Single-Arm, Open-Label, Phase II Study of Pembrolizumab Plus Androgen Deprivation Therapy (ADT) in Combination With Radiotherapy (RT) for High Risk Localized Prostate Cancer
Overview
- Phase
- Phase 2
- Intervention
- Gonadotropin Releasing Hormone Agonists and Antagonists
- Conditions
- High Risk Prostate Carcinoma
- Sponsor
- OHSU Knight Cancer Institute
- Enrollment
- 32
- Primary Endpoint
- Biopsy-complete response determined by post-treatment biopsy
- Status
- Withdrawn
- Last Updated
- 7 months ago
Overview
Brief Summary
This phase II trial tests how well pembrolizumab along with standard of care androgen deprivation therapy, with bicalutamide and gonadotropin releasing hormone agonist, and radiotherapy for the treatment of patients with high risk prostate cancer that has not spread to other parts of the body (localized). A monoclonal antibody, such as pembrolizumab, is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Bicalutamide is in a class of medications called androgen receptor inhibitors. It works by blocking the effects of androgen (a male reproductive hormone) to stop the growth and spread of tumor cells. Gonadotropin-releasing hormone agonists prevent the body from making luteinizing hormone-releasing hormone (LHRH) and luteinizing hormone (LH). This causes the testicles to stop making testosterone (a male hormone) in men and may stop the growth of prostate cancer cells that need testosterone to grow. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Giving pembrolizumab with androgen deprivation therapy and radiotherapy may kill more tumor cells in patients with high risk localized prostate cancer.
Detailed Description
PRIMARY OBJECTIVES: I. Determine the rate of prostate biopsy positivity at 6 months (mo.) in patients receiving pembrolizumab plus androgen deprivation therapy (ADT) in combination with radiotherapy. II. Determine the safety of pembrolizumab in combination with ADT and radiotherapy. SECONDARY OBJECTIVES: I. Compare 6-month post-treatment biopsy positive rate in patients stratified by pre-treatment prostate infiltrating T-cell PD-1 and PD-L1 expression. II. Measures changes in health related quality of life (HRQOL). III. Determine the rate of grade 3 or higher Immune-related adverse events (irAEs). IV. Determine the rate of biochemical relapse-free survival (bRFS) stratified by tumor PD-1 and PD-L1 expression. EXPLORATORY OBJECTIVES: I. Determine the time to cancer-directed treatment in subjects undergoing experimental treatment. II. Determine the 5-year rate of biochemical relapse-free survival (\[bRFS,\] i.e. prostate specific antigen \[PSA\] \> nadir + 2 ng/mL) III. Determine the nadir biochemical response rate (nadir PSA ≤ 0.5 ng/mL) IV. Determine the clinical and bRFS at five years. V. Report safety and tolerability of pembrolizumab, defined as pembrolizumab related adverse event of any grade and drug dose modification. VI. Determine metastases-free survival based on conventional imaging (not positron emission tomography \[PET\] based). VII. Determine the serum castration recovery rate (testosterone above 50 ng/dL) VIII. Determine the serum testosterone recovery rate (testosterone above 200 ng/dL) IX. Assess the effect of pembrolizumab combined with ADT + radiation therapy (RT) on serum, blood and tissue markers of the immune response. X. Correlate changes in markers of inflammatory response with clinical outcomes including post-treatment biopsy rate, PSA response and tumor free survival. XI. Correlate baseline prostate specific membrane antigen (PSMA) scan findings with efficacy endpoints. XII. Changes from pre- to post-treatment serum, peripheral blood mononuclear cells (PBMC), blood, microbial and tissue markers of the immune response. XIII. Correlation of changes in markers of inflammatory response with clinical outcomes including biopsy-complete response, PSA response and disease free survival. XIV. Determine the rate of local tumor eradication at 12 months for those who had persistent tumor at 6 months. OUTLINE: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 of each cycle. Cycles repeat every 3 weeks for 51 weeks in the absence of disease progression or unacceptable toxicity. Patients receive standard of care ADT with GNRH agonist (leuprolide, goserelin, triptorelin) or GNRH antagonist (relugolix, degarelix) given orally (PO), subcutaneously (sub-Q) or via sub-Q implant for a total of 24 months, bicalutamide PO once per day (QD) for 6 months or up to 24 months per the discretion of the treating physician and radiation therapy per standard of care. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo bone scan and/or computed tomography (CT) scan/ magnetic resonance imaging (MRI) during screening and prostate biopsy and blood sample collection throughout the study. After completion of study therapy, patients are followed up at 30 days and yearly thereafter.
Investigators
Arthur Hung
Principal Investigator
OHSU Knight Cancer Institute
Eligibility Criteria
Inclusion Criteria
- •Participants who are at least 18 years of age on the day of signing informed consent with newly diagnosed histologically confirmed non-metastatic adenocarcinoma of the prostate (regional spread as defined by National Comprehensive Cancer Network \[NCCN\] guidelines is allowed) will be enrolled in this study with any one of the following three high risk features:
- •Gleason grade \> 8-10
- •PSA \> 20 ng/ml
- •Clinical stage T3a or T3b (T4 not allowed, see exclusion criteria)
- •Participants must agree to use a contraception as detailed in the protocol during the treatment period and for at least 12 months plus an additional 90 days (a spermatogenesis cycle) after the last dose of study treatment and refrain from donating sperm during this period
- •The participant (or legally acceptable representative if applicable) provides written informed consent for the trial
- •Archival tumor tissue sample or newly obtained \[core, incisional or excisional\] biopsy of a tumor lesion not previously irradiated has been provided. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides
- •Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to
- •Evaluation of ECOG is to be performed within 30 days prior to the first dose of study intervention
- •Absolute neutrophil count (ANC) ≥ 1500/µL. (Specimens must be collected within 10 days prior to the start of study intervention)
Exclusion Criteria
- •Has received prior therapy with an anti-PD-1, anti-PD-L1, 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)
- •Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to allocation
- •Has received prior radiotherapy or radiation-related toxicities requiring corticosteroids. Note: Two weeks or fewer of palliative radiotherapy for non-central nervous system (CNS) disease, with a 1-week washout, is permitted
- •Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed
- •Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
- •Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
- •Known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder that have undergone potentially curative therapy are not excluded
- •Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention
- •Has severe hypersensitivity (≥ grade 3) to pembrolizumab and/or any of its excipients
- •Has active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid)
Arms & Interventions
Treatment (Pembrolizumab, ADT, radiotherapy)
Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 3 weeks for 51 weeks in the absence of disease progression or unacceptable toxicity. Patients receive standard of care ADT with GNRH agonist (leuprolide, goserelin, triptorelin) or GNRH antagonist (relugolix, degarelix) for a total of 24 months, bicalutamide PO QD for 6 months or up to 24 months per the discretion of the treating physician and radiation therapy per standard of care. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo bone scan and/or CT scan/MRI during screening and prostate biopsy and blood sample collection throughout the study.
Intervention: Gonadotropin Releasing Hormone Agonists and Antagonists
Treatment (Pembrolizumab, ADT, radiotherapy)
Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 3 weeks for 51 weeks in the absence of disease progression or unacceptable toxicity. Patients receive standard of care ADT with GNRH agonist (leuprolide, goserelin, triptorelin) or GNRH antagonist (relugolix, degarelix) for a total of 24 months, bicalutamide PO QD for 6 months or up to 24 months per the discretion of the treating physician and radiation therapy per standard of care. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo bone scan and/or CT scan/MRI during screening and prostate biopsy and blood sample collection throughout the study.
Intervention: Bicalutamide
Treatment (Pembrolizumab, ADT, radiotherapy)
Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 3 weeks for 51 weeks in the absence of disease progression or unacceptable toxicity. Patients receive standard of care ADT with GNRH agonist (leuprolide, goserelin, triptorelin) or GNRH antagonist (relugolix, degarelix) for a total of 24 months, bicalutamide PO QD for 6 months or up to 24 months per the discretion of the treating physician and radiation therapy per standard of care. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo bone scan and/or CT scan/MRI during screening and prostate biopsy and blood sample collection throughout the study.
Intervention: Biopsy Procedure
Treatment (Pembrolizumab, ADT, radiotherapy)
Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 3 weeks for 51 weeks in the absence of disease progression or unacceptable toxicity. Patients receive standard of care ADT with GNRH agonist (leuprolide, goserelin, triptorelin) or GNRH antagonist (relugolix, degarelix) for a total of 24 months, bicalutamide PO QD for 6 months or up to 24 months per the discretion of the treating physician and radiation therapy per standard of care. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo bone scan and/or CT scan/MRI during screening and prostate biopsy and blood sample collection throughout the study.
Intervention: Biospecimen Collection
Treatment (Pembrolizumab, ADT, radiotherapy)
Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 3 weeks for 51 weeks in the absence of disease progression or unacceptable toxicity. Patients receive standard of care ADT with GNRH agonist (leuprolide, goserelin, triptorelin) or GNRH antagonist (relugolix, degarelix) for a total of 24 months, bicalutamide PO QD for 6 months or up to 24 months per the discretion of the treating physician and radiation therapy per standard of care. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo bone scan and/or CT scan/MRI during screening and prostate biopsy and blood sample collection throughout the study.
Intervention: Computed Tomography
Treatment (Pembrolizumab, ADT, radiotherapy)
Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 3 weeks for 51 weeks in the absence of disease progression or unacceptable toxicity. Patients receive standard of care ADT with GNRH agonist (leuprolide, goserelin, triptorelin) or GNRH antagonist (relugolix, degarelix) for a total of 24 months, bicalutamide PO QD for 6 months or up to 24 months per the discretion of the treating physician and radiation therapy per standard of care. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo bone scan and/or CT scan/MRI during screening and prostate biopsy and blood sample collection throughout the study.
Intervention: Magnetic Resonance Imaging
Treatment (Pembrolizumab, ADT, radiotherapy)
Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 3 weeks for 51 weeks in the absence of disease progression or unacceptable toxicity. Patients receive standard of care ADT with GNRH agonist (leuprolide, goserelin, triptorelin) or GNRH antagonist (relugolix, degarelix) for a total of 24 months, bicalutamide PO QD for 6 months or up to 24 months per the discretion of the treating physician and radiation therapy per standard of care. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo bone scan and/or CT scan/MRI during screening and prostate biopsy and blood sample collection throughout the study.
Intervention: Pembrolizumab
Treatment (Pembrolizumab, ADT, radiotherapy)
Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 3 weeks for 51 weeks in the absence of disease progression or unacceptable toxicity. Patients receive standard of care ADT with GNRH agonist (leuprolide, goserelin, triptorelin) or GNRH antagonist (relugolix, degarelix) for a total of 24 months, bicalutamide PO QD for 6 months or up to 24 months per the discretion of the treating physician and radiation therapy per standard of care. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo bone scan and/or CT scan/MRI during screening and prostate biopsy and blood sample collection throughout the study.
Intervention: Questionnaire Administration
Treatment (Pembrolizumab, ADT, radiotherapy)
Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 3 weeks for 51 weeks in the absence of disease progression or unacceptable toxicity. Patients receive standard of care ADT with GNRH agonist (leuprolide, goserelin, triptorelin) or GNRH antagonist (relugolix, degarelix) for a total of 24 months, bicalutamide PO QD for 6 months or up to 24 months per the discretion of the treating physician and radiation therapy per standard of care. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo bone scan and/or CT scan/MRI during screening and prostate biopsy and blood sample collection throughout the study.
Intervention: Radiation Therapy
Treatment (Pembrolizumab, ADT, radiotherapy)
Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 3 weeks for 51 weeks in the absence of disease progression or unacceptable toxicity. Patients receive standard of care ADT with GNRH agonist (leuprolide, goserelin, triptorelin) or GNRH antagonist (relugolix, degarelix) for a total of 24 months, bicalutamide PO QD for 6 months or up to 24 months per the discretion of the treating physician and radiation therapy per standard of care. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo bone scan and/or CT scan/MRI during screening and prostate biopsy and blood sample collection throughout the study.
Intervention: Bone Scan
Outcomes
Primary Outcomes
Biopsy-complete response determined by post-treatment biopsy
Time Frame: From first dose of pembrolizumab Cycle 1 Day 1 to 6 months after Cycle 1 Day 1. Cycle length is 21 days.
Will be defined as absence of detectable malignant cells in cores evaluated by established histologic techniques. An exact one-sided confidence interval will also be estimated and provided.
Incidence of adverse events
Time Frame: From first dose of pembrolizumab to 30 days after last dose of pembrolizumab
Using Common terminology Criteria for Adverse Events (CTCAE) version 5.
Secondary Outcomes
- Post-treatment cancer detection rates in tumors by levels of PD-1 and PD-L1 expression(From first dose of pembrolizumab to 6 months after Cycle 1 Day 1. Cycle length is 21 days.)
- Health related quality of life(From screening up to 5 years)
- Incidence of grade 3 or higher immune related adverse events(From first dose of pembrolizumab to 30 days after last dose of pembrolizumab)
- Rate of biochemical relapse-free survival(From enrollment of trial to 30 days post last dose of pembrolizumab)