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
Phase: PHASE1
Conditions: Prostate Cancer, Adenocarcinoma of the Prostate
Sponsor: Mark Stein

 
 
 
 
 
 
 
 
 
 
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 
 
 
 
 
 
 
 
NCT03689699 
 
July 12, 2023 
 
 
 
 
 
 
 
 
 
 
 

 
 
INTRODUCTION 
 
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Columbia University Medical Center institutional research policies and procedures. 
 
Prostate cancer is a major contributor to cancer morbidity and mortality in men (Jemal A et al, 
2017). Treatment of localized disease typically involves either surgery or radiation. However, a 
significant number of men treated with definitive local therapy will eventually have PSA 
recurrence and develop clinical metastases (Roehl KA et al, 2004). Although some patients will 
demonstrate clear metastatic disease on imaging, a significant number of men will only have 
biochemical recurrence (BCR) with a rising PSA (Freedland SJ et al 2005). 
 
Androgen deprivation therapy (ADT) can lead to rapid disease control for men with metastatic or 
non-metastatic hormone-sensitive prostate cancer. However, ADT is associated with significant 
side effects including decreased libido, increased fat mass, insulin resistance and osteoporosis 
(Litwin MS et al, 2017). Intermittent ADT (IADT) which has been shown to be non-inferior to 
continuous ADT allows for reduced ADT exposure (Crook JM et al 2012; Magnan S et al 2015; 
Klotz L et al 2017). However, the ADT free interval typically decreases with each cycle of IADT 
and all men will eventually progress to a castration-resistant state (Crook JM et al 2012). 
Therefore, developing novel strategies to prolong the ADT free interval and allow for recovery of 
testosterone while maintaining adequate disease control are essential to improving outcomes for 
prostate cancer patients. 
 
Immunotherapy has shown mixed efficacy in prostate cancer to date. Although Sipuleucel T (Sip- 
T), an autologous cancer vaccine, can improve overall survival in castration-resistant prostate 
cancer (CRPC), other immunotherapy approaches like checkpoint blockade have been relatively 
unsuccessful when tested in patients with CRPC. However, it is becoming increasingly clear that 
the immune tumor microenvironment changes dramatically during disease progression and in 
response to ADT. For example initially ADT induces thymic output of T-cells with subsequent 
tumor infiltration (Drake CG et al, 2005). However, with prolonged ADT and disease progression 
a more immunosuppressive tumor microenvironment develops with increased regulatory T cells 
(Tregs) and myeloid-derived suppressor cells (MDSCs) (Drake et al, 2005; Gannon PO et al, 
2009). Recent data from Antonarakis et al also demonstrated that sequencing immunotherapy with 
Sipuleucel-T prior to ADT elicits a more robust immune response than ADT followed by 
Sipuleucel-T (Antonarakis et al, 2017). However, whether checkpoint blockade in combination 
with standard ADT can lead to more effective disease control and less exposure to ADT exposure 
for patients with less advanced hormone-sensitive disease remains unknown. In addition, data 
from our group and others have identified infiltration of PMN-MDSCs through increased 
production of IL-8 as an important mechanism of immune resistance in prostate cancer. In 
particular, pre-clinical data demonstrate a process by which ADT leads to secretion of IL-8 and 
attraction of PMN-MDSCs, thereby promoting immune resistance (Gannon PO et al, 2010; Drake 
lab unpublished data). Therefore, adding IL-8 targeted therapy to checkpoint blockade and ADT 
could further enhance anti-tumor immunity and offer patients with prostate cancer the potential to 
develop durable immune responses. 

 
 
This 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 PSA 
(30 patients per group), with a primary endpoint of rate of PSA recurrence 12 months after 
completion of therapy. We hypothesize that immunotherapy with either Nivolumab alone or 
Nivolumab plus BMS-986253 combined with Degarelix will decrease the percentage of men with 
hormonse-sensitive prostate cancer and a rising PSA who have PSA recurrence 12 months after 
completion of therapy from 50% (historical reference; McKay RR et al, 2016) to 25%. Baseline 
and on-treatment biopsies will be obtained for a subgroup of patients with biopsy accessible lesions 
in each group to characterize the immune effects of therapy. 
 
STUDY OBJECTIVES 
 
Primary Objective 
 
• 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 other primary therapies 
(e.g. radiation, cryotherapy, brachytherapy) at a time point of 10 months after start of 
therapy. 
 
• Determine the safety and tolerability of either nivolumab or nivolumab plus BMS-986253 
in combination with degarelix in men with hormone-sensitive prostate cancer. 
 
Secondary Objectives 
 
• To assess the relapse-free survival (RFS) after recovery of testosterone with relapse defined 
as a PSA >0.2ng/ml for radical prostatectomy patients or PSA >2.0ng/ml for patients who 
received other primary therapies and recovery of testosterone defined as a testosterone 
(>150ng/dl). 
 
• Determine the % change in PSA to immunotherapy by comparing the PSA prior to and 
following 8 weeks of immunotherapy and before initiation of ADT. 
 
Exploratory Objectives 
 
• To assess the anti-tumor immune response 
o Quantification of CD8 T cell, CD4 T cell, Treg, CD8/Treg, CD4/Treg, 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). Immune cell density and proximity will also be assessed using 
polychromatic immunofluorescence. 
o Quantification a range of immunologic markers in a subset of patients (at least 10 
per arm) with tumor specimens before and after treatment. 
o Quantification of tumor cell apoptosis by TUNEL and caspase-3 staining. 
o Quantification of circulating IL-8 and other cytokines before and after treatment 
and correlation with response to therapy. 
o Quantification of circulating PMN-MDSCs and other immune cell populations 
before and after treatment and correlation with response to therapy. 

 
 
o Assess whether treatment can induce an increased IgG response to tumor antigens 
(epitope spreading) by comparing pre- and post-treatment sera. 
o Assess the DNA or RNA-related molecular characteristics of tumor specimens and 
correlate with response to treatment (if adequate tissue available). 
 
 
INVESTIGATIONAL AGENTS 
 
Nivolumab 
 
Pharmaceutical and Therapeutic Background 
 
Nivolumab (also referred to as BMS-936558, MDX1106, or ONO-4538) is a human 
monoclonal antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the 
programmed death-1 (PD-1) cluster of differentiation 279 (CD279) cell surface membrane 
receptor. PD-1 is a negative regulatory molecule expressed by activated T and B 
lymphocytes.1 Binding of PD-1 to its ligands, programmed death–ligands 1 (PD-L1) and 2 
(PD-L2), results in the down-regulation of lymphocyte activation. Inhibition of the interaction 
between PD-1 and its ligands promotes immune responses and antigen-specific T-cell 
responses to both foreign antigens as well as self-antigens. Nivolumab is expressed in Chinese 
hamster ovary (CHO) cells and is produced using standard mammalian cell cultivation and 
chromatographic purification technologies. The clinical study product is a sterile solution for 
parenteral administration. 
 
OPDIVO (nivolumab) is approved for the treatment of several types of cancer in multiple 
regions including the United States (US, Dec-2014), the European Union (EU, Jun-2015), and 
Japan (Jul-2014). Nivolumab is also now FDA-approved for treatment at a dose of 480mg 
every 4 weeks as a 30 minute infusion (US, Mar-2018). Nivolumab is also being investigated 
in various other types of cancer as monotherapy or in combination with other therapies, and 
as single-dose monotherapy for the treatment of sepsis. 
 
BMS-986253 
 
Pharmaceutical and Therapeutic Background 
 
BMS-986253 (also known as Humax-IL8 and formerly referred to as Humax-Inflam) is a fully 
human immunoglobulin subclass G1 kappa monoclonal antibody (mAb) directed against IL-8, also 
known as CXCL8. IL-8 is a well-described proinflammatory cytokine that has immunosuppressive 
and protumoral effects in the tumor microenvironment. BMS-986253 potently binds free IL-8. 
Disruption of the IL-8:CXCR1/2 signaling axis may inhibit recruitment of immunosuppressive 
myeloid-derived suppressor cells (MDSCs) to the tumor microenvironment, reduce cancer stem 
cell (CSC) renewal, reverse epithelial mesenchymal transition (EMT), and inhibit angiogenesis, 
all of which are important mechanisms for cancer-induced immunosuppression, tumor recurrence, 
and metastasis. 
 
The drug was initially investigated for the treatment of inflammatory skin diseases under the name 
Humax-Inflam. HuMax-Inflam was in a Phase 1/2 dose-escalation, safety, and efficacy trial in 
patients with palmoplantar pustulosis (PPP). The antibody demonstrated a tolerable profile and 
sign of activity based on a reduced inflammation index at doses up to 8 mg/kg weekly. 
 

 
 
Subsequently, the product is now being developed for the treatment of cancer under the product 
code BMS-986253. The clinical development strategy for BMS-986253 as an anticancer agent will 
be in combination with other therapeutic approaches such as immune checkpoint inhibitors. 
 
The transition from hybridoma-derived to Chinese hamster ovary (CHO) cell-derived BMS- 
986253 was accomplished by the cloning and expression of the heavy and light chains of the 
antibody cDNAs in CHO cells to produce BMS-986253. A comparability exercise between CHO 
cell-derived material and hybridoma material has not revealed any significant differences in 
antigen-binding fragment (Fab) to IL-8 and other critical quality attributes, but has demonstrated 
a more complete processing and decreased heterogeneity in isoelectric point with the CHO cell- 
derived BMS-986253. Based on molecular characterization, the main difference between the 
hybridoma-derived and CHO cell-derived materials is glycosylation patterns. The transition from 
hybridoma-derived to Chinese hamster ovary (CHO) cell-derived BMS-986253 was accomplished 
by the cloning and expression of the heavy and light chains of the antibody cDNAs in CHO cells 
to produce BMS-986253. A comparability exercise between CHO cell-derived material and 
hybridoma material has not revealed any significant differences in antigen-binding fragment (Fab) 
to IL-8 and other critical quality attributes, but has demonstrated a more complete processing and 
decreased heterogeneity in isoelectric point with the CHO cell-derived BMS-986253. Based on 
molecular characterization, the main difference between the hybridoma-derived and CHO cell- 
derived materials is glycosylation patterns. 
 
BMS-986253 was tested as monotherapy in 15 participants with advanced solid tumors (Study 
CA027-001) and demonstrated a tolerable profile at doses up to 32 mg/kg. Of these 15 participants, 
11 had a best overall response of stable disease (SD) and 4 had a best overall response of 
progressive disease. In an ongoing Phase 1/2a study of BMS-986253 in combination with 
nivolumab in advanced cancers, safety data from the first 8 participants suggest that the drug 
combination is well tolerated. 
 
The clinical development strategy for BMS-986253 as an anti-cancer agent will be in combination 
with other therapeutic approaches such as immune checkpoint inhibitors. It is hypothesized that 
inhibition of MDSC and neutrophil tumor infiltration, reduction of CSC renewal, and reversal of 
cancer cell EMT driven by anti-IL-8 disruption of the IL-8:CXCR1/2 signaling axis will further 
sensitize IL-8 producing tumors to other therapeutic approaches such as immune checkpoint 
blockade. 
 
STUDY DESIGN 
 
General Design 
 
This is a multi-center, two-arm, open-label, phase 1b/2 study evaluating the anti-tumor effect of 
either Nivolumab alone or Nivolumab plus BMS-986253 with androgen deprivation therapy using 
Degarelix in men with hormone-sensitive prostate cancer and a rising PSA. Patients will be 
recruited from outpatient clinics at participating sites and randomized to either Nivolumab alone 
(Arm A) or Nivolumab plus BMS-986253 (Arm B). 
 
Study Interventions: Eligible patients in Arm A will receive Nivolumab every 4 weeks for 2 
doses and then Nivolumab + Degarelix every 4 weeks x 4 doses. Eligible patients in Arm B will 
receive Nivolumab every 4 weeks x2 doses + BMS-986253 every 2 weeks x 4 doses and then 

 
 
Nivolumab every 4 weeks x 4 doses + BMS-986253 every 2 weeks x 8 doses + Degarelix every 4 
weeks x 4 doses. 
 
Schedule of Evaluations: During treatment patients will have safety assessments including 
routine bloodwork and physical examinations at each visit. (See Section 12 for detailed study 
evaluations and the study schedule). Safety evaluations will also occur until 100 days after the last 
treatment doses. 
 
The primary endpoint will be evaluated by assessing the PSA 10 months after start of therapy. 
PSA and serum testosterone will be checked monthly during treatment (+/- 3 days), the end of 
treatment visit (+/- 1 week), every 2 months (+/- 1 week) or until progression of disease during 
year 1 of follow up and every 3 months (+/- 1 month) or until progression of disease during year 
2 of follow up. Sera, whole blood and CBC with differential will be collected for immunoassays 
at initiation of immunotherapy, at initiation of degarelix, end of treatment visit and 10, 14 and 18 
month (+/- 1 week). Patients will also have CT or MRI scans (chest, abdomen and pelvis) and bone 
scan at screening, end of treatment and 10 months after start of therapy. Toxicity evaluation will 
utilize CTCAE v5.0 criteria. 
 
Duration of Treatment: Subjects will receive treatment for a total of 6 months or intolerable 
toxicity or side effects. 
 
Duration of Follow up: Toxicity and laboratory tests will be graded using the NCI CTCAE v5.0 
scoring system. Adverse events will be assessed continuously during the study and for 100 days 
after the last dose of treatment. In addition, patients will have PSA, serum testosterone checked 
every 2 months (+/- 1 week) or until progression of disease for year 1 of follow up and every 3 
months (+/- 1 month) or until progression of disease for year 2 of follow up. Sera, PMBCs and 
CBC with differential will be collected for immunoassays collected at end of treatment visit and 
10, 14 and 18 months following start of therapy. Patients will also need to have imaging done at 
end of treatment visit and 10 months after start of therapy. Subjects who are removed from the 
study for reasons other than progression of disease will be followed every 2 months to evaluate 
disease status and survival while the study remains open. 
 
Number of Subjects 
 
The study will include a total of approximately 30 patients per arm to achieve at least 23 evaluable 
patients per arm. This study design yields at least 80% power to detect a PSA recurrence rate of 
25% at 10 months after start of therapy (compared to the null hypothesis of 50%) at a significance 
level of 5%. Accounting for a dropout rate of 20%, we will plan to enroll a total of 30 patients per 
arm. 
 
TREATMENT PLAN 
 
 
REGIMEN DESCRIPTION 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 

 
 
BMS-986253* 
No specific 
premedications 
or precautions 
2400mg 
IV over 120 
minutes (+/- 10 
minutes) before 
Nivolumab 
Days 1, 15 
of each 
cycle 
4 weeks 
(28 
days) 
Nivolumab 
No specific 
premedications 
or precautions 
480mg 
IV over 30 
minutes (-5 
minutes/+10 
minutes) after 
BMS-986253 
Day 1 of 
each cycle 
Degarelix 
No specific 
premedications 
or precautions 
240mg loading 
dose (cycle 3), 
80mg (cycle 4- 
6) 
SQ after BMS- 
986253 and 
Nivolumab 
Day 1 of 
each cycle 
* For patients weighing less than 35 kg BMS-986253 should be infused over 180 minutes. . 
 
MEASUREMENT OF EFFECT 
 
Biochemical Response/Progression 
All participants who complete study requirements after treatment with androgen deprivation 
therapy using Degarelix with either Nivolumab alone or Nivolumab plus BMS- 986253 will 
follow-up until they reach PSA relapse defined as at least two serial rises in PSA (≥2 
weeks apart) with PSA >0.2ng/ml for radical prostatectomy patients or PSA 
>2.0ng/ml for patients who received other primary therapies (e.g. radiation cryotherapy, 
brachytherapy). 
Radiographic Progression 
Radiographic progression will be defined as the appearance of new lesions for men who 
initially have biochemically recurrent, non-metastatic disease. For men with metastatic 
disease at baseline, Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST) 
will be used for soft tissue lesions and Prostate Cancer Clinical Trials Working Group 3 
(PCWG3) criteria will be used for osseus disease 
STATISTICAL CONSIDERATIONS 
 
Study Design and Sample Size 
 
This is a multicenter, 2-arm phase 1b/2 trial to evaluate the activity of Nivolumab or 
Nivolumab plus BMS-986253 with IADT using Degarelix in men with hormone sensitive 
prostate cancer with a rising PSA. The primary endpoints of this trial is rate of PSA 
recurrence 10 months after start of therapy. Within the context of this proposed trial, we will 
target a decrease in post-therapy PSA recurrence at 10 months of 25% compared to a 
historical recurrence rate of 50% with intermittent ADT alone. Probabilities of type I and 
type II error will be set at 0.05 and 0.2 respectively. The study will include a total of 23 
evaluable patients per arm. This study design yields at least 80% power to detect a PSA 
recurrence rate of 25% at 10 months after start of therapy (compared to the null hypothesis 
of 50%) at a significance level of 5%. Accounting for a dropout rate of 20%, we will plan to 
enroll a total of 30 patients per arm. 
 

 
 
Study Endpoints 
We will use one-sided binomial tests to compare the post-therapy PSA recurrence rate in 
each arm with the historical recurrence rate of 50%. To compare the secondary outcomes 
between the two arms, Kaplan-Meier estimators and log-rank tests will be used to compare 
time-to-event variables (e.g., time to PSA recurrence, time to recovery of testosterone, and 
time to next anti-cancer treatment); Chi-squared tests will be used to compare incidence 
rates (e.g., incidence of metastases); t-tests will be used to compare continuous 
measurements (e.g., changes immune cell density and proximity). We will set the nominal 
significance level at 5%. Only patients undergoing randomization to the treatment arms will 
be used for comparison between the treatment arms. 
 
Analysis Populations 
Intention-to-treat population 
All patients who meet eligibility criteria and receive at least one dose of the study drug will 
be included in the analysis of the primary and secondary endpoints, even if there are 
subsequent protocol deviations. 
Safety population 
All patients enrolled in the study will be included in the safety analysis population and 
considered evaluable for toxicity from the time of their first dose of the study drug(s). 
Patients never receiving any of the study drugs will not be included in this analysis. 
Demographic and baseline characteristics for the safety population will be summarized by 
number and percent for categorical data and by descriptive statistics for continuous data. 
 
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