E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Homologous recombination repair mutation (HRRm) or Homologous recombination deficiency (HRD) positive cancer |
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E.1.1.1 | Medical condition in easily understood language |
Male and female participants with previously treated, advanced (metastatic and/or unresectable) HRRm and/or HRD-positive solid tumors |
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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 | LLT |
E.1.2 | Classification code | 10065252 |
E.1.2 | Term | Solid tumor |
E.1.2 | System Organ Class | 100000004864 |
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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 evaluate the objective response rate (ORR) as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) or Prostate Cancer Working Group (PCWG)-modified RECIST 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, following olaparib administration in Cohort 1 and Cohort 2 |
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E.2.2 | Secondary objectives of the trial |
-To evaluate the duration of response(DOR)as assessed by BICR according to RECIST1.1 or PCWGmodified RECIST1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, following olaparib administration in Cohort 1 and 2
-To evaluate overall survival(OS), following administration of olaparib in Cohort 1 and 2
-To evaluate progression free survival(PFS)as assessed by BICR according to RECIST1.1 or PCWGmodified RECIST1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, following olaparib administration in Cohort 1 and 2
-To evaluate the safety and tolerability of olaparib
-To evaluate the ORR, DOR, OS, and PFS in participants who are HRRm, HRD positive, and in all participants regardless of biomarker status following olaparib administration in Cohort 1 and 2
-To assess time to earliest progression by CA-125 following olaparib administration in participants with BRCA1/2 non mutated ovarian cancer |
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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 |
Merck will conduct Future Biomedical Research on DNA (Blood and tissue) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose
of the correct drug at the correct time |
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E.3 | Principal inclusion criteria |
1. Participant has a histologically- or cytologically-confirmed advanced (metastatic and/or unresectable) solid tumor (except breast or ovarian cancers whose tumor has a germline or somatic BRCA mutation) that is not eligible for curative treatment and for which standard of care therapy has failed. Participants must have progressed on or be intolerant to standard of care therapies that are known to provide clinical benefit. There is no limit on the number of prior treatment regimens
2. Participant has either centrally-confirmed known or suspected deleterious mutations in at least 1 of the specified 15 genes involved in HRR (ie, BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L) or centrally-confirmed HRD based on the Lynparza HRR-HRD assay
3. If participants have received prior platinum (cisplatin, carboplatin, or oxaliplatin either as monotherapy or in combination) for advanced (metastatic and/or unresectable) solid tumor, they are eligible to enter the study provided there has been no evidence of disease progression during the platinum chemotherapy
4. Participant has measurable disease per RECIST 1.1 or PCWG-modified RECIST 1.1 as assessed by the local site Investigator/radiology and confirmed by BICR. BICR must confirm the presence of radiologically measureable disease based on RECIST 1.1 or PCWG-modified RECIST 1.1 for the participant to be eligible for the study. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
5. Participant is able to provide a newly obtained core or excisional biopsy of a tumor lesion or either an archival formalin-fixed paraffin embedded (FFPE) tumor tissue block or slides. A newly obtained biopsy is preferred, but not required if archival tissue is available for analysis
6. Participant has a life expectancy of at least 3 months
7. Participant is Male or Female who is at least 18 years of age at the time of signing the informed consent
8. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of either 0 or 1, as assessed within 3 days of treatment initiation
9. A male participant must agree to use contraception during the treatment period and for at least 90 days (3 months), corresponding to time needed to eliminate any study intervention(s) (ie, olaparib) plus a spermatogenesis cycle, after the last dose of study intervention and refrain from donating sperm during this period
10. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies:
a) Not a woman of childbearing potential (WOCBP)
OR
b) A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 30 days (1 month) after the last dose of study intervention, corresponding to time needed to eliminate any study intervention(s (ie, olaparib) plus 30 days (a menstruation cycle) for study interventions with risk of genotoxicity
11. The participant (or legally acceptable representative if applicable) provides written informed consent for the study. The participant may also provide consent for FBR. However, the participant may participate in the main study without participating in FBR
12. Participant has adequate organ function |
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E.4 | Principal exclusion criteria |
1. Participant has a known additional malignancy that is progressing or has required active treatment in the last 5 years
2. Participant has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML
3. Participant has persistent toxicities (>CTCAE Grade 2) caused by previous cancer therapy, excluding alopecia
4. Participant has known central nervous system (CNS) metastases and/or carcinomatous meningitis
5. Participant has an active infection requiring systemic therapy
6. Participant has a history or current evidence of any condition (eg, cytopenia, transfusion-dependent anemia, or thrombocytopenia), therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s involvement for the full duration of the study, or is not in the best interest of the participant to be involved, in the opinion of the treating Investigator
7. Participant received colony-stimulating factors (eg, granulocyte colony-stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor [GM-CSF] or recombinant erythropoietin) within 28 days prior to the first dose of study intervention
8. Participant is considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent
9. Participant has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study
10. Participant has a known history of human immunodeficiency virus (HIV) infection. Testing for HIV at screening is only required if mandated by local health authority.
11. Participant has known active hepatitis (ie, Hepatitis B or C)
a) Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result. Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible
b) Participants positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
12. Participant is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (eg, gastrectomy, partial bowel obstruction, malabsorption)
13. Participant has received prior therapy with olaparib or with any other PARP inhibitor.
14. Participant has a known hypersensitivity to the components or excipients in olaparib
15. Participant is currently receiving either strong (eg, itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 2 weeks
16. Participant is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate (eg. bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 5 weeks for phenobarbital and 3 weeks for other agents
17. Participant has received previous allogenic bone-marrow transplant or double umbilical cord transplantation (dUCBT)
18. Participant has received a whole blood transfusion in the last 120 days prior to entry to the study. Packed red blood cells and platelet transfusions are acceptable if not performed within 28 days of the first dose of study intervention
19. Participant is currently enrolled in and receiving study therapy, was enrolled in a study of an investigational agent and received study therapy, or used an investigational device within 4 weeks (28 days) of the first dose of study intervention
20. Participant either had major surgery within 2 weeks of starting study intervention or has not recovered from any effects of any major surgery
21. Participant is involved in the planning and/or conduct of the study (applies to both Sponsor staff and/or staff at the study site)
22. Participant, in the judgement of the Investigator, is unlikely to comply with the study procedures, restrictions, and requirements of the study |
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E.5 End points |
E.5.1 | Primary end point(s) |
Objective response rate (ORR) based on RECIST 1.1 or PCWG-modified RECIST 1.1 (participants with prostate cancer) as assessed by blinded independent central review |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis will be conducted when all enrolled participants have at least 9 months follow-up |
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E.5.2 | Secondary end point(s) |
1) Duration of response(DOR)
2) Evaluate overall survival(OS
3) Progression free survival(PFS)
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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 | 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 | 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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 |
Canada |
Colombia |
Denmark |
France |
Guatemala |
Ireland |
Israel |
Italy |
Japan |
Korea, Republic of |
Mexico |
New Zealand |
Peru |
Romania |
Russian Federation |
Spain |
Switzerland |
Turkey |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |