Homologous recombination repair mutation (HRRm) or Homologous recombination deficiency (HRD) positive cancer MedDRA version: 21.1 Level: LLT Classification code 10065252 Term: Solid tumor System Organ Class: 100000004864
Conditions
Sponsors
Merck Sharp & Dohme LLC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Cohorts 1 and 2: 1. Has a histologically- or cytologically-confirmed advanced (metastatic and/or unresectable) solid tumor (except ovarian cancer whose tumor has a germline or somatic BRCA mutation and breast cancer whose tumor has a germline BRCA) 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. If participants have received prior platinum (cisplatin, carboplatin, or oxaliplati, etc. 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 or = 4 weeks of completing the platinum-containing regimen. Cohorts 1, 2 and 3 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 measurable 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. 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. Has a life expectancy of at least 3 months 7. Is Male or Female who is at least 18 years of age at the time of signing the informed consent 8. 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 95 days (3 months and 5 days), 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: • Not a woman of childbearing potential (WOCBP) OR • A WOCBP and * uses a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The length of time required to continue contraception for each study intervention is as follows: - Olaparib: 180 days The investigator should evaluate the potent
Exclusion criteria
Exclusion criteria: Participant 1.has a known additional malignancy that is progressing or has required active treatment in the last 5 years 2.has MDS/AML or with features suggestive of MDS/AML 3.has persistent toxicities(>CTCAE Grade 2)caused by previous cancer therapy, excluding alopecia 4.has known central nervous system(CNS)metastases and/or carcinomatous meningitis 5.has an active infection requiring systemic therapy 6.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.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.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.has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study 10.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.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.is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption(eg, gastrectomy, partial bowel obstruction, malabsorption) 13.has received prior therapy with olaparib or with any other PARP inhibitor 14.has a known hypersensitivity to the components or excipients in olaparib 15.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.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.has received previous allogenic bone-marrow transplant
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the objective response rate (ORR) as assessed by blinded independent central review (BICR) according to modified Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) or Prostate Cancer Working Group (PCWG)-modified RECIST 1.1, following olaparib administration in Cohort 1, Cohort 2 and Cohort 3;Secondary Objective: To evaluate -DOR as assessed by BICR according to modified RECIST 1.1 or PCWG-modified RECIST 1.1, following olaparib administration in Cohorts 1, 2 and 3. -OS, following administration of olaparib in Cohorts 1, 2, and 3. -PFS as assessed by BICR according to modified RECIST 1.1 or PCWG- modified RECIST 1.1, following olaparib administration in Cohorts 1, 2, and 3. -the safety and tolerability of olaparib in Cohorts 1, 2, and 3. -the ORR, DOR, OS, and PFS in participants who are {1) HRRm, {2) HRD positive, and {3) in all participants regardless of biomarker status following olaparib administration in Cohorts 1 and 2. -time to earliest progression by CA-125 following olaparib administration in participants with BRCA1/2 non-mutated ovarian cancer. -the PSA response rate to olaparib administration in participants with prostate cancer. -progression-free survival after next-line treatment {PFS2), as assessed by the investigator, in participants with sBRCAm breast cancer.;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;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 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1) Duration of response(DOR) 2) Evaluate overall survival(OS 3) Progression free survival(PFS) 4) Progression Free Survival after next-line treatment (PFS2) ;Timepoint(s) of evaluation of this end point: To be determined | — |
Countries
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
Outcome results
None listed