临床试验/NCT02861573

NCT02861573

招募中

1 期

Phase Ib/II Trial of Pembrolizumab (MK-3475) Combination Therapies in Metastatic Castration-Resistant Prostate Cancer (mCRPC) (KEYNOTE-365)

Merck Sharp & Dohme LLC28 个研究点分布在 15 个国家目标入组 1,200 人2016年11月17日

概览

阶段: 1 期
干预措施: Pembrolizumab 200 mg
疾病 / 适应症: Metastatic Castration-Resistant Prostate Cancer
发起方: Merck Sharp & Dohme LLC
入组人数: 1200
试验地点: 28
主要终点: Number of Participants with Adverse Events (AEs)
状态: 招募中
最后更新: 2个月前

概览研究者入排标准研究组 & 干预措施结局指标研究点相似试验

概览

简要总结

The purpose of this study is to assess the safety and efficacy of pembrolizumab (MK-3475) combination therapy in participants with metastatic castration resistant prostate cancer (mCRPC). There will be ten 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 pembrolizumab/vibostolimab coformulation (MK-7684A), Cohort H will receive pembrolizumab/vibostolimab coformulation, Cohort I will receive pembrolizumab+carboplatin+etoposide in Arm 1 and carboplatin+etoposide in Arm 2 and Cohort J will receive belzutifan in Arm1 and Pembrolizumab+belzutifan in Arm 2. Outcome measures will be assessed individually for each cohort.

详细描述

Assignment of patients to a cohort will be based on prior treatment as outlined in the eligibility criteria. Participants who discontinue pembrolizumab or vibostolimab+pembrolizumab after 35 infusions for reasons other than disease progression or intolerability, or who discontinue pembrolizumab or coformulation of pembrolizumab/vibostolimab after attaining a complete response (and had at least 8 administrations of pembrolizumab or pembrolizumab/vibostolimab coformulation and at least 2 treatments with pembrolizumab or pembrolizumab/vibostolimab coformulation beyond initial complete response) may be eligible to receive a second course of treatment that includes up to 17 additional infusions (approximately 1 year) of pembrolizumab monotherapy or pembrolizumab/vibostolimab coformulation after they have experienced radiographic disease progression after stopping first course treatment. Effective with Protocol Amendment 08, enrollment into Cohorts A, B, C, and D was closed. Effective with Protocol Amendment 14, enrollment into Cohorts E, F, G, and H was closed (not due to any safety issues). No further efficacy and survival follow-up assessments will be collected in Cohorts A through H. Effective with Protocol Amendment 16, enrollment into Cohort J was closed (not due to any safety issues).

注册库

clinicaltrials.gov

开始日期

2016年11月17日

结束日期

2028年7月24日

最后更新

2个月前

研究类型

Interventional

研究设计

Parallel

性别

Male

研究者

发起方

Merck Sharp & Dohme LLC

责任方

Sponsor

入排标准

入选标准

•For Cohorts A, B, C, D, E, G, J: Has histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology
•For Cohorts F, H, I: Has t-NE or de novo metastatic prostate cancer defined by ≥1% neuroendocrine cells that are located in discrete regions of a recent biopsy specimen from a metastasis as determined by the investigational site and confirmed by central histology review prior to enrollment. Epstein criteria of neuroendocrine differentiation in prostate cancer is used for eligibility. Specimens must have one of the morphologies of Small cell carcinoma or Large cell neuroendocrine carcinoma (LCNEC) or Mixed (small or large cell) NE carcinoma - acinar adenocarcinoma with positive IHC confirmed by central pathology review
•Is able to provide tumor tissue from a site not previously irradiated as follows: Cohorts A, E, G and J: 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; 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; and Cohorts F, H, and I must provide a core or excisional biopsy from soft tissue or a bone biopsy. For de novo metastatic neuroendocrine prostate participants, biopsies must be performed within 1 year of screening. 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. Participants with de novo neuroendocrine prostate cancer will not need to provide evidence of progression within 6 months
•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 with de novo metastatic NE prostate cancer will not be required to have been previously treated with androgen deprivation therapy (ADT). ADT must be started in these participants by the time of treatment allocation/randomization
•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
•Must be abstinent from heterosexual intercourse, refrain from donating sperm, or agree to use contraception (unless confirmed to be azoospermic) during the intervention period starting with the first dose of study therapy. The length of time required to continue contraception after the last dose of study intervention for each study intervention is as follows: 7 days for abiraterone acetate and lenvatinib; 30 days for enzalutamide; and 95 days for olaparib, docetaxel, and carboplatin/etoposide. No contraception measures are required during and after the intervention period for pembrolizumab/vibostolimab coformulation
•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 Cohorts B, D, E, F, G, H, I and J 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

排除标准

•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/randomization
•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/randomization
•Has had prior treatment with therapeutic radiopharmaceuticals for prostate cancer, such as Radium-223 or Leutitium-177, within 4 weeks prior to the first dose of trial treatment
•Has an active autoimmune disease that has required systemic treatment in past 2 years
•Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease
•Has previously participated in any other pembrolizumab 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

研究组 & 干预措施

Pembrolizumab+Olaparib

Participants with adenocarcinoma (AC) mCRPC 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.

干预措施: Pembrolizumab 200 mg

Pembrolizumab+Olaparib

干预措施: Olaparib 400 mg

Pembrolizumab+Olaparib

干预措施: Olaparib 300 mg

Pembrolizumab+Docetaxel+Prednisone

Participants with AC mCRPC 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.

干预措施: Pembrolizumab 200 mg

Pembrolizumab+Docetaxel+Prednisone

干预措施: Docetaxel 75 mg/m^2

Pembrolizumab+Docetaxel+Prednisone

干预措施: Prednisone 5 mg

Pembrolizumab+Docetaxel+Prednisone

干预措施: Dexamethasone 8 mg

Pembrolizumab+Enzalutamide

Participants with AC mCRPC 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.

干预措施: Pembrolizumab 200 mg

Pembrolizumab+Enzalutamide

干预措施: Enzalutamide 160 mg

Pembrolizumab+Abiraterone+Prednisone

Participants with AC mCRPC 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.

干预措施: Pembrolizumab 200 mg

Pembrolizumab+Abiraterone+Prednisone

干预措施: Prednisone 5 mg

Pembrolizumab+Abiraterone+Prednisone

干预措施: Abiraterone acetate 1000 mg

Pembrolizumab+Lenvatinib: AC

Participants with AC mCRPC in Cohort E will receive pembrolizumab 200 mg IV on Day 1 Q3W, and lenvatinib 20 mg PO QD 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.

干预措施: Pembrolizumab 200 mg

Pembrolizumab+Lenvatinib: AC

干预措施: Lenvatinib

Pembrolizumab+Lenvatinib:t-NE

Participants with neuroendocrine (t-NE) mCRPC in Cohort F will receive pembrolizumab 200 mg IV on Day 1 Q3W, and lenvatinib 20 mg PO QD 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.

干预措施: Pembrolizumab 200 mg

Pembrolizumab+Lenvatinib:t-NE

干预措施: Lenvatinib

Pembrolizumab/Vibostolimab coformulation

Participants with AC mCRPC in Cohort G will receive a coformulation fixed dose combination of 200 mg pembrolizumab and 200 mg vibostolimab (MK-7684) Q3W IV from Day 1 of Cycle 1. Treatment will continue for a maximum of 35 cycles (up to 2 years) or until progression.

干预措施: Pembrolizumab/Vibostolimab coformulation

Pembrolizumab/Vibostolimab coformulation:t-NE

Participants with t-NE mCRPC in Cohort H will receive a coformulation fixed dose combination of 200 mg pembrolizumab and 200 mg vibostolimab (MK-7684) Q3W IV from Day 1 of Cycle 1. Treatment will continue for a maximum of 35 cycles (up to 2 years) or until progression.

干预措施: Pembrolizumab/Vibostolimab coformulation

Pembrolizumab+Carboplatin+Etoposide

Participants with neuroendocrine mCRPC in Cohort I Arm 1 will receive pembrolizumab 200 mg IV on Day 1 Q3W + carboplatin titrated to an area under the plasma drug concentration-time curve \[AUC\] 5 IV on Day 1 Q3W + etoposide 100 mg/m\^2 IV on Days 1, 2, and 3 Q3W. Treatment with pembrolizumab will continue for a maximum of 35 cycles (up to 2 years) or until progression. Treatment with carboplatin+etoposide will continue for a maximum of 4 cycles (up to 2.8 months). Participants who must discontinue 1 or 2 of the 3 drugs due to adverse events in the combination may continue the study with the other combination drug/drugs.

干预措施: Pembrolizumab 200 mg

Pembrolizumab+Carboplatin+Etoposide

干预措施: Carboplatin

Pembrolizumab+Carboplatin+Etoposide

干预措施: Etoposide

Carboplatin+Etoposide

Participants with neuroendocrine mCRPC in Cohort I Arm 2 will receive carboplatin titrated to an area under the plasma drug concentration-time curve \[AUC\] 5 IV on Day 1 Q3W + etoposide 100 mg/m\^2 IV on Days 1, 2, and 3 Q3W. Treatment will continue for a maximum of 35 cycles (up to 2 years) or until progression. Treatment with carboplatin+etoposide will continue for a maximum of 4 cycles (up to 2.8 months). 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.

干预措施: Carboplatin

Carboplatin+Etoposide

干预措施: Etoposide

Belzutifan

Participants with AC mCRPC in Cohort J will receive belzutifan 120mg QD in the initial cohort. If an efficacy signal is detected in this arm based on a totality of evidence, Cohort J may be expanded further where participants will be randomized 1:1 to receive either belzutifan 120 mg QD or belzutifan 120 mg QD and pembrolizumab 200 mg Q3W. Treatment will continue for a maximum of 35 cycles (up to 2 years) or until progression.

干预措施: Belzutifan 120mg

Pembrolizumab+Belzutifan

干预措施: Pembrolizumab 200 mg

Pembrolizumab+Belzutifan

干预措施: Belzutifan 120mg

结局指标

主要结局

Number of Participants with Adverse Events (AEs)

时间窗: 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

时间窗: 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)

时间窗: Assessed Over the Duration of the Study Which is Estimated to be Approximately 2 Years

Percentage of Participants With a Decrease of ≥50% in Prostatic Specific Antigen (PSA)

时间窗: From Baseline Measured Every 3 Weeks Until Radiographic Progression Estimated to be Approximately 2 Years

次要结局

Overall Survival (OS)(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(Assessed Over the Duration of the Study Which is Estimated to be Approximately 2 Years)
Time to PSA Progression(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)(Assessed Over the Duration of the Study Which is Estimated to be Approximately 2 Years)
Disease Control Rate (DCR) Based on Prostate Cancer Working Group 3 (PCWG3)-modified RECIST 1.1 Assessed by BICR(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(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(Assessed Over the Duration of the Study Which is Estimated to be Approximately 2 Years)