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Pembro With Radiation With or Without Olaparib

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ClinicalTrials.gov Identifier: NCT05568550
Recruitment Status : Not yet recruiting
First Posted : October 5, 2022
Last Update Posted : October 5, 2022
Sponsor:
Collaborator:
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):
Zin W Myint, University of Kentucky

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
Prostate Cancer Biological: Pembrolizumab Drug: Olaparib Drug: Androgen Deprivation Therapy Radiation: Radiation Therapy 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 64 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 1:1
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of Pembrolizumab in Combination With Radiation With or Without Olaparib in Localized High-risk Prostate Cancer
Estimated Study Start Date : January 2, 2023
Estimated Primary Completion Date : January 2, 2025
Estimated Study Completion Date : January 2, 2028

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

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 Name: Keytruda

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 Name: Lynparza

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 Name: Keytruda

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.




Primary Outcome Measures :
  1. Clinical Response Rate [ Time Frame: 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 :
  1. Biochemical-Free Survival [ Time Frame: 3 years ]
    Biochemical-free survival rate at 3 years as defined by Phoenix Criteria.

  2. Metastasis-Free Survival [ Time Frame: 3 years ]
    Metastasis-free survival rate at 3 years as defined by RECIST v1.1 criteria.

  3. Time to Normalization of Serum Testosterone [ Time Frame: 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.

  4. Molecular Alterations in Homologous Recombination Repair Genes [ Time Frame: 3 years ]
    Molecular alterations in the homologous recombination repair (HHR) genes.


Other Outcome Measures:
  1. PSA Progression-Free Survival [ Time Frame: 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.

  2. Correlation between clinical outcome and immune cell subtype. [ Time Frame: 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).

  3. Correlation between clinical outcome and cytokine levels. [ Time Frame: 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.

  4. Correlation between clinical outcomes and TCR repertories clonotypes. [ Time Frame: 3 years (Pre-treatment baseline, cycle 3, 6 months or at disease progression) ]
    Correlation between T cell receptor (TCR) repertories clonotypes and clinical outcomes.

  5. Percent changes in plasma circulating tumor DNA [ Time Frame: Baseline and on-treatment (6 months) ]
    Percent changes in plasma circulating tumor DNA (ctDNA).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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
  • No pelvic nodes >2 cm in long axis as established by CT imaging
  • 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.
  • Ability to understand and the willingness to sign a written informed consent document.
  • Adequate organ and marrow function
  • 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
  • Prior 5-alpha reductase inhibitor (for example, finasteride) for prostatic hypertrophy is allowed if discontinued at least 60 days prior to registration.
  • 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
  • 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.
  • Prior radiation to the prostate. Previous pelvic RT or major surgery (colorectal anastomosis, total cystectomy, radical prostatectomy, TURP, etc.). History of Ulcerative proctitis.
  • Concurrent active, additional malignancy in the last 2 years.
  • Prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to randomization.
  • Patients with distant metastases

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05568550


Contacts
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Contact: Yvonne Taul, RN,CCRC 859-323-2354 Yvonne.Taul@uky.edu

Locations
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United States, Kentucky
University of Kentucky
Lexington, Kentucky, United States, 40536
Contact: Yvonne Taul, RN,CCRC    859-323-2354    yvonne.taul@uky.edu   
Sponsors and Collaborators
Zin W Myint
Merck Sharp & Dohme LLC
Investigators
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Principal Investigator: Zin W Myint, MD University of Kentucky
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Responsible Party: Zin W Myint, Assistant Professor, University of Kentucky
ClinicalTrials.gov Identifier: NCT05568550    
Other Study ID Numbers: MCC-22-GU-80
First Posted: October 5, 2022    Key Record Dates
Last Update Posted: October 5, 2022
Last Verified: October 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Zin W Myint, University of Kentucky:
immunotherapy
PARP
radiation
androgen deprivation therapy
ADT
PD-1
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Prostatic Diseases
Pembrolizumab
Olaparib
Androgens
Antineoplastic Agents, Immunological
Antineoplastic Agents
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs