Summary

This phase Ib/II trial studies the side effects and how well nivolumab and degarelix with or without BMS-986253 work in treating patients with prostate cancer that is sensitive to hormone therapy. Immunotherapy with monoclonal antibodies, such as nivolumab and BMS-986253, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Testosterone can cause the growth of prostate cancer cells. Drugs, such as degarelix, may lessen the amount of testosterone made by the body. It is not yet known whether giving nivolumab and degarelix with or without BMS-986253 will work better in treating patients with hormone-sensitive prostate cancer.

Objectives

PRIMARY OBJECTIVES:
I. Determine the rate of prostate-specific antigen (PSA) recurrence defined as a PSA > 0.2 ng/ml for radical prostatectomy patients or PSA > 2.0 ng/ml for patients who received other primary therapies (e.g. radiation, cryotherapy, brachytherapy) at a time point of 10 months after start of therapy.
II. Determine the safety and tolerability of either nivolumab or nivolumab plus anti-IL-8 monoclonal antibody humax-IL8 (BMS-986253) in combination with degarelix in men with hormone-sensitive prostate cancer.

SECONDARY OBJECTIVES:
I. To assess the relapse-free survival (RFS) after recovery of testosterone with relapse defined as a PSA > 0.2 ng/ml for radical prostatectomy patients or PSA > 2.0 ng/ml for patients who received other primary therapies and recovery of testosterone defined as a testosterone (> 150 ng/dl).
II. Determine the RFS with relapse defined as a PSA > 0.2 ng/ml for radical prostatectomy patients or PSA > 2.0 ng/ml for patients who received other primary therapies.
III. Determine the time to PSA > 5.0 ng/ml after start of therapy.
IV. Determine the time to recovery of testosterone in all arms of the study and measured as the time from start of therapy to the time of testosterone recovery, defined as a testosterone level > 150 ng/dl.
V. Determine the time to next anti-cancer treatment in all arms of the study and measured as the time from start of therapy to the time of next treatment.
VI. Determine the rate of metastatic progression 10 months after start of therapy.
VII. Determine the percent (%) change in PSA to immunotherapy by comparing the PSA prior to and following 8 weeks of immunotherapy and before initiation of androgen deprivation therapy (ADT).
VIII. To compare the rate of PSA recurrence at 10 months following start of therapy, RFS, RFS after recovery of testosterone, time to recovery of testosterone, time to next anti-cancer treatment and rate of metastatic progression 10 months after start of therapy between patients treated with nivolumab plus degarelix versus patients treated with nivolumab plus BMS-986253 plus degarelix.

EXPLORATORY OBJECTIVES:
I. To assess the anti-tumor immune response.
Ia. Quantification of CD8 T cell, CD4 T cell, regulatory T cells (Treg), CD8/Treg, CD4/Treg, polymorphonucler-myeloid-derived suppressor cells (PMN-MDSC) and other immune cell populations in a subset of patients (at least 10 per arm) with tumor specimens before and after treatment by immunohistochemistry (IHC).
Ib. Quantification a range of immunologic markers in a subset of patients (at least 10 per arm) with tumor specimens before and after treatment.
Ic. Quantification of tumor cell apoptosis by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling assay (TUNEL) and caspase-3 staining.
Id. Quantification of circulating IL-8 and other cytokines before and after treatment and correlation with response to therapy.
Ie. Quantification of circulating PMN-MDSCs and other immune cell populations before and after treatment and correlation with response to therapy.
If. Assess whether treatment can induce an increased immunoglobulin G (IgG) response to tumor antigens (epitope spreading) by comparing pre- and post-treatment sera.
Ig. Assess the deoxyribonucleic acid (DNA) or ribonucleic acid (RNA)-related molecular characteristics of tumor specimens and correlate with response to treatment (if adequate tissue available).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes and degarelix subcutaneously (SC) on day 1. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive anti-IL-8 monoclonal antibody humax-IL8 IV over 120 minutes on days 1 and 15, and nivolumab IV over 30 minutes on day 1. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive anti-IL-8 monoclonal antibody humax-IL8 IV over 120 minutes on days 1 and 15, nivolumab IV over 30 minutes on day 1, and degarelix SC on day 1. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 100 days, every 2 months for 1 year and then every 3 months for 1 year.

Eligibility

1. Histologically documented prostatic adenocarcinoma confirmed by a pathology report from prostate biopsy or a radical prostatectomy specimen
2. Age >= 18 years
3. Previously undergone primary therapy for prostate cancer. Salvage radiation therapy (XRT) or cryotherapy following primary therapy >= 6 months prior to randomization is allowed.
4. A rising PSA defined as the following: * If the subject’s primary therapy was RP (with or without adjuvant or salvage XRT), rising PSA is defined as 2 consecutive rising values above 0.2 ng/mL, each taken >= 3 weeks apart, and the last value >= 2.0 ng/mL * If the subject received other primary therapies (e.g. XRT, cyrosurgery, brachytherapy), rising PSA is defined per the Phoenix definition, i.e., 2 consecutive rising values above the PSA nadir plus 2.0 ng/mL
5. For the biopsy sub-groups, patients must be willing to undergo pre and on-treatment biopsies
6. PSA doubling time (PSADT) =< 12 months. PSADT will be determined from all non-zero PSA values collected preferable, however not limited to, from the 12 months prior to randomization. To calculate PSADT, there must be at least THREE PSA values, with at least 4 weeks between each measurement. The PSADT will be computed from the formula: PSADT = (loge2)/k, with k being the estimated slope of the logarithm of PSA over time
7. Eastern Cooperative Oncology Group (ECOG) performance status 0-1, or Karnofsky score >= 70%
8. Testosterone >= 150 ng/dL =< 28 days of prior to registration
9. White blood count (WBC) > 3,000 cells/mm^3
10. Absolute neutrophil count (ANC) > 1,500 cells/mm^3
11. Hemoglobin > 9.0 g/dL
12. Platelet count > 100,000 cells/mm^3
13. Serum creatinine < 1.5 x upper limit of normal (ULN)
14. Serum total bilirubin < 1.5 x ULN
15. Alanine aminotransferase (ALT) < 3 x ULN
16. Aspartate aminotransferase (AST) < 3 x ULN
17. Willingness to provide written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for the release of personal health information, and the ability to comply with the study requirements (note: HIPAA authorization will be included in the informed consent)
18. Willingness to use barrier contraception during treatment plus 5 half-lives of nivolumab (~125 days) plus 90 days (duration of sperm turnover) for a total of 215 days post-treatment completion (azospermic men are not exempt from contraceptive requirements)

Treatment Sites in Georgia