Clinical Trials /

Study of Pembrolizumab (MK-3475) Combination Therapies in Metastatic Castration-Resistant Prostate Cancer (MK-3475-365/KEYNOTE-365)

NCT02861573

Description:

The purpose of this study is to assess the safety and efficacy of pembrolizumab (MK-3475) combination therapy in patients with metastatic castrate resistant prostate cancer (mCRPC). There will be nine cohorts in this study: Cohort A will receive pembrolizumab + olaparib, Cohort B will receive pembrolizumab + docetaxel + prednisone, Cohort C will receive pembrolizumab + enzalutamide, Cohort D will receive pembrolizumab + abiraterone + prednisone Cohort E will receive pembrolizumab+lenvatinib, Cohort F will receive pembrolizumab+lenvatinib, Cohort G will receive MK-7684A, Cohort H will receive MK-7684A, and Cohort I will receive pembrolizumab+carboplatin+etoposide in Arm 1 and carboplatin+etoposide in Arm 2. Outcome measures will be assessed individually for each cohort.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of Pembrolizumab (MK-3475) Combination Therapies in Metastatic Castration-Resistant Prostate Cancer (MK-3475-365/KEYNOTE-365)
  • Official Title: Phase Ib/II Trial of Pembrolizumab (MK-3475) Combination Therapies in Metastatic Castration-Resistant Prostate Cancer (mCRPC) (KEYNOTE-365)

Clinical Trial IDs

  • ORG STUDY ID: 3475-365
  • SECONDARY ID: 2016-002312-41
  • SECONDARY ID: KEYNOTE-365
  • NCT ID: NCT02861573

Conditions

  • Metastatic Castration-Resistant Prostate Cancer

Interventions

DrugSynonymsArms
Pembrolizumab 200 mgKEYTRUDA®Pembrolizumab + Olaparib
Olaparib 400 mgLYNPARZA®, MK-7339Pembrolizumab + Olaparib
Docetaxel 75 mg/m^2TAXOTERE®Pembrolizumab + Docetaxel + Prednisone
Prednisone 5 mgPembrolizumab + Docetaxel + Prednisone
Enzalutamide 160 mgXTANDI®Pembrolizumab + Enzalutamide
Olaparib 300 mgLYNPARZA®Pembrolizumab + Olaparib
Abiraterone acetate 1000 mgZYTIGA®Pembrolizumab + Abiraterone + Prednisone

Purpose

The purpose of this study is to assess the safety and efficacy of pembrolizumab (MK-3475) combination therapy in patients with metastatic castrate resistant prostate cancer (mCRPC). There will be four cohorts in this study: Cohort A will receive pembrolizumab + olaparib, Cohort B will receive pembrolizumab + docetaxel + prednisone, Cohort C will receive pembrolizumab + enzalutamide, and cohort D will receive pembrolizumab + abiraterone + prednisone. Outcome measures will be assessed individually for each cohort.

Detailed Description

      Assignment of patients to a cohort will be based on prior treatment. Participants assigned to
      Cohort A must have previously received docetaxel for mCRPC. Participants assigned to Cohort B
      must have previously received either abiraterone acetate or enzalutamide (but not both) in
      the pre-chemotherapy mCRPC state. Participants assigned to Cohort C must have previously
      received abiraterone acetate in the pre-chemotherapy mCRPC state (prior docetaxel for
      metastatic hormone-sensitive prostate cancer is allowed if ≥4 weeks have elapsed from the
      last dose of docetaxel). Participants assigned to Cohort D must have not received
      chemotherapy for mCRPC and have either 1) not had prior second generation hormonal
      manipulation for mCRPC or 2) previously been treated with enzalutamide for mCRPC and failed
      treatment or become intolerant of the drug.
    

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab + OlaparibExperimentalParticipants in Cohort A will receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week dosing cycle (Q3W) and olaparib 400 mg capsules or 300 mg tablets by mouth (PO) twice a day (BID) continuously from Day 1 of Cycle 1. Treatment with pembrolizumab will continue until progression or a maximum of 35 treatment cycles (up to 2 years). Treatment with olaparib will continue until progression. Participants who must discontinue 1 of the 2 drugs in the combination due to adverse events may continue the study with the other combination drug.
  • Pembrolizumab 200 mg
  • Olaparib 400 mg
  • Olaparib 300 mg
Pembrolizumab + Docetaxel + PrednisoneExperimentalParticipants in Cohort B will receive pembrolizumab 200 mg IV on Day 1 Q3W, docetaxel 75 mg/m^2 IV on Day 1 Q3W, and prednisone 5 mg tablet PO BID continuously from Day 1 of Cycle 1. Participants will only be permitted to receive a maximum of 10 cycles of docetaxel and prednisone. Treatment with pembrolizumab will continue for a maximum of 35 cycles (up to 2 years) or until progression. Participants who must discontinue 1 of the 2 drugs due to adverse events in the combination may continue the study with the other combination drug.
  • Pembrolizumab 200 mg
  • Docetaxel 75 mg/m^2
  • Prednisone 5 mg
Pembrolizumab + EnzalutamideExperimentalParticipants in Cohort C will receive pembrolizumab 200 mg IV on Day 1 Q3W and enzalutamide 160 mg PO every day (QD) continuously from Day 1 of Cycle 1. Treatment with pembrolizumab will continue until progression or a maximum of 35 treatment cycles (up to 2 years). Treatment with enzalutamide will continue until progression. Participants who must discontinue 1 of the 2 drugs in the combination due to adverse events may continue the study with the other combination drug.
  • Pembrolizumab 200 mg
  • Enzalutamide 160 mg
Pembrolizumab + Abiraterone + PrednisoneExperimentalParticipants in Cohort D will receive pembrolizumab 200 mg IV on Day 1 Q3W, abiraterone acetate 1000 mg PO QD and prednisone 5 mg tablet PO BID continuously from Day 1 of Cycle 1. Treatment with pembrolizumab will continue for a maximum of 35 cycles (up to 2 years) or until progression. Participants who must discontinue 1 of the 2 drugs due to adverse events in the combination may continue the study with the other combination drug.
  • Abiraterone acetate 1000 mg

Eligibility Criteria

        Inclusion Criteria:

          -  Has histologically- or cytologically-confirmed adenocarcinoma of the prostate without
             small cell histology

          -  Is able to provide tumor tissue from a site not previously irradiated as follows:
             Cohort A must provide a core or excisional biopsy from soft tissue or bone biopsy
             within 1 year of screening and after developing mCRPC; Cohort B: must provide an
             archival tumor tissue sample or tumor tissue from a newly obtained core or excisional
             biopsy from soft tissue if the lesion is clinically accessible; and Cohorts C and D
             with soft tissue disease must provide a core or excisional biopsy from a soft tissue
             lesion if clinically accessible within 1 year of screening and after developing mCRPC
             and an archival specimen if available. Participants with bone metastasis only must
             provide an archival tumor tissue specimen

          -  Has prostate cancer progression within 6 months prior to screening, as determined by
             the investigator, by means of one of the following: PSA progression as defined by a
             minimum of 2 rising PSA levels with an interval of ≥1 week between each assessment
             where the PSA value at screening should be ≥2 ng/mL; radiographic disease progression
             in soft tissue based on Response Evaluation Criteria In Solid Tumors Version 1.1
             criteria with or without PSA progression; radiographic disease progression in bone
             defined as the appearance of 2 or more new bone lesions on bone scan with or without
             PSA progression

          -  Has ongoing androgen deprivation with serum testosterone <50 ng/dL (<2.0 nM).
             Treatment with luteinizing hormone-releasing hormone agonists or antagonists for all
             Cohorts must have been initiated ≥4 weeks prior to first dose of study therapy and
             must be continued throughout the study

          -  Participants receiving bone resorptive therapy (including, but not limited to
             bisphosphonate or receptor activator of nuclear factor kappa-β ligand inhibitor) must
             be on stable doses for ≥4 weeks prior to first dose of study therapy

          -  Women of childbearing potential and male participants must agree to use adequate
             contraception starting with the first dose of study therapy through 120 days after the
             last dose of study therapy

          -  Has a performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group
             (ECOG) Performance Scale for Cohorts A and C and a performance status of 0 or 1 for
             Cohort B within 10 days of study start

          -  For Cohort A: Has received docetaxel for mCRPC. Prior treatment with 1 other
             chemotherapy for mCRPC is allowed. Up to 2 second-generation hormonal manipulations
             (e.g., abiraterone acetate and/or enzalutamide) are allowed. Prior docetaxel for
             metastatic hormone-sensitive prostate cancer is allowed if ≥4 weeks have elapsed from
             the last dose of docetaxel prior to day 1 of Cycle 1

          -  For Cohort B: Has received prior treatment with either abiraterone acetate or
             enzalutamide (but not both) in the prechemotherapy mCRPC state. Participants in Cohort
             B must have received at least 4 weeks of either abiraterone or enzalutamide treatment
             (but not both) who failed treatment or became intolerant of the drug

          -  For Cohort C: Has received prior treatment with abiraterone acetate in the
             pre-chemotherapy mCRPC state without prior enzalutamide. Participants in Cohort C must
             have received at least 4 weeks of abiraterone treatment who failed treatment or become
             intolerant of the drug. Participants who received abiraterone acetate in the
             hormone-sensitive state will not be eligible

          -  For Cohort D: Has not received chemotherapy for mCRPC and has either not had prior
             second generation hormonal manipulation for mCRPC OR has previously been treated with
             enzalutamide for mCRPC and failed treatment or has become intolerant of the drug.
             Prior docetaxel for metastatic hormone-sensitive prostate cancer is allowed if ≥4
             weeks have elapsed from the last dose of docetaxel. Prior treatment with abiraterone
             acetate in the hormone-sensitive metastatic setting is allowed as long as there was no
             progression on this agent and abiraterone acetate was not discontinued due to adverse
             events (AEs). Participants in Cohort D must have a performance status of 0 or 1 on the
             ECOG Performance Scale

        Exclusion Criteria:

          -  Has had a prior anticancer monoclonal antibody (mAb) within 4 weeks prior to first
             dose study therapy or who has not recovered (i.e., Grade ≤1 or at baseline) from AEs
             due to mAbs administered >4 weeks earlier

          -  Has had prior chemotherapy, targeted small molecule therapy abiraterone treatment,
             enzalutamide treatment, or radiation therapy within 2 weeks prior to first dose of
             study therapy or who has not recovered (ie, Grade ≤1 or at baseline) from AEs due to a
             previously administered agent

          -  Is currently participating in and receiving study therapy or has participated in a
             study of an investigational agent and received study drug or used an investigational
             device within 4 weeks of treatment allocation

          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior to treatment allocation

          -  Has had a prior radium treatment or treatment with other therapeutic
             radiopharmaceuticals for prostate cancer

          -  Has an active autoimmune disease that has required systemic treatment in past 2 years

          -  Has a history of (non-infectious) pneumonitis that required steroids or current
             pneumonitis

          -  Has previously participated in any other pembrolizumab (MK-3475) trial, or received
             prior therapy with an anti-programmed cell death 1 (anti-PD-1), anti-programmed cell
             death ligand 1 (anti-PD-L1), and anti-programmed cell death ligand 1 (anti-PD-L2)

          -  Has a known history of Human Immunodeficiency Virus (HIV)

          -  Has known active Hepatitis B or Hepatitis C

          -  Has received a live vaccine within 30 days of the first dose of study therapy

          -  Has known active central nervous system metastases and/or carcinomatous meningitis

          -  Has a "superscan" bone scan defined as an intense symmetric activity in the bones and
             diminished renal parenchymal activity on baseline bone scan such that the presence of
             additional metastases in the future could not be evaluated

          -  Has had prior solid, organ or bone marrow transplant

          -  For Cohort A: Has experienced a seizure or seizures within 6 months of study start or
             is currently being treated with cytochrome P450 enzyme (CYP) inducing anti-epileptic
             drugs for seizures

          -  For Cohort A: Is currently receiving strong or moderate inhibitors of CYP3A4 including
             azole antifungals; macrolide antibiotics; or protease inhibitors

          -  For Cohort A: Is currently receiving strong or moderate inducers of CYP3A4

          -  For Cohort A: Has myelodysplastic syndrome

          -  For Cohort A: Has symptomatic congestive heart failure (New York Heart Association
             Class III or IV heart disease), unstable angina pectoris, cardiac arrhythmia, or
             uncontrolled hypertension

          -  For Cohort B: Has received prior treatment with docetaxel or another chemotherapy
             agent for metastatic prostate cancer

          -  For Cohort B: Has peripheral neuropathy Common Terminology Criteria for Adverse Events
             ≥2 except due to trauma

          -  For Cohort B: Has ascites and/or clinically significant pleural effusion

          -  For Cohort B:Has symptomatic congestive heart failure (New York Heart Association
             Class III or IV heart disease)

          -  For Cohort B: Is currently receiving any of the following classes of inhibitors of
             CYP3A4: azole antifungals; macrolide antibiotics; or protease inhibitors

          -  For Cohort C: Has received prior chemotherapy for mCRPC. Prior docetaxel for
             metastatic hormone-sensitive prostate cancer is allowed if ≥4 weeks elapsed from last
             dose of docetaxel. Participants who received abiraterone acetate in the
             hormone-sensitive state will not be eligible

          -  For Cohort C: Has a history of seizure or any condition that may predispose to seizure
             (including, but not limited to prior cerebrovascular accident, transient ischemic
             attack, or brain arteriovenous malformation; or intracranial masses such as a
             schwannoma or meningioma that is causing edema or mass effect)

          -  For Cohort C:Has known or suspected brain metastasis or leptomeningeal carcinomatosis

          -  For Cohort C: Has a history of loss of consciousness within 12 months of the screening
             visit

          -  For Cohort C: Has hypotension (systolic blood pressure <86 millimeters of mercury
             [mmHg]) or uncontrolled hypertension (systolic blood pressure >170 mmHg or diastolic
             blood pressure >105 mmHg) at the screening visit

          -  For Cohort C: Has received treatment with 5-α reductase inhibitors (e.g., finasteride,
             dutasteride), estrogens, and/or cytproterone within 4 weeks prior to Cycle 1

          -  For Cohort C: Has a history of prostate cancer progression on ketoconazole

          -  For Cohort D: Has received prior treatment with docetaxel or another chemotherapy
             agent for metastatic prostate cancer

          -  For Cohort D: Has progressed on prior abiraterone acetate for treatment of castration
             sensitive or resistant metastatic prostate cancer

          -  For Cohort D: Has discontinued prior treatment with abiraterone acetate due to AEs

          -  For Cohort D: Has previously been treated with ketoconazole for prostate cancer for >7
             days

          -  For Cohort D: Has received prior systemic treatment with an azole drug (eg,
             fluconazole, itraconazole) within 4 weeks of Cycle 1, Day 1

          -  For Cohort D: Has uncontrolled hypertension (systolic BP ≥ 160 mm Hg or diastolic BP ≥
             95 mm Hg)

          -  For Cohort D: Has a history of pituitary or adrenal dysfunction

          -  For Cohort D: Has clinically significant heart disease as evidenced by myocardial
             infarction, or arterial thrombotic events in the past 6 months, severe or unstable
             angina, or New York Heart Association Class II-IV heart disease or cardiac ejection
             fraction measurement of <50% at baseline

          -  For Cohort D: Has atrial fibrillation, or other cardiac arrhythmia requiring therapy

          -  For Cohort D: Has a history of chronic liver disease

          -  For Cohort D: Is currently receiving strong CYP3A4 inducers (eg, phenytoin,
             carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) during abiraterone
             acetate treatment, CYP2D6 substrates with a narrow therapeutic index (for example
             thioridazine), or CYP2C8 substrates with a narrow therapeutic index (for example
             pioglitazone)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of Participants With a Decrease of ≥50% in Prostatic Specific Antigen (PSA)
Time Frame:From Baseline Measured Every 3 Weeks Until Radiographic Progression Estimated to be Approximately 2 Years
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Disease Control Rate (DCR) Based on Prostate Cancer Working Group 3 (PCWG3)-modified RECIST 1.1 Assessed by BICR
Time Frame:Assessed Over the Duration of the Study Which is Estimated to be Approximately 2 Years
Safety Issue:
Description:
Measure:Overall Survival (OS)
Time Frame:Assessed Over the Duration of the Study Which is Estimated to be Approximately 2 Years
Safety Issue:
Description:
Measure:Duration of Response (DOR) Based on PCWG3-modified RECIST 1.1 Assessed by BICR
Time Frame:Assessed Over the Duration of the Study Which is Estimated to be Approximately 2 Years
Safety Issue:
Description:
Measure:ORR Based on PCWG3-modified RECIST 1.1 Assessed by BICR
Time Frame:Assessed Over the Duration of the Study Which is Estimated to be Approximately 2 Years
Safety Issue:
Description:
Measure:Time to PSA Progression
Time Frame:Assessed Over the Duration of the Study Which is Estimated to be Approximately 2 Years
Safety Issue:
Description:
Measure:Radiographic Progression-free Survival (rPFS) Based on PCWG3-modified RECIST 1.1 Assessed by BICR
Time Frame:Assessed Over the Duration of the Study Which is Estimated to be Approximately 2 Years
Safety Issue:
Description:
Measure:Composite Response Rate Defined as Any One of the Following: A. Response Based on RECIST 1.1; B. PSA Decrease of ≥50%; or C. Circulating Tumor-cell Count Conversion (Pembrolizumab + Olaparib Cohort Only)
Time Frame:Assessed Over the Duration of the Study Which is Estimated to be Approximately 2 Years
Safety Issue:
Description:
Measure:ORR Based on PCWG3-modified RECIST 1.1 Criteria Assessed by BICR
Time Frame:Assessed Over the Duration of the Study Which is Estimated to be Approximately 2 Years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Merck Sharp & Dohme Corp.

Trial Keywords

  • Metastatic Castration-Resistant Prostate Cancer
  • mCRPC
  • PD1
  • PD-1
  • PDL1
  • PD-L1

Last Updated

July 18, 2019