An Open-label, Randomized, Phase 2/3 Study of Olaparib Plus Pembrolizumab Versus Chemotherapy Plus Pembrolizumab After Induction of Clinical Benefit With First-line Chemotherapy Plus Pembrolizumab in Participants With Locally Recurrent Inoperable or Metastatic Triple Negative Breast Cancer (TNBC) (KEYLYNK 009)
- Trial ID
- 2022-500418-24-00
- Protocol
- MK-7339-009
- Sponsor
- Merck Sharp & Dohme LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the efficacy of **olaparib** plus **pembrolizumab** versus chemotherapy plus pembrolizumab in terms of progression-free survival (PFS) and overall survival (OS) in participants with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC). The evaluation of PFS will be conducted according to the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by blinded independent central review (BICR). This is clinically relevant as it aims to determine the potential benefits of combining olaparib, a PARP inhibitor, with pembrolizumab, an immune checkpoint inhibitor, compared to the standard chemotherapy regimen, potentially offering a more effective treatment option for TNBC, a subtype of breast cancer with limited therapeutic options.
Secondary objectives include:
- Evaluating OS and PFS according to RECIST 1.1 by BICR in participants with PD-L1 positive tumors (CPS ≥10) and those with BRCAm tumors following treatment with olaparib plus pembrolizumab or chemotherapy plus pembrolizumab.
- Assessing health-related quality-of-life (HRQoL) and time to deterioration (TTD) using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the breast cancer module (EORTC QLQ-BR23) in participants with BRCAm tumors and irrespective of BRCAm status.
- Evaluating the visual analogue scale (VAS) using the EuroQoL 5-dimension, 5-level questionnaire (EQ-5D-5L) in participants with BRCAm tumors and irrespective of BRCAm status.
- Assessing the safety and tolerability of olaparib plus pembrolizumab or chemotherapy plus pembrolizumab.
Participants
The clinical trial involves a total of **165 participants** diagnosed with **locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC)**. The study population includes both male and female subjects, with an age range starting from 18 years and above. Participants were selected based on specific criteria, including having TNBC that has not been previously treated with chemotherapy and demonstrating adequate organ function. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are in relatively good health despite their cancer diagnosis. Lifestyle considerations such as diet and physical activity are not specified, but participants must agree to use contraception and refrain from donating reproductive cells during the study period. The trial also includes a vulnerable population, ensuring comprehensive representation. Key inclusion criteria focus on the cancer's treatment history and measurable disease status, while exclusion criteria are not detailed in the provided data.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **olaparib** plus **pembrolizumab** compared to chemotherapy plus pembrolizumab in participants with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC). This is a randomized, open-label, Phase 2/3 study. The trial aims to assess progression-free survival (PFS) and overall survival (OS) as primary endpoints, with secondary endpoints including health-related quality of life and adverse events. The study is expected to run from December 30, 2019, to January 26, 2026.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as having TNBC that has not been previously treated with chemotherapy. The inclusion visit will involve assessments to ensure participants meet all necessary conditions, including adequate organ function and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Following the inclusion visit, participants will receive up to 6 cycles of induction therapy, with evaluations at Week 18 to determine response based on RECIST 1.1 criteria.
Post-induction, participants will be randomized to receive either olaparib plus pembrolizumab or chemotherapy plus pembrolizumab. Follow-up visits will occur regularly to monitor treatment response, adverse events, and quality of life. The end-of-study visit will conclude the participant's involvement, with assessments to gather final data on the primary and secondary endpoints. The expected length of participant involvement is approximately 69 weeks for olaparib and 73 weeks for chemotherapy, with conditions for early termination including significant adverse events or disease progression.
Treatment
The clinical trial involves the administration of **Olaparib**, a chemical compound provided in the form of a film-coated tablet. The pharmaceutical form is designed for oral administration. The maximum daily dose of Olaparib is 600 mg, with a total maximum dose of 289,800 mg over a treatment period of up to 69 days. The product is manufactured by Merck & Co. Inc. and is identified by the sponsor product code MK-7339. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.
**Carboplatin** is utilized as a comparator treatment in the study. It is provided as a solution for infusion, administered via intravenous infusion. The maximum daily dose is 600 mg, with a total maximum dose of 600 mg over a treatment period of up to 73 days. The chemical nature of Carboplatin is noted, and its administration is carefully monitored to ensure participant safety and adherence to the protocol.
**Gemcitabine** is another comparator treatment used in the trial, also provided as a solution for infusion. It is administered intravenously, with a maximum daily dose of 1000 mg/m² and a total maximum dose of 1000 mg/m² over a treatment period of up to 73 days. The chemical origin of Gemcitabine is documented, and dosing schedules are strictly followed to maintain consistency and reliability in the study outcomes.
**Pembrolizumab**, marketed as Keytruda, is included in the trial as a standard-of-care therapy. It is provided as a concentrate for solution for infusion, administered intravenously. The maximum daily dose is 200 mg, with a total maximum dose of 7000 mg over a treatment period of up to 24 days. Pembrolizumab is a protein-based therapeutic agent, and its administration is closely monitored to ensure compliance and evaluate its efficacy in combination with other treatments in the study.
Efficacy
Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Progression-Free Survival (PFS)** according to the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) and **Overall Survival (OS)**. These endpoints will be evaluated by a blinded independent central review (BICR) to ensure objectivity and accuracy in the assessment of tumor response and patient survival.
Secondary endpoints will further explore the efficacy of the treatment in specific subgroups and include OS and PFS in participants with Programmed Cell Death Ligand 1 (PD-L1) positive tumors with a Combined Positive Score (CPS) ≥10, as well as in participants with Breast Cancer Susceptibility Gene Mutation (BRCAm) tumors. Additionally, changes from baseline in health-related quality of life (QoL) will be measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the Breast Cancer-Specific Quality-of-Life Questionnaire (EORTC QLQ-BR23). These assessments will focus on physical and emotional functioning, systemic therapy side effects, and overall health outcomes using the European Quality of Life 5-dimension, 5-level Questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS) score.
The trial will also monitor the time to deterioration in QoL and the number of participants experiencing adverse events (AEs) or discontinuing treatment due to AEs. These efficacy parameters will be collected and analyzed at specified timepoints throughout the study to provide comprehensive data on the treatment's impact on disease progression, survival, and patient quality of life.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Has locally recurrent inoperable Triple Negative Breast Cancer (TNBC) that has not previously been treated with chemotherapy and that cannot be treated with curative intent OR has metastatic TNBC that has not been previously treated with chemotherapy
- Has been treated with anthracycline and/or a taxane in the neoadjuvant/adjuvant setting, if they received systemic treatment in the neoadjuvant/adjuvant setting, unless anthracycline and/or taxane was contraindicated or not considered the best treatment option for the participant in the opinion of the treating physician
- Has measurable disease based on RECIST 1.1
- Has provided a recently obtained or archival (no more than 3 years old) core or excisional biopsy of a tumor lesion not previously irradiated
- Be a male or female at least 18 years of age
- Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 as assessed within 7 days prior to the start of induction study treatment
- Has a life expectancy ≥27 weeks from the day of first study treatment
- Demonstrate adequate organ function within 10 days prior to the start of study treatment
- A male participant must agree to be abstinent or use contraception and refrain from donating sperm during the intervention period and for at least the time needed to eliminate each study intervention (95 days for olaparib and chemotherapy; no requirement for pembrolizumab)
- A female participant must not be pregnant or breastfeeding and must agree to the following if is a woman of childbearing potential (WOCBP): have a negative pregnancy test within 24 hours before the start of study treatment and agree to be abstinent or use contraception and refrain from donating eggs (ova, oocytes) during the intervention period and for at least the time needed to eliminate each study intervention (180 days for olaparib and chemotherapy; 120 days for pembrolizumab)
- Has received up to 6 cycles but not less than 4 cycles of induction therapy without permanently discontinuing from pembrolizumab or both carboplatin and gemcitabine
- Has achieved complete response (CR), partial response (PR), or stable disease (SD) based on RECIST 1.1 by Blinded Independent Central Review (BICR) at the Week 18 evaluation
- Is able to complete during post-induction at least the Cycle 1, Day 1 doses of olaparib and pembrolizumab or the Cycle 1, Day 1 doses of at least one of the chemotherapy agents being administered at the end of induction (carboplatin and/or gemcitabine) in addition to pembrolizumab
- Has ECOG performance status of 0 or 1, as assessed within 7 days prior to the start of post-induction study treatment
- Has no higher than Grade 1 toxicities related to induction therapy (excluding alopecia) prior to randomization
Exclusion Criteria
- Has a known additional malignancy that is progressing or has required active treatment within the past 5 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, cervical cancer in situ) that have undergone potentially curative therapy
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study treatment
- Has an active autoimmune disease that has required systemic treatment in the past 2 years
- Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
- Has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or has features suggestive of MDS/AML
- Has a history of (non-infectious) pneumonitis\interstitial lung disease that required steroids or current pneumonitis\interstitial lung disease
- Has active, or a history of, interstitial lung disease
- Has a known history of active tuberculosis
- Has an active infection requiring systemic therapy
- Has a known history of human immunodeficiency virus (HIV) infection
- Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection
- Has a history of class II-IV congestive heart failure or myocardial infarction within 6 months of first study treatment
- Has neuropathy ≥Grade 2
- Has not recovered (eg, to ≤Grade 1 or to baseline) from AEs due to a previously administered therapy
- Has a known history of hypersensitivity or allergy to pembrolizumab, olaparib and any of its components, and/or to any of the study chemotherapies (eg, carboplatin or gemcitabine) and any of their components
- Has severe hypersensitivity (≥Grade 3) to the study treatments and/or any of their excipients
- Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the Screening Visit through 180 days after the last dose of study treatment
- Is a WOCBP who has a positive urine pregnancy test within 24 hours prior to randomization or treatment allocation
- Has received prior therapy with either olaparib or any other poly adenosine diphosphate ribose polymerase (PARP) inhibitor
- Has received prior radiotherapy within 2 weeks of start of study treatment
- Has received colony-stimulating factors (eg, granulocyte colony stimulating factor [G-CSF], granulocyte macrophage colony stimulating factor [GM-CSF] or recombinant erythropoietin) within 2 weeks prior to the first dose of study treatment
- Has had an allogenic tissue/solid organ transplant
- Has received previous allogenic bone marrow transplant or double umbilical cord transplantation (dUCBT)
- Has 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 or live-attenuated vaccine within 30 days prior to first study treatment
- Is receiving any medication prohibited in combination with study chemotherapies unless medication was stopped within 7 days prior to first study treatment
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T cell receptor (such as cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX-40, CD137) or has previously participated in a study evaluating pembrolizumab regardless of treatment received
- Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment
- Has presence of uncontrolled, potentially reversible cardiac conditions, as judged by the investigator
- 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
- Is either unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (eg, gastrectomy, partial bowel obstruction, malabsorption)
- Is unlikely to comply with the study procedures, restrictions, and requirements of the study; as judged by the investigator
- Has severe hypersensitivity (≥Grade 3) to the study treatments and/or any of their excipients
- Has permanently discontinued from both carboplatin and gemcitabine during induction due to toxicity
- Has permanently discontinued from pembrolizumab during induction due to toxicity
- Has received less than 4 cycles of chemotherapy plus pembrolizumab during induction
- Is currently receiving either strong or moderate inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study
- Is currently receiving either strong or moderate inducers of CYP3A4 that cannot be discontinued for the duration of the study
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 30 Dec 2019 | 36 |
 Germany | Not Recruiting | 30 Dec 2019 | 7 |
 Hungary | Not Recruiting | 30 Dec 2019 | 22 |
 Ireland | Not Recruiting | 30 Dec 2019 | 19 |
 Poland | Not Recruiting | 30 Dec 2019 | 19 |
 Spain | Not Recruiting | 30 Dec 2019 | 8 |
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 |
|---|---|---|---|---|---|---|
Olaparib | Test | FILM-COATED TABLET | ORAL | 600 | 69 | PRD9414227 |
CARBOPLATIN | Test | — | IV INFUSION | 600 | 73 | SUB06614MIG |
Olaparib | Test | FILM-COATED TABLET | ORAL | 600 | 69 | PRD9414228 |
GEMCITABINE | Test | — | INTRAVENOUS | 1000 | 73 | SUB07892MIG |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 200 | 24 | PRD4323105 |