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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02861573
Recruitment Status : Recruiting
First Posted : August 10, 2016
Last Update Posted : November 25, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Tracking Information
First Submitted Date  ICMJE August 3, 2016
First Posted Date  ICMJE August 10, 2016
Last Update Posted Date November 25, 2019
Actual Study Start Date  ICMJE November 17, 2016
Estimated Primary Completion Date March 15, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 28, 2018)
  • 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 ]
  • Number of Participants with Adverse Events (AEs) [ Time Frame: Assessed Every 3 Weeks Over the Duration of the Study Which is Estimated to be Approximately 2 Years ]
  • Number of Participants Discontinuing Study Drug Due to AEs [ Time Frame: Assessed Every 3 Weeks Over the Duration of the Study Which is Estimated to be Approximately 2 Years ]
  • Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) [ Time Frame: Assessed Over the Duration of the Study Which is Estimated to be Approximately 2 Years ]
Original Primary Outcome Measures  ICMJE
 (submitted: August 5, 2016)
  • 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 ]
  • Number of Participants with Adverse Events (AEs) [ Time Frame: Assessed Every 3 Weeks Over the Duration of the Study Which is Estimated to be Approximately 2 Years ]
  • Number of Participants Discontinuing Study Drug Due to AEs [ Time Frame: Assessed Every 3 Weeks Over the Duration of the Study Which is Estimated to be Approximately 2 Years ]
Change History Complete list of historical versions of study NCT02861573 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 28, 2018)
  • 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 ]
  • Overall Survival (OS) [ Time Frame: Assessed Over the Duration of the Study Which is Estimated to be Approximately 2 Years ]
  • 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 ]
  • 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 ]
  • Time to PSA Progression [ Time Frame: Assessed Over the Duration of the Study Which is Estimated to be Approximately 2 Years ]
  • 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 ]
  • 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 ]
  • 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: August 5, 2016)
  • Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 [ Time Frame: Over the Duration of the Study Which is Estimated to be Approximately 2 Years ]
  • Disease Control Rate Based on Prostate Cancer Working Group 3 (PCWG3)-modified RECIST 1.1 [ Time Frame: Over the Duration of the Study Which is Estimated to be Approximately 2 Years ]
  • Overall Survival [ Time Frame: Over the Duration of the Study Which is Estimated to be Approximately 2 Years ]
  • Duration of Response Based on PCWG3-modified RECIST 1.1 [ Time Frame: Over the Duration of the Study Which is Estimated to be Approximately 2 Years ]
  • ORR Based on PCWG3-modified RECIST 1.1 [ Time Frame: Over the Duration of the Study Which is Estimated to be Approximately 2 Years ]
  • Time to PSA Progression [ Time Frame: Over the Duration of the Study Which is Estimated to be Approximately 2 Years ]
  • Radiographic Progression-free Survival Based on PCWG3-modified RECIST 1.1 [ Time Frame: Over the Duration of the Study Which is Estimated to be Approximately 2 Years ]
  • 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: Over the Duration of the Study Which is Estimated to be Approximately 2 Years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Pembrolizumab (MK-3475) Combination Therapies in Metastatic Castration-Resistant Prostate Cancer (MK-3475-365/KEYNOTE-365)
Official Title  ICMJE Phase Ib/II Trial of Pembrolizumab (MK-3475) Combination Therapies in Metastatic Castration-Resistant Prostate Cancer (mCRPC) (KEYNOTE-365)
Brief Summary 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Metastatic Castration-Resistant Prostate Cancer
Intervention  ICMJE
  • Biological: Pembrolizumab 200 mg
    IV Q3W
    Other Name: KEYTRUDA®
  • Drug: Olaparib 400 mg
    Eight 50-mg capsules PO BID
    Other Names:
    • LYNPARZA®
    • MK-7339
  • Drug: Docetaxel 75 mg/m^2
    IV Q3W
    Other Name: TAXOTERE®
  • Drug: Prednisone 5 mg
    One 5-mg tablet PO BID
  • Drug: Enzalutamide 160 mg
    Four 40-mg capsules, four 40-mg tablets, or two 80-mg tablets PO QD
    Other Name: XTANDI®
  • Other: Dexamethasone 8 mg
    Premedication for Cohort B given PO at 12, 3, and 1 hours prior to docetaxel infusion Q3W
  • Drug: Olaparib 300 mg
    Two 150-mg tablets PO BID
    Other Name: LYNPARZA®
  • Drug: Abiraterone acetate 1000 mg
    Two 500-mg or four 250-mg tablets PO QD
    Other Name: ZYTIGA®
Study Arms  ICMJE
  • Experimental: Pembrolizumab + Olaparib
    Participants 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.
    Interventions:
    • Biological: Pembrolizumab 200 mg
    • Drug: Olaparib 400 mg
    • Drug: Olaparib 300 mg
  • Experimental: Pembrolizumab + Docetaxel + Prednisone
    Participants 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.
    Interventions:
    • Biological: Pembrolizumab 200 mg
    • Drug: Docetaxel 75 mg/m^2
    • Drug: Prednisone 5 mg
    • Other: Dexamethasone 8 mg
  • Experimental: Pembrolizumab + Enzalutamide
    Participants 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.
    Interventions:
    • Biological: Pembrolizumab 200 mg
    • Drug: Enzalutamide 160 mg
  • Experimental: Pembrolizumab + Abiraterone + Prednisone
    Participants 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.
    Intervention: Drug: Abiraterone acetate 1000 mg
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 28, 2018)
400
Original Estimated Enrollment  ICMJE
 (submitted: August 5, 2016)
210
Estimated Study Completion Date  ICMJE May 18, 2022
Estimated Primary Completion Date March 15, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Gender Based Eligibility: Yes
Gender Eligibility Description: Participants must be male and be ≥18 years of age on day of signing informed consent.
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com
Listed Location Countries  ICMJE Canada,   France,   New Zealand,   United States
Removed Location Countries Australia,   Germany,   Spain,   United Kingdom
 
Administrative Information
NCT Number  ICMJE NCT02861573
Other Study ID Numbers  ICMJE 3475-365
2016-002312-41 ( EudraCT Number )
KEYNOTE-365 ( Other Identifier: Merck )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pd
URL: http://engagezone.msd.com/ds_documentation.php
Responsible Party Merck Sharp & Dohme Corp.
Study Sponsor  ICMJE Merck Sharp & Dohme Corp.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme Corp.
PRS Account Merck Sharp & Dohme Corp.
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP