request can be considered to perform a gBRCA test prior to full screening. Investigator judgement of patient's potential eligibility to the study should be
assessed as per Protocol Table 1 and by reviewing the below exclusion criteria).
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)*
2. Previous enrolment in the present study*
3. Participation in another clinical study with an investigational product (IP) during the most recent chemotherapy course*
4. Patients receiving any systemic hormonal therapy, chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to start of study treatment
5. Any previous treatment with PARP inhibitor, including olaparib*
6. Patients with a germline BRCA mutation that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental / lead to loss of function).
7. Other malignancy unless curatively treated with no evidence of disease 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*
8. Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks*.
9. Concomitant use of known strong (e.g., phenobarbital, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5
weeks for phenobarbital and 3 weeks for other agents*
10. Persistent toxicities (≥ Grade 2 Common Terminology Criteria for Adverse Event (CTCAE) adverse event) caused by previous cancer therapy, excluding alopecia
11. Patients with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML*
12. Patients with symptomatic uncontrolled brain metastases. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment. Patients with spinal cord compression unless considered to have
received definitive treatment for this and evidence of clinically stable disease (SD) for 28 days*
13. Major surgery within 3 weeks of starting study treatment and patients must have recovered from any effects of any major surgery
14. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection.
15. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication*
16. Currently pregnant (confirmed with a positive pregnancy test) or breastfeeding women*
17. Immuno-compromised patients e.g., Human Immunodeficiency Virus (HIV) requiring treatment or active Hepatitis B or C*
18. Patients with a known hypersensitivity to olaparib or any of the excipients of the product*
19. Patients with known active hepatitis (i.e., hepatitis B or C) due to risk of transmitting the infection through blood or other body fluids*
20. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)*
21. Patients having gBRCA testing should not have had whole blood transfusions in the last 30 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable)
22. Judgement by the Investigator that the patient should not participate in the study if the patient is unlikely or unable to comply with study procedures, restrictions and requirements. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS: Time from date of first dose until the date of objective radiological disease progression according to modified RECIST 1.1 or death (by any cause in the absence of progression) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At visit 4 and on the first day of each 8 week visit period, relative to the date of the first olaparib dose, for the first 12 months on treatment, and subsequently each 12-week visit period, until the earlier of progression, death or end of study for up to 36 months. |
|
| E.5.2 | Secondary end point(s) |
(1) - TFST: Time from date of first dose to date of first subsequent treatment commencement or death due to any cause if this occurs before commencement of first subsequent treatment
(2) - TDT: Time from date of first dose to date of study drug discontinuation or death due to any cause if this occurs before study drug discontinuation
(3) - PFS in the following subgroups:
1. Somatic BRCA mutated and HRD scar positive;
2. HRD scar positive, non-BRCA mutated;
3. HRD scar negative, non-BRCA mutated
(4) - CT-FI: Time from the date of the last dose of platinum chemotherapy prior to olaparib maintenance therapy until the date of initiation of the next anticancer therapy
(5) - OS: Time from the date of first dose of olaparib to date of death from any cause
(6) - Proportion of patients with any improvement from baseline in TOI score
(7) - Proportion of patients with a 10 point deterioration from baseline in TOI score
(8) - AE/SAE. Collection of clinical chemistry/haematology parameters. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
(1) (2) - TFST/TDT : visit 2, 3, 4 and at every tumor assessment visit (TAV), at disc. of study drug, at 30 days post last dose, every 12 weeks during long term FUP
(3) - visit 4 and every 8 week for the first 12 months, and each 12 week until earlier progr., death or EOS for up to 30 months
(4) - Screening, Visit 2, 3, 4 and subs. TAV, Visit 5 and subs. safety visits (SV) (at day 85 and then every 8 weeks), until 30 days after last dose and then every 12 weeks until EOS
(5) OS : when 135 death events recorded (54% maturity) expected at approx. 36 months
(6 and 7) - Visit 2, 3, 4 and at every TAV until progression, at disc. of study drug visit and at 30 days post last dose
(8) - Screening, Visit 2, 3, 4 and subs. TAV , Visit 5 and subs. SV, until 30 days after last dose of study drug |
|
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | 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 | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| 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 | 52 |
| 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 |
| Bulgaria |
| Canada |
| Czech Republic |
| Denmark |
| Finland |
| Israel |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Portugal |
| Romania |
| Slovenia |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
|
| 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
|
| The end of the study is defined as '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 | 2 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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