A Study of CHeckpoint Inhibitors in Men With prOgressive Metastatic Castrate Resistant Prostate Cancer Characterized by a Mismatch Repair Deficiency or Biallelic CDK12 Inactivation

NCT04104893 | Active Not Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: CSDR-003-18FCX002006
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 13

Brief Summary

The primary objective is to assess the activity and efficacy of pembrolizumab, a checkpoint inhibitor, in Veterans with metastatic castration-resistant prostate cancer (mCRPC) characterized by either mismatch repair deficiency (dMMR) or biallelic inactivation of CDK12 (CDK12-/-). The secondary objectives involve determining the frequency with which dMMR and CDK12-/- occur in this patient population, as well as the effects of pembrolizumab on various clinical endpoints (time to PSA progression, maximal PSA response, time to initiation of alternative anti-neoplastic therapy, time to radiographic progression, overall survival, and safety and tolerability). Lastly, the study will compare the pre-treatment and at-progression metastatic tumor biopsies to investigate the molecular correlates of resistance and sensitivity to pembrolizumab via RNA-sequencing, exome-sequencing, selected protein analyses, and multiplexed immunofluorescence.

Conditions

Metastatic Castration Resistant Prostate Cancer

Keywords

Metastatic Prostate Cancer; Pembrolizumab; Checkpoint Inhibitor; Mismatch Repair Deficiency; CDK12

Outcome Measures

Primary Outcomes (2)

• PSA Decline

  Decline in PSA of 50% or more (PSA50) 12 weeks of therapy (ng/mL)

  12 weeks of therapy

• Objective Response Rate

  Objective response in measurable disease by immunotherapy response criteria (iRECIST) or radiographic progression free survival (rPFS) after 6 months of therapy.

  First day of Pembrolizumab administration to 6 months after

Secondary Outcomes (4)

• Time to Progression of Disease

  Date of enrollment to the date of the last patient in plus one year after

• Overall Survival

  From enrollment until death assessed up to 36 months

• Maximum PSA Response

  Date of Enrollement to the date of the last patient in plus one year after

• Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]

  Date of first patient in to the date of the last patient in plus one year after

Other Outcomes (1)

• Identification of Molecular Correlates and Biomarkers of Resistance and Sensitivity to Pembrolizumab

  Date of enrollment to the date of the last patient in plus one year after

Study Arms (1)

Single Arm

EXPERIMENTAL

This is a single-arm, open-label study of the checkpoint inhibitor, pembrolizumab, in Veterans with mCRPC who have progressed on at least 1 prior novel androgen receptor (AR) signaling inhibitor, inclusive of abiraterone acetate, enzalutamide, apalutamide, and darolutamide. In addition to progressive mCRPC, a patient must have a somatic tumor mutation characterized by dMMR or CDK12-/- detected by next generation sequencing (NGS). Patients enrolled in this study will be treated with pembrolizumab at the FDA approved dosage of 200 mg intravenously every 3 weeks (21 days) until disease progression or unacceptable toxicity. During study, patients will maintain a castrate level of testosterone, = 50 ng/dL by ongoing treatment with a GnRH analogue or prior bilateral orchiectomy. Prior to initiating treatment with pembrolizumab, patients will undergo a baseline biopsy of a metastatic lesion. An additional biopsy of a metastatic lesion at the time of progression will be encouraged as well.

Drug: Pembrolizumab

Interventions

Pembrolizumab DRUG

Pembrolizumab is a programmed death receptor-1 (PD 1)-blocking antibody. Pembrolizumab is a humanized monoclonal IgG4 kappa antibody with an approximate molecular weight of 149 kDa. Pembrolizumab is produced in recombinant Chinese hamster ovary (CHO) cells.

Also known as: Keytruda

Single Arm

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: This study involves the treatment of patients with metastatic castration resistant prostate cancer with Pembrolizumab. Since only men have prostates, our study will be limited to only enrolling male subjects.
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject must be 18 years of age or older at the time the Informed Consent is signed.
• The subject (or legally acceptable representative if applicable) must provide written informed consent for the trial.
• Pathologic diagnosis of prostate cancer of adenocarcinoma or small cell histology.
• Metastatic disease as documented by technetium-99m (99mTc) bone scan or metastatic lesions by computed tomography (CT) or magnetic resonance imaging (MRI) scans (visceral or lymph node disease). CT-portion of FDG-PET/CT or scan may be used for eligibility. NaF PET-CT is an alternative to 99mTc bone scan. If lymph node metastasis is the only evidence of metastatic disease, it must be 1.5 cm in short axis and above the level of the iliac bifurcation. Imaging studies for the purpose of determining eligibility must be completed within 60 days of Day 1.
• Progressive castration resistant prostate cancer as defined by serum testosterone \< 50 ng/mL and one of the following:
• PSA progression confirmed per Prostate Cancer Clinical Trials Working Group (PCWG3),
• Radiographic progression of soft tissues according to Response Evaluation Criteria in Solid Tumors, version 1.1 (iRECIST 1.1) modified based on PCWG3, or radiographic progression of bone according to PCWG3.
• Prior use of a novel AR signaling inhibitor for 4 weeks, including abiraterone acetate plus prednisone/prednisolone, enzalutamide, apalutamide, and/or darolutamide.
• NOTE: These AR signaling inhibitors may have been used for mCSPC, M0CRPC, and/or mCRPC.
• Ongoing surgical or medical castration, with testosterone levels of \<50 ng/dL. If the subject is being treated with GnRH analogs (subject who has not undergone bilateral orchiectomy), this therapy must have been initiated at least 30 weeks prior to initiation of pembrolizumab and must be continued throughout the study.
• ECOG PS grade of 0-1.
• Metastatic lesion that is amenable to biopsy and performed within 180 days of Day 1.
• dMMR or CDK12-/- as determined by somatic tumor DNA NGS.
• Either monoallelic or biallelic inactivation of CDK12 on NGS is considered sufficient for eligibility purposes.
• MMR genes include: MLH1, MSH2, MLH3, PMS1, MSH6, and PMS2.

You may not qualify if:

• Brain metastases.
• Prior treatment with an anti-PD1, anti-PDL1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).
• Anti-neoplastic therapies for prostate cancer must be completed \> 2 weeks prior to Day 1 (initiation of pembrolizumab); chemotherapy must be completed \> 4 weeks prior to Day 1.
• Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks \[could consider shorter interval for kinase inhibitors or other short half-life drugs\] prior to \[randomization /allocation\].
• Note: Participants must have recovered from all AEs due to previous therapies to Grade 1 or baseline. Participants with Grade 2 neuropathy may be eligible.
• Herbal and non-herbal products that may decrease PSA levels other than medical castration and megestrol (up to 40 mg/day is allowed) for hot flashes.
• Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation ( 2 weeks of radiotherapy) to non-CNS disease.
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
• Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
• If a subject has undergone major surgery, they must have recovered adequately from the toxicities or complications from the intervention within 4 weeks prior to starting therapy.
• History of non-prostate active malignancy requiring treatment in the 24 months prior to Day 1 except for non-muscle invasive urothelial cancer and non-melanoma skin cancer.
• Active infection or conditions requiring treatment with antibiotics.
• Immunosuppressive doses of systemic medications, such as corticosteroids (doses \> 10 mg/day prednisone or equivalent), within 2 weeks of Day 1.
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Has a known history of active TB (Bacillus Tuberculosis).

Sponsors & Collaborators

• VA Office of Research and Development: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (13)

San Francisco VA Medical Center, San Francisco, CA

San Francisco, California, 94121, United States

Location

VA Greater Los Angeles Healthcare System, West Los Angeles, CA

West Los Angeles, California, 90073-1003, United States

Location

Washington DC VA Medical Center, Washington, DC

Washington D.C., District of Columbia, 20422-0001, United States

Location

Bay Pines VA Healthcare System, Pay Pines, FL

Bay Pines, Florida, 33744, United States

Location

Jesse Brown VA Medical Center, Chicago, IL

Chicago, Illinois, 60612, United States

Location

VA Ann Arbor Healthcare System, Ann Arbor, MI

Ann Arbor, Michigan, 48105, United States

Location

Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY

New York, New York, 10010, United States

Location

James J. Peters VA Medical Center, Bronx, NY

The Bronx, New York, 10468, United States

Location

Durham VA Medical Center, Durham, NC

Durham, North Carolina, 27705, United States

Location

VA Portland Health Care System, Portland, OR

Portland, Oregon, 97207-2964, United States

Location

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA

Philadelphia, Pennsylvania, 19104, United States

Location

Hunter Holmes McGuire VA Medical Center, Richmond, VA

Richmond, Virginia, 23249, United States

Location

VA Puget Sound Health Care System Seattle Division, Seattle, WA

Seattle, Washington, 98108, United States

Location

MeSH Terms

Conditions

Prostatic Neoplasms; Turcot syndrome

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Study Officials

• Matthew B. Rettig, MD

  VA Greater Los Angeles Healthcare System, West Los Angeles, CA

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: FED
• Responsible Party: SPONSOR

Model Details: Patients with either a mismatch repair deficiency or biallelic inactivation of CDK12 in their tumor are eligible for this study. Patients with these mutations will be identified primarily through standard of care genetic testing with either archival tissue or blood. Once enrolled the patient will undergo a biopsy of a metastatic lesion (baseline biopsy) to identify molecular correlates. Pembrolizumab will be administered at a starting dose of 200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity. During the treatment, patients will either simultaneously receive a GnRH analogue or undergo a bilateral orchiectomy prior to treatment to maintain a castrate level of testosterone ( 50 ng/dl). At progression, patients will undergo a second biopsy of the same metastatic lesion of the baseline biopsy. The baseline (pre-treatment) and at-progression biopsies will be used for correlative analyses to determine the efficacy of pembrolizumab.

Study Record Dates

• First Submitted: September 18, 2019
• First Posted: September 26, 2019
• Study Start: February 20, 2020
• Primary Completion: February 2, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: February 27, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (13)