Study of Pembrolizumab (MK-3475) in Participants With Metastatic Castration-Resistant Prostate Cancer (mCRPC)(MK-3475-199/KEYNOTE-199)

• Sponsor: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Merck Sharp & Dohme Corp.

Study Description

Brief Summary:

This is a study of pembrolizumab (MK-3475) in participants with metastatic castration-resistant prostate cancer (mCRPC). Participants will be enrolled into one of five cohorts: Cohort 1 (participants with programmed cell death ligand 1 [PD-L1]-positive, measurable disease), Cohort 2 (participants with PD-L1 negative, measurable disease), Cohort 3 (participants with bone-metastases and non-measurable disease) post-chemotherapy, Cohort 4 (participants with Response Evaluation Criteria in Solid Tumors version 1.1- [RECIST 1.1]-measureable disease) and Cohort 5 (participants with bone metastases only or bone-predominant disease) pre-chemotherapy.

Condition or disease	Intervention/treatment	Phase
Metastatic Castration-resistant Prostate Cancer	Biological: Pembrolizumab; Drug: Enzalutamide	Phase 2

Detailed Description:

Participants with mCRPC previously treated with docetaxel-based chemotherapy in Cohorts 1 to 3 will receive monotherapy with pembrolizumab. Chemotherapy-naïve subjects with mCRPC either having failed or showing signs of failure with enzalutamide in Cohorts 4 and 5 will receive pembrolizumab monotherapy in addition to their current regimen of enzalutamide. In all cohorts, pembrolizumab administration will occur on Day 1 of each 3-week dosing cycle and will continue for a maximum of 35 cycles (approximately 2 years) unless specific withdrawal/discontinuation criteria are met. Participants who discontinue after 35 infusions of pembrolizumab for reasons other than disease progression or intolerability, or who discontinue after attaining a complete response may be eligible for up to 17 additional infusions (approximately 1 year) after they have experienced disease progression.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	370 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Phase II Trial of Pembrolizumab (MK-3475) in Subjects With Metastatic Castration-Resistant Prostate Cancer (mCRPC) (KEYNOTE-199)
Actual Study Start Date :	July 1, 2016
Estimated Primary Completion Date :	December 14, 2020
Estimated Study Completion Date :	December 14, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1: PD-L1 positive with measurable disease; Participants with programmed cell death ligand 1 (PD-L1)-positive, measurable disease receive pembrolizumab 200 mg via intravenous infusion on Day 1 of every 3-week cycle for up to 2 years.	Biological: Pembrolizumab; Intravenous infusion; Other Names: MK-3475; KEYTRUDA®
Experimental: Cohort 2: PD-L1 negative with measurable disease; Participants with PD-L1 negative, measurable disease receive pembrolizumab 200 mg via intravenous infusion on Day 1 of every 3-week cycle for up to 2 years.	Biological: Pembrolizumab; Intravenous infusion; Other Names: MK-3475; KEYTRUDA®
Experimental: Cohort 3: Bone metastases with non-measurable disease; Participants with bone metastases and non-measurable disease receive pembrolizumab 200 mg via intravenous infusion on Day 1 of every 3-week cycle for up to 2 years.	Biological: Pembrolizumab; Intravenous infusion; Other Names: MK-3475; KEYTRUDA®
Experimental: Cohort 4: RECIST 1.1-measureable disease; Participants with Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1)-measureable disease receive pembrolizumab 200 mg via intravenous infusion on Day 1 of every 3-week cycle and enzalutamide via oral capsules once daily for up to 2 years. The dose of enzalutamide will be the same dose each participant was receiving before the start of pembrolizumab treatment.	Biological: Pembrolizumab; Intravenous infusion; Other Names: MK-3475; KEYTRUDA®; Drug: Enzalutamide; Oral capsules; Other Name: XTANDI®
Experimental: Cohort 5: Bone metastases only or bone-predominant disease; Participants with bone metastases only or bone-predominant disease receive pembrolizumab 200 mg via intravenous infusion on Day 1 of every 3-week cycle and enzalutamide via oral capsules once daily for up to 2 years. The dose of enzalutamide will be the same dose each participant was receiving before the start of pembrolizumab treatment.	Biological: Pembrolizumab; Intravenous infusion; Other Names: MK-3475; KEYTRUDA®; Drug: Enzalutamide; Oral capsules; Other Name: XTANDI®

Outcome Measures

Primary Outcome Measures :

1. Objective Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by central imaging vendor (Cohorts 1 and 2 combined, Cohort 1, Cohort 2 and Cohort 4) [ Time Frame: Up to 2 years ]

Secondary Outcome Measures :

1. Disease Control Rate (DCR) (Cohorts 1 and 2 combined, Cohorts 1, 2, and 3 combined, Cohorts 4 and 5 combined, and by each cohort) [ Time Frame: Up to 2 years ]
2. Prostate-specific Antigen (PSA) response rate (Cohorts 1 and 2 combined, Cohorts 1, 2, and 3 combined, Cohorts 4 and 5 combined, and by each cohort) [ Time Frame: Up to 2 years ]
3. Percentage of participants who experience an adverse event (AE) (All cohorts combined and by each cohort) [ Time Frame: Up to 27 months ]
4. Percentage of participants who discontinue study drug due to an AE (All cohorts combined and by each cohort) [ Time Frame: Up to 2 years ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	Male
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Has histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology. Disease must be either metastatic or locally confined inoperable disease that cannot be treated with definitive intent (no chance for a curative intervention).
• Has supplied tumor tissue from a newly obtained biopsy or a biopsy obtained ≤12 months prior to study start and an archival specimen, if available, from a site not previously irradiated. Participants in Cohorts 1, 2, and 4 with visceral/measurable lesions must provide a newly obtained biopsy performed after the last line of systemic therapy or a biopsy obtained ≤12 months prior to study start and an archival specimen, if available. Participants in Cohorts 3 and 5 must at least provide an archival specimen.

For Cohorts 1, 2, and 3 only:

• Has been treated with:
• At least 1 targeted endocrine therapy (defined as second generation antiandrogen therapies that include but are not limited to abiraterone acetate with prednisone, enzalutamide, and next generation targeted agents such as ARN-509).
• At least 1 regimen/line of chemotherapy that contained docetaxel.
• No more than 2 chemotherapy regimens.
• No more than 3 regimens/lines of the aforementioned treatments (having failed/progressed on chemotherapy and targeted endocrine therapy).

For Cohorts 4 and 5 only:

• Failing or showing early signs of failure on current pre-chemotherapy enzalutamide treatment as defined by Prostate Cancer Working Group 3 PCWG3 guidelines. Participants can have failed prior abiraterone treatment before current enzalutamide treatment. Participants must have had a clinically meaningful response to enzalutamide treatment. Enzalutamide must have been initiated no less than 4 weeks prior to the first dose of trial treatment and be continued throughout the study.

For All Cohorts:

• Has documented prostate cancer progression within 6 months prior to screening, as determined by the Investigator, by means of one of the following: 1) PSA progression as defined by a minimum of 3 rising PSA levels with an interval of ≥1 week between each assessment where the PSA value at screening should be ≥2 ng/mL, OR, 2) Radiographic disease progression in soft tissue or bone with or without PSA progression
• Has ongoing androgen deprivation with total serum testosterone <50 ng/dL (<2.0 nM).
• Participants receiving bone resorptive therapy (including but not limited to bisphosphonate or Receptor activator of nuclear factor kappa-B ligand [RANK-L inhibitor]) must have been on stable doses for ≥4 weeks prior to first dose of study drug.
• Has a performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale
• Males of reproductive potential must agree to use an adequate method of contraception, starting with the first dose of study drug through 120 days after the last dose of study drug.
• Demonstrates adequate organ function.

Exclusion Criteria:

For All Cohorts:

• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of study drug.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to the first dose of study drug or who has not recovered (i.e., ≤ Grade 1 or at Baseline) from AEs due to mAbs administered more than 4 weeks earlier.
• Has had prior chemotherapy, targeted small molecule therapy, or external beam radiation therapy within 4 weeks prior to the first dose of study drug or who has not recovered (i.e., ≤ Grade 1 or at Baseline) from AEs due to a previously administered agent.
• Has a known additional malignancy that has had progression or has required active treatment in the last 3 years. Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of the skin that has undergone potentially curative therapy.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
• Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
• Has evidence of interstitial lung disease and/or a history of (non-infectious) pneumonitis that required steroids, or current pneumonitis.
• Has an active infection requiring systemic therapy.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• 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 [including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways]).
• 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 planned start of study drug.

For Cohorts 4 and 5 only:

• Has received prior chemotherapy (e.g., docetaxel) for mCPRC.
• Has any condition (cardiac, neurologic, absorption) other than clinically failing or showing early signs of failure on enzalutamide treatment that would require imminent discontinuation of enzalutamide treatment.

Contacts and Locations

Sponsors and Collaborators

Merck Sharp & Dohme Corp.

Investigators

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Study Director:	Medical Director	Merck Sharp & Dohme Corp.

More Information

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Responsible Party:	Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:	NCT02787005 History of Changes
Other Study ID Numbers:	3475-199; 2015-003644-40 ( EudraCT Number ); 163366 ( Registry Identifier: JAPIC-CTI ); MK-3475-199 ( Other Identifier: Merck Protocol Number )
First Posted:	June 1, 2016
Last Update Posted:	January 21, 2019
Last Verified:	January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes
Plan Description:	http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL:	http://engagezone.msd.com/ds_documentation.php

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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.:

PD1; PD-1; PDL1; PD-L1

Additional relevant MeSH terms:

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Prostatic Neoplasms; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms	Genital Diseases, Male; Prostatic Diseases; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents