Metastatic Castration-Resistant Prostate Cancer (mCRPC) MedDRA version: 21.1 Level: LLT Classification code 10076506 Term: Castration-resistant prostate cancer System Organ Class: 100000004864
Conditions
Sponsors
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
Eligibility
Sex/Gender
Male
Inclusion criteria
Inclusion criteria: 1. Be willing and able to provide written informed consent for the trial. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research. 2. Be =18 years of age on day of signing informed consent. 3. Have histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology. Diagnosis must be stated in a pathology report and confirmed by the Investigator. 4. Have RECIST 1.1-measurable prostate cancer on computed tomography (CT) or magnetic resonance imaging (MRI) scans (Cohorts 1 ,2 and 4) or detectable bone metastases by whole body bone scintigraphy and no RECIST 1.1-measurable tumors (Cohorts 3 and 5), as determined by central review. Disease must be either metastatic or locally confined inoperable disease that cannot be treated with definitive intent. 5. Have supplied tumor tissue from a newly obtained biopsy or provided a tumor tissue specimen =12 months prior to the screening date and an archival specimen, if available, from a site not previously irradiated (tumors progressing in a prior site of radiation are allowed for PD-L1 characterization; other exceptions may be considered after Sponsor consultation). Adequacy of these specimens for PD-L1 biomarker analysis will be required by a central laboratory prior to enrollment. Subjects in Cohorts 1, 2, and 4 with visceral/measurable lesions must provide a newly obtained biopsy performed after the last line of systemic therapy where safely available or a specimen obtained =12 months prior to the screening date and an archival specimen, if available. Subjects in Cohort 3 and 5 must at least provide an archival specimen. For Cohorts 1, 2, and 3 only: 6. Have been treated with: a. At least one 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). b. At least one regimen/line of chemotherapy that contained docetaxel. c. No more than two chemotherapy regimens. d. No more than three regimens/lines of the aforementioned treatments (having failed/progressed on hemotherapy and targeted endocrine therapy). For Cohorts 4 and 5 only: 7. For chemotherapy-naïve subjects with mCRPC either having failed or showing early signs of failing on enzalutamide treatment as defined by PCWG3 guidelines (eg, signs of clinical progression, increased alkaline phosphatase, PSA increase, or positive imaging assessments). Subjects can have failed prior abiraterone treatment before current enzalutamide treatment. Subjects 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. All Cohorts: 8. Have documented prostate cancer progression within 6 months prior to screening, as determined by the Investigator, by means of one of the following: a. 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. b. Radiographic disease progression in soft tissue or bone with or without PSA progression 9. Have ongoing androgen deprivation with total serum testosterone < 50 ng/dL (< 2.0 nM). If the subject is currently being treated with LHRH agonists (s
Exclusion criteria
Exclusion criteria: 1. 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 trial treatment. 2. 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 trial treatment. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor (replacement therapy for adrenal insufficiency is permitted). 3. Has had a prior anti-cancer mAb within 4 weeks prior to the first dose of trial treatment or who has not recovered (i.e., = Grade 1 or at baseline) from AEs due to mAbs administered more than 4 weeks earlier. 4. Has had prior chemotherapy, targeted small molecule therapy, or external beam radiation therapy within 4 weeks prior to the first dose of trial treatment or who has not recovered (i.e., = Grade 1 or at baseline) from AEs due to a previously administered agent. Treatment with Radium-223 is allowed as long as the last dose has been administered no less than 4 weeks prior to the first dose. 5. 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. 6. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to the first dose of trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. 7. 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). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 8. Has evidence of interstitial lung disease and/or a history of (non-infectious) pneumonitis that required steroids, or current pneumonitis. 9. Has an active infection requiring systemic therapy. 10. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator. 11. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 12. Has previously participated in any other pembrolizumab (MK-3475) trial, or received prior therapy with an anti-PD-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). 13. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 14. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., H
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1)To estimate the objective response rate (ORR) by RECIST 1.1 in subjects with measurable disease assessed by central imaging vendor in Cohorts 1 and 2 combined, Cohort 1, Cohort 2, and Cohort 4. ;Secondary Objective: 1)To determine the safety and tolerability of pembrolizumab for all cohorts combined(Cohorts 1, 2, 3, 4, and 5) and by each cohort 2)To estimate disease control rate(DCR) and radiographic progression-free survival(rPFS) by PCWG3-modified RECIST 1.1 assessed by central imaging vendor and PSA response rate, time to PSA progression, and OS for Cohorts 1 and 2 combined, Cohorts 1, 2, and 3 combined, Cohorts 4 and 5 combined, and by each cohort 3)To estimate the duration of response(DOR) by PCWG3-modified RECIST 1.1 in subjects with measurable disease assessed by central imaging vendor in Cohorts 1 and 2 combined, Cohort 1, Cohort 2, and Cohort 4 4)To estimate the DOR by RECIST 1.1 in subjects with measurable disease assessed by central imaging vendor in Cohorts 1 and 2 combined, Cohort 1, Cohort 2, and Cohort 4 5)To estimate duration of PSA response, time to initiation of cytotoxic chemotherapy, time to new-anticancer therapy, and time to first skeletal-related event in Cohorts 4 and 5;Primary end point(s): Cohorts 1, 2, and 4 - Objective response rate (ORR) per RECIST 1.1 assessed by central imaging vendor: Proportion of subjects in the analysis population who have complete response (CR) or partial response (PR) where responses are determined by RECIST 1.1 assessed by central imaging vendor. ;Timepoint(s) of evaluation of this end point: Interim analysis: To be performed about 27 weeks after the first 100 subjects with RECIST 1.1-measurable disease (Cohorts 1 and 2) and all subjects in Cohort 3 have been enrolled. Scope of analyses: ORR Final Analysis: The final analysis of ORR in the population with measurable disease by RECIST 1.1 will be performed after all subjects have been enrolled and all subjects have accumulated mature data and | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1.Duration of Response (DOR ) per PCWG3-modified RECIST 1.1 assessed by central imaging vendor. For subjects who demonstrated CR or PR, DOR is defined as the time from first documented evidence of CR or PR until disease progression assessed by central imaging vendor where progressive disease (PD) in bone-only tumors will be determined by radionuclide bone scan using RECIST 1.1/PCWG3 criteria and PD for all other tumors will be determined using RECIST 1.1 or death due to any cause, whichever occurs first 2. Duration of Response (DOR) – per RECIST 1.1 assessed by central imaging vendor. For subjects who demonstrated CR or PR, DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) assessed by central imaging using RECIST 1.1 or death due to any cause, whichever occurs first. 3.Disease Control Rate (DCR) - assessed by central imaging vendor Proportion of subjects in the analysis population who have CR or PR or stable disease (SD) for at least 6 months, by central imaging vendor where progressive disease (PD) in bone-only tumors will be determined by radionuclide bone scan using PCWG3 criteria and PD for all other tumors will be determined using RECIST 1.1 4. PSA Response Rate Proportion of subjects in the analysis population who have PSA response defined as more than 50% decline from baseline measured twice at least 3 weeks apart. 5. Time to PSA Progression, defined as the time from first day of study treatment to the date of PSA progression. Subjects without PSA progression will be censored at the last PSA assessment date. PSA progression is defined as the date that an increase of 25% or more and an absolute increase of 2 ng/mL or more from the nadir are documented. For subjects who had an initial PSA decline during treatment, this must be confirmed by a second value 3 or more weeks later. 6. Radiographic progression-free survival (rPFS) -per PCWG3-modified RECIST 1.1 assessed by central imaging | — |
Countries
Australia, Brazil, Canada, Estonia, Finland, France, Germany, Hong Kong, Ireland, Israel, Italy, Japan, Korea, Republic of, Netherlands, New Zealand, Poland, Spain, Sweden, Switzerland, Taiwan, Turkey, United Kingdom, United States
Outcome results
None listed