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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)

NCT04191135

Description:

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: 1. Olaparib plus pembrolizumab prolongs progression-free survival (PFS) compared with chemotherapy plus pembrolizumab. 2. Olaparib plus pembrolizumab is non-inferior to chemotherapy plus pembrolizumab in terms of overall survival (OS). 3. Olaparib plus pembrolizumab prolongs OS compared with chemotherapy plus pembrolizumab.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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)
  • Official Title: 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)

Clinical Trial IDs

  • ORG STUDY ID: 7339-009
  • SECONDARY ID: 2019-001892-35
  • SECONDARY ID: MK-7339-009
  • SECONDARY ID: KEYLYNK-009
  • SECONDARY ID: 195082
  • NCT ID: NCT04191135

Conditions

  • Triple Negative Breast Neoplasms

Interventions

DrugSynonymsArms
PembrolizumabKEYTRUDA®, MK-3475pembrolizumab + carboplatin and gemcitabine
OlaparibLYNPARZA®, MK-7339, AZD2281, KU-0059436pembrolizumab + olaparib
CarboplatinPARAPLATIN®pembrolizumab + carboplatin and gemcitabine
GemcitabineGEMZAR®pembrolizumab + carboplatin and gemcitabine

Purpose

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: 1. Olaparib plus pembrolizumab prolongs progression-free survival (PFS) compared with chemotherapy plus pembrolizumab. 2. Olaparib plus pembrolizumab is non-inferior to chemotherapy plus pembrolizumab in terms of overall survival (OS). 3. Olaparib plus pembrolizumab prolongs OS compared with chemotherapy plus pembrolizumab.

Trial Arms

NameTypeDescriptionInterventions
pembrolizumab + carboplatin and gemcitabineExperimentalParticipants 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.
  • Pembrolizumab
  • Carboplatin
  • Gemcitabine
pembrolizumab + olaparibExperimentalParticipants 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.
  • Pembrolizumab
  • Olaparib
  • Carboplatin
  • Gemcitabine

Eligibility Criteria

        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

          -  A male participant must agree to be abstinent or use contraception and refrain from
             donating sperm during the intervention period and for at least 180 days after the last
             dose of study treatment

          -  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 180 days after the last dose of study treatment

        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 that required steroids or current
             pneumonitis

          -  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 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 a resting electrocardiogram (ECG) indicating 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
Time Frame:Up to approximately 72 months
Safety Issue:
Description:PFS is defined as the time from randomization to the first documented disease progression or death due to any cause, whichever occurs first.

Secondary Outcome Measures

Measure:Overall Survival (OS) in Participants with Breast Cancer Susceptibility Gene Mutation (BRCAm) Tumors
Time Frame:Up to approximately 72 months
Safety Issue:
Description:OS is the time from randomization to death due to any cause.
Measure: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
Time Frame:Up to approximately 72 months
Safety Issue:
Description:PFS is defined as the time from randomization to the first documented disease progression or death due to any cause, whichever occurs first.
Measure:Change From Baseline in Health-Related Quality-of-Life (HRQoL) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 29 and 30 Score
Time Frame:Baseline and up to approximately 72 months
Safety Issue:
Description: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.
Measure: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
Time Frame:Baseline and up to approximately 72 months
Safety Issue:
Description: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.
Measure: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
Time Frame:Baseline and up to approximately 72 months
Safety Issue:
Description: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.
Measure: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
Time Frame:Baseline and up to approximately 72 months
Safety Issue:
Description: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.
Measure:Time to Deterioration in Health-Related Quality-of-Life (HRQoL) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 29 and 30 Score
Time Frame:Up to approximately 72 months
Safety Issue:
Description: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 (at randomization) 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.
Measure: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
Time Frame:Up to approximately 72 months
Safety Issue:
Description: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 (at randomization) 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.
Measure: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
Time Frame:Up to approximately 72 months
Safety Issue:
Description: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 (at randomization) 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.
Measure: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
Time Frame:Up to approximately 72 months
Safety Issue:
Description: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 (at randomization) 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.
Measure:Change From Baseline in Health Outcomes using the European Quality of Life 5-dimension, 5-level Questionnaire (EuroQoL EQ-5D-5L) Visual Analogue Scale (VAS) Score
Time Frame:Baseline and up to approximately 72 months
Safety Issue:
Description:The EuroQoL 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 EuroQoL 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 EuroQoL EQ-5D-5L score will be presented.
Measure:Number of Participants Who Experienced At Least One Adverse Event (AE)
Time Frame:Up to approximately 72 months
Safety Issue:
Description: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.
Measure:Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
Time Frame:Up to approximately 72 months
Safety Issue:
Description: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.

Details

Phase:Phase 2/Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Merck Sharp & Dohme Corp.

Trial Keywords

  • 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)

Last Updated

December 30, 2019