E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HRRm and/or HRD-positive cancer |
|
E.1.1.1 | Medical condition in easily understood language |
Second line and beyond HHRm and HRD pan tumor cancers |
|
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 | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065252 |
E.1.2 | Term | Solid tumor |
E.1.2 | System Organ Class | 100000004864 |
|
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 |
1. To evaluate the Objective Response Rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) or Prostate Cancer Working Group (PCWG)-modified RECIST 1.1 |
|
E.2.2 | Secondary objectives of the trial |
1. To evaluate Duration of Response (DOR) as assessed by RECIST 1.1 or PCWG-modified RECIST 1.1 2. To evaluate Progression-Free Survival (PFS) as assessed by RECIST 1.1 or PCWG-modified RECIST 1.1 3. To evaluate Overall Survival (OS) 4. To evaluate the safety and tolerability of study treatment 5. To evaluate ORR, DOR and PFS as assessed by RECIST 1.1 or PCWG-modified RECIST 1.1 and OS based on tumor biomarker status 6. To evaluate the time to earliest progression by cancer antigen-125 (CA-125) in participants with ovarian cancer 7. To evaluate the prostate-specific antigen (PSA) response rate in participants with prostate cancer
|
|
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 - tumor specimen) 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. |
|
E.3 | Principal inclusion criteria |
1. 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. 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. Has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology and confirmed in real time by BICR. BICR must confirm the presence of radiologically measurable disease per 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. 4. Has a life expectancy of at least 3 months. 5. Is male or female, who is at least 18 years of age at the time of signing the informed consent. 6. Has an Eastern Cooperative Oncology Group (ECOG) performance status of either 0 or 1, as assessed within 3 days of treatment initiation. 7. A male participant must agree to use contraception as detailed in the protocol during the treatment period and for at least 120 days (4 months), corresponding to time needed to eliminate any study intervention(s) and refrain from donating sperm during this period. 8. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies: - Not a woman of childbearing potential (WOCBP) OR - A WOCBP who agrees to follow the contraceptive guidance in the Protocol during the treatment period and for at least 180 days (6 months) after the last dose of study intervention, corresponding to time needed to eliminate any study intervention(s). 9. 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. 10. Has adequate organ function; all screening laboratory tests should be performed within 10 days prior to the first dose of study intervention. |
|
E.4 | Principal exclusion criteria |
1. Has a known additional malignancy that is progressing or has required active treatment in the last 3 years 2. Has a history of non-infectious pneumonitis that required treatment with steroids or currently has pneumonitis 3. Has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML 4. Has known central nervous system (CNS) metastases and/or carcinomatous meningitis 5. Has an active infection requiring systemic therapy 6. Has active tuberculosis 7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (dosing in the Protocol) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention 8. Has an active autoimmune disease that has required systemic treatment in the past 2 years 9. Has a history or current evidence of any condition (please refer to the Protocol), 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 10. 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 11. Is considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease or active, uncontrolled infection 12. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study 13. Has a known history of human immunodeficiency virus (HIV) infection. Testing for HIV at screening is only required if mandated by local health authority 14. Has known active hepatitis (ie, Hepatitis B or C) 15. Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption 16. A WOCBP who has a positive urine pregnancy test within 72 hours before the first dose of study intervention. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required 17. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137) 18. Has received prior therapy with olaparib or with any other PARP inhibitor 19. Were refractory to prior platinum therapy for advanced (metastatic and/or unresectable) solid tumor 20. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to administration of study intervention 21. Must have recovered from all AEs due to previous therapies, excluding alopecia, to ≤Grade 1 or baseline 22. Has a known hypersensitivity to the study treatments and/or any of their excipients 23. Is currently receiving either strong or moderate 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 24. Is currently receiving either strong or moderate 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 25. Has received previous allogenic bone-marrow transplant or double umbilical cord transplantation (dUCBT) 26. 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 27. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease 28. 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 29. Participant has resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (please refer to the Protocol), or participant has congenital long QT syndrome 30. Either had major surgery within 2 weeks of starting study intervention or has not recovered from any effects of any major surgery 31. Has received a live vaccine within 30 days prior to the first dose of study drug. 32. Is involved in the planning and/or conduct of the study 33. In the judgement of the investigator, is unlikely to comply with the study procedures, restrictions, and requirements of the study |
|
E.5 End points |
E.5.1 | Primary end point(s) |
1. Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or Prostate Cancer Working Group (PCWG)-modified RECIST 1.1 in Biomarker Subgroups |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
1. Duration of Response (DOR) as Assessed by RECIST 1.1 or PCWG-modified RECIST 1.1 in Biomarker Subgroups 2. Progression-Free Survival (PFS) as Assessed by RECIST 1.1 or PCWG-modified RECIST 1.1 in Biomarker Subgroups 3. Overall Survival (OS) in Biomarker Subgroups 4. Number of Participants Who Experience an Adverse Event (AE) 5. Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) 6. Objective Response Rate (ORR) Based on Tumor Biomarker Status as Assessed by RECIST 1.1 or PCWG-modified RECIST 1.1 in Additional Biomarker Subpopulations 7. Duration of Response (DOR) Based on Tumor Biomarker Status as Assessed by RECIST 1.1 or PCWG-modified RECIST 1.1 in Additional Biomarker Subpopulations 8. Progression-Free Survival (PFS) Based on Tumor Biomarker Status as Assessed by RECIST 1.1 or PCWG-modified RECIST 1.1 in Additional Biomarker Subpopulations 9. Overall Survival (OS) in Additional Biomarker Subpopulations 10. Number of Participants with Cancer Antigen-125 (CA-125) Level of ≥2 × Upper Limit of Normal (ULN) Among Participants with Ovarian Cancer 11. Number of Participants with Cancer Antigen-125 (CA-125) Level ≥2 × Nadir (Lowest) Value Among Participants with Ovarian Cancer Who Had Elevated CA-125 Levels ≥ULN at Baseline 12. Number of Participants with a Change from Baseline in Prostate-Specific Antigen (PSA) Level of ≥50% Among Participants with Prostate Cancer
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to ~3 years 2. Up to ~3 years 3. Up to ~3 years 4. Up to ~3 years 5. Up to ~3 years 6. Up to ~3 years 7. Up to ~3 years 8. Up to ~3 years 9. Up to ~3 years 10. Up to ~3 years 11. Up to ~3 years 12. Up to ~3 years
|
|
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 | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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 |
France |
Germany |
Guatemala |
Israel |
Italy |
Korea, Republic of |
Latvia |
Mexico |
Peru |
Poland |
Puerto Rico |
Romania |
South Africa |
Spain |
Sweden |
Turkey |
Ukraine |
United States |
|
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
|
|
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 | 6 |
E.8.9.1 | In the Member State concerned days | |
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 | 6 |