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

This study is currently recruiting participants.
Verified September 2017 by Merck Sharp & Dohme Corp.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02861573
First Posted: August 10, 2016
Last Update Posted: September 22, 2017
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.
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
  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 three cohorts in this study with 70 participants enrolled in each cohort: Cohort A will receive pembrolizumab + olaparib, Cohort B will receive pembrolizumab + docetaxel + prednisone, and Cohort C will receive pembrolizumab + enzalutamide. Outcome measures will be assessed individually for each cohort.

Condition Intervention Phase
Metastatic Castration-Resistant Prostate Cancer Biological: Pembrolizumab 200 mg Drug: Olaparib 400 mg Drug: Docetaxel 75 mg/m^2 Drug: Prednisone 5 mg Drug: Enzalutamide 160 mg Other: Dexamethasone 8 mg Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase Ib/II Trial of Pembrolizumab (MK-3475) Combination Therapies in Metastatic Castration-Resistant Prostate Cancer (mCRPC) (KEYNOTE-365)

Resource links provided by NLM:


Further study details as provided by Merck Sharp & Dohme Corp.:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 180
Actual Study Start Date: November 17, 2016
Estimated Study Completion Date: April 18, 2020
Estimated Primary Completion Date: April 18, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 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.
Biological: Pembrolizumab 200 mg
IV Q3W
Other Name: KEYTRUDA®
Drug: Olaparib 400 mg
Eight 50-mg capsules PO BID
Other Name: LYNPARZA®
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.
Biological: Pembrolizumab 200 mg
IV Q3W
Other Name: KEYTRUDA®
Drug: Docetaxel 75 mg/m^2
IV Q3W
Other Name: TAXOTERE®
Drug: Prednisone 5 mg
One 5-mg tablet PO BID
Other: Dexamethasone 8 mg
Premedication for Cohort B given PO at 12, 3, and 1 hours prior to docetaxel infusion Q3W
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.
Biological: Pembrolizumab 200 mg
IV Q3W
Other Name: KEYTRUDA®
Drug: Enzalutamide 160 mg
Four 40-mg capsules PO QD
Other Name: XTANDI®

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).
  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
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.
Accepts Healthy Volunteers:   No
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 Cohort C 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 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
  • 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.

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-PD ligand 1 [anti-PD-L1], and 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.
  • 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
  • For Cohort C: Has a history of seizure or any condition that may predispose to seizure
  • 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 of the screening visit
  • For Cohort C: Has a history of prostate cancer progression on ketoconazole
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02861573


Contacts
Contact: Toll Free Number 1-888-577-8839

  Show 20 Study Locations
Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.
  More Information

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT02861573     History of Changes
Other Study ID Numbers: 3475-365
2016-002312-41 ( EudraCT Number )
First Submitted: August 3, 2016
First Posted: August 10, 2016
Last Update Posted: September 22, 2017
Last Verified: September 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Merck Sharp & Dohme Corp.:
Metastatic Castration-Resistant Prostate Cancer
mCRPC
PD1
PD-1
PDL1
PD-L1

Additional relevant MeSH terms:
Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Dexamethasone
Prednisone
Docetaxel
Pembrolizumab
Olaparib
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors