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

NCT ID: NCT02787005

Last Updated: 2024-11-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 388 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-07-01
• Study Completion Date: 2022-02-28

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.

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.

Conditions

Metastatic Castration-resistant Prostate Cancer

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Pembrolizumab

Intervention Type: BIOLOGICAL

Intravenous infusion

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.

Group Type: EXPERIMENTAL

Pembrolizumab

Intervention Type: BIOLOGICAL

Intravenous infusion

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.

Group Type: EXPERIMENTAL

Pembrolizumab

Intervention Type: BIOLOGICAL

Intravenous infusion

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 for up to 2 years.

Group Type: EXPERIMENTAL

Pembrolizumab

Intervention Type: BIOLOGICAL

Intravenous infusion

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 for up to 2 years.

Group Type: EXPERIMENTAL

Pembrolizumab

Intervention Type: BIOLOGICAL

Intravenous infusion

Interventions

Pembrolizumab

Intravenous infusion

Intervention Type: BIOLOGICAL

Other Intervention Names

MK-3475; KEYTRUDA®

Eligibility 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
• Participants of reproductive potential must agree to use an adequate method of contraception, starting with the first dose of study drug through at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception after the last dose of enzalutamide is 30 days.
• 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. Any licensed coronavirus disease 2019 (COVID-19) vaccine (including for Emergency use) in a particular country is allowed in the study as long as they are messenger ribonucleic acid (mRNA) vaccines, adenoviral vaccines, or inactivated vaccines. Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not allowed.

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Merck Sharp & Dohme LLC

References

Antonarakis ES, Piulats JM, Gross-Goupil M, Goh J, Ojamaa K, Hoimes CJ, Vaishampayan U, Berger R, Sezer A, Alanko T, de Wit R, Li C, Omlin A, Procopio G, Fukasawa S, Tabata KI, Park SH, Feyerabend S, Drake CG, Wu H, Qiu P, Kim J, Poehlein C, de Bono JS. Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study. J Clin Oncol. 2020 Feb 10;38(5):395-405. doi: 10.1200/JCO.19.01638. Epub 2019 Nov 27.

Reference Type: RESULT

PMID: 31774688 (View on PubMed)

Graff JN, Hoimes CJ, Gerritsen WR, Vaishampayan UN, Elliott T, Hwang C, Ten Tije AJ, Omlin A, McDermott RS, Fradet Y, Tagawa ST, Kilari D, Ferrario C, Uemura H, Jones RJ, Fukasawa S, Peer A, Niu C, Poehlein CH, Qiu P, Suttner L, de Wit R, Schloss C, de Bono JS, Antonarakis ES. Pembrolizumab plus enzalutamide for metastatic castration-resistant prostate cancer progressing on enzalutamide: cohorts 4 and 5 of the phase 2 KEYNOTE-199 study. Prostate Cancer Prostatic Dis. 2025 Jun;28(2):411-418. doi: 10.1038/s41391-024-00865-5. Epub 2024 Aug 12.

Reference Type: RESULT

PMID: 39134652 (View on PubMed)

Cristescu R, Aurora-Garg D, Albright A, Xu L, Liu XQ, Loboda A, Lang L, Jin F, Rubin EH, Snyder A, Lunceford J. Tumor mutational burden predicts the efficacy of pembrolizumab monotherapy: a pan-tumor retrospective analysis of participants with advanced solid tumors. J Immunother Cancer. 2022 Jan;10(1):e003091. doi: 10.1136/jitc-2021-003091.

Reference Type: DERIVED

PMID: 35101941 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

http://merckoncologyclinicaltrials.com

Merck Oncology Clinical Trials Information

Other Identifiers

163366

Identifier Type: REGISTRY

Identifier Source: secondary_id

MK-3475-199

Identifier Type: OTHER

Identifier Source: secondary_id

KEYNOTE-199

Identifier Type: OTHER

Identifier Source: secondary_id

2015-003644-40

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

3475-199

Identifier Type: -

Identifier Source: org_study_id