A Phase 2 Study of Olaparib Monotherapy in Participants with Previously Treated, Homologous Recombination Repair Mutation (HRRm) or Homologous Recombination Deficiency (HRD) Positive Advanced Cancer

Trial ID: 2022-500797-34-00
Protocol: MK-7339-002
Sponsor: Merck Sharp & Dohme LLC

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Diseases & Conditions

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Objectives

The primary objective of this study is 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 the administration of olaparib in Cohort 1, Cohort 2, and Cohort 3. This is clinically relevant as it provides insight into the efficacy of olaparib in inducing tumor response in participants with advanced cancer characterized by homologous recombination repair mutation (HRRm) or homologous recombination deficiency (HRD).

Secondary objectives include:

Evaluating the duration of response (DOR) as assessed by BICR according to modified RECIST 1.1 or PCWG-modified RECIST 1.1.
Assessing overall survival (OS) following olaparib administration.
Evaluating progression-free survival (PFS) as assessed by BICR according to modified RECIST 1.1 or PCWG-modified RECIST 1.1.
Assessing the safety and tolerability of olaparib.
Evaluating ORR, DOR, OS, and PFS in participants who are HRRm, HRD positive, and in all participants regardless of biomarker status.
Assessing time to earliest progression by CA-125 in participants with BRCA1/2 non-mutated ovarian cancer.
Evaluating the PSA response rate in participants with prostate cancer.
Assessing progression-free survival after next-line treatment (PFS2) in participants with sBRCAm breast cancer.

These secondary objectives aim to provide a comprehensive understanding of the therapeutic impact of olaparib across various cancer types and genetic profiles, contributing to personalized treatment strategies.

Participants

The clinical trial involves a total of **81 participants** diagnosed with cancer characterized by **homologous recombination repair mutations (HRRm)** or **homologous recombination deficiency (HRD)**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on their measurable disease status as per RECIST 1.1 or PCWG-modified RECIST 1.1 criteria, confirmed by blinded independent central review. The trial includes individuals with a life expectancy of at least three months and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Participants are required to have adequate organ function and must adhere to specific contraceptive guidelines if of childbearing potential. The trial population includes individuals with advanced or metastatic solid tumors, excluding those with ovarian cancer with a germline or somatic BRCA mutation and breast cancer with a germline BRCA mutation, who have progressed on or are intolerant to standard therapies. Lifestyle considerations such as diet and physical activity are not specified, but participants must not be pregnant or breastfeeding. The trial also includes a vulnerable population, ensuring comprehensive representation in the study.

Plans and Procedures

The clinical trial is designed to evaluate the **objective response rate** (ORR) of **olaparib** monotherapy in participants with previously treated, homologous recombination repair mutation (HRRm) or homologous recombination deficiency (HRD) positive advanced cancer. This is a Phase 2, randomized, double-blind, controlled study. The trial is expected to run from January 17, 2019, to December 1, 2025, with a maximum treatment period of 294 days for each participant. The study involves multiple cohorts, and the primary endpoint is the 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.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as measurable disease per RECIST 1.1 or PCWG-modified RECIST 1.1, adequate organ function, and a life expectancy of at least three months. Following the screening, participants will be randomized to receive **olaparib** in the form of film-coated tablets, administered orally. The maximum daily dose is 600 mg, with a total dose not exceeding 1,534,200 mg over the treatment period. Follow-up visits will be scheduled to monitor the participants' response to the treatment, assess any adverse events, and ensure compliance with the study protocol. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to evaluate the treatment's efficacy and safety.

The expected length of participant involvement is approximately 294 days, although this may vary depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent by the participant. Secondary endpoints of the trial include duration of response (DOR), overall survival (OS), progression-free survival (PFS), and the number of participants experiencing adverse events or discontinuing treatment due to adverse events. The trial aims to provide valuable insights into the efficacy and safety of **olaparib** for treating HRRm or HRD positive advanced cancer.

Treatment

The clinical trial involves the administration of **Olaparib**, a pharmaceutical product developed by Merck & Co. Inc. Olaparib is provided in the form of a **film-coated tablet** and is intended for oral administration. The active substance in Olaparib is of chemical origin, specifically identified as olaparib. The maximum daily dose of Olaparib is 600 mg, with a total maximum dose of 1,534,200 mg over a treatment period of 294 days. The dosing schedule is designed to ensure consistent administration, and participant compliance is monitored throughout the trial to maintain the integrity of the study results.

In this study, Olaparib is used as a monotherapy to evaluate its efficacy in participants with previously treated, homologous recombination repair mutation (HRRm) or homologous recombination deficiency (HRD) positive advanced cancer. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The primary objective is to assess the objective response rate (ORR) as evaluated 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.

Efficacy

The efficacy of **Olaparib** in the clinical trial will be assessed primarily through the **Objective Response Rate (ORR)**, as evaluated by a blinded independent central review (BICR) using modified Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) or Prostate Cancer Working Group (PCWG)-modified RECIST 1.1. This assessment will be conducted following the administration of Olaparib in participants across three cohorts. Secondary endpoints include the **Duration of Response (DOR)**, **Overall Survival (OS)**, **Progression-Free Survival (PFS)**, and the number of participants experiencing or discontinuing treatment due to adverse events. Additional secondary endpoints involve specific measures such as the **Objective Response Rate (ORR) in participants with HRRm or HRD positive cancer**, **Time to Earliest Progression by Cancer Antigen-125 (CA-125)**, **Prostate-specific Antigen (PSA) Response Rate in participants with prostate cancer**, and **Progression-Free Survival After Next-Line Treatment in participants with sBRCAm breast cancer**.

Inclusion and Exclusion Criteria

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Inclusion Criteria

(For all participants) 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.
(For all participants) 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.
(For all participants) Has a life expectancy of at least 3 months.
(For all participants) Has an Eastern Cooperative Oncology Group (ECOG) performance status of either 0 or 1, as assessed within 7 days of treatment initiation.
(For all participants) Male participants must agree to use contraception during the treatment period and for at least 95 days (3 months and 5 days) after the last dose of study treatment and refrain from donating sperm during this period.
(For all participants) A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: 1. Is not a woman of childbearing potential (WOCBP). 2. Is a WOCBP and using a contraceptive method that is highly effective 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 180 days 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. Abstains from breastfeeding during the study intervention period and for at least 30 days after the last dose of study intervention.
(For all participants) Has adequate organ function.
(For participants who have non-breast or -ovarian cancers that are breast cancer susceptibility gene 1/2 (BRCA1/2) mutated (BRCAm), or who have cancers that are BRCA1/2 non-mutated and homologous recombination repair mutated, or homologous recombination deficient without a mutation in HRR pathway) 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 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.
(For participants who have non-breast or -ovarian cancers that are breast cancer susceptibility gene 1/2 (BRCA1/2) mutated (BRCAm), or who have cancers that are BRCA1/2 non-mutated and homologous recombination repair nonmutated) Has either centrally-confirmed known or suspected deleterious mutations in at least 1 of the genes involved in HRR or centrally-confirmed HRD.
(For participants who have non-breast or -ovarian cancers that are breast cancer susceptibility gene 1/2 (BRCA1/2) mutated (BRCAm), or who have cancers that are BRCA1/2 non-mutated and homologous recombination repair nonmutated) For participants receiving prior platinum (cisplatin, carboplatin, or oxaliplatin either as monotherapy or in combination) for advanced (metastatic and/or unresectable) solid tumor, have no evidence of disease progression during the platinum chemotherapy or ≤4 weeks of completing the platinum-containing regimen.
(For participants who have somatic BRCAm breast cancer) Has histologically- or cytologically-confirmed breast cancer with evidence of metastatic disease.
(For participants who have somatic BRCAm breast cancer) Has a known or suspected deleterious mutation in breast cancer susceptibility gene (BRCA) 1 or BRCA2 and does not harbor a germline BRCA1 or BRCA2 mutation - testing can be done centrally or locally. Blood and tissue samples must be provided by all participants.
(For participants who have somatic BRCAm breast cancer) Has received treatment with an anthracycline unless contraindicated and a taxane in either the neoadjuvant/adjuvant or metastatic setting.
(For participants who have somatic BRCAm breast cancer) Participants with estrogen and/or progesterone receptor-positive disease must have received and progressed on at least one endocrine therapy (adjuvant or metastatic), or have disease that the treating physician believes to be inappropriate for endocrine therapy.

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Exclusion Criteria

Has a known additional malignancy that is progressing or has required active treatment in the last 5 years. Note: 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 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. Note: Participants with previously treated brain metastases may participate if radiologically stable, clinically stable, and without requirement for steroid treatment for at least 14 days prior to the first dose of study treatment.
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 infection (i.e., Hepatitis B or C).
Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (e.g., gastrectomy, partial bowel obstruction, malabsorption).
Has received prior therapy with olaparib or with any other polyadenosine 5' diphosphoribose (poly[ADP ribose]) polymerization (PARP) inhibitor.
Has a known hypersensitivity to the components or excipients in olaparib.
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. Packed red blood cells and platelet transfusions are acceptable if not performed within 28 days of the first dose of study treatment.
Has received any anti-neoplastic systemic chemotherapy or biological therapy, targeted therapy, or an anticancer hormonal therapy within 3 weeks prior to the first dose of study intervention.
Has a primary cancer of unknown origin.
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.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Denmark	Not Recruiting	17 Jan 2019	3
France	Not Recruiting	17 Jan 2019	7
Ireland	Not Recruiting	17 Jan 2019	5
Italy	Not Recruiting	17 Jan 2019	3
Romania	Not Recruiting	17 Jan 2019	7
Spain	Not Recruiting	17 Jan 2019	2