Phase 2 Trial Pembrolizumab or Pembrolizumab in Combination With Intratumoral SD-101 Therapy in Patients With Hormone-Naïve Oligometastatic Prostate Cancer Receiving Stereotactic Body Radiation Therapy and Intermittent Androgen Deprivation Therapy
Overview
- Phase
- Phase 2
- Intervention
- Pembrolizumab
- Conditions
- Prostatic Neoplasms
- Sponsor
- David Oh
- Enrollment
- 23
- Locations
- 1
- Primary Endpoint
- Change Rate of Prostate-specific Antigen (PSA) < Nadir + 2 ng/mL From First Day of Treatment to 15 Months (Cohort 2)
- Status
- Completed
- Last Updated
- 4 months ago
Overview
Brief Summary
This is a non-comparative open-label multicenter Phase 2 clinical trial combining stereotactic body radiation therapy (SBRT) and pembrolizumab with or without intratumoral SD-101 in participants with newly diagnosed hormone-naive oligometastatic prostate cancer.
Detailed Description
This randomized phase II trial studies how well androgen deprivation therapy, pembrolizumab, and stereotactic body radiation therapy with or without toll-like receptor 9 (TLR9) agonist SD-101 in treating participants with prostate cancer and cancer in all oligometastatic sites that has spread to other places in the body. Androgen can cause the growth of tumor cells. Androgen deprivation therapy, such as leuprolide acetate, prednisone, and abiraterone acetate may lessen the amount of androgen made by the body. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Stereotactic body radiation therapy is a specialized radiation therapy that sends x-rays directly to the tumor using smaller doses over several days and may cause less damage to normal tissue. Colony-stimulating factors, such as TLR9 agonist SD-101, may increase the production of blood cells. It is not yet known whether giving androgen deprivation therapy, pembrolizumab, and stereotactic body radiation therapy with or without TLR9 agonist SD-101 may work better in treating participants with prostate cancer and cancer in all oligometastatic sites. PRIMARY OBJECTIVES COHORT 1: \-- To assess the safety associated with giving RT and pembrolizumab with or without intratumoral SD-101. COHORT 2: * To continue to assess the safety associated with giving RT and pembrolizumab with or without intratumoral SD-101. * To assess if the rate of PSA \< nadir + 2 ng/mL at 15 months in participants with non-castrate levels of testosterone is greater than the historical control in each study arm. SECONDARY OBJECTIVES COHORT 2 ONLY: * To determine the rate of testosterone-prostate specific antigen (PSA) uncoupling in each study arm in Cohort 2. Testosterone-PSA uncoupling is defined as PSA \< 50% baseline and \< 20ng/mL for at least 3 months after testosterone recovers to \>150 ng/dL. In participants with metastatic hormone sensitive prostate cancer off hormonal therapy, \>90% of participants are expected to have PSA increase to \> 50% baseline after 3 months of testosterone recovery. * To estimate time to clinical progression in each study arm in Cohort 2. * To estimate progression-free survival (PFS) in each study arm Cohort 2. EXPLORATORY OBJECTIVE * To assess peripheral and tumor-based biomarkers of response and resistance in both cohorts. * To define the treatment-induced effects on circulating immune cells in both cohorts. * To explore remodeling of circulating T cell repertoire in both cohorts. * To explore the concordance of Prostate-Specific Membrane Antigen (PSMA) - Positron Emission Tomography (PET) scanning with conventional imaging in oligometastatic prostate cancer participants in both cohorts.
Investigators
David Oh
Assistant Professor
University of California, San Francisco
Eligibility Criteria
Inclusion Criteria
- •Be willing and able to provide written informed consent/assent for the trial.
- •Be \>=18 years of age on day of signing informed consent.
- •Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
- •Histologically documented adenocarcinoma of the prostate
- •Oligometastatic disease. In order to be eligible, the participant must have a total of \<4 metastatic bone and/or metastatic lymph node sites based on bone and/or soft tissue lesions as defined by any of the following:
- •Bone metastases will be defined by bone imaging. If the participant has technetium bone scan, and/or sodium fluoride (NaF) PET performed, either study may be used for documenting metastases; both scans do not need to show the number of metastases required for study entry. For participants undergoing PSMA PET, only PSMA avid lesions that are consistent with metastasis will be counted as a site of metastasis.
- •Distant metastatic lymph node disease. A lymph node ≥1 cm in shortest dimension will be noted as involved with disease. Distant metastatic lymph nodes will be determined as any lymph nodes outside the confines of the true pelvis. For participants undergoing PSMA PET, only PSMA avid lesions that are consistent with metastasis will be counted as a site of metastasis.
- •Any other soft tissue lesion deemed by the physician to be consistent with distant metastatic disease. For participants undergoing PSMA PET, only PSMA avid lesions that have a CT or MRI correlate consistent with metastasis will be counted as a site of metastasis.
- •Note: Radiographic imaging performed as standard of care prior to obtaining informed consent and within 60 days of initiating study treatment may be used to assess oligometastatic disease during screening, rather than repeating scans. For participants who have started on ADT, they must have had imaging prior to initiation of hormonal therapy
- •Treatment naïve, defined as less than 2 months of standard of care ADT (e.g. GnRH agonist or antagonist with or without antiandrogen, including abiraterone) for metastatic hormone-sensitive prostate cancer prior to enrollment (at the time of consent)
Exclusion Criteria
- •Participants who are not appropriate candidates for prostate or oligometastasis-directed SBRT
- •Participants with neuroendocrine or small cell features are not eligible.
- •Participants with evidence of liver metastasis are excluded.
- •Gonadotropin-releasing hormone (GnRH) agonists or GnRH antagonists (e.g., leuprorelin, degarelix) for \> 2 months prior to consenting
- •Antiandrogens (e.g., bicalutamide, flutamide, nilutamide, abiraterone, enzalutamide) for \> 2 months prior to consenting. Participants on 5-alpha reductase inhibitors are allowed on study.
- •Estrogen containing compounds for \> 2 months prior to consenting
- •PC-SPES or PC-x products. Other herbal therapies or supplements will be considered by the Principle Investigator on a case-by-case basis based on their potential for hormonal or anti-cancer therapies.
- •Prior immunotherapy or chemotherapy for prostate cancer
- •Prior radiation therapy to the prostate
- •Prior prostatectomy
Arms & Interventions
Cohort 2, Arm 1: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab)
Three month androgen deprivation therapy (ADT) run-in followed by leuprolide injected intramuscularly every 3 months for 3 doses (or another FDA approved gonadotropin-releasing hormone agent for 9 months) + abiraterone by mouth daily with prednisone by mouth daily (or equivalent medication per local standard practice) for 9 months starting on Day 1. Pembrolizumab: Given IV every 21 days for up to 13 doses Radiotherapy: Given every other day over 10-14 days delivered to the whole prostate gland and oligometastatic sites via stereotactic body radiation therapy (SBRT) starting 1-2 weeks after marker placement.
Intervention: Pembrolizumab
Cohort 2, Arm 1: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab)
Three month androgen deprivation therapy (ADT) run-in followed by leuprolide injected intramuscularly every 3 months for 3 doses (or another FDA approved gonadotropin-releasing hormone agent for 9 months) + abiraterone by mouth daily with prednisone by mouth daily (or equivalent medication per local standard practice) for 9 months starting on Day 1. Pembrolizumab: Given IV every 21 days for up to 13 doses Radiotherapy: Given every other day over 10-14 days delivered to the whole prostate gland and oligometastatic sites via stereotactic body radiation therapy (SBRT) starting 1-2 weeks after marker placement.
Intervention: Leuprolide acetate
Cohort 2, Arm 1: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab)
Three month androgen deprivation therapy (ADT) run-in followed by leuprolide injected intramuscularly every 3 months for 3 doses (or another FDA approved gonadotropin-releasing hormone agent for 9 months) + abiraterone by mouth daily with prednisone by mouth daily (or equivalent medication per local standard practice) for 9 months starting on Day 1. Pembrolizumab: Given IV every 21 days for up to 13 doses Radiotherapy: Given every other day over 10-14 days delivered to the whole prostate gland and oligometastatic sites via stereotactic body radiation therapy (SBRT) starting 1-2 weeks after marker placement.
Intervention: Abiraterone Acetate
Cohort 2, Arm 1: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab)
Three month androgen deprivation therapy (ADT) run-in followed by leuprolide injected intramuscularly every 3 months for 3 doses (or another FDA approved gonadotropin-releasing hormone agent for 9 months) + abiraterone by mouth daily with prednisone by mouth daily (or equivalent medication per local standard practice) for 9 months starting on Day 1. Pembrolizumab: Given IV every 21 days for up to 13 doses Radiotherapy: Given every other day over 10-14 days delivered to the whole prostate gland and oligometastatic sites via stereotactic body radiation therapy (SBRT) starting 1-2 weeks after marker placement.
Intervention: Prednisone
Cohort 2, Arm 1: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab)
Three month androgen deprivation therapy (ADT) run-in followed by leuprolide injected intramuscularly every 3 months for 3 doses (or another FDA approved gonadotropin-releasing hormone agent for 9 months) + abiraterone by mouth daily with prednisone by mouth daily (or equivalent medication per local standard practice) for 9 months starting on Day 1. Pembrolizumab: Given IV every 21 days for up to 13 doses Radiotherapy: Given every other day over 10-14 days delivered to the whole prostate gland and oligometastatic sites via stereotactic body radiation therapy (SBRT) starting 1-2 weeks after marker placement.
Intervention: Stereotactic Body Radiation Therapy
Cohort 2, Arm 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab, SD-101)
Three month androgen deprivation therapy (ADT) run-in followed by leuprolide injected intramuscularly every 3 months for 3 doses (or another FDA approved gonadotropin-releasing hormone agent for 9 months) + abiraterone by mouth daily with prednisone by mouth daily (or equivalent medication per local standard practice) for 9 months starting on Day 1. TLR9 agonist SD-101: Injected into the dominant prostatic tumor lesion at time of fiducial marker placement (1-5weeks prior to Cycle 1 Day 1) and 1-3 weeks after Cycle 1 Day 1 Pembrolizumab: Given IV every 21 days for up to 13 doses Radiotherapy: Given every other day over 10-14 days delivered to the whole prostate gland and oligometastatic sites via stereotactic body radiation therapy (SBRT) starting 1-2 weeks after marker placement.
Intervention: Pembrolizumab
Cohort 2, Arm 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab, SD-101)
Three month androgen deprivation therapy (ADT) run-in followed by leuprolide injected intramuscularly every 3 months for 3 doses (or another FDA approved gonadotropin-releasing hormone agent for 9 months) + abiraterone by mouth daily with prednisone by mouth daily (or equivalent medication per local standard practice) for 9 months starting on Day 1. TLR9 agonist SD-101: Injected into the dominant prostatic tumor lesion at time of fiducial marker placement (1-5weeks prior to Cycle 1 Day 1) and 1-3 weeks after Cycle 1 Day 1 Pembrolizumab: Given IV every 21 days for up to 13 doses Radiotherapy: Given every other day over 10-14 days delivered to the whole prostate gland and oligometastatic sites via stereotactic body radiation therapy (SBRT) starting 1-2 weeks after marker placement.
Intervention: SD-101
Cohort 2, Arm 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab, SD-101)
Three month androgen deprivation therapy (ADT) run-in followed by leuprolide injected intramuscularly every 3 months for 3 doses (or another FDA approved gonadotropin-releasing hormone agent for 9 months) + abiraterone by mouth daily with prednisone by mouth daily (or equivalent medication per local standard practice) for 9 months starting on Day 1. TLR9 agonist SD-101: Injected into the dominant prostatic tumor lesion at time of fiducial marker placement (1-5weeks prior to Cycle 1 Day 1) and 1-3 weeks after Cycle 1 Day 1 Pembrolizumab: Given IV every 21 days for up to 13 doses Radiotherapy: Given every other day over 10-14 days delivered to the whole prostate gland and oligometastatic sites via stereotactic body radiation therapy (SBRT) starting 1-2 weeks after marker placement.
Intervention: Leuprolide acetate
Cohort 2, Arm 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab, SD-101)
Three month androgen deprivation therapy (ADT) run-in followed by leuprolide injected intramuscularly every 3 months for 3 doses (or another FDA approved gonadotropin-releasing hormone agent for 9 months) + abiraterone by mouth daily with prednisone by mouth daily (or equivalent medication per local standard practice) for 9 months starting on Day 1. TLR9 agonist SD-101: Injected into the dominant prostatic tumor lesion at time of fiducial marker placement (1-5weeks prior to Cycle 1 Day 1) and 1-3 weeks after Cycle 1 Day 1 Pembrolizumab: Given IV every 21 days for up to 13 doses Radiotherapy: Given every other day over 10-14 days delivered to the whole prostate gland and oligometastatic sites via stereotactic body radiation therapy (SBRT) starting 1-2 weeks after marker placement.
Intervention: Abiraterone Acetate
Cohort 2, Arm 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab, SD-101)
Three month androgen deprivation therapy (ADT) run-in followed by leuprolide injected intramuscularly every 3 months for 3 doses (or another FDA approved gonadotropin-releasing hormone agent for 9 months) + abiraterone by mouth daily with prednisone by mouth daily (or equivalent medication per local standard practice) for 9 months starting on Day 1. TLR9 agonist SD-101: Injected into the dominant prostatic tumor lesion at time of fiducial marker placement (1-5weeks prior to Cycle 1 Day 1) and 1-3 weeks after Cycle 1 Day 1 Pembrolizumab: Given IV every 21 days for up to 13 doses Radiotherapy: Given every other day over 10-14 days delivered to the whole prostate gland and oligometastatic sites via stereotactic body radiation therapy (SBRT) starting 1-2 weeks after marker placement.
Intervention: Prednisone
Cohort 2, Arm 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab, SD-101)
Three month androgen deprivation therapy (ADT) run-in followed by leuprolide injected intramuscularly every 3 months for 3 doses (or another FDA approved gonadotropin-releasing hormone agent for 9 months) + abiraterone by mouth daily with prednisone by mouth daily (or equivalent medication per local standard practice) for 9 months starting on Day 1. TLR9 agonist SD-101: Injected into the dominant prostatic tumor lesion at time of fiducial marker placement (1-5weeks prior to Cycle 1 Day 1) and 1-3 weeks after Cycle 1 Day 1 Pembrolizumab: Given IV every 21 days for up to 13 doses Radiotherapy: Given every other day over 10-14 days delivered to the whole prostate gland and oligometastatic sites via stereotactic body radiation therapy (SBRT) starting 1-2 weeks after marker placement.
Intervention: Stereotactic Body Radiation Therapy
Outcomes
Primary Outcomes
Change Rate of Prostate-specific Antigen (PSA) < Nadir + 2 ng/mL From First Day of Treatment to 15 Months (Cohort 2)
Time Frame: Start of treatment and 15 months (approx. 15 months total)
Only participants in cohort 2, who achieve testosterone recovery to non-castrate levels (\>150 ng/dL) at 15 months, will be analyzed for the primary endpoint. The rate of PSA \< nadir + 2 ng/mL at 15 months from the start of radiotherapy and cycle 1, day 1 of pembrolizumab, among participants whose testosterone recovers to non-castrate levels (\>150 ng/dL). The point estimate of the rate of PSA \< nadir + 2 ng/mL will be obtained with its 95% confidence interval for participants by arm in cohort 2. All participants who receive any part of a dose of RT, SD-101 or pembrolizumab will be analyzed for efficacy.
Number of Participants With Treatment-related Adverse Events
Time Frame: Up to 15 months
Adverse events occurring on study will be summarized for all participants that received study intervention (including pembrolizumab, SD-101, SBRT to prostate, SBRT to oligometastatic sites) by maximum toxicity grade across study arms.
Secondary Outcomes
- Rate of Testosterone-PSA Uncoupling (Cohort 2)(Up to 15 months)
- Median Time to Clinical Progression (Cohort 2)(Up to 3 years)
- Median Progression-free Survival (PFS) (Cohort 2)(Up to 3 years)