Pembrolizumab in Metastatic Castration Resistant Prostate Cancer (mCRPC) With or Without DNA Damage Repair Defects

NCT03248570 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: 16557NCI-2017-02408R01CA223484
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

Brief Summary

This is a multicenter phase 2 open label study of pembrolizumab in patients with metastatic castrate resistant prostate cancer (mCRPC) with or without DNA damage repair defects.

Conditions

Castration Resistant Prostatic Cancer; Metastatic Prostate Cancer

Outcome Measures

Primary Outcomes (2)

• Radiographic Progression-Free Survival Rate (rPFS) at 6 Months

  The rPFS rate is defined as the proportion of participants still alive at 6 months starting from the first day of study treatment with pembrolizumab. Participants will be censored on the date of documented tumor progression according to the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) guidelines or death due to any cause at 6 months. Participants who did not progress or die will be censored on the date of their last evaluable tumor assessment. The 6-month rPFS rate and the 95% confidence interval will be reported by study group.

  Up to 6 months

• Median Overall Radiographic Progression-free Survival (rPFS)

  The median overall radiographic progression free survival (rPFS) is defined as the time from the first day of study treatment with pembrolizumab to the date of documented radiographic tumor progression according to the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) guidelines or death due to any cause, whichever occurs first. Participants who did not progress or die will be censored on the date of their last evaluable tumor assessment. The median time in months and the 95% confidence interval will be reported by study group.

  Up to 24 months

Secondary Outcomes (8)

• Immune-related Progression-free Survival Rate (irPFS) at 20 Weeks

  Up to 20 weeks

• Immune-related Progression-free Survival Rate (irPFS) at 28 Weeks

  Up to 28 weeks

• Overall Progression-Free Survival Rate (PFS) at 20 Weeks

  Up to 20 weeks

• Overall Progression-Free Survival Rate (PFS) at 28 Weeks

  Up to 28 weeks

• Percentage of Participants Achieving Any Prostate Specific Antigen (PSA) Response

  Up to 24 months

Study Arms (2)

DNA damage repair proficient group

EXPERIMENTAL

Participants with mismatch repair (MMR) intact receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. If disease worsens while receiving pembrolizumab, participants may receive standard of care chemotherapy for 2-8 cycles

Drug: Pembrolizumab; Drug: Chemotherapy

DNA damage repair defective group

EXPERIMENTAL

Participants with defective DNA repair receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. If disease worsens while receiving pembrolizumab, participants may receive standard of care chemotherapy for 2-8 cycles

Drug: Pembrolizumab; Drug: Chemotherapy

Interventions

Pembrolizumab DRUG

All subjects will receive pembrolizumab 200mg IV every 3 weeks until disease progression or unacceptable toxicity.

Also known as: KEYTRUDA, MK-3475

DNA damage repair defective group; DNA damage repair proficient group

Chemotherapy DRUG

At time of progression, all subjects will also have the option of receiving taxane-based chemotherapy followed by repeat pembrolizumab for those who have a clinical response to chemotherapy. Chemotherapy regimen will be at the discretion of the treating physician, and may consist of docetaxel or cabazitaxel with or without a platinum agent (e.g. carboplatin). A minimum of 4 cycles and a maximum of 8 cycles of chemotherapy will be given.

DNA damage repair defective group; DNA damage repair proficient group

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Documented histology of adenocarcinoma of the prostate.
• Metastatic castration resistant prostate cancer with castrate-level testosterone (\<50 ng/dL).
• a. Subjects must maintain a castrate-level testosterone during the study.
• Disease progression defined by one or more of the following three criteria:
• Prostate-specific antigen (PSA) \> 2.0 ng/mL and rising PSA by at least 2 consecutive measurements a minimum of 1-week apart.
• Soft tissue progression as defined by RECIST v1.1 criteria.
• Bone disease progression as defined by Prostate Cancer Clinical Trials Working Group 3 (PCWG3).
• Have received prior secondary hormonal therapy including abiraterone, enzalutamide and/or apalutamide.
• Be taking prednisone at a dose of ≤ 10mg/day, 7 days prior to starting treatment (Cycle 1, Day 1).
• Be willing and able to provide written informed consent/assent for the trial.
• Be \>= 18 years of age on day of signing informed consent.
• Patients must agree to have a tumor tissue biopsy at baseline, and there must be a lesion that can be biopsied with acceptable clinical risk as judged by the investigator.
• Patients with inconclusive DNA damage repair status testing on this baseline biopsy must have one of the following (per the investigator's discretion): (i) Sufficient archival tissue, or (ii) An additional biopsy attempt.
• Patients with previously identified homozygous deletion or deleterious germline or somatic mutation(s) in DNA damage repair gene(s) (such as BReast CAncer gene 1 (BRCA1) , BReast CAncer gene 2 (BRCA2), and ATM) identified in a Clinical Laboratory Improvement Amendments of 1988 (CLIA)-certified laboratory are allowed in Group 2. (i) Somatic mutation(s) in DNA damage repair gene(s) needs to be identified on the biopsy of a castration-resistant tumor site (ii) Archival FFPE tissue will be requested for determination of MSI (if not already assessed by gene sequencing) signature status.(iia) A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or at least 10 slides containing unstained, freshly cut, serial sections must be available along with an associated pathology report before study enrollment. (iii) If archival FFPE tissue is unable to be obtained or is insufficient, patients will be required to undergo tumor tissue biopsy if feasible for determination of MSI signature status.
• Patients with germline mutation(s) in mismatch repair (MMR) gene(s) (i.e. Lynch syndrome),or have previously identified Microsatellite instability (MSI)-high tumor by Polymerase chain reaction (PCR) or MMR deficient tumor by Immunohistochemistry (IHC) are also allowed in Group 2. (i) Archival FFPE tissue will be requested for determination of Fanconi anaemia (FA)/BRCA signature status. (ia) A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or at least 10 slides containing unstained, freshly cut, serial sections must be available along with an associated pathology report before study enrollment. (ii) If archival FFPE tissue is unable to be obtained or is insufficient, patients will be required to undergo tumor tissue biopsy if feasible for determination of FA/BRCA signature status.

You may not qualify if:

• Significant liver metastasis.
• Prior taxane-based chemotherapy with progressive disease on chemotherapy.
• Prior docetaxel for metastatic hormone sensitive prostate cancer is allowed, if no progression of disease on docetaxel as defined by RECIST v1.1 and PCWG3.
• Prior taxane-based chemotherapy (i.e. docetaxel or cabazitaxel with or without platinum agent) for mCRPC is allowed if no progression of disease on chemotherapy as defined by RECIST v1.1 and PCWG3.
• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy \>10mg/day or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
• Has a known history of active Bacillus Tuberculosis (TB).
• Hypersensitivity to pembrolizumab or any of its excipients.
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., \<= Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., \<= Grade 1 or at baseline) from adverse events due to a previously administered agent.
• Note: Subjects with \<= Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
• Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
• 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 four 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 trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
• Has active autoimmune disease that has required systemic treatment in the 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 \<= 10 mg of prednisone/day for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.

Sponsors & Collaborators

• University of California, San Francisco: lead
• Merck Sharp & Dohme LLC: collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (1)

University of California, San Francisco

San Francisco, California, 94143, United States

Location

MeSH Terms

Conditions

Prostatic Neoplasms, Castration-Resistant; Prostatic Neoplasms

Interventions

pembrolizumab; Drug Therapy

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Therapeutics

Limitations and Caveats

Study enrollment closed earlier than expected due to low enrollment. Some participants are still in follow-up.

Results Point of Contact

• Title: Dr. David Oh, MD
• Organization: University of California, San Francisco

David.Oh@ucsf.edu

(415) 476-1000

Study Officials

• David Oh, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: After determination of DNA damage repair status, subjects will be assigned to one of two treatment groups: * Group 1 (DNA damage repair proficient group): Twenty-five subjects * Group 2 (DNA damage repair deficient group): Twenty-five subjects All subjects will receive pembrolizumab 200mg IV every 3 weeks until disease progression or unacceptable toxicity.

Study Record Dates

• First Submitted: August 9, 2017
• First Posted: August 14, 2017
• Study Start: February 20, 2018
• Primary Completion: September 28, 2023
• Study Completion: September 28, 2023
• Last Updated: November 20, 2024
• Results First Posted: November 20, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)