Phase 2 Evaluation of Olaparib and Pembrolizumab in HRRm and HRD-Positive Advanced Cancer
- Trial ID
- 2023-503831-17-00
- Protocol
- MK-7339-007
- Sponsor
- Merck Sharp & Dohme LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **Objective Response Rate (ORR)** in participants with previously treated, homologous recombination repair mutation (HRRm) and/or homologous recombination deficiency (HRD)-positive advanced cancer. This is assessed using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) or Prostate Cancer Working Group (PCWG)-modified RECIST 1.1. The clinical relevance of this objective lies in its potential to provide insights into the efficacy of the combination treatment of Olaparib and Pembrolizumab in this specific patient population, which could inform future therapeutic strategies.
Secondary objectives include:
- Evaluating the **Duration of Response (DOR)** and **Progression-Free Survival (PFS)** as assessed by RECIST 1.1 or PCWG-modified RECIST 1.1.
- Assessing **Overall Survival (OS)**.
- Evaluating the safety and tolerability of the study treatment.
- Assessing ORR, DOR, and PFS based on tumor biomarker status, and OS.
- Evaluating the time to earliest progression by cancer antigen-125 (CA-125) in participants with ovarian cancer.
- Assessing the prostate-specific antigen (PSA) response rate in participants with prostate cancer.
Participants
The clinical trial involves a total of **318 participants** diagnosed with HRRm and/or HRD-positive cancer. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, indicating adult participants. The participants were selected based on specific criteria, including having a histologically- or cytologically-confirmed advanced solid tumor, excluding breast or ovarian cancers with BRCA mutations, 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 therapies known to provide clinical benefit. 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. Both male and female participants are required to adhere to contraception guidelines during and after the treatment period. The trial population is characterized by adequate organ function and includes a vulnerable population. Lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the **Objective Response Rate (ORR)** in participants with previously treated, homologous recombination repair mutation (HRRm) and/or homologous recombination deficiency (HRD)-positive advanced cancer. This is a Phase 2, randomized, double-blind, controlled trial involving the administration of **Olaparib** in combination with **Pembrolizumab**. The trial is expected to span approximately 24 months, with an estimated recruitment start date of November 18, 2019, and an estimated end date of July 24, 2025.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as having a histologically- or cytologically-confirmed advanced solid tumor, measurable disease per RECIST 1.1, and adequate organ function. The trial will include follow-up visits to monitor the participants' response to treatment and any adverse events. The end-of-study visit will assess the overall outcomes and any long-term effects of the treatment.
The expected length of participant involvement is up to 24 months, depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, disease progression, or withdrawal of consent by the participant. The trial aims to provide valuable insights into the efficacy and safety of the combination therapy in the specified patient population.
Treatment
The clinical trial involves the administration of **Olaparib**, a chemical compound provided in the form of a **film-coated tablet**. The active substance, **olaparib**, is manufactured by Merck & Co. Inc. The medication is administered **orally** with a maximum daily dose of 600 mg and a total maximum dose of 438 g over a treatment period of up to 24 months. The trial does not involve a pediatric formulation, and the product is not classified as an orphan drug. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen.
Additionally, the trial includes the use of **KEYTRUDA**, a **25 mg/mL concentrate for solution for infusion** containing the active substance **pembrolizumab**, a biological protein. This product is manufactured by Merck Sharp & Dohme BV. The administration route is via **intravenous infusion**, with a maximum daily dose of 200 mg and a total maximum dose of 7000 mg over a 24-month treatment period. As with Olaparib, this product is not formulated for pediatric use and is not designated as an orphan drug. Participant compliance with the infusion schedule is closely monitored to ensure accurate dosing and administration.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the **Objective Response Rate (ORR)**, as evaluated by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) or the Prostate Cancer Working Group (PCWG)-modified RECIST 1.1. This primary endpoint will be measured in biomarker subgroups to determine the response to the treatment regimen. Secondary endpoints include the **Duration of Response (DOR)**, **Progression-Free Survival (PFS)**, and **Overall Survival (OS)**, all assessed using RECIST 1.1 or PCWG-modified RECIST 1.1 in biomarker subgroups. Additionally, the trial will monitor the number of participants experiencing adverse events and those discontinuing treatment due to adverse events.
Further secondary endpoints involve evaluating the ORR, DOR, and PFS based on tumor biomarker status in additional biomarker subpopulations. The trial will also assess the number of participants with specific changes in cancer antigen-125 (CA-125) levels among those with ovarian cancer and changes in prostate-specific antigen (PSA) levels among participants with prostate cancer. These efficacy parameters will be collected and analyzed at various timepoints throughout the trial to provide a comprehensive evaluation of the treatment's impact on the participants' conditions.
Inclusion and Exclusion Criteria
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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 18 Nov 2019 | 15 |
 Germany | Not Recruiting | 18 Nov 2019 | 9 |
 Italy | Not Recruiting | 18 Nov 2019 | 15 |
 Latvia | Not Recruiting | 18 Nov 2019 | 12 |
 Poland | Not Recruiting | 18 Nov 2019 | 12 |
 Romania | Not Recruiting | 18 Nov 2019 | 18 |
 Spain | Not Recruiting | 18 Nov 2019 | 17 |
 Sweden | Not Recruiting | 18 Nov 2019 | 9 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 200 | 24 | PRD4323105 |
Olaparib | Test | FILM-COATED TABLET | ORAL | 600 | 24 | PRD9414227 |
Olaparib | Test | FILM-COATED TABLET | ORAL | 600 | 24 | PRD9414228 |