Nivolumab and BMS-986253 for Hormone-Sensitive Prostate Cancer (MAGIC-8)

Randomized Phase 1b/2 Study of Nivolumab or Nivolumab Plus BMS-986253 in Combination With Intermittent Androgen Deprivation Therapy in Men With Hormone-Sensitive Prostate Cancer

MAGIC-8 is a two-arm, multicenter, phase 1b/2 study to assess the efficacy of immunotherapy with either Nivolumab (anti-PD-1) or Nivolumab plus BMS-986253 combined with ADT using Degarelix (LHRH antagonist) for men with hormone-sensitive prostate cancer and a rising prostate-specific antigen (PSA). The purpose of this study is to see whether immunotherapy with either Nivolumab alone or Nivolumab plus BMS-986253 combined with Degarelix, which suppresses testosterone, is safe and can decrease the chance that the cancer will come back. The primary objectives are to 1) determine the rate of PSA recurrence defined as a PSA >0.2ng/ml for radical prostatectomy patients or PSA >2.0ng/ml for patients who received primary radiation therapy at a time point of 10 months after start of therapy; and 2) determine the safety and tolerability of either nivolumab or nivolumab plus BMS-986253 in combination with degarelix in men with hormone-sensitive prostate cancer. The secondary objectives include determining relapse-free survival (RFS) and % change in PSA to immunotherapy alone.

Prostate cancer is common and remains a major cause of death in men. Following local therapy with surgery or radiation, a significant number of men recur either with a rising PSA only (biochemical recurrence (BCR)) or clear metastatic disease on imaging. Although androgen deprivation therapy (ADT) is a frequently used and effective treatment for prostate cancer, it is associated with significant side effects including fatigue, hot flashes, decreased libido and bone loss. Therefore, new approaches to decrease the time on ADT are crucial to improving quality of life for men with prostate cancer. Once initiated, ADT can be given either continuously or intermittently. However, even with an intermittent approach the ADT-free interval typically decreases with each cycle and most men eventually develop castration resistance. Therefore new treatment strategies are needed to improve disease control while minimizing ADT exposure for men with early prostate cancer.

The study will include a total of approximately 30 patients per arm to achieve at least 23 evaluable patients per arm.

Men with hormone-sensitive prostate cancer will receive Nivolumab alone every 4 weeks for 8 weeks (2 doses), followed by Nivolumab + Degarelix every 4 weeks for 16 weeks (4 doses).

Men with hormone-sensitive prostate cancer will receive Nivolumab plus BMS-986253 every 4 weeks for 8 weeks (2 doses), followed by Nivolumab + BMS-986253 + Degarelix every 4 weeks for 16 weeks (4 doses).

A dose of 480mg every 4 weeks as a 30 minute IV infusion for 6 doses has been selected for this study. 6 total doses.

Standard treatment at a dose of 240mg subcutaneously (SQ) as a loading dose followed by 80mg SQ every 4 weeks for 4 doses.

BMS-986253 (also referred to as anti-IL8 mAb or HuMax IL8) is a fully human-sequence IgG1κ monoclonal antibody (mAb) directed against human interleukin-8 (IL-8). Subjects will be treated with an intravenous (IV) flat dose of 2400mg every 2 weeks.

Defined as a PSA >0.2ng/ml for radical prostatectomy patients or PSA >2.0ng/ml for patients who received primary radiation therapy at a time point of 10 months after start of therapy.

All participants receiving at least one dose of the study drug will be evaluated for safety and toxicity. Adverse events will be classified and graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Determine the % change in PSA in response to immunotherapy by comparing the PSA prior to and following 8 weeks of immunotherapy and before initiation of ADT

Relapse defined as a PSA >0.2ng/ml for radical prostatectomy patients or PSA >2.0ng/ml for patients who received primary radiation therapy.

Inclusion Criteria: Histologically documented prostatic adenocarcinoma confirmed by a pathology report from prostate biopsy or a radical prostatectomy specimen. Age ≥18 years Previously undergone primary therapy for prostate cancer. Salvage XRT or cryotherapy following primary therapy ≥ 6 months prior to randomization is allowed. A rising PSA defined as the following: If the subject's primary therapy was RP (radical prostatectomy) (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, cryosurgery, brachytherapy), rising PSA is defined per the Phoenix definition, i.e., 2 consecutive rising values above the PSA nadir plus 2.0 ng/mL. For the biopsy sub-groups, patients must be willing to undergo pre and on- treatment biopsies. PSADT ≤ 12 months. PSADT(prostate-specific antigen doubling time) will be determined from all non-zero PSA values collected preferably, 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. The following web site may also be used: http://www.mskcc.org/applications/nomograms/prostate/PsaDoublingTime.aspx Eastern Cooperative Oncology Group (ECOG) performance status 0-1, or Karnofsky score ≥ 70% (see Appendix A) Testosterone ≥ 150 ng/dL ≤ 28 days of prior to registration Adequate bone marrow, hepatic, and renal function: White Blood Cell (WBC)>3,000 cells/mm3 Absolute neutrophil count (ANC)>1,500 cells/mm3 Hemoglobin >9.0 g/dL Platelet count >100,000 cells/mm3 Serum creatinine <1.5 × upper limit of normal (ULN) Serum total bilirubin <1.5 × ULN ALT (alanine aminotransferase) <3 × ULN AST(aspartate aminotransferase) <3 × ULN Willingness to provide written informed consent and 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) 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 (azoospermic men are not exempt from contraceptive requirements) Exclusion Criteria: Received any experimental immunotherapy on an experimental clinical trial ≤ 1 year prior to randomization PSA > 50 at time of enrollment High volume disease defined as >5 bone metastases or lymph nodes >3cm in size. Histologic predominance of other types of prostate cancers such as sarcomatous, lymphoma, small cell, and neuroendocrine tumors (note: a maximum of 5 subjects with ductal prostate cancer will be allowed to enroll to each arm of study treatment across all sites). Received salvage XRT ≤ 6 months prior to randomization Received ADT ≤ 6 months prior to randomization Received any form of chemotherapy ≤ 90 days prior to randomization Received granulocyte colony-stimulating factor or GM-CSF ≤ 90 days prior to randomization Any major surgery requiring general anesthesia ≤ 28 days prior to randomization. Any other concurrent or prior treatment for prostate cancer ≤ 28 days prior to randomization. An active infection requiring parenteral antibiotic therapy or causing fever (temperature > 100.5 o F or 38.1 o C) within 1 week prior to randomization Prior systemic, ongoing immunosuppressive therapy ≤ 14 days prior to study treatment administration (except for adrenal replacement steroid doses ≤ 10mgdaily prednisone equivalent in the absence of active autoimmune disease or a short course of steroids (<5 days) up to 7 days prior to initiating study treatment). Prior participation in an anti-IL8 clinical study A candidate is scheduled or likely to be scheduled for salvage external beam XRT or surgery for prostate cancer during the study period Concomitant treatment with other hormonal therapy or 5α-reductase inhibitors such as Dutasteride or Finasteride (prior use of these agents is allowed if ≥3 months prior to randomization). History of known or suspected autoimmune disease with the following exceptions: Asthma and/or allergic rhinitis (seasonal allergies) Vitiligo Resolved childhood atopic dermatitis Psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger. Residual hypothyroidism due to an autoimmune condition only requiring hormone replacement Euthyroid participants with a history of Grave's disease (participants with suspected autoimmune thyroid disorders must be negative for thyroglobulin and thyroid peroxidase antibodies and thyroid stimulating immunoglobulin (Ig) prior to the first dose of study treatment). Type 1 diabetes mellitus History of malignancy within the last 2 years (except non-melanoma skin cancers and superficial bladder cancer) and for which no additional therapy is required or anticipated to be required during the study period. Uncontrolled major active infectious, cardiovascular, pulmonary, hematologic, or psychiatric illnesses that would make the patient a poor study candidate Known prior or current history of HIV and/or hepatitis B/C Prior organ allograft