Study of Olaparib (MK-7339) in Combination With Pembrolizumab (MK-3475) in the Treatment of Homologous Recombination Repair Mutation (HRRm) and/or Homologous Recombination Deficiency (HRD)-Positive Advanced Cancer (MK-7339-007/KEYLYNK-007)

Study Overview
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Brief Summary
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The purpose of this study is to assess the efficacy and safety of treatment with olaparib (MK-7339) in combination with pembrolizumab (MK-3475) in adults with previously treated, advanced (metastatic and/or unresectable) Homologous Recombination Repair Mutation (HRRm) and/or Homologous Recombination Deficiency (HRD)-positive solid tumors.

Official Title
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A Phase 2 Study of Olaparib in Combination With Pembrolizumab in Participants With Previously Treated, Homologous Recombination Repair Mutation (HRRm) and/or Homologous Recombination Deficiency (HRD)-Positive Advanced Cancer

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: Olaparib
* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Has either centrally-confirmed known or suspected deleterious mutations in ≥1 of the specified 15 genes involved in HRR or centrally-confirmed HRD based on the Lynparza HRR-HRD assay. Has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology and confirmed in real time by blinded independent central review (BICR). BICR must confirm the presence of radiologically measurable disease per RECIST 1.1 for the participant to be eligible for the study. Has a life expectancy of ≥3 months. Must have had CR or PR while on the last treatment with prior cisplatin or carboplatin, or if received only oxaliplatin had CR, PR, or stable disease (SD) while on the last treatment with prior oxaliplatin (either as monotherapy or in combination) for advanced (metastatic and/or unresectable) solid tumor. Participant must also not have been refractory to prior platinum-containing therapy. Has an Eastern Cooperative Oncology Group (ECOG) performance status of either 0 or 1, as assessed within 3 days of study treatment initiation. Male participants must agree to use contraception during the treatment period and for ≥90 days (3 months) after the last dose of olaparib and refrain from donating sperm during this period. Female participants must not be pregnant or breastfeeding, and ≥1 of the following conditions applies: Is not a woman of childbearing potential (WOCBP) OR Is a WOCBP who agrees to use contraception during the treatment period and for ≥120 days (3 months) after the last dose of pembrolizumab and 180 days (6 months) after the last dose of olaparib, has a highly sensitive pregnancy test within 24 hours for urine or within 72 hours for serum before the first dose of study intervention, and abstains from breastfeeding during the study intervention period and for at least 120 days after the last dose of the study intervention. Has adequate organ function Exclusion Criteria: Has a known additional malignancy that is progressing or has required active treatment in the last 3 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, ductal carcinoma in situ, or cervical carcinoma in situ that has undergone potentially curative therapy are not excluded. Has a history of non-infectious pneumonitis/interstitial lung disease that required treatment with steroids or currently has pneumonitis/interstitial lung disease. Has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML. Has known central nervous system (CNS) metastases and/or carcinomatous meningitis. Has an active infection requiring systemic therapy. Has active tuberculosis (Bacillus tuberculosis [TB]). Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (dosing >10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. Has an active autoimmune disease that has required systemic treatment in the past 2 years. Has received colony-stimulating factors (e.g. 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 treatment. Has a known history of human immunodeficiency virus (HIV) infection. Has known active hepatitis B or hepatitis C. Is unable to swallow orally administered medication or has a gastrointestinal (GI) disorder affecting absorption (e.g. gastrectomy, partial bowel obstruction, malabsorption). Has received prior therapy with an anti-programmed death-1 (anti-PD-1), anti-programmed death-ligand 1 (anti-PD-L1), or anti-programmed death-ligand 2 (anti-PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX 40 [Tumor necrosis factor receptor superfamily, member 4 (TNFRSF4)], CD137 [tumor necrosis factor receptor superfamily member 9 (TNFRSF9)]). Has received prior therapy with olaparib or with any other polyadenosine 5' diphosphoribose (poly[ADP ribose]) polymerization (PARP) inhibitor. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to administration of study treatment. Must have recovered from all adverse events (AEs) due to previous therapies, excluding alopecia, to ≤Grade 1 or Baseline. Has a known hypersensitivity to the study treatments and/or any of their excipients. Is currently receiving either strong inhibitors of cytochrome P450 (CYP)3A4 (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate inhibitors of CYP3A4 (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 2 weeks. Is currently receiving either strong inducers of CYP3A4 (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate inducers of CYP3A4 (e.g. bosentan, efavirenz, modafinil) 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. Has received previous allogenic bone-marrow transplant or double umbilical cord transplantation (dUCBT). Has received a whole blood transfusion in the last 120 days prior to entry to the study. Has received prior radiotherapy within 2 weeks of start of study treatment. 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 treatment. The presence of uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g. unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, corrected QT interval by Fredericia [QTcF] prolongation >500 msec, electrolyte disturbances), or participant has congenital long QT syndrome. Has either had major surgery within 2 weeks of starting study treatment or has not recovered from any effects of any major surgery. Has received a live vaccine within 30 days prior to the first dose of study treatment. Has had an allogenic tissue/solid tumor organ transplant.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Olaparib+Pembrolizumab<br>Participants receive olaparib 300 mg via oral tablet 2 times each day PLUS pembrolizumab 200 mg via intravenous infusion on Day 1 of each 21-day cycle. Participants may receive olaparib+pembrolizumab for up to approximately 2 years. | Drug: Olaparib<br>* Oral tablet<br>* Other names: LYNPARZA®;Biological: Pembrolizumab<br>* Intravenous infusion<br>* Other names: KEYTRUDA®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | ORR is defined as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. The ORR for all participants will be presented by biomarker subgroup. | Up to  3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) as Assessed by RECIST 1.1 or PCWG-modified RECIST 1.1 in Biomarker Subgroups | For participants who demonstrate a confirmed complete response (CR: Disappearance of all target lesions) or confirmed Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until disease progression or death. The DOR for all participants who experience a CR or PR will be presented by biomarker subgroup. | Up to  3 years | 
| Progression-Free Survival (PFS) as Assessed by RECIST 1.1 or PCWG-modified RECIST 1.1 in Biomarker Subgroups | PFS is defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more lesions is also considered PD. The PFS for all participants will be presented by biomarker subgroup. | Up to  3 years | 
| Overall Survival (OS) in Biomarker Subgroups | OS is the time from randomization to death due to any cause. The OS for all participants will be presented by biomarker subgroup. | Up to  3 years | 
| Number of Participants Who Experience an Adverse Event (AE) | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experience at least one AE will be presented. | Up to  3 years | 
| Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who discontinue study treatment will be presented. | Up to  3 years | 
| 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 | ORR is defined as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. ORR will be presented by biomarker subpopulation. | Up to  3 years | 
| 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 | For participants who demonstrate a confirmed complete response (CR: Disappearance of all target lesions) or confirmed Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until disease progression or death. The DOR for all participants who experience a CR or PR will be presented by biomarker subpopulation. | Up to  3 years | 
| 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 | PFS is defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more lesions is also considered PD. PFS will be presented by biomarker subpopulation. | Up to  3 years | 
| Overall Survival (OS) in Additional Biomarker Subpopulations | OS is the time from randomization to death due to any cause. OS will be presented by biomarker subpopulation. | Up to  3 years | 
| Number of Participants with Cancer Antigen-125 (CA-125) Level of ≥2 × Upper Limit of Normal (ULN) Among Participants with Ovarian Cancer | The number of participants who have ovarian cancer and have a CA-125 level ≥2 × upper limit of normal (ULN) at 2 different assessments that are measured at least 1 week apart will be presented. | Up to  3 years | 
| 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 | The number of participants who have ovarian cancer with an elevated CA-125 level ≥ ULN at Baseline and have a CA-125 level ≥2 × the nadir (lowest) value at 2 different assessments that are measured at least 1 week apart will be presented. | Up to  3 years | 
| Number of Participants with a Change from Baseline in Prostate-Specific Antigen (PSA) Level of ≥50% Among Participants with Prostate Cancer | A PSA response is defined as a reduction in the PSA level of ≥50% from Baseline measured at 2 different times at least 3 weeks apart. The number of participants who have prostate cancer and have a change from Baseline in PSA level ≥50% will be presented. | Up to  3 years |