Study of Olaparib Plus Pembrolizumab Versus Chemotherapy Plus Pembrolizumab After Induction With First-Line Chemotherapy Plus Pembrolizumab in Triple Negative Breast Cancer (TNBC) (MK-7339-009/KEYLYNK-009)

Study Overview
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Brief Summary
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The purpose of this study is to compare the efficacy of olaparib (MK-7339) plus pembrolizumab (MK-3475) with chemotherapy plus pembrolizumab after induction with first-line chemotherapy plus pembrolizumab in triple negative breast cancer (TNBC). The primary hypotheses are: Olaparib plus pembrolizumab is superior to chemotherapy plus pembrolizumab with respect to progression-free survival (PFS). Olaparib plus pembrolizumab is superior to chemotherapy plus pembrolizumab with respect to overall survival (OS). As of Amendment 3, study enrollment is being discontinued. Participants who are receiving benefit from the study intervention may continue treatment until criteria for discontinuation are met. Participants who are on study treatment or in follow-up phase will no longer have tumor response assessments by BICR.

Official Title
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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)

Conditions
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Triple Negative Breast Neoplasms

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Olaparib
* Drug: Carboplatin
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Induction Period: Has locally recurrent inoperable 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 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) Post-induction Period: 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: Induction Period: 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 Post-induction Period: 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

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: pembrolizumab + carboplatin and gemcitabine<br>Participants receive both carboplatin Area Under The Curve (AUC) 2 with gemcitabine 1000 mg/m^2 intravenously on Days 1 and 8 of each 21-day cycle plus pembrolizumab 200 mg intravenously on Day 1 of each 21-day cycle during the induction period for 4-6 cycles. After the induction period, participants will continue to receive both carboplatin AUC 2 with gemcitabine 1000 mg/m^2 intravenously on Days 1 and 8 of each 21-day cycle in addition to pembrolizumab 200 mg intravenously on Day 1 of each 21-day cycle in the post-induction period. | Biological: Pembrolizumab<br>* intravenous (IV) infusion<br>* Other names: MK-3475;Drug: Carboplatin<br>* IV infusion<br>* Other names: PARAPLATIN®;Drug: Gemcitabine<br>* IV infusion<br>* Other names: GEMZAR®;|
| Experimental: pembrolizumab + olaparib<br>Participants receive both carboplatin AUC 2 with gemcitabine 1000 mg/m^2 intravenously on Days 1 and 8 of each 21-day cycle plus pembrolizumab 200 mg intravenously on Day 1 of each 21-day cycle during the induction period for 4-6 cycles. After the induction period, participants will receive pembrolizumab 200 mg intravenously on Day 1 of each 21-day cycle plus olaparib 300 mg orally twice daily during the post-induction period. | Biological: Pembrolizumab<br>* intravenous (IV) infusion<br>* Other names: MK-3475;Drug: Olaparib<br>* oral tablets<br>* Other names: KU-0059436;Drug: Carboplatin<br>* IV infusion<br>* Other names: PARAPLATIN®;Drug: Gemcitabine<br>* IV infusion<br>* Other names: GEMZAR®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | PFS is defined as the time from randomization to the first documented disease progression or death due to any cause, whichever occurs first. | Up to approximately 35 months | 
| Overall Survival (OS) | OS is the time from randomization to death due to any cause. | Up to approximately 35 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) in Participants with Programmed Cell Death-Ligand 1 (PD-L1) Positive Tumors with a Combined Positive Score (CPS) ≥10 | OS is the time from randomization to death due to any cause. | Up to approximately 35 months | 
| Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants with Programmed Cell Death-Ligand 1 (PD-L1) Positive Tumors with a Combined Positive Score (CPS) ≥10 | PFS is defined as the time from randomization to the first documented disease progression or death due to any cause, whichever occurs first. | Up to approximately 35 months | 
| Overall Survival (OS) in Participants with Breast Cancer Susceptibility Gene Mutation (BRCAm) Tumors | OS is the time from randomization to death due to any cause. | Up to approximately 35 months | 
| Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants with Breast Cancer Susceptibility Gene Mutation (BRCAm) Tumors | PFS is defined as the time from randomization to the first documented disease progression or death due to any cause, whichever occurs first. | Up to approximately 35 months | 
| Change From Baseline in Health-Related Quality-of-Life (QoL) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 29 and 30 Score | The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the questions How would you rate your overall health during the past week? and How would you rate your overall quality of life during the past week? are scored on a 7-point scale (1= Very poor to 7=Excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better overall health status. The change from baseline in EORTC QLQ-C30 Items 29 and 30 scores will be presented. | Baseline and up to approximately 35 months | 
| Change From Baseline in Physical Functioning Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 1- 5 Score | The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better quality of life. The change from baseline in physical functioning (EORTC QLQ-C30 Items 1-5) score will be presented. | Baseline and up to approximately 35 months | 
| Change From Baseline in Emotional Functioning Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 21-24 Score | The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to 4 questions about their emotional functioning are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better quality of life. The change from baseline in emotional functioning (EORTC QLQ-C30 Items 21-24) score will be presented. | Baseline and up to approximately 35 months | 
| Change From Baseline in Systemic Therapy Side Effects Using the European Organization for Research and Treatment of Cancer Breast Cancer-Specific Quality-of-Life (QoL) Questionnaire (EORTC QLQ-BR23) Items 1-4, 6, 7, and 8 Score | EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual enjoyment, sexual functioning, future perspective) and four symptom scales (systemic therapy side effects, upset by hair loss, arm symptoms, breast symptoms). Participant responses to 7 questions about their systemic therapy side effects are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better quality of life. The change from baseline in systemic therapy side effects (EORTC QLQ-BR23 Items 1-4, 6, 7, and 8) score will be presented. | Baseline and up to approximately 35 months | 
| Time to Deterioration in Health-Related Quality-of-Life (QoL) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 29 and 30 Score | The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the questions How would you rate your overall health during the past week? and How would you rate your overall quality of life during the past week? are scored on a 7-point scale (1= Very poor to 7=Excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better overall health status. TTD was defined as the time from baseline to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in Items 29 and 30 scale scores. | Up to approximately 35 months | 
| Time to Deterioration in Physical Functioning Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 1- 5 Score | The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better quality of life. TTD was defined as the time from baseline to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in physical functioning Items 1 to 5 scale scores. | Up to approximately 35 months | 
| Time to Deterioration in Emotional Functioning Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 21-24 Score | The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to 4 questions about their emotional functioning are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better quality of life. TTD was defined as the time from baseline to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in emotional functioning Items 21-24 scale scores. | Up to approximately 35 months | 
| Time to Deterioration in Systemic Therapy Side Effects Using the European Organization for Research and Treatment of Cancer Breast Cancer-Specific Quality-of-Life (QoL) Questionnaire (EORTC QLQ-BR23) Items 1-4, 6, 7, and 8 Score | EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual enjoyment, sexual functioning, future perspective) and four symptom scales (systemic therapy side effects, upset by hair loss, arm symptoms, breast symptoms). Participant responses to 7 questions about their systemic therapy side effects are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better quality of life. TTD was defined as the time from baseline to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in systemic therapy side effects Items 1-4, 6, 7 and 8 scale scores. | Up to approximately 35 months | 
| Change From Baseline in Health Outcomes using the European Quality of Life 5-dimension, 5-level Questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS) Score | The EQ-5D-5L measured health-related outcomes, assessing 5 health state dimensions (mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression) on a 5-point scale from 1 (no problem) to 5 (unable to/extreme problems). The EQ-5D-5L also includes a graded (0 to 100) vertical visual analog scale on which the participant rates their general state of health. The change from baseline in EQ-5D-5L score will be presented. | Baseline and up to approximately 35 months | 
| Number of Participants Who Experienced At Least One Adverse Event (AE) | An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study therapy and irrespective of causality to study therapy. | Up to approximately 35 months | 
| Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study therapy and irrespective of causality to study therapy. | Up to approximately 35 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death Receptor 1 (PD-1, PD1), Programmed Cell Death Receptor Ligand 1 (PD-L1, PDL1), Programmed Cell Death Receptor Ligand 2 (PD-L2, PDL2)