Pembro With Radiation With or Without Olaparib
Study Details
Study Description
Brief Summary
This trial will evaluate whether the immune-sensitizing effects of immunotherapy (Pembrolizumab) and radiation with or without a PARP-inhibitor (Olaparib) will increase the effects of immunotherapy in men with high-risk localized prostate cancer.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
Immunotherapy and PARP-inhibitor are known to have radio-sensitizing effects when combined with radiation therapy. In addition, the combination with PARP-inhibitor and radiation can increase neoantigen expression, cytotoxic lymphocyte infiltration within the tumor microenvironment and increased immune stimulating cytokine concentration. Thus, there is a potential synergy of combining immunotherapy and PARP-inhibitor.
This is a phase 2 randomized 1:1 study. Subjects will be randomized to one arm (pembro + PARPi + standard of care therapy which is definitive radiation therapy combined with hormonal therapy) vs. another arm (pembro + standard of care therapy). All subjects will receive adjuvant immunotherapy for one year once they are done with definitive radiation treatment.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Arm 1 - Pembrolizumab and Olaparib Patients with high-risk prostate cancer receiving combination therapy with Pembrolizumab and Olaparib. |
Biological: Pembrolizumab
Pembrolizumab will be delivered via IV at 200mg on day 1 of each 3-week cycle for approximately 12 months. Cycle 1 begins 21 days prior to radiation therapy and cycles 2-17 are administered during and after radiation therapy.
Other Names:
Drug: Olaparib
200mg Olaparib will be given twice daily for a total of 3 cycles. Cycle 1 begins 21-days prior to radiation therapy.
Other Names:
Drug: Androgen Deprivation Therapy
Androgen Deprivation Therapy (either LHRH agonist or LHRH antagonist) as per treating physician choice will be allowed within 3 months prior to randomization. Duration is per institutional standards.
Radiation: Radiation Therapy
Definitive radiation (total dose and fractions) will be dosed per institutional standards. Definitive radiation may include external beam radiation therapy with or without brachytherapy, based on NCCN risk score and as per treating physicians.
|
| Experimental: Arm 2 - Pembrolizumab Patients with high-risk prostate cancer receiving combination therapy with Pembrolizumab. |
Biological: Pembrolizumab
Pembrolizumab will be delivered via IV at 200mg on day 1 of each 3-week cycle for approximately 12 months. Cycle 1 begins 21 days prior to radiation therapy and cycles 2-17 are administered during and after radiation therapy.
Other Names:
Drug: Androgen Deprivation Therapy
Androgen Deprivation Therapy (either LHRH agonist or LHRH antagonist) as per treating physician choice will be allowed within 3 months prior to randomization. Duration is per institutional standards.
Radiation: Radiation Therapy
Definitive radiation (total dose and fractions) will be dosed per institutional standards. Definitive radiation may include external beam radiation therapy with or without brachytherapy, based on NCCN risk score and as per treating physicians.
|
Outcome Measures
Primary Outcome Measures
- Clinical Response Rate [6 months]
The proportion of patients who achieve a PSA nadir level of ≤ 0.06ng/mL six months after completion of radiation therapy.
Secondary Outcome Measures
- Biochemical-Free Survival [3 years]
Biochemical-free survival rate at 3 years as defined by Phoenix Criteria.
- Metastasis-Free Survival [3 years]
Metastasis-free survival rate at 3 years as defined by RECIST v1.1 criteria.
- Time to Normalization of Serum Testosterone [3 years]
Time from normalization is the date of first return to normal serum testosterone 270 ng/ml or greater after withdrawal of androgen deprivation therapy.
- Molecular Alterations in Homologous Recombination Repair Genes [3 years]
Molecular alterations in the homologous recombination repair (HHR) genes.
Other Outcome Measures
- PSA Progression-Free Survival [3 years (Pre-treatment baseline, cycle 3, 6 months or at disease progression)]
PSA progression-free survival (PSA-PFS) stratified by PDL1 immunohistochemistry expression on baseline or /archival biopsy tissue, if tissue is available.
- Correlation between clinical outcome and immune cell subtype. [3 years (Pre-treatment baseline, cycle 3, 6 months or at disease progression)]
Correlation between the clinical outcomes and changes in immune cell subtype frequencies (% CD4 T cells, % CD8 T cells, % naïve, effector memory, and T regulatory cells) immune functions (T cell ability to induce cytokine following stimulation).
- Correlation between clinical outcome and cytokine levels. [3 years (Pre-treatment baseline, cycle 3, 6 months or at disease progression)]
Correlation between the serum cytokines (IL2, IL-10, and INF-γ) and clinical outcomes.
- Correlation between clinical outcomes and TCR repertories clonotypes. [3 years (Pre-treatment baseline, cycle 3, 6 months or at disease progression)]
Correlation between T cell receptor (TCR) repertories clonotypes and clinical outcomes.
- Percent changes in plasma circulating tumor DNA [Baseline and on-treatment (6 months)]
Percent changes in plasma circulating tumor DNA (ctDNA).
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Male participants with histologically confirmed adenocarcinoma of the prostate
-
High-risk / very high-risk status per NCCN guidelines
-
ECOG performance status 0 to 1
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No pelvic nodes >2 cm in long axis as established by CT imaging
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Agree to use contraception during the treatment period and for at least 120 days after the last dose of study intervention and refrain from donating sperm during this period.
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Ability to understand and the willingness to sign a written informed consent document.
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Adequate organ and marrow function
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Prior pharmacologic androgen ablation for prostate cancer is allowed only if the onset of androgen ablation is ≤90 days prior to the date of registration
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Prior 5-alpha reductase inhibitor (for example, finasteride) for prostatic hypertrophy is allowed if discontinued at least 60 days prior to registration.
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Known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.
Exclusion Criteria:
-
PSA > 150ng/ml
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Prior hormonal therapy with LHRH agonists (e.g., Lupron) and LHRH antagonists (e.g., Degarelix)for prostate cancer continuously for more than 90-days prior to study enrollment.
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Prior radiation to the prostate. Previous pelvic RT or major surgery (colorectal anastomosis, total cystectomy, radical prostatectomy, TURP, etc.). History of Ulcerative proctitis.
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Concurrent active, additional malignancy in the last 2 years.
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Prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to randomization.
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Patients with distant metastases
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Kentucky | Lexington | Kentucky | United States | 40536 |
Sponsors and Collaborators
- Zin W Myint
- Merck Sharp & Dohme LLC
Investigators
- Principal Investigator: Zin W Myint, MD, University of Kentucky
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- MCC-22-GU-80