Conditions: Prostate Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 351
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the effectiveness, safety and tolerability of nivolumab followed by ipilimumab, in subjects with metastatic castration resistant prostate cancer (mCRPC).

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None arm 7: None

Interventions: intervention 1: Nivolumab intervention 2: Ipilimumab intervention 3: Cabazitaxel intervention 4: Prednisone
Intervention descriptions: intervention 1: Specified dose on specified days intervention 2: Specified dose on specified days intervention 3: Specified dose on specified days intervention 4: Specified dose on specified days

Protocol document:
Prot_SAP_000.pdf: 
Official Title of Study: 
A Phase 2 Trial of Nivolumab Plus Ipilimumab, Ipilimumab Alone, or Cabazitaxel in Men 
with Metastatic Castration-Resistant Prostate Cancer 
 
Protocol Number: CA209-650 
 
NCT Number: NCT02985957 
 
Document Date (Date in which document was last revised): 01-Dec-2021 


Page:
1
Protocol Number:
CA209650
IND Number:
122,840
EUDRACT Number
2016-001928-54
Date:
30-Sep-2016
Revised Date:
01-Dec-2021
CLINICAL PROTOCOL CA209650
A Phase 2 Trial of Nivolumab Plus Ipilimumab, Ipilimumab Alone, or Cabazitaxel in Men 
with Metastatic Castration-Resistant Prostate Cancer
Protocol Amendment Number: 05
Incorporates Administrative Letter 05
Study Director/Medical Monitor
Clinical Scientists
3401 Princeton Pike
Lawrence Township, NJ 08648
Telephone (office): 
Fax: 
Email: 
3401 Princeton Pike
Lawrenceville, NJ 08648
Telephone (office): 
Email: 
3401 Princeton Pike
Lawrenceville, NJ 08648
Telephone (office): 
Email: 
24-hr Emergency Telephone Number
USA:
International: 
Bristol-Myers Squibb Research and Development
Route 206 & Province Line Road
Lawrenceville, NJ 08543
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
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Protocol Amendment No.: 05
Date: 01-Dec-2021
2
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
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Protocol Amendment No.: 05
Date: 01-Dec-2021
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol 
Amendment 05
01-Dec-2021
•
Modified sample size to reflect actual enrollment.
•
Modified accrual duration for Cohort D to reflect actual time.
•
Modified timing of dual primary endpoint analyses.
•
Removed references to Cohort D Part 1 and 2; renamed as simply
Cohort D.
•
•
Added COVID-19 guidance
Administrative 
Letter 05
15-Sept-2021
•
Study personnel updated.
Administrative 
Letter 04
01-Apr-2021
•
Study personnel updated.
Administrative 
Letter 03
23-Mar-2021
•
Study personnel updated.
Revised 
Protocol 04
26-Mar-2020
•
Modified the maximum tumor sample age from 5 years to 1 year. The 
study will allow submission of tumor samples obtained more than 
1 year prior to enrollment if collected in the metastatic setting and if 
approved by the BMS Medical Monitor/designee. 
•
Allowed starting dose of cabazitaxel of 20 mg/m2 to align with 
cabazitaxel labeling
•
Clarified the population for analyses in Cohort D Part 1
•
Clarified the exclusion criteria for prior pelvic radiotherapy
•
Incorporated updated nivolumab clinical program protocol standards
•
Made minor clarifications for consistency throughout document.
•
Incorporates Administrative Letter 02
Administrative 
Letter 02
20-Jun-2019
To correct the potency of Cabazitaxel and Prednisone.
Revised 
Protocol 03
21-Feb-2019
•
Added new treatment Cohort D (Arms D1, D2, D3, and D4)
•
Updated study objectives and endpoints with new study design
•
Updated outcomes measures and healthcare resource utilization
•
Allowed reinduction and crossover treatment with new study design
•
Updated prohibited/restricted treatments
•
•
Updated statistical section with new study design
Revised 
Protocol 02
28-Aug-2017
•
 
•
Updated eligibility criteria
•
Updated dose delay and dose discontinuation criteria
•
Corrected typographical and formatting errors
•
Incorporates Administrative Letter 01
Administrative 
Letter 01
24-Apr-2017
This Administrative Letter updates the Medical Monitor for the study, as 
well as clarify Cohort A.
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Protocol Amendment No.: 05
Date: 01-Dec-2021
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Document
Date of Issue
Summary of Change
Revised 
Protocol 01
01-Feb-2017
Incorporates Amendment 01
Amendment 01
01-Feb-2017
This amendment adds planned interim reviews of early toxicities and 
early disease control as well as stopping rules for safety to the protocol. 
The amendment also incorporates other minor changes to correct and/or 
clarify protocol requirements and procedures. This amendment applies to 
all subjects. 
Original 
Protocol
30-Sep-2016
Not applicable
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OVERALL RATIONALE FOR PROTOCOL AMENDMENT 05
Study enrollment closed on 08-Sep-2021. Several enrollment challenges significantly impacted 
study timelines, notably the coronavirus disease 2019 (COVID-19) pandemic 
 
. In addition, enrollment of patients with measurable 
disease at baseline was difficult after reaching the cap on patients with non-measurable disease. 
Bristol-Myers Squibb Company (BMS) determined that the number of patients enrolled will be 
sufficient to inform the efficacy and safety for the 4 arms of Cohort D.
Protocol Amendment 05 includes changes to modify the sample size, accrual duration for Cohort 
D, and timing of dual primary endpoint analyses to reflect actual enrollment and time. Due to 
prolonged enrollment from Cohort D-Part 1 and BMS reprioritization, Cohort D-Part 2 will no 
longer be conducted. Additional guidance related to COVID-19 was also added to the amendment.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 05
Section Number & Title
Description of Change
Brief Rationale
Synopsis
Changes to ensure alignment with protocol 
amendment body.
To ensure alignment with 
protocol amendment body.
Section 1, Introduction and 
Study Rationale; Section 1.3.1, 
Primary Objectives; Section 
3.1, Study Design and 
Duration; Figure 3.1-2, Study 
Design Schematic for Addition 
of Cohort D; Section 3.2, Post 
Study Access to Therapy; 
Table 5.1-1, Screening 
Procedural Outline for All 
Treatment Arms (Cohorts A, 
B, C, and D); Section 5.5, 
Efficacy Assessments; Section 
8.1, Sample Size 
Determination; Section 8.1.1, 
Populations for Analyses; 
Section 8.2.1, Dual Primary 
Endpoints; Section 8.2.2, 
Secondary Endpoint(s); 
Section 8.2.9, Outcomes 
Research Analyses; Section 
8.2.9.2, Change in Cancer-
related Symptoms and Quality 
of Life; Section 8.2.9.3, 
Change in Health Status and 
Health Utility
Removed all text related to 
Cohort D-Part 2. Changed all references of 
Cohort D-Part 1 to Cohort D.
Due to prolonged enrollment 
from Cohort D-Part 1 and BMS 
reprioritization, Cohort D-Part 2 
will no longer be pursued.
Cohort D-Part 1 is now referred 
to simply as Cohort D.
Section 1.1.13, Rationale for 
Duration of Treatment with 
Nivolumab plus Ipilimumab; 
Section 4.5, Selection and 
Timing of Dose for Each 
Subject
Added “For subjects in these cohorts who 
receive immunotherapy treatment beyond 2 
years, treatment will be given for a 
maximum of 5 years from the start of study 
treatment.”
No clinical benefit has been 
demonstrated after 24 months of 
immunotherapy. However, for 
subjects that receive 
immunotherapy beyond 2 years,
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 05
Section Number & Title
Description of Change
Brief Rationale
a maximum treatment duration 
was added.
Section 1.3.1, Primary 
Objectives; Section 8.1, 
Sample Size Determination; 
Section 8.1, Populations for 
Analyses; Section 8.2.1, Dual 
Primary Endpoints; Section 
8.2.5, Efficacy Analyses
Clarified that measurable disease is per 
investigator assessment (as entered in the 
interactive web response system [IWRS]).
To clarify language.
Section 3.1, Study Design and 
Duration; Section 5.5.1, 
Primary Efficacy Endpoints
Added “If exceptional circumstances 
preclude the continued administration of 
measures using planned modalities, then 
alternate administration methods may be 
required after consultation with a sponsor 
or a sponsor’s representative.”
To allow for virtual follow up 
visits and assessments as needed.
Protocol Amendment No.: 05
Date:01-Dec-2021
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 05
Section Number & Title
Description of Change
Brief Rationale
Section 3.1, Study Design and 
Duration
•
Modified the accrual duration of the 
study for Cohort D to reflect actual 
accrual time of 24 months instead of 
previously written 8 months.
•
Clarified time period for long-term 
survival analysis.
•
Analyses for the dual primary endpoints 
of rPFS and ORR were modified for 
timing of the analyses from “minimum 
9 months” to “approximately 9 months
of minimum follow up and from “all” 
to “90%” subjects
•
Added “Additional survival analysis 
may be conducted for up to 5 years
from the date of randomization of the 
last patients following analysis of the 
primary endpoint.”
•
Accrual duration was 
updated to reflect a more 
accurate accrual time.
•
 
 
 
 
 
•
To maintain consistency with 
Cohorts A, B, and C,
language has been added to 
allow possible survival 
analyses.
Section 3.1, Study Design and 
Duration; Section 3.3.4, 
Exclusion Criteria for 
Crossover Phase for Subjects 
Originally Randomized to Arm 
D3 or Arm D4 only; Section 
4.5.1, Dose Delay Criteria for 
Nivolumab and Ipilimumab; 
Section 4.5.5, Dose Delay, 
Modification, and 
Discontinuation for 
Cabazitaxel; Section 4.5.5.5, 
Criteria to Resume Study 
Treatment following SARS-
CoV-2 Infection; Table 5.1-1, 
Screening Procedural Outline 
for All Treatment Arms 
(Cohorts A, B, C, and D); 
Table 5.1-2, On Treatment Part 
1: Sequential Treatment with 
Nivolumab and Ipilimumab 
Procedural Outline - Cohorts 
A, B, and C; Table 5.1-3, On 
Treatment Part 2: Nivolumab 
Monotherapy Phase Procedural 
Outline for Cohorts A, B, and 
C; Table 5.1-4, On Treatment 
Procedural Outline for Cohort 
D; Table 5.1-5, Follow-up 
Assessments for All Treatment 
Arms (Cohorts A, B, C, and 
D); Section 6.1.1, Serious 
Adverse Event Collection and 
Added guidance regarding severe acute 
respiratory syndrome (SARS-CoV-2)
infection.
To mitigate chances that SARS-
CoV-2 infection sequelae 
increase toxicity of study drug. 
To aid in interpretation of study
AEs. To offer guidance on when 
to safely resume study drug in 
participants with SARS-CoV-2 
infection.
Protocol Amendment No.: 05
Date:01-Dec-2021
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BMS-936558
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 05
Section Number & Title
Description of Change
Brief Rationale
Reporting; Section 6.2.1, 
Nonserious Adverse Event 
Collection and Reporting
Section 3.1, Study Design and 
Duration; Figure 3.1-2, Study 
Design Schematic for Addition 
of Cohort D; Section 8.1, 
Sample Size Determination
Decreased enrollment in Cohort D from 
315 to 259 subjects.
Several enrollment challenges 
significantly impacted study 
timelines, notably the COVID-
19 pandemic
 
In addition, 
enrollment of patients with 
measurable disease at baseline 
was difficult after reaching the 
cap on patients with non-
measurable disease. BMS 
determined that the number of 
patients enrolled will be 
sufficient to inform the efficacy 
and safety for the 4 arms of 
Cohort D.
Section 3.3.3, Exclusion 
Criteria
Added exclusion criterion 5) d): 
“Participation in another clinical trial 
concurrent with this study.”
To align with the current 
protocol model document
(PMD).
Section 4, Study Treatment
Added ipilimumab 50 mg as a study 
treatment.
Ipilimumab 50 mg will be 
available starting Q3 2022 and 
may be used in this study.
Section 4.5, Selection and 
Timing of Dose for Each 
Subject
Clarified that dose reductions are only 
allowed for cabazitaxel.
To clarify language.
Section 4.5.5, Dose Delay, 
Modification, and 
Discontinuation for 
Cabazitaxel
Added “Regardless of whether or not the 
event is attributed to cabazitaxel, study 
treatment must be delayed until treatment 
can resume. Tumor assessments for all 
subjects should continue as per protocol 
even if dosing is delayed.”
To clarify language.
Section 5.8, Outcomes 
Research Assessments
Added “If exceptional circumstances 
preclude the continued administration of 
measures using planned modalities, then 
alternate administration methods may be 
required after consultation with a sponsor 
or a sponsor’s representative.”
This allows flexibility to 
continue data collection when 
feasible to accommodate 
subject’s changing health or 
personal circumstances during 
treatment and in follow-up.
Section 8.1, Sample Size 
Determination
•
Updated accrual duration.
•
Updated timing of the dual primary 
endpoint analyses.
•
Combined database locks.
•
Updated the 95% confidence interval
per new sample size
•
Enrollment has now been 
closed, thus sample size 
updated more closely reflect 
final actual sample size 
•
 
 
Protocol Amendment No.: 05
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 05
Section Number & Title
Description of Change
Brief Rationale
 
 
•
 
 
•
Updated the precision for 
the response rate per new 
sample size
Section 8.1.1, Populations for 
Analyses; Section 8.2.2, 
Secondary Endpoints;
 
Clarified populations for analyses by 
cohort.
To clarify language.
Section 8.2.1, Dual Primary 
Endpoints
•
Added “In Cohort D, the radiographic 
progression-free survival (rPFS) is 
defined as the time between the date of 
randomization and the first date of 
documented progression per BICR 
(radiographic a-b) or death due to any 
cause, whichever occurs first.”
•
Added details regarding assessment of 
best overall response (BOR) for Cohort 
D.
To clarify language.
Section 8.2.4, Demographics 
and Baseline Characteristics
Added “For Cohort D, similar analyses will 
be repeated by treatment group and total for 
all randomized subjects.”
To specify that analyses in 
Cohort D are for all 
“randomized” subjects instead of 
all “treated” subjects.
Section 8.2.5, Efficacy 
Analyses; Section 8.2.6, Safety 
Analyses
Clarified planned efficacy and safety 
analyses and the populations for analyses.
To clarify language.
Section 8.2.9.1, Change in Pain 
Intensity
Clarified that the primary analysis will be 
“pain intensity change over time” rather 
than “time to deterioration of pain 
intensity.”
To clarify language.
Section 9.1.2, Monitoring
•
Removed “BMS or designee 
representatives will review data 
centrally to identify potential issues to 
determine a schedule of on-site visits 
for targeted review of study records.”
•
Added “Monitoring details describing 
strategy, including definition of study 
critical data items and processes (eg, 
risk-based initiatives in operations and 
To align with mandatory updates 
to the PMD.
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 05
Section Number & Title
Description of Change
Brief Rationale
quality such as risk management and 
mitigation strategies and analytical 
risk-based monitoring), methods, 
responsibilities, and requirements, 
including handling of noncompliance 
issues and monitoring techniques 
(central, remote, or on-site 
monitoring) are provided in the 
monitoring plan.”
Section 9.3, Dissemination of 
Clinical Study Data
Added new section: “In order to benefit 
potential study participants, patients, 
healthcare providers and researchers, and to 
help BMS honor its commitments to study 
participants, BMS will make information 
about clinical research studies and a 
summary of their results available to the 
public as per regulatory and BMS 
requirements. BMS will post study 
information on local, national, or regional 
databases in compliance with national and 
international standards for disclosure. BMS 
may also voluntarily disclose information 
to applicable databases.”
To align with mandatory updates 
to the PMD.
Protocol Amendment No.: 05
Date:01-Dec-2021
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Clinical Protocol
CA209650
BMS-936558
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SYNOPSIS
Clinical Protocol CA209650
Protocol Title: A Phase 2 Trial of Nivolumab Plus Ipilimumab, Ipilimumab Alone, or Cabazitaxel in Men with 
Metastatic Castration-Resistant  Prostate Cancer
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s):
Cohorts A, B, and C: nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then 
flat dose nivolumab 480 mg every 4 weeks until disease progression or unacceptable toxicity.
Cohort D contains the following dose regimens:
•
Arm D1: Nivolumab 3 mg/kg Q3W + ipilimumab 1 mg/kg Q3W up to 4 cycles, then nivolumab 480 mg Q4W
•
Arm D2: Nivolumab 1 mg/kg Q3W (8 doses)+ ipilimumab 3 mg/kg Q6W (4 doses), then nivolumab 480 mg 
Q4W
•
Arm D3: Ipilimumab 3 mg/kg Q3W up to 4 cycles
•
Arm D4: Cabazitaxel 20 mg/m2 or 25 mg/m2 (at investigator’s discretion and according to country-specific label) 
Q3W + prednisone 10mg PO D1-D21 up to 10 cycles
Study Phase: II
Research Hypothesis: Treatment with nivolumab combined with ipilimumab will have clinical activity in subjects 
with metastatic castrate resistant prostate cancer (mCRPC).
Objectives:
Primary Objectives: 
•
Evaluate objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 assessed 
by Blinded Independent Central Review (BICR) in subjects with mCRPC and measurable disease at baseline per 
investigator assessment as entered in the interactive web response system (IWRS).
•
Assess Radiographic Progression Free Survival (rPFS) assessed by BICR in all treated subjects with mCRPC in 
Cohorts B and C, and all randomized subjects with mCRPC in Cohort D using RECIST v1.1 for soft tissue disease 
progression and PCWG2 for bone disease progression.
Secondary Objectives:
•
Assess radiographic/clinical Progression Free Survival (rcPFS) .
•
Assess overall survival (OS).
•
Evaluate PSA response rate (PSA-RR)
•
Determine the safety and tolerability in all treated subjects.
•
Estimate changes in pain as measured by the Brief Pain Inventory-Short Form (BPI-SF)
•
Estimate changes in cancer-related symptoms and quality of life (QoL) using the FACT-P questionnaire (Cohort 
D only)
•
Estimate changes in health status and health utility as measured by the 3-level EuroQol Five Dimensions 
questionnaire (EQ-5D-3L)
Study Design for Cohorts A, B, C: This is a Phase 2 open-label study of nivolumab plus ipilimumab in subjects with
metastatic castration-resistant prostate cancer (mCRPC). 
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Clinical Protocol
CA209650
BMS-936558
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The trial will include 3 treatment cohorts dosed with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (see Study Design 
Schema below). No dose increases or reductions will be allowed for either drug.
Approximately 90 subjects will be treated in 3 cohorts as follows:
Cohort A: Asymptomatic or minimally symptomatic mCRPC subjects who have not been treated with and are unable 
or unwilling to receive second generation hormone therapies or cytotoxic chemotherapy in mCRPC setting. 
Enrollment discontinued per Revised Protocol 02.
Cohort B: Asymptomatic or minimally symptomatic mCRPC subjects who must have progressed after second 
generation hormone therapies in mCRPC setting and have not been treated with cytotoxic chemotherapy in mCRPC 
setting.
Cohort C: Subjects must have progressed after prior taxane-based cytotoxic chemotherapy in the mCRPC setting.
Per Revised Protocol 02, Cohort A enrollment will be discontinued due to slow accrual and to reflect the changing 
landscape of mCRPC (see Section 1.1.10). Addendum in the protocol). Per Revised Protocol 02, the remainder of 
planned number of patients for Cohort A will be allocated to Cohorts B and C in order to have more precise efficacy 
estimates in those arms. In each of the 2 cohorts B and C, at least 30 subjects must have RECIST v1.1 defined 
measurable disease and no more than 15 subjects will have non-measurable disease by RECIST v1.1.
Subjects will be treated with up to 4 cycles of nivolumab in combination with ipilimumab (Part 1, See Section 4.3.1 
of the protocol), followed by monotherapy nivolumab monotherapy (Part 2, Section 4.3.2 of the protocol) until 
progression of disease, unacceptable toxicity,  or subject withdrawal of consent. In Part 1, a minimum of 1 combination 
cycle of nivolumab and ipilimumab is required. 
In Part 1, each treatment cycle will be 3 weeks in duration. Nivolumab and ipilimumab will be dosed every 3 weeks 
for four doses. After completion of the last combination cycle in Part 1 (i.e. 6 weeks after the last dose of nivolumab 
plus ipilimumab), subjects will then receive nivolumab monotherapy every four weeks in Part 2 until progression of 
disease, unacceptable toxicity, or subject withdrawal of consent. 
Subjects experiencing adverse events (AEs) related to combination dose therapy (Part 1) that do not meet dose 
discontinuation criteria, may proceed to nivolumab monotherapy dosing (Part 2) without completing all 4 combination 
doses, after consultation with Bristol-Myers Squibb (BMS) Medical Monitor, on a case-by-case basis.
Subjects from Cohorts B and C who entered the maintenance period may be permitted re-induction with the 
combination upon PSA progression or radiographic progression (whichever occurs first) and after approval by the 
BMS medical monitor.
It is strongly recommended that subjects in Arms A, B, and C limit treatment duration with immunotherapy treatment 
for up to 2 years. See Section 1.1.13.
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Schema for Cohorts A, B, and C
Study Design for Cohort D: This is a phase 2 open-label study evaluating different dosing regimens containing
nivolumab plus ipilimumab, ipilimumab alone, or cabazitaxel in subjects with mCRPC who have progressed and 
have received docetaxel-containing regimen.
The addition of Cohort D to the trial will include 4 treatment arms. For Cohort D, approximately 259 subjects will be 
randomized in a 2:2:1:2 ratio to one of 4 open-label treatment arms including two new combination arms (Arm D1 
and Arm D2) evaluating alternative nivolumab plus ipilimumab doses and schedules, one arm (Arm D3) evaluating 
ipilimumab monotherapy, and one reference arm (Arm D4) evaluating SOC treatment in this setting cabazitaxel (see 
study schema below). Randomization will be stratified by the presence or absence of measurable disease (measurable 
vs non-measurable disease) at study entry to ensure treatment arms are balanced. 
Subjects in Arms D1 and D2 experiencing drug-related AEs with combination dose therapy that do not lead to study 
treatment discontinuation due to toxicity may proceed to nivolumab monotherapy dosing without completing all 
4 combination cycles. Subjects must have received at least 1 dose of combination therapy before proceeding to 
nivolumab monotherapy after consultation with the Medical Monitor, on a case-by-case basis. 
Nivolumab monotherapy in Arms D1 and D2 may continue until progression of disease, unacceptable toxicity, 2 year 
maximum treatment duration, or subject withdrawal of consent.
Furthermore, subjects from these Arms D1 and D2 who entered the maintenance period may be permitted re-induction 
with the combination upon PSA progression or radiographic progression (whichever occurs first) and after approval 
by the BMS medical monitor.
Subjects treated in Arms D3 and D4 who demonstrate radiographic progression on or after treatment may be eligible 
to receive optional crossover nivolumab in combination with ipilimumab (Arm D1) upon BICR confirmed 
radiographic progression if their case is reviewed with and approved by the BMS Medical Monitor. 
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Clinical Protocol
CA209650
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The aim of Cohort D is to select a combination immunotherapy regimen with optimal benefit/risk profile 
 
. 
Schema for Cohort D 
NOTES:
a.
Subjects with investigator-assessed non-measurable disease at baseline will be capped when approximately 105 
subjects are randomized.
b.
Subjects in Arms D1 and D2 experiencing drug-related AEs with combination dose therapy that do not lead to 
study treatment discontinuation due to toxicity may proceed to nivolumab monotherapy dosing without 
completing all 4 combination cycles. Subjects who entered the maintenance period may be permitted re-induction 
with the combination after approval by the BMS medical monitor.
c.
Subjects in Arms D3 and D4 who have BICR confirmed progression on or after treatment have the option to 
crossover to Arm D1 after approval by the BMS medical monitor
d.
Radiographic progression per RECIST 1.1 or PCWG2 (Section 5.5.3). Treatment beyond investigator-assessed 
RECIST 1.1-defined progression may be considered for subjects meeting criteria according to Section 4.5.4
In accordance with Revised Protocol 03, additional subjects who have progressed after prior docetaxel-containing 
regimen will be enrolled into Cohort D.
Interim reviews of safety and efficacy data will be performed on all subjects receiving IO therapy by the Sponsor and 
participating investigators from the Study Steering Committee for Cohort D after the first 15 treated subjects for each 
cohort/arm have at least 8 weeks of follow-up after first dose and at least one post-baseline tumor assessment. This 
interim review will be used to evaluate early severe toxicity events and early disease control at Week 8 in order to 
provide information regarding safety and futility to make decisions about whether to continue patient accrual onto the 
study. 
Protocol Amendment No.: 05
Date:01-Dec-2021
14
6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab 
Study Population:
Key Inclusion Criteria: (see Protocol Section 3.3.1 for full list of criteria)
•
Men, 18 years or older with histologic confirmation of adenocarcinoma of the prostate and current evidence of
metastatic disease documented by either bone lesions on radionuclide bone scan and/or soft tissue lesions on 
CT/MRI. Metastases may be in regional lymph nodes (N1 per AJCC staging criteria, 8th edition) and/or distant 
metastases (M1 per AJCC staging criteria, 8th edition).
−
Subjects whose disease spread is limited to regional pelvic lymph nodes (N1M0) must have a lymph node 
measuring at least 2 cm in short axis to be considered eligible.
•
Ongoing androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone (GnRH) analogue or 
bilateral orchiectomy (ie, surgical or medical castration) confirmed by testosterone level ≤1.73 nmol/L 
(50 ng/dL) at the screening visit
•
Subjects with castrate levels of testosterone while receiving ADT with evidence of progressive disease within 
6 months prior to screening defined by the Prostate Cancer Working Group (PCWG2) criteria (confirmed rise in 
prostate-specific antigen (PSA) with (i) soft tissue disease progression per RECIST 1.1 or (ii) bone disease 
progression by PCWG2 criteria or both (i) and (ii) are eligible for the study)
•
mCRPC subjects will be enrolled in the following cohorts as follows:
♦
Cohort A: Subjects with asymptomatic or minimally symptomatic mCPRC who have not been treated 
with and are unable or unwilling to receive second generation hormone therapies or cytotoxic 
chemotherapy. Enrollment discontinued per Revised Protocol 02.
♦
Cohort B: Subjects with asymptomatic or minimally symptomatic mCPRC who have progressed after 
second generation hormone therapies and have not been treated with cytotoxic chemotherapy.
♦
Cohort C: Subjects must have progressed after prior taxane-based cytotoxic chemotherapy in the 
mCRPC setting. 
♦
Cohort D: Subjects must have progressed after prior docetaxel-containing regimen. Cohort D will 
contain 4 treatments arms, as previously described.
•
Subjects already on agents for the management of skeletal-related events (SREs) are allowed to continue with 
anti-bone resorptive therapy that was initiated more than 28 days prior to study treatment
•
Sufficient tumor samples from either a fresh biopsy (collected during screening period) or archival tumor tissue 
in the form of formalin-fixed paraffin-embedded [FFPE] block or a minimum of 15 unstained tumor tissue slides. 
Archival tumor samples must be obtained within 1 year prior to enrollment date, either from a metastatic tumor 
lesion (preferred) or from a primary tumor lesion that has not been previously irradiated. Tumor samples collected 
more than 1 year prior to enrollment date may be acceptable if obtained in the metastatic setting and following 
discussion with and approval by the BMS Medical Monitor/designee. Tumor sample may be from core biopsy, 
punch biopsy, excisional biopsy, or surgical specimen). Fine needle aspiration is unacceptable for submission.
 Central laboratory must confirm receipt of tumor samples prior to randomization.
Key Exclusion Criteria: (see Protocol Section 3.3.2 for full list of criteria)
•
Visceral metastases in the liver
•
Active brain metastases or leptomeningeal metastases
•
Ongoing systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days 
of start of study therapy
•
Less than 1 month since resolution of ≥ Grade 2 toxicity related to pelvic-targeted therapy (eg, radiation enteritis)
•
Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently 
cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the breast
•
Prior I-O agents (ie, any antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
•
Prior radiation therapy within 14 days prior to starting study therapy. Any toxicity related to prior radiation 
therapy must have resolved to Grade ≤1 or baseline prior to starting study therapy.
Protocol Amendment No.: 05
Date:01-Dec-2021
15
6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab 
Study Treatment: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational 
[Medicinal] Products (Non-IP/Non-IMP) as listed:
Study Treatment for CA209650
Medication 
Potency 
IP/Non-IP 
Nivolumab BMS-936558 Solution for Injection
100 mg (10 mg/mL) or
40 mg (10 mg/mL)
IP
Ipilimumab
200 mg (5 mg/mL)
IP
Ipilimumab
50 mg (5 mg/mL)
IP
Cabazitaxel
60 mg
IP
Prednisone
5 mg
Non-IP
Key Study Assessments:
•
Adverse Events will be collected to determine the incidence of drug-related adverse events in each cohort
•
Subjects will be assessed by computer tomography (CT) or magnetic resonance imaging (MRI) and radionuclide 
bone scans at baseline and on-treatment beginning Week 8 (± 7 days) from first dose of study therapy and 
continuing every 8 weeks (± 7 days) for the first 6 months and then every 12 weeks (± 7 days) weeks until disease 
progression
•
Patient-reported outcomes will be collected using the EQ-5D-3L, FACT-P, and BPI-SF. See Section 5.8 for 
assessment for Cohorts A, B, C, and D. 
Statistical Considerations:
Sample Size: 
Study Design (Cohorts A, B, and C) Approximately 90 subjects with mCRPC will be enrolled and treated in 2 
cohorts, subjects who must have progressed after second-generation hormone therapies but have not received 
cytotoxic chemotherapy, and subjects who have progressed following cytotoxic chemotherapy (Cohorts B and C,
respectively). Each cohort will consist of 30 or more subjects with measurable disease at baseline per RECIST v1.1 
and no more than 15 with non-measurable disease. 
This open-label Phase 2 study is not designed to statistically test specific hypotheses. Therefore the sample size is not 
based on statistical power calculations, but the size in each cohort is calculated using the observed objective response 
rate among treated subjects with measurable disease at baseline.
Study Design for Cohort D: Approximately 259 subjects with mCRPC, previously treated with docetaxel, will be 
randomized and treated in Cohort D. These 259 subjects will be randomized between 4 arms in a 2:2:1:2 ratio (74, 74, 
37, and 74 subjects in Arms D1, D2, D3, and D4, respectively) and stratified by presence/absence of measurable 
disease by RECIST v1.1 per investigator assessment at study entry to ensure treatment arms are balanced. Subjects 
with non-measurable disease at baseline by RECIST v1.1 per investigator assessment will be capped when 
approximately 105 subjects are randomized so that the remaining 154 subjects (44, 44, 22, and 44 subjects in Arms
D1, D2, D3, and D4, respectively) will have measurable disease at baseline.
Cohort D will evaluate the above immunotherapy regimens and the standard of care comparator cabazitaxel in 
unselected mCRPC patients.
 
Protocol Amendment No.: 05
Date:01-Dec-2021
16
6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab 
Endpoints:
The dual primary endpoints are Objective Response Rate (ORR) and radiographic Progression-Free Survival (rPFS)
by BICR (BICR assessment will be performed retrospectively in Cohorts B and C, and prospectively in Cohort D).
The secondary endpoints are Radiographic/Clinical Progression-Free Survival (rcPFS), Overall Survival (OS), PSA 
response rate (PSA-RR), overall safety and tolerability, changes in pain (measured by BPI-SF), changes in disease-
related symptoms and quality of life (measured by the FACT-P), and changes in health status and utility (measured 
by EQ-5D-3L).
Statistical Analyses:
For Cohorts B and C, all efficacy analyses will be performed by cohort as applicable to either (i) subjects with 
investigator-assessed measurable disease by RECIST v1.1 and/or (ii) total number of subjects within each cohort. All 
efficacy data for treated subjects in Cohort A, if any, will be listed. For Cohort D, efficacy analysis will be performed 
by treatment arm for all randomized subjects.
For the dual primary endpoint of ORR, estimated rates and corresponding 95% exact confidence intervals (CIs) will 
be calculated using the Clopper-Pearson method for all treated subjects with measurable disease at baseline per 
RECIST v1.1 in Cohorts B and C and for all randomized subjects with measurable disease at baseline per RECIST 
v1.1 as entered in IWRS in Cohort D. In Cohorts B and C, estimated odds ratios and differences and corresponding 
95% CIs between cohorts will be calculated for descriptive purpose. In Cohort D, sensitivity analysis of ORR may 
also be performed for all randomized subjects with measurable disease at baseline as entered in the CRF if the 
discrepancy rate is higher than 5%.
For time to event endpoints (eg, dual primary endpoint of rPFS, and secondary endpoints of rcPFS and OS), medians 
and rates at months 6 and 12 and corresponding 95% CIs will be estimated for each cohort via the Kaplan-Meier 
methodology for all treated subjects in Cohorts B and C, and similar analyses will be done for each treatment arm for 
all randomized subjects in Cohort D. Kaplan-Meier plots will be presented for each cohort for Cohorts B and C; 
similarly, Kaplan-Meier plots will be displayed by treatment arm for all randomized subjects in Cohort D. Note that 
these analyses will be stratified by the stratification factor when these are conducted for Cohort D.
Estimate of PSA-RR and corresponding 2-sided exact 95% CI using the Clopper-Pearson method will be performed
on all treated subjects with PSA values at baseline and at least one post-baseline assessment for Cohorts B and C;
similar analysis will be done for each treatment arm in Cohort D with PSA values at baseline and at least one post-
baseline assessment. Note that this analysis will be stratified by the stratification factor when conducted for Cohort D.
For all treated subjects with measurable disease at baseline in Cohorts B and C, 
 will be summarized by cohort 
for subjects with a BOR of PR or CR using the Kaplan-Meier methodology. Median values, along with two-sided 
95% CIs will also be calculated. Summary statistics of 
 will be provided by cohort for subjects with a BOR of 
CR or PR. For all randomized subjects with measurable disease at baseline by RECIST v1.1 per investigator 
assessment as entered in IWRS in Cohort D, similar 
 and 
 analyses will be repeated by treatment arm.
Protocol Amendment No.: 05
Date:01-Dec-2021
17
6.0
Approved
930104999
6.0
v
Approved
1.0
v


TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
 
DOCUMENT HISTORY .............................................................................................. 
 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 05 ............................. 
 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 05 ................ 
 
SYNOPSIS .................................................................................................................... 
 
TABLE OF CONTENTS .............................................................................................. 
 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
 
1.1 Study Rationale ................................................................................................. 
 
1.1.1 Disease Background ................................................................................ 
 
1.1.2 Rationale for Immunotherapy in Castrate Resistant Prostate Cancer 
(CRPC) ........................................................................................................ 
 
1.1.4 Rationale for Nivolumab and Ipilimumab in Prostate Cancer ................ 
 
1.1.5 Rationale to Support Nivolumab plus Ipilimumab Dose and Schedule 
Selection for Cohorts A, B, and C ............................................................... 
 
1.1.6 Rationale to Support Dose and Schedule Selection in Cohort D ............. 
 
1.1.6.1 Arm D1 Rationale for Combination Regimen (nivolumab 3 mg/kg 
plus ipilimumab 1 mg/kg)...................................................................... 
 
1.1.6.2 Arm D2 Rationale for Combination Regimen (nivolumab 1mg/kg 
Q3W (8 Doses) plus ipilimumab 3 mg/kg Q6W (4 Doses) .................... 
 
1.1.6.3 Arm D3 Rationale for Ipilimumab 3 mg/kg Q3W ........................... 
 
1.1.6.4 Arm D4 Rationale for Cabazitaxel in Prostate Cancer .................. 
 
1.1.7 Rationale for Shorter Infusion Times for Nivolumab and Ipilimumab .... 
 
1.1.8 Rationale for Flat Dose 480 mg Nivolumab every 4 weeks (Nivolumab 
Monotherapy Phase) ................................................................................... 
 
1.1.9 Rationale for Shorter Infusion Times with 480 mg Flat Dosing .............. 
 
1.1.10 Rationale for Evaluating Chemotherapy-Naive, Second-Generation 
Hormone Therapy-Naive, Asymptomatic or Minimally Symptomatic 
Metastatic CPRC Subjects (Cohort A Subjects) ......................................... 
 
1.1.11 Rationale for Treatment Beyond PSA Elevation .................................... 
 
1.1.12 Rationale for Optional Crossover Combination for Monotherapy Arms 
(Arm D3 and D4) ........................................................................................ 
 
1.1.13 Rationale for Duration of Treatment with Nivolumab plus Ipilimumab
..................................................................................................................... 
 
1.2 Research Hypothesis ......................................................................................... 
 
1.3 Objectives(s) ..................................................................................................... 
 
1.3.1 Primary Objectives .................................................................................. 
 
1.3.2 Secondary Objectives ............................................................................... 
 
1.4 Product Development Background ................................................................... 
 
1.4.1 Mechanism of Action of Nivolumab ......................................................... 
 
1.4.2 Mechanism of Action of Ipilimumab ........................................................ 
 
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Clinical Protocol
BMS-936558
CA209650
nivolumab
Protocol Amendment No.: 05
Date:01-Dec-2021
18
6.0
Approved
930104999
6.0
v
Approved
1.0
v


1.4.3 Nivolumab-plus-Ipilimumab Mechanism of Action ................................. 
 
1.4.4 Overview of Nivolumab and Ipilimumab Clinical Pharmacology ........... 
 
1.4.4.1 Population Pharmacokinetics of Nivolumab .................................. 
 
1.4.4.2 Population Pharmacokinetics of Ipilimumab ................................. 
 
1.4.4.3 Pharmacokinetics of Nivolumab and Ipilimumab ........................... 
 
1.4.5 Safety Summary ........................................................................................ 
 
1.4.5.1 Nivolumab Safety Summary ............................................................ 
 
1.4.5.2 Ipilimumab Safety Summary ........................................................... 
 
1.4.5.3 Ipilimumab Safety in Prostate Cancer ............................................ 
 
1.4.5.4 Nivolumab-plus-Ipilimumab Safety Summary ................................ 
 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
 
1.5.1 Based on these data, nivolumab 480 mg Q4W is expected to have similar 
efficacy and safety profiles to nivolumab 3 mg/kg Q2W.Overall 
Risk/Benefit Assessment for Additional Cohort D ...................................... 
 
2 ETHICAL CONSIDERATIONS ............................................................................... 
 
2.1 Good Clinical Practice ...................................................................................... 
 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
 
2.3 Informed Consent.............................................................................................. 
 
3 INVESTIGATIONAL PLAN .................................................................................... 
 
3.1 Study Design and Duration ............................................................................... 
 
3.2 Post Study Access to Therapy ........................................................................... 
 
3.3 Study Population ............................................................................................... 
 
3.3.1 Inclusion Criteria ..................................................................................... 
 
3.3.2 Inclusion Criteria for Crossover Phase for Subjects Originally 
Randomized to Arm D3 or Arm D4 only ..................................................... 
 
3.3.3 Exclusion Criteria .................................................................................... 
 
3.3.4 Exclusion Criteria for Crossover Phase for Subjects Originally 
Randomized to Arm D3 or Arm D4 only ..................................................... 
 
3.3.5 Women of Childbearing Potential ........................................................... 
 
3.4 Concomitant Treatments ................................................................................... 
 
3.4.1 Prohibited and/or Restricted Treatments for All Arms ............................ 
 
3.4.1.1 Prohibited and/or Restricted Treatments on Nivolumab and 
Ipilimumab ............................................................................................ 
 
3.4.1.2 Prohibited and/or Restricted Treatments on Cabazitaxel .............. 
 
3.4.2 Other Restrictions and Precautions ......................................................... 
 
3.4.3 Permitted Therapy ................................................................................... 
 
3.4.4 Other Restrictions and Precautions ......................................................... 
 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
 
3.6 Follow up after discontinuation of study drug .................................................. 
 
3.6.1 Withdrawal of Consent ............................................................................ 
 
3.6.2 Lost to Follow-Up .................................................................................... 
 
4 STUDY TREATMENT ............................................................................................. 
 
4.1 Investigational Product ..................................................................................... 
 
4.2 Non-investigational Product ............................................................................. 
 
4.3 Storage and Dispensing..................................................................................... 
 
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Clinical Protocol
BMS-936558
CA209650
nivolumab
Protocol Amendment No.: 05
Date:01-Dec-2021
19
6.0
Approved
930104999
6.0
v
Approved
1.0
v


4.3.1 Arms A, B, and C Part 1 Study Treatment Administration - Nivolumab 
and Ipilimumab Combination Phase (Cycles 1-4) ...................................... 
 
4.3.2 Arms A, B, and C Part 2 Study Treatment Administration - Nivolumab 
Monotherapy Phase (Cycle 5 and beyond) ................................................. 
 
4.3.3 Arm D1 Study Treatment Administration - Nivolumab and Ipilimumab . 
 
4.3.4 Arm D2 Study Treatment Administration for Nivolumab and Ipilimumab
..................................................................................................................... 
 
4.3.5 Re-Induction of Study Therapy For Subjects in Cohorts B, C, Arms D1 
and D2 ......................................................................................................... 
 
4.3.6 Arm D3 Study Treatment Administration ................................................ 
 
4.3.7 Arm D4 Study treatment administration - cabazitaxel plus prednisone .. 
 
4.3.8 Study Treatment Preparation and Infusion.............................................. 
 
4.4 Method of Assigning Treatment ....................................................................... 
 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
 
4.5.1 Dose Delay Criteria for Nivolumab and Ipilimumab .............................. 
 
4.5.2 Criteria to Resume Treatment for Nivolumab and Ipilimumab ............... 
 
4.5.3 Dose Discontinuation for Nivolumab and Ipilimumab ............................ 
 
4.5.4 Treatment Beyond Disease Progression .................................................. 
 
4.5.5 Dose Delay, Modification, and Discontinuation for Cabazitaxel............ 
 
4.5.5.1 Other Toxicities for Cabazitaxel ..................................................... 
 
4.5.5.2 Dose Reduction for cabazitaxel ...................................................... 
 
4.5.5.3 Special Precautions for Cabazitaxel ............................................... 
 
4.5.5.4 Prednisone Dose Modifications and Dose Delays .......................... 
 
4.5.5.5 Criteria to Resume Study Treatment following SARS-CoV-2 
Infection ................................................................................................ 
 
4.5.6 Management Algorithms for Immuno-Oncology Agents ......................... 
 
4.5.7 Treatment of Related Infusion Reactions ................................................. 
 
4.5.7.1 Nivolumab and Ipilimumab Treatment of Related Infusion 
Reactions ............................................................................................... 
 
4.5.7.2 Hypersensitivity Reactions for Cabazitaxel .................................... 
 
4.6 Blinding/Unblinding ......................................................................................... 
 
4.7 Treatment Compliance ...................................................................................... 
 
4.8 Return of Study Treatment ................................................................................ 
 
4.9 Retained Samples for Bioavailability/Bioequivalence ..................................... 
 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
 
5.2 Re-Testing During Screening or Lead-in Period .............................................. 
 
5.3 Study Materials ................................................................................................. 
 
5.4 Safety Assessments ........................................................................................... 
 
5.4.1 Imaging Assessment for the Study............................................................ 
 
5.5 Efficacy Assessments ........................................................................................ 
 
5.5.1 Primary Efficacy Endpoints ..................................................................... 
 
5.5.2 Method of Tumor Response Assessment .................................................. 
 
5.5.3 Disease Progression Criteria .................................................................. 
 
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Clinical Protocol
BMS-936558
CA209650
nivolumab
Protocol Amendment No.: 05
Date:01-Dec-2021
20
6.0
Approved
930104999
6.0
v
Approved
1.0
v


5.8 Outcomes Research Assessments ..................................................................... 
 
5.8.1 The Brief Pain Inventory - Short Form .................................................... 
 
5.8.2 The Functional Assessment Of Cancer Therapy - Prostate Cancer 
(FACT-P) .................................................................................................... 
 
5.8.3 The 3-level EQ-5D-3L .............................................................................. 
 
5.9 Additional Research Collection ........................................................................ 
 
5.10 Health Economics OR Medical Resource Utilization and Health Economics
........................................................................................................................... 
 
6 ADVERSE EVENTS ................................................................................................. 
 
6.1 Serious Adverse Events .................................................................................... 
 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
 
6.2 Nonserious Adverse Events .............................................................................. 
 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
 
6.3 Laboratory Test Result Abnormalities .............................................................. 
 
6.4 Pregnancy .......................................................................................................... 
 
6.5 Overdose ........................................................................................................... 
 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
 
6.7 Other Safety Considerations ............................................................................. 
 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
 
8 STATISTICAL CONSIDERATIONS....................................................................... 
 
8.1 Sample Size Determination ............................................................................... 
 
8.1.1 Populations for Analyses ......................................................................... 
 
8.2 Endpoints .......................................................................................................... 
 
8.2.1 Dual Primary Endpoints .......................................................................... 
 
8.2.2 Secondary Endpoint(s) ............................................................................. 
 
8.2.4 Demographics and Baseline Characteristics........................................... 
 
8.2.5 Efficacy Analyses ..................................................................................... 
 
8.2.6 Safety Analyses......................................................................................... 
 
8.2.9 Outcomes Research Analyses .................................................................. 
 
8.2.9.1 Change in Pain Intensity ................................................................. 
 
8.2.9.2 Change in Cancer-Related Symptoms and Quality of Life ............. 
 
8.2.9.3 Change in Health Status and Health Utility ................................... 
 
8.2.10 Other Analyses ....................................................................................... 
 
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Clinical Protocol
BMS-936558
CA209650
nivolumab
Protocol Amendment No.: 05
Date:01-Dec-2021
21
6.0
Approved
930104999
6.0
v
Approved
1.0
v


9 STUDY MANAGEMENT ........................................................................................ 
 
9.1 Compliance ....................................................................................................... 
 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
 
9.1.2 Monitoring ............................................................................................... 
 
9.1.2.1 Source Documentation .................................................................... 
 
9.2 Records ............................................................................................................. 
 
9.2.1 Records Retention .................................................................................... 
 
9.2.2 Study Treatment Records ......................................................................... 
 
9.2.3 Case Report Forms .................................................................................. 
 
9.3 Dissemination of Clinical Study Data............................................................... 
 
9.4 Clinical Study Report ........................................................................................ 
 
9.5 SCIENTIFIC PUBLICATIONS ....................................................................... 
 
10 GLOSSARY OF TERMS ........................................................................................ 
 
11 LIST OF ABBREVIATIONS .................................................................................. 
 
12 REFERENCES ........................................................................................................ 
 
APPENDIX 1 MANAGEMENT ALGORITHMS ....................................................... 
 
APPENDIX 2 PERFORMANCE STATUS SCALES - ECOG ................................... 
 
APPENDIX 3 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
 
APPENDIX 4 COUNTRY SPECIFIC REQUIREMENTS ......................................... 
 
APPENDIX 5 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ........ 
 
 
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Clinical Protocol
BMS-936558
CA209650
nivolumab
Protocol Amendment No.: 05
Date:01-Dec-2021
22
6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab 
1
INTRODUCTION AND STUDY RATIONALE
CA209650 is a Phase 2, open-label study of the evaluation of efficacy, safety and tolerability of 
same day sequential dosing of nivolumab followed by ipilimumab, in subjects with metastatic 
castration resistant prostate cancer (mCRPC). Subjects with mCRPC, defined as castrate resistant 
prostate cancer and M1 metastatic disease on bone, CT and/or MRI scan per NCCN criteria1, who 
are either asymptomatic or minimally symptomatic, will be evaluated in 3 cohorts as follows: 
(A) Subjects who have never received treatment either with cytotoxic chemotherapy or second-
generation hormone therapies such as enzalutamide and/or abiraterone, (B) Subjects who have 
progressed after second-generation hormone therapies such as enzalutamide and/or abiraterone but 
have not been treated with cytotoxic chemotherapy (C) Subjects who have progressed after 
treatment with cytotoxic chemotherapy. Cohort A enrollment will be discontinued in Revised 
Protocol 02 due to slow accrual and to reflect the changing landscape of metastatic castration-
resistant prostate cancer (Section 1.1.10, Addendum).
The study aims to demonstrate that treatment with nivolumab combined with ipilimumab will have 
clinical activity in subjects with mCRPC. Additional objectives of the study include further 
characterization of efficacy, safety and tolerability, determining changes in patient-reported 
outcomes for quality of life assessments and pain measures, as well as pharmacokinetics, 
 
.
In accordance with Revised Protocol 03, the study will enroll a new cohort of subjects (Cohort D) 
who have progressed after prior docetaxel-containing regimen. In Cohort D, subjects will be 
randomized to one of four open-label treatment arms including two new combination arms 
evaluating alternative nivolumab plus ipilimumab doses and schedules, one arm evaluating 
ipilimumab monotherapy, and one reference arm evaluating SOC treatment in this setting 
(cabazitaxel). The aim of Cohort D is to select a combination immunotherapy regimen with 
optimal benefit/risk profile
.
1.1
Study Rationale
1.1.1
Disease Background
Prostate cancer is a leading cause of cancer mortality in men worldwide.2 With an estimated 
incidence of 220,800 new cases and 27,540 deaths in 2015, prostate cancer is the most frequently 
diagnosed cancer and second most frequent cause of cancer deaths in US males.3 In Europe 
prostate cancer was the third most common cancer in 2012, with 417,000 new cases and 92,000 
deaths from prostate cancer being reported in that year.4
In 1941, Huggins and Hodges first noted the beneficial effects of castration and injection of 
estrogens in subjects with metastatic prostate cancer.5 Over time, androgen deprivation therapy 
(ADT), defined as medical castration, became the cornerstone of treatment for subjects with 
metastatic disease, as well as for subjects with localized or locally advanced prostate cancers when 
administered as neoadjuvant, concomitant or adjuvant therapy in combination with radiation. 
While ADT results in disease remission in 90% of metastatic prostate cancer subjects evidenced 
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by a decline in levels of prostate-specific antigen (PSA),6 most subjects become resistant with 
disease progression occurring within a median of 18–24 months of continuous hormonal 
manipulation.7
Prostate Cancer Working Group 2 (PCWG2)8 categorizes the disease continuum of prostate cancer 
as a rising PSA state as non-castrate or castrate subjects, with either non-measurable disease or 
with distant metastases, on the basis of (i) whether the serum testosterone level is in the castrate 
range of ≤ 50 ng/dL by surgical orchiectomy or medical therapy with gonadotropin-releasing 
hormone analogs and anti-androgens and (ii) presence or absence of metastases detectable 
clinically or by imaging.1 Metastatic castration resistant prostate cancer (mCRPC) is defined as 
subjects with confirmed castrate levels of testosterone following orchiectomy or treatment with 
ADT, and presence of distant soft tissue or bony metastases by NCCN criteria.1 Subjects with 
established metastatic CRPC (mCRPC) have a life expectancy in the range of 27 to 
32 months.9,10,11
In 1996, mitoxantrone plus prednisone was approved for the treatment of subjects with mCRPC 
based on improvement in pain palliation.12 In 2004, 2 Phase 3 studies (TAX327 and SWOG 
S9916) demonstrated that docetaxel- based regimens can improve overall survival of subjects with 
mCRPC.13,14 However, docetaxel-based treatment is associated with clinically significant 
toxicities that greatly limit its use in the management of lower risk, asymptomatic and minimally 
symptomatic mCRPC subjects without visceral metastases. 
Since 2010, six new therapeutic agents with diverse mechanisms of action have been added to the 
therapeutic armamentarium, five of which sipuleucel-T, cabazitaxel, abiraterone, enzalutamide, 
and radium-223, have been approved for the treatment of mCRPC based on improvement in 
median overall survival. While the availability of these new treatment options allows for tailoring 
therapy to patient characteristics such as presence or absence of symptoms, prior treatments, 
patient preferences and life expectancy, it is also recognized that none of these therapies result in 
durable clinical responses. Despite high initial response rates, remissions following second-
generation hormone therapies are temporary15 due to the occurrence of resistance mechanisms 
including androgen receptor reactivation.16 At this time, with judicious sequencing and use of 
available new therapies, subjects with established metastatic CRPC (ie, without prior 
chemotherapy) have life expectancy in the range of 27 to 32 months.9,10,11Thus mCRPC remains 
a disease with a lethal outcome with the urgent need for treatment options that will provide durable 
disease control and long term survival.
1.1.2
Rationale for Immunotherapy in Castrate Resistant Prostate Cancer 
(CRPC)
Immunotherapy agents represent a promising approach for chemotherapy-free alternatives for the 
management of asymptomatic and minimally symptomatic CRPC subjects.
1) Like most types of cancer, prostate cancer develops in an immune-competent environment. 
Immune responses against prostate tumors are noted in the form of intratumoral leukocyte 
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infiltration and inflammatory pathway activation.17 Evidence from animal models and human 
prostate cancer suggests that despite the presence of immune effector cells that recognize tumor 
antigens, these cells are actively tolerized and become incapable of mediating tumor 
destruction.18 The induction of regulatory or suppressor T cells19 with increased CD4+CD25+ 
and CD8+Foxp3+ regulatory T cells (Treg) detected both within prostate glands and in the 
peripheral blood of prostate cancer subjects, suggests the presence of active immune 
suppression of antitumor immunity.20,21
These lines of evidence support targeting the immune system itself via activation of T cells 
and overcoming T-cell tolerance, to result in durable antitumor activity in prostate cancer. 
2) The inherent characteristics of prostate cancer also make it an ideal target for immunotherapy. 
Prostate cancer is generally considered a slow-growing-tumor, which may allow adequate time 
for an immunotherapy agent to activate the immune system. 
Furthermore, prostate cancer has many well-described tumor-associated antigens (TAAs), 
which may be ideal targets for immunotherapy such as vaccines because they are specific to 
the cancer. Examples of TAA for prostate cancer include PSA, prostatic acid phosphatase 
(PAP), and prostate-specific membrane antigen (PSMA). This has led to the evaluation of 
therapeutic cancer vaccines designed to break immune tolerance22 being explored in subjects 
with early CRPC, ie, before chemotherapy, with vaccines of autologous origin,23 poxvirus,24
and PSA TRICOM.25
Prostvac (developed by the National Cancer Institute and licensed to BN Immunotherapeutics, 
Mountain View, CA), is a prostate cancer vaccine consisting of a recombinant vaccinia vector 
as a primary vaccination, engineered to express prostate-specific antigen (PSA) and a triad of 
human T-cell costimulatory molecules (designated TRICOM). A multicenter randomized 
phase II study that randomized minimally symptomatic mCRPC subjects to Prostvac vs 
placebo showed preliminary evidence of improved overall survival.26 The IMPACT study 
evaluated Sipuleucel-T (Dendreon Corp., Seattle, WA) an autologous vaccine vs. placebo in 
chemotherapy-naïve CRPC subjects and reported a 4.1 month survival improvement in 
asymptomatic or minimally symptomatic CRPC subjects.27 While these preliminary data show
little overall impact on delaying progression of disease, the reported benefits in overall survival
may be considered “proof of concept” that immunotherapeutic agents can play an important 
role in treating advanced prostate cancer.28
While antigen-specific therapies such as vaccines have shown evidence of potential for benefit 
in the clinic, this approach has many limitations,29,30,31,32 underscoring the need to explore 
immunotherapy that does not rely mainly on the expression of a specific antigen.
3) Androgen-deprivation therapy (ADT), a mainstay of treatment for both high-risk early prostate 
cancer and recurrent and/or metastatic disease, has been shown to alter the immune 
environment in prostate cancer.33 For example, neoadjuvant ADT of prostate cancer subjects 
results in increased numbers of infiltrating CD4 T cells, CD8 T cells, natural killer cells, and 
macrophages in prostate tissues.34,35 Mouse models have shown that ADT increases the 
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number of T cells in peripheral lymphoid tissues and prostate glands, enhances T-cell 
proliferation to antigen, promotes recovery of T- and B-cell populations following 
chemotherapy36 and mitigates tolerance of prostate-specific CD4 T cells. Furthermore, ADT 
has also been shown to reverse age-related thymic atrophy in mice and to restore thymic T-cell 
output in both mice and prostate cancer subjects.37
Immunotherapy agents in conjunction with standard of care therapy ie, ADT could potentially 
result in increasing immune-mediated anti-tumor activity in subjects with prostate cancer.
Taken together, these lines of evidence strongly support the continued investigation of 
immunotherapy agents to improve outcomes in mCRPC. Accordingly, alternate approaches 
aimed at targeting the immune system itself to result in durable antitumor activity, including 
evaluation of combination checkpoint blockade inhibition, are warranted.
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1.1.4
Rationale for Nivolumab and Ipilimumab in Prostate Cancer
(i) Ipilimumab in prostate cancer:
Due to its potentially broad mechanism of action, ipilimumab has been investigated in several 
other solid tumor settings, including mCRPC. In fact, the first in-human study of ipilimumab was 
in prostate cancer: an investigation of a single 3 mg/kg dose of ipilimumab in 14 subjects with 
CRPC.42 Ipilimumab as a single dose had acceptable pharmacokinetic and safety profiles, but only 
two of the 14 subjects experienced PSA declines of > 50%. Results have since been reported for 
six other clinical studies of ipilimumab in mCRPC42. Together, these seven trials encompassed 
240 subjects across multiple settings of advanced CRPC, roughly 20% of whom had progressed 
on or relapsed after docetaxel.43 These studies utilized multiple doses (ranging from 0.5 to 
10 mg/kg as either monotherapy or in combination studies) and schedules (ranging from a single 
dose of ipilimumab to recurring doses every 3 weeks for four cycles) and demonstrated the clinical 
activity of ipilimumab 3, 5 and 10 mg/kg, defined as PSA response, in the treatment of mCRPC 
(Table 1.1.4-1) whether used as monotherapy,42 with ADT 44 or with other interventions such as 
radiotherapy,45 or other immunotherapeutics with different mechanisms of action.46,47,48,49 In 
3 studies which included ipilimumab monotherapy at 3 mg/kg in mCRPC, PSA responses were 
observed in 6 of 44 evaluable patients (13.6%). In one study which included ipilimumab 
monotherapy at 10 mg/kg, PSA responses were observed in 4 of 16 patients (25%).
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Table 1.1.4-1:
Phase 1/2 Studies with Ipilimumab in Prostate Cancer
Protocol
Population
Combination
Subjects Treated/Target
PSA
Response
PSA Response
Rate (%)
MDX010-21
(CA184017)
Docetaxel failure and 
docetaxel eligible
Monotherapy and single-dose 
radiation combination
3 mg/kg: 8/6
2
13/70 evaluable
(18.6%)
5 mg/kg: 6/6
10 mg/kg:16/16
3 mg/kg + RT: 6/6
1
4
2
10 mg/kg + RT: 34/34
4
MDX010-17
(CA184119)
Docetaxel eligible
GVAX
(CellGenesys)
< 3 mg/kg: 6/6
3
5/28 (18%)
3 mg/kg: 19/19
5 mg/kg: 3/3
2
CTEP 7207a
(CA184066)
Docetaxel failure and 
docetaxel eligible
Prostavac (fixed dose)
1 mg/kg: 3/3
1
3
1
5/28 (7%)
3 mg/kg: 6/6
5 mg/kg: 6/6
10 mg/kg: 13/16
CTEP 6032 
(CA184067)
Docetaxel eligible
GM-CSF (on Days 1-14)
< 3 mg/kg: 15/15 3 mg/kg: 9/9
5 mg/kg: 5/6
10 mg/kg: 1/16
3
3/30 (10%)
MDX010-01
(CA184009)
Metastatic HRPC
Monotherapy
3 mg/kg: 14/14
2
2/14 (14%)
MDX010-07
(CA184019)
Docetaxel eligible
Docetaxel
3 mg/kg alone: 24/20
3 mg/kg + docetaxel: 20/20
2
1
3/42 evaluable
(7%)
HRPC (subtotal)
190/225
31
16%
MDX010-06
(CA184118)
Unresectable PC 
(< 90 days prior hormonal Rx)
3 months androgen ablative 
therapy
3 mg/kg: 50/108
11
11/50 (22%)
Total Subjects
240/333
44
17%
a Ongoing accrual
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Two Phase 3 Studies (CA184043 and CA184095) carried out subsequently have failed to show a 
clear-cut survival advantage for ipilimumab (10 mg/kg) over placebo. An updated, double-blind, 
randomized Phase 3 study in subjects with mCRPC who had received prior treatment with 
docetaxel for their disease, did not meet its primary endpoint of demonstrating a statistically 
significant prolongation of survival for the ipilimumab group compared with the placebo group. 
No difference in overall survival was noted between subjects who received ipilimumab and those 
who received placebo after bone-directed radiotherapy.50 However, the assessment of the 
proportional hazards assumption showed that it was violated (p=0.0031) in the primary analysis.
A piecewise hazard model showed that the HR changed over time: the HR for 0–5 months was 
1.46 (95% CI 1.10–1.95), for 5–12 months was 0.65 (0.50–0.85), and beyond 12 months was 0.60 
(0.43–0.86). Kaplan-Meier (K-M) survival curves show the ipilimumab group to be below the 
placebo group through approximately Month 8, after which time the K-M survival curves crossed, 
and the ipilimumab group remained above the placebo group for the remainder of the follow-up 
phase (See Figure 1.1.4-1). In addition, ipilimumab was associated with reductions in PSA 
concentration (13.1% [95% CI.9·5–17.5] for ipilimumab and 5.2% [3.0–8.4] for placebo) and an 
improvement in PFS compared with placebo (median 4.0 [95% CI 3.6–4.3] vs 3.1 [2.9–3.4] 
months; HR 0.70, 95% CI 0.61–0.82; p<0.0001). PFS was a composite endpoint based on 
confirmed PSA progression, confirmed radiological progression, clinical deterioration, or death. 
A long-term survival analysis with 2-years of additional follow-up from the primary analysis of 
the CA184-043 study showed that survival significantly favored the ipilimumab arm (HR =0.83 
(95% CI: 0.71-0.96); p=0.013).51 Landmark OS rates in the ipilimumab and placebo arms were 
15.3% (95% CI: 11.7, 18.9) versus 7.9% (95% CI: 5.2, 10.6) at 3 years, 10.1% (95% CI: 6.9, 13.3) 
vs. 3.3% (95% CI: 1.3, 5.3) at 4 years, and 7.9% (95% CI: 4.4, 11.4) vs. 2.7% (95% CI: 0.8, 4.7) 
at 5 years. There were 49/399 long-term survivors in the ipilimumab arm and 29/400 in the placebo 
arm. 
Similarly, study CA184095 a double-blind, randomized Phase 3 study in subjects with 
asymptomatic or minimally symptomatic, chemotherapy-naïve, mCRPC with no known visceral 
metastases did not meet its primary endpoint based on intent-to-treat analysis (HR 1.11; 95.87% 
CI: 0.88, 1.39; P value = 0.3667) for OS. However, treatment with ipilimumab was associated with
longer median PFS (defined as time to confirmed PSA or radiological progression, clinical 
deterioration, or death) in the ipilimumab group (5.6 months) versus the placebo group 
(3.8 months, HR, 0.67; 95.87% CI, 0.55 to 0.81), longer median time to non-hormonal cytoxic 
chemotherapy (HR, 0.65; 95.87% CI, 0.52 to 0.83) and to docetaxel therapy (HR, 0.70; 95% CI,
0.55 to 0.88) in the ipilimumab arm versus placebo. In addition, a higher PSA response rate was 
observed with ipilimumab (23%; 95% CI, 19% to 27%) compared to placebo (8%, 95% CI, 5% to 
13%).
Given the improved tolerability of ipilimumab 3 mg/kg compared to 10 mg/kg and the clinical 
activity observed at the 3 mg/kg dose, the current study will assess ipilimumab 3 mg/kg in Arm 
D3 
 with the aim 
of identifying a subset of men with CRPC who may benefit from ipilimumab treatment. Arm D3 
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also aims to characterize the contribution of ipilimumab to the nivolumab + ipilimumab 
combinations evaluated in this study. 
Figure 1.1.4-1:
Kaplan-Meier Plot of Overall Survival -Randomized Subjects
(ii) PD-1/PD-L1 pathway in Prostate cancer
Prostate cancer has been shown to have low tumor expression of PD-L1.52 However, in a study 
evaluating human prostate cancer cell lines for PD-L1 expression and loss of phosphatase and 
tensin homolog (PTEN) by flow cytometry and western blotting, many prostate cancer cell lines 
upregulated PD-L1 expression in response to inflammatory cytokines in vitro, consistent with 
adaptive immune resistance. In these cell lines, no association between PTEN loss and PD-L1 
expression was apparent. In primary prostate tumors, PD-L1 expression was rare, and was not 
associated with PTEN loss suggesting that innate immune resistance was not a likely mechanism 
of immune resistance as a mechanism resulting in decreased antitumor immune responses in 
prostate cancer (as opposed to an adaptive immune resistance response mechanisms (refer to 
Section 1.1.2).53 Furthermore, an analysis of the prognostic significance of PD-1 and/or PD-L1 
expression in a cohort of 535 prostate cancer tumors showed that a high density of PD-1+ 
lymphocytes independently predicted shorter clinical failure-free survival.54 This may indicate that 
tumor immune escape, and thus tumor immune elimination, are important mechanisms in prostate 
cancer, and the association of pathway molecules with poor prognosis makes them attractive 
targets for inhibition. 
Nivolumab monotherapy was evaluated in a cohort of 17 subjects with mCRPC.55 All subjects 
with mCRPC were treated with nivolumab 10 mg/kg, and no objective responses were observed. 
One out of 10 subjects evaluable for PSA response demonstrated a PSA reduction ≥50% from 
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baseline. Prostate tumor samples were available in 2 subjects with mCRPC, and tumor PD-L1 
expression was 0% in both subjects. 
Other anti-PD-(L)1 inhibitors have also demonstrated limited clinical activity in mCRPC. 
Atezolizumab monotherapy was evaluated in a phase 1a study, including 15 heavily pretreated 
subjects with mCRPC.56 There were no objective responses per RECIST v1.1, although 1 subject 
had a PR per immune-related response criteria (irRC). Analysis of tumor tissue in this subject 
revealed no PD-L1 IHC expression at baseline but did demonstrate an ATM mutation, a 
component of the DNA damage response pathway.
Pembrolizumab was recently evaluated in a phase 2 study of mCRPC patients previously treated 
with docetaxel.57 Among those with measurable disease, ORR was 3% and 5% in PD-L1 negative
(n=67) and positive (n=131) patients, respectively. PSA responses were observed in 11% of 
evaluable patients (n = 193). Among 19 patients with somatic aberrations in BRCA1/2 or ATM,
ORR was 11%, suggesting that DNA repair defects may be associated with anti-tumor activity. In 
conclusion, single-agent PD-(L)1 inhibitors appear to have limited anti-tumor activity in mCRPC.
(iii) Role for dual checkpoint blockade inhibition: (anti-CTLA4 and anti-PD-1) in prostate cancer
Consistent with the above pre-clinical data, it has been observed that ipilimumab induces an 
adaptive immune response within the prostate tumor microenvironment.58 In a clinical trial, 
subjects with localized prostate cancer who were treated with ADT plus 2 doses of anti-CTLA4 
antibody (ipilimumab) observed an increased frequency of CD4 and CD8 T cell infiltration into 
tumor tissues. Treatment with ipilimumab also led to increased expression of PD-1 and PD-L1 (on 
both immune and epithelial cells).58 Of particular interest was the finding that PD-L1 expression 
in the tumor microenvironment co-localized with CD8 T cells in prostate tumors after ipilimumab 
treatment. Since CD8 T cells are the key effector immune cells that mediate tumor rejection, it is 
possible that increased expression of PD-L1, as well as PD-1, occurs on T cells as a critical 
mechanism to suppress T cell responses in tissues, resulting in tumor growth. These results are 
consistent with recent reports that CD8 T cells and PD-L1 expression are co-localized in the 
melanoma tumor microenvironment.59,60
In summary, while treatment with ipilimumab resulted in expected immune augmentation, it was 
also associated with the induction of immune inhibitory PD-1/PD-L1 pathway, providing perhaps 
a potential explanation as to why a significant proportion of subjects with prostate cancer did not 
benefit from treatment with ipilimumab or nivolumab as monotherapy. Accordingly, utilizing a 
combination checkpoint blockade inhibition approach with anti-CTLA-4 and anti-PD-1 agents 
may be necessary to boost anti-tumor activity for maximum clinical benefit in prostate cancer.
Combination of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg Q3W for up to 4 doses, followed by
nivolumab 480 mg every 4 weeks has been evaluated in Cohorts B and C of this study. A safety 
and efficacy analysis (Database lock date 03-Jul-2018) was conducted in all treated patients with 
at least 24 weeks of follow-up in Cohort B (n=33) and Cohort C (n=45). Among patients with 
baseline measurable disease, ORR was 26% in Cohort B and 10% in Cohort C. Among patients 
with measurable disease, 33 subjects had tumor samples that underwent whole exome sequencing 
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for HRD and TMB testing (TMB “high” and “low” represent above and below the median of 74.5 
mutations per patient). ORR were higher in HRD positive (67% [2/3] in Cohort B and 50% [1/2] 
in Cohort C) compared to HRD negative patients (25% [4/16] in Cohort B and 17% [2/12] in 
Cohort C). Similarly, ORR was higher in TMB-high patients (60% [6/10] in Cohort B and 50% 
[3/6] in Cohort C) compared to TMB-low patients (0% in both Cohorts B and C).
Confirmed/unconfirmed PSA decline ≥50% in patients with baseline and ≥1 post-baseline PSA 
result were 21% Cohort B and 15% in Cohort C.
Grade 3–4 treatment-related adverse events occurred in 39% and 51% of pts in cohorts B and C, 
respectively; one grade 5 event occurred in each cohort (sudden death in Cohort B and septic shock
in Cohort C). Although the safety profile was consistent with studies in other malignancies using 
the same dosing schedule, early toxicity prevented the majority of patients from completing 4 
combination doses.
Furthermore, combination of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four 
doses, then maintenance nivolumab 3 mg/kg every 2 weeks was recently evaluated in 15 patients 
with AR-V7-positive mCRPC.61 Overall, the PSA response rate was 2/15 (13%), ORR was 2/8 
(25%) in those with measurable disease, median PSA-PFS was 3.0 (95% CI 2.1– NR) months, 
PFS was 3.7 (95%CI 2.8–7.5) months, and OS was 8.2 (95%CI 5.5– 10.4) months. Outcomes 
appeared generally better in DNA repair deficiency (DRD) + versus DRD– tumors with respect to 
PSA responses (33% vs. 0%; P=0.14), ORR (40% vs. 0%; P=0.46), PSA-PFS (HR 0.19; P<0.01), 
PFS (HR 0.31; p=0.01), and OS (HR 0.41; P=0.11). No new safety concerns were observed and
the most common toxicities were fatigue, AST elevation, diarrhea and anorexia. Seventeen grade 
3-4 adverse events occurred in 7 of 15 patients (46%). There were no treatment-related deaths.
Given that nivolumab in combination with ipilimumab appears to be active in patients with 
mCRPC and existing data have shown that anti-CTLA-4 therapy can enhance immune cell 
infiltration into prostate tumors and increase PD-L1 expression,62 the addition of Cohort D in this
study will explore two different dosing schedules of nivolumab in combination with ipilimumab
to identify a dose combination which reduces toxicity and increases the potential clinical benefit 
from dual checkpoint inhibition.
 
 
1.1.5
Rationale to Support Nivolumab plus Ipilimumab Dose and Schedule 
Selection for Cohorts A, B, and C
The nivolumab plus ipilimumab combination dosing regimen selected for evaluation in Cohorts 
A, B, and C of this study is nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg administered 
every 3 weeks (Q3W) for 4 doses. The nivolumab plus ipilimumab combination dosing regimen 
will be followed by 480 mg flat dose of nivolumab every 4 weeks (Q4W) until progression of 
disease, unacceptable toxicity, or subject withdrawal of consent.
Multiple doses (ranging from 0.5 to 10 mg/kg as either monotherapy or in combination studies) 
and schedules (ranging from a single dose of ipilimumab to recurring doses every 3 weeks for four 
cycles) were evaluated in several Phase 1/2 trials of ipilimumab in CRPC.43 Although efficacy 
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endpoints varied amongst the studies, ipilimumab showed clinical activity in CRPC with PSA 
responses (≥50% decline) across doses of 3, 5, and 10 mg/kg administered as monotherapy.43
Declines in PSA were consistently noted (15–20%) at doses of ≥3 mg/kg with varying patterns of 
PSA response including at treatment onset, after a short period of stable disease, late responses 
after 6 months of treatment), as well as PSA responses observed after an initial PSA rise within 
6 months.43 All trials utilized the Prostate Cancer Working Group 2 (PCWG2) criteria.63
Exposure-response analysis of nivolumab monotherapy have been performed across dose ranges 
of 1 mg/kg to 10 mg/kg and show a relatively flat dose-response relationship for safety and efficacy 
in most tumor types evaluated (except for non-small cell lung cancer/NSCLC).64 Minimum serum 
concentration after first dose (Cmin1) produced by 3 mg/kg nivolumab was not a significant 
predictor of probability of overall response in treatment refractory squamous non-small cell lung 
cancer (NSCLC), and advanced melanoma. Nivolumab steady state time-averaged concentration 
(Cavgss) was not a significant predictor of hazard of death in subjects with advanced RCC after 
accounting for the effect of nivolumab clearance (CL). Clinical prognostic factors such as sex, 
baseline Memorial Sloan-Kettering Cancer Center risk score, baseline Karnofsky performance 
status, and baseline weight, were significant predictors of OS in subjects with advanced RCC. The 
risk of time to first Grade 3+ drug-related AEs and AEs leading to discontinuation did not increase 
with Cavgss produced by doses ranging from 0.1 to 10 mg/kg nivolumab, and at 3 mg/kg dose in 
advanced melanoma. (Subjects with NSCLC appeared to have a higher risk of AEs leading to 
discontinuation than subjects with other tumor types including melanoma).64
Exposure-response relationships of ipilimumab monotherapy for efficacy (ie, overall survival, OS) 
and safety (ie, immune-related adverse events, irAEs) were characterized using data from 4 Phase 
2 studies (CA184004, CA184007, CA184008, and CA184022) and 1 Phase 3 study (CA184024) 
in subjects with advanced melanoma.65 In contrast to nivolumab, OS increased with increasing 
ipilimumab steady state trough concentration (Cminss) over the range of exposures achieved with 
both the 3- and 10-mg/kg doses.66 Exposure-response analysis of escalating doses (0.3 mg/kg, 
3 mg/kg, and 10 mg/kg) of ipilimumab monotherapy have demonstrated increasing activity with 
increase in dose in the phase 2 study CA184022.67 The probability of experiencing Grade ≥2 and 
≥3 irAEs also increased with increasing ipilimumab Cminss.65
Hence, to balance the concern of potential toxicity due to the combination of 2 checkpoint 
inhibitors, the lowest clinically active ipilimumab dose of 3 mg/kg was chosen in combination 
with nivolumab dose of 1 mg/kg (given the somewhat flat dose-response relationship noted with 
nivolumab across the dose range of 1 to 10 mg/kg). Accordingly nivolumab 1 mg/kg plus 
ipilimumab 3 mg/kg will be evaluated within 2 cohorts of metastatic castration-resistant metastatic 
prostate cancer subjects (mCRPC).
1.1.6
Rationale to Support Dose and Schedule Selection in Cohort D
Three additional immunotherapy arms will be explored in Cohort D including two different 
nivolumab and ipilimumab combination regimens and ipilimumab monotherapy arm. The 
combination regimens were selected with the objective to improve the tolerability profile and to 
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maintain or improve the efficacy observed from preliminary results from Cohorts B and C. The 
inclusion of the ipilimumab monotherapy arm will support assessment of the contribution of 
ipilimumab to the nivolumab + ipilimumab combination, particularly in biomarker-defined sub-
groups which were not evaluated in prior ipilimumab studies in mCRPC.
1.1.6.1
Arm D1 Rationale for Combination Regimen (nivolumab 3 mg/kg plus 
ipilimumab 1 mg/kg)
The combination regimen is nivolumab 3mg/kg plus ipilimumab 1 mg/kg given every three weeks 
(Q3W) (N3I1) for up to 4 cycles, followed by nivolumab 480 mg every four weeks (Q4W) starting 
three weeks after the last combination dose for up to 2 years or until disease progression. This
combination regimen is currently approved in the US to treat 1L RCC and MSI-High or dMMR 
mCRC.68 The nivolumab dose is higher and the ipilimumab dose is lower in this regimen compared 
to the regimen evaluated in Cohorts A, B, and C, and has shown activity in AR-V7 mCRPC,69
with a manageable safety profile as described in Section 1.1.4. Further support for the N3I1 
regimen having an improved safety profile comes from the metastatic RCC setting in study 
CA209016 
 and the metastatic melanoma setting, where the safety profile of 
N3I1 Q3W and N1I3 Q3W, followed by 480 mg Q4W nivolumab maintenance were compared in 
clinical study CA209511.70 N3I1 demonstrated a reduced rate of drug-related Grade 3-4 AEs 
compared with N1I3, with rates of 33.3 % (60/180) and 48.3% (86/178), respectively.
1.1.6.2
Arm D2 Rationale for Combination Regimen (nivolumab 1mg/kg Q3W 
(8 Doses) plus ipilimumab 3 mg/kg Q6W (4 Doses)
The combination regimen is nivolumab 1 mg/kg every 3 weeks plus ipilimumab 3 mg/kg every 
2 cycles (ie, every 6 weeks) for up to 4 ipilimumab doses, followed by nivolumab 480 mg every 
4 weeks, starting six weeks after the last ipilimumab combination dose for up to 2 years or until 
disease progression. This combination regimen maintains the nivolumab and ipilimumab dose to 
that of the regimen in Cohorts A, B, and C, but lowers the ipilimumab time-averaged concentration 
(Cavgss) by ~ 2-fold by extending the dosing interval from Q3W to Q6W. A prior clinical study 
in advanced NSCLC (CA209012) supports the rationale to decrease ipilimumab dosing frequency 
to improve tolerability, while maintaining efficacy. Promising clinical activity with a favorable 
safety profile was observed in cohort P (nivolumab 3 mg/kg Q2W+ ipilimumab 1 mg/kg Q12W, 
ORR 47.4 % [18/38]) and cohort Q (nivolumab 3 mg/kg Q2W+ ipilimumab 1 mg/kg Q6W, ORR 
38.5 % [15/39]) in CA209-012. A notable improvement in drug-related AEs leading to 
discontinuation was observed in cohorts P (15.8%, 6/38) and Q (17.9%, 7/39) compared to the 
combination nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W for 4 cycles, followed by nivolumab 
3 mg/kg Q2W (40%, 10/25).71
1.1.6.3
Arm D3 Rationale for Ipilimumab 3 mg/kg Q3W
The ipilimumab monotherapy arm will be dosed at 3 mg/kg Q3W for 4 cycles with no maintenance 
dosing. This is the approved ipilimumab dose for metastatic melanoma and, as described in 
Section 1.1.4 above, has shown some clinical activity as measured by PSA response in prior 
studies where ipilimumab monotherapy at this dose was evaluated in mCRPC (CA184009, 
CA184019, and CA184017). Arm D3 will provide an estimation of the relative benefit of the 
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combination regimens evaluated in Arms D1 and D2 compared to ipilimumab alone. 
 
 
1.1.6.4
Arm D4 Rationale for Cabazitaxel in Prostate Cancer
Taxanes bind microtubules, promoting their stabilization and preventing cellular mitosis and 
division. Additionally, taxanes inhibit androgen receptor (AR) signaling by binding cellular 
microtubules and the microtubule-associated motor protein dynein, and consequently preventing 
AR nuclear translocation.72 Docetaxel, a second-generation semisynthetic taxane analog, became 
the first chemotherapeutic agent to show an OS benefit in mCRPC in two randomized controlled 
clinical trials (TAX 32773 and SWOG 99-1674), and was approved in combination with prednisone 
for this indication in the US in 2004. 
Cabazitaxel is another taxane-based chemotherapy that was approved by the FDA in 2010 for 
patients with mCRPC previously treated with docetaxel.75 Cabazitaxel retains significant 
cytotoxicity in docetaxel-resistant cell lines due to p-glycoprotein 1 (gp-1) overexpression. 
Another attractive property of cabazitaxel is its enhanced solubility in water-based solutions 
compared with other taxanes, enabling better blood–brain barrier penetration, resulting in higher 
central nervous system drug concentrations with systemic administration in mouse models. In the 
TROPIC study, 755 men with mCRPC who previously received docetaxel chemotherapy were 
randomized to receive either cabazitaxel 25 mg/ m2 (n = 378) or mitoxantrone 12 mg/m2 (n = 377) 
every 3 weeks for a maximum of 10 cycles, concurrently with prednisone 10 mg daily.76 At the 
first interim analysis, with a median follow up of 12.7 months, median overall survival was 15.1 
months for the cabazitaxel group versus 12.7 months for the mitoxantrone group, corresponding 
to a 30% reduction in relative risk of death (hazard ratio 0.70, 95% confidence interval 0.59–0.83, 
p < 0·0001). Other clinical endpoints, including PSA response (39.2% v 17.8%, respectively; 
P < .001), PFS (2.8 v 1.4 months, respectively; P < .001), objective tumor response (14.4% vs 
4.4% respectively; P < .001) and pain progression all favored the cabazitaxel treatment arm. The 
most common toxic effects of cabazitaxel were hematological; the most frequent hematological 
grade 3 or higher adverse events were neutropenia, leukopenia, and anemia. The most common 
non-hematological grade 3 or higher adverse event was diarrhea. Overall, peripheral neuropathy 
(all grades) was reported in 14% of patients, but G3 peripheral neuropathy was uncommon (1%). 
Peripheral edema (all grades) occurred in 9% of patients treated with cabazitaxel. An updated 
analysis 2 years after the original TROPIC data cutoff (March 2012) confirmed a sustained 
survival benefit with longer follow up, with cabazitaxel treatment being predictive of survival over 
2 years.77
Randomization to a cabazitaxel arm in Cohort D is included as a reference for the immunotherapy 
arms in the cohort.
 
 
 
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Dosing of cabazitaxel in this study is based upon doses recommended in the current prescribing 
information. Please see prescribing information for this agent for more information.
1.1.7
Rationale for Shorter Infusion Times for Nivolumab and Ipilimumab
Long infusion times place a burden on patients and treatment centers. Establishing that nivolumab 
and ipilimumab can be safely administered using shorter infusion times of 30 minutes’ duration 
will diminish the burden, provided that there is no change in the safety profile. Previous clinical 
studies of nivolumab and ipilimumab monotherapies and the combination of nivolumab and 
ipilimumab have used a 60-minute infusion duration for nivolumab and a 90-minute infusion 
duration for ipilimumab (1 - 3 mg/kg dosing for both). However, both nivolumab and ipilimumab 
have been administered at up to 10 mg/kg with the same infusion duration (ie, 60 minutes).
Establishing that nivolumab can be safely administered using a shorter infusion time (30 minutes) 
is under investigation. Previous clinical studies of nivolumab monotherapy have used a 60-minute 
infusion duration wherein, nivolumab has been safely administered up to 10 mg/kg over long 
treatment periods. Infusion reactions including high-grade hypersensitivity reactions have been 
uncommon across nivolumab clinical program. In CA209010, a dose association was observed for 
infusion site reactions and hypersensitivity reactions (1.7% at 0.3 mg/kg, 3.7% at 2 mg/kg and 
18.5% at 10 mg/kg). All the events were Grade 1-2 and were manageable. An infusion duration of 
30 minutes for 3 mg/kg nivolumab (30% of the dose provided at 10 mg/kg) is not expected to 
present any safety concerns compared to the prior experience at 10 mg/kg nivolumab dose infused 
over a 60-minute duration. The safety of nivolumab 3 mg/kg administered as a 30-min infusion 
was assessed in CA209153 in patients (n = 322) with previously treated advanced NSCLC. 
Overall, 
there 
were 
no 
clinically 
meaningful 
differences 
in 
the 
frequency 
of 
hypersensitivity/infusion-related reactions (of any cause or treatment-related) in patients 
administered nivolumab over a 30-minute infusion compared with that reported for patients with 
the 60-minute infusion. Thus, it was shown that nivolumab can be safely infused over 30 minutes. 
Similarly, ipilimumab at 10 mg/kg has been safely administered over 90 minutes. In subjects with 
advanced Stage II or Stage IV melanoma (CA184022 Study), where ipilimumab was administered 
up to a dose of 10 mg/kg, on-study drug related hypersensitivity events (Grade 1/2) were reported 
in 1 subject (1.4%) in the 0.3 mg/kg and in 2 subjects (2.8%) in the 10 mg/kg group. There were 
no drug-related hypersensitivity events reported in the 3 mg/kg group. Across the 3 treatment 
groups, no Grade 3/4 drug-related hypersensitivity events were reported and there were no reports 
of infusion reactions. Ipilimumab 10 mg/kg monotherapy has also been safely administered as a 
90-minute infusion in a large Phase 3 study in prostate cancer (CA184043) and as adjuvant therapy 
for Stage III melanoma (CA184029), with infusion reactions occurring in subjects. Administering 
3 mg/kg of ipilimumab represents approximately one-third of the 10 mg/kg dose.
Overall, infusion reactions including high-grade hypersensitivity reactions have been uncommon 
across clinical studies of nivolumab, ipilimumab, and nivolumab/ipilimumab combinations. 
Furthermore, a 30-minute break after the first infusion for the combination cohort will ensure the 
appropriate safety monitoring before the start of the second infusion. Overall, a change in safety 
profile is not anticipated with 30-minute infusions of nivolumab, ipilimumab or combination.
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1.1.8
Rationale for Flat Dose 480 mg Nivolumab every 4 weeks (Nivolumab 
Monotherapy Phase)
Nivolumab monotherapy has been extensively studied in a number of tumor types including 
non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), and colorectal 
cancer (CRC) with body weight normalized dosing (mg/kg). Nivolumab pharmacokinetics (PK) 
and exposures of subjects in these studies have been characterized by population pharmacokinetic 
(PPK) analysis of data collected together with PK data from several Phase 1, 2, and 3 clinical 
studies of nivolumab monotherapy in solid tumors. PPK analyses have shown that the PK of 
nivolumab are linear, with dose proportional exposures over a dose range of 0.1 mg/kg to 
10 mg/kg, and are similar across tumor types. Nivolumab clearance and volume of distribution 
were found to increase with increasing body weight, but the increase was less than proportional, 
indicating that a mg/kg dose represents an over-adjustment for the effect of body weight on 
nivolumab PK. Given the relationship between nivolumab PK and body weight, a flat dose is 
expected to lead to lower exposures in heavier subjects, relative to the exposures in lighter subjects. 
Using the PPK model, nivolumab steady-state trough, peak and time-averaged concentration 
(Cminss, Cmaxss, and Cavgss, respectively) were predicted for a flat nivolumab dose of 240 mg 
Q2W and compared to those following administration of 3 mg/kg Q2W in NSCLC, melanoma, 
and RCC subjects. A dose of 240 mg nivolumab is identical to a dose of 3 mg/kg for subjects 
weighing ~ 80 kg, which is the approximate median body weight of subjects in the Phase 2 and 3 
BMS clinical studies of nivolumab monotherapy. Using a PPK model, the overall distributions of 
nivolumab exposures (Cavgss, Cminss, Cmaxss, and Cmin1) are comparable after treatment with 
either 3 mg/kg or 240 mg nivolumab. The predicted range of nivolumab exposures (median and 
90% prediction intervals) resulting from a 240 mg flat dose across the 35 to 160 kg weight range 
is maintained well below the corresponding exposures observed with the well tolerated 10 mg/kg 
nivolumab Q2W dosage. Given the similarity of nivolumab PK across tumor types and the similar 
exposures predicted following administration of a 240 mg flat dose compared to 3 mg/kg, it is 
expected that the safety and efficacy profile of nivolumab following a flat dose will be similar to 
that of 3 mg/kg nivolumab dose.
Across the various tumor types in the BMS clinical program, nivolumab has been shown to be safe 
and well tolerated up to a dose level of 10 mg/kg, and the relationship between nivolumab exposure 
produced by 3 mg/kg and efficacy has been found to be relatively flat. Taken together, the PK, 
safety, and efficacy data indicate that the safety and efficacy profile of flat nivolumab dose every 
2 weeks will be similar to that of a 3 mg/kg nivolumab every 2 weeks.
While 480 mg Q4W is predicted to provide greater (approximately 40%) maximum steady state 
concentrations and lower (approximately 15 to 20%) steady state trough concentrations, these 
exposures are predicted to be within the exposure ranges observed at doses up to 10 mg/kg Q2W 
used in the Phase 1 nivolumab clinical program, and are not considered to put subjects at increased 
risk. Similar to the nivolumab Q2W dosing monotherapy regimen, the exposures predicted 
following administration of nivolumab 480 mg Q4W, are on the flat part of the exposure-response 
curves for previously investigated tumors, melanoma and NSCLC, and are not predicted to affect 
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efficacy. Based on these data, nivolumab 480 mg Q4W is expected to have similar efficacy and 
safety profiles to nivolumab 3 mg/kg Q2W.
In this study, subjects will receive flat dose 480 mg nivolumab every 4 weeks (Q4W), which 
provides a more convenient dosing regimen for subjects. Subjects Arm D1 will start nivolumab 
monotherapy 3 weeks after the last combination dose, while subjects in Arm D2 will start 
nivolumab monotherapy 6 weeks after the last combination dose.
Hence, doubling the dose of nivolumab from 240 mg to 480 mg would extend the dosing interval 
from 2 weeks to 4 weeks.
Thus, a flat dose of 480 mg every 4 weeks is recommended for investigation in the nivolumab 
monotherapy phase of this study.
1.1.9
Rationale for Shorter Infusion Times with 480 mg Flat Dosing
Long infusion times place a burden on subjects and treatment centers. Establishing that nivolumab 
can be safely administered using shorter infusion times of 30 minutes duration in subjects will 
diminish the burden provided there is no change in safety profile. Previous clinical studies show 
that nivolumab has been administered safely over 60 minutes at doses ranging up to 10 mg/kg over 
long treatment duration. For example, in Study CA209010 (a Phase 2, randomized, 
double-blinded, dose-ranging study of nivolumab in subjects with advanced/metastatic, clear cell 
RCC), a dose association was observed for infusion site reactions and hypersensitivity reactions 
(1.7% at 0.3 mg/kg, 3.7% at 2 mg/kg and 18.5% at 10 mg/kg). All the events were Grade 1/2 and 
were manageable. Establishing that nivolumab can be safely administered using a shorter infusion 
time (30 minutes) is under investigation. The safety of nivolumab 3 mg/kg administered as a 
30-min infusion was assessed in CA209153 in subjects with previously treated advanced NSCLC. 
Overall, 
there 
were 
no 
clinically 
meaningful 
differences 
in 
the 
frequency 
of 
hypersensitivity/infusion-related reactions (of any cause or treatment-related) in subjects 
administered nivolumab over a 30 min infusion compared with that reported for subjects with the 
60 min infusion. An infusion duration of 30 minutes for 1 mg/kg nivolumab and nivolumab 
480 mg is not expected to present any safety concerns compared to the prior experience at 
10 mg/kg nivolumab dose infused over a 60-minute duration. 
1.1.10
Rationale for Evaluating Chemotherapy-Naive, Second-Generation 
Hormone Therapy-Naive, Asymptomatic or Minimally Symptomatic 
Metastatic CPRC Subjects (Cohort A Subjects)
Docetaxel became the first approved therapy to prolong survival for men with mCRPC in 
2004.13,14 Subsequently, since 2010, six novel therapies have been shown to prolong survival in 
men with mCRPC.78 The trials have demonstrated prolongation of overall survival as well as 
trends toward preserved quality of life (QoL), albeit less rigorously assessed and documented.79
Of note, all these new therapies in mCRPC have distinct mechanisms of action and include unique 
classes of agents: novel androgen receptor (AR) pathway inhibitors abiraterone acetate 
(abiraterone) and enzalutamide as well as a bone targeting alpha-emitting radionuclide, 
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radium-223 chloride (radium-223), taxanes, docetaxel and cabazitaxel, and sipuleucel-T, an 
immunotherapeutic agent.
Of the six new therapies that have been approved since 2010 for mCRPC, sipuleucel-T has been 
tested predominantly (~85%) in chemotherapy-naïve men with mCRPC and showed no effect on 
response rates or progression free survival (PFS).27 More recently, two second-generation 
hormone therapies, abiraterone acetate10 and enzalutamide9 targeting inhibition of the androgen 
receptor (AR) signaling pathway have been investigated and shown to prolong overall survival in 
large phase III trials in minimally symptomatic subjects in the pre- docetaxel states. See Table 
1.1.10-1. Enzalutamide also extended time to radiographic progression and death as well as 
improved overall survival in men with mCRPC prior to receiving chemotherapy.9 Delay in time 
to chemotherapy was also reported.9 Similar to enzalutamide, abiraterone was also shown to delay 
radiographic progression and time to chemotherapy in men with mCRPC.10 Despite the success of 
these second-generation AR-targeted therapies, inherent or acquired resistance remains a major 
clinical challenge and most subjects will progress.80 Clinical data from a number of small 
retrospective cohort studies suggests that once subjects progress response rates to abiraterone after 
enzalutamide and conversely enzalutamide after abiraterone are low and no robust criteria exist 
clinically to select one drug rather than the other.81,82 The presence of androgen receptor splice 
variants without the ligand-binding domain has been associated with resistance to abiraterone and 
enzalutamide and could be one explanation for this significant cross-resistance.83 Docetaxel after 
one or both of newer AR pathway inhibitors may have less activity than in the pivotal trials.84
Thus there is still an unmet need in mCRPC for treatment options that will provide durable disease 
control and long term survival.
Table 1.1.10-1:
Summary of key data from sipuleucel-T, abiraterone acetate and 
enzalutamide registrational trials
Endpoints
Asymptomatic mCRPC 
(no liver mets) IMPACT 
trial (Sipuleucel-T)27
Asymptomatic or minimally 
symptomatic mCRPC9
Enzalutamide pre-
chemotherapy
Asymptomatic or 
minimally symptomatic 
mCRPC 
Abiraterone+prednisone 
pre-chemotherapy10
mOS
4.1 months (25.8 vs 
21.7 mo, HR=0.78)
2.2 mo (32.4 vs 30.2 mo, 
HR=0.71)- study was stopped 
after a planned IA (rPFS/OS 
co-primary)
NR vs 27.2 mo, HR 0.75
m-rPFS
No difference vs placebo at 
3.7 mo (vs3.6 mo)
At 12 mo f/u, rPFS rate= 65% vs 
14%, HR=0.19; m-rPFS was not 
reached, 3.9 mo in placebo arm
16.5 mo vs 8.3 mo, HR 
=0.53
Objective soft 
tissue response
No difference vs placebo
59% vs 5%
36% vs 16%
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While the successful registration of several drugs for mCRPC provided new options for treatment, 
they have also led to considerable uncertainty as to the best treatment choices, sequence of 
treatment options and appropriate patient selection with the achievement of durable, long term 
responses remaining an elusive goal.
In daily practice, clinicians often face the difficult task of choosing among treatment options with 
different mechanisms of action, administration and toxicity profiles and the desire to tailor novel 
treatment options to the specific needs of the individual mCRPC subjects.85 The first St Gallen 
Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel reviewed the available 
evidence for the ten most important areas of controversy in advanced prostate cancer (APC) 
management to provide management recommendations based on expert opinion in these 
situations.79 Of note, for subjects with mCRPC in the absence of symptoms and imminent 
complications, two-thirds of the APCCC panel recommended that agents with potential for 
survival prolongation should be initiated within 4–8 weeks.79
Although 2 Phase 3 studies of ipilimumab monotherapy in pre- and post-docetaxel mCRPC 
(CA184095 and CA184043, respectively) failed to show an overall survival advantage, additional 
analyses of outcome data from both studies are important to consider (See Section 1.1.10), given 
the understanding that (i) currently available therapies do not result in durable, long term 
remissions in mCRPC subjects and (ii) emerging data from other solid tumors that have been 
studied, notably, melanoma, the use of checkpoint blockade inhibition suggests the potential for 
prolonged duration of response with immunotherapy in a subset of subjects.86
As noted previously in Section 1.1.5, ipilimumab has been shown to induce an adaptive immune 
response within the prostate tumor microenvironment.87 In a clinical trial, subjects with localized 
prostate cancer who were treated with ADT plus 2 doses of anti-CTLA4 antibody (ipilimumab) 
observed an increased frequency of CD4 and CD8 T cell infiltration into tumor tissues and 
increased expression of PD-1 and PD-L1 (on both immune and epithelial cells).87 These findings 
suggest that while treatment with ipilimumab resulted in expected immune augmentation, it was 
also associated with the induction of immune inhibitory PD-1/PD-L1 pathway. These preliminary 
clinical data provide a potential explanation as to why a significant proportion of subjects with 
prostate cancer did not benefit from treatment with ipilimumab or nivolumab monotherapy. 
Accordingly, utilizing a combination checkpoint blockade inhibition approach, with anti-CTLA4 
and anti-PD-1 antibodies may be necessary to augment T cell responses for greater anti-tumor 
activity in prostate cancer.
Taken together these data suggest that in mCRPC subjects the activity of ipilimumab monotherapy 
could potentially be strongly enhanced by the combination with another checkpoint inhibitor to 
result in durable anti-tumor responses. And asymptomatic or minimally symptomatic mCRPC 
subjects who are early on in the disease state of mCRPC may in fact be optimal candidates for the 
evaluation of combination of checkpoint blockade inhibitors, ipilimumab and nivolumab, with the 
possibility of achieving long term remission from disease.
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Addendum:
Cohort A enrollment was discontinued in Revised Protocol 02 due to slow accrual and to reflect 
the changing landscape of metastatic castration-resistant prostate cancer. 
Both enzalutamide and abiraterone are currently approved for the treatment of patients with 
mCRPC who have not received chemotherapy. These drugs, which have now become the standard 
of care in this setting, have a well-established safety profile and have demonstrated OS 
improvement and delay of
radiographic disease progression and need for cytotoxic 
chemotherapy.9,10,88 Furthermore, the addition of abiraterone to first-line ADT resulted in a 
significant improvement in OS in men with prostate cancer, according to recently reported results 
from the LATITUDE 89 and STAMPEDE 90 clinical trials. The abiraterone/prednisone/ADT arm 
had a 38% reduction in risk of death when compared to the control in the LATITUDE trial (OS: 
not reached vs. 34.7 months, HR: 0.62, 95% CI: 0.51-0.76; P<0.0001). The 3-year OS rate was 
66% in the abiraterone arm versus 49% in the placebo arm. Overall survival benefit persisted 
across all of the pre-specified subgroups. In the Phase 3 STAMPEDE trial, ADT plus abiraterone 
and prednisolone was associated with significantly higher rates of overall survival (HR: 0.63, 95% 
CI: 0.52-0.76; P=0.001) and failure-free survival (HR: 0.29; 95% CI, 0.25 to 0.34; P<0.001) than 
ADT alone among men with locally advanced or metastatic prostate cancer. 
Thus, the use of abiraterone is expected to continue expanding in earlier settings of the prostate 
cancer treatment landscape and eligibility criteria for participation in Cohort A are anticipated to 
be less relevant in future practice due to changes in standard of care.
This trial will now include 2 cohorts in mCRPC, Cohorts B and C, and the remainder of Cohort A 
subjects will be allocated to Arms B and C in order to have more precise efficacy estimates in 
those arms.
1.1.11
Rationale for Treatment Beyond PSA Elevation
For consistency of trial reporting, the PCWG2 defines PSA progression as the date that an increase 
of 25% or more and an absolute increase of 2 ng/mL or more from the nadir are documented.8 For 
subjects who had an initial PSA decline during treatment, this must be confirmed by a second 
value 3 or more weeks later. However, PSA progression alone is not necessarily an indication to 
stop treatment, because in some cases, PSA levels may rise slowly or stabilize after an initial rise 
with no other sign of clinical progression.91 Because there are cases in which additional years of 
disease control would not have been realized had therapy been stopped on the basis of PSA change 
alone, therapy will not be stopped for subjects with apparent PSA progression alone. However, 
subjects meeting criteria for discontinuation of therapy (Section 3.5) and PSA elevation will come 
off study.
1.1.12
Rationale for Optional Crossover Combination for Monotherapy Arms 
(Arm D3 and D4)
In some cancer types, combined blockade of both PD-1 and CTLA-4 has proven more efficacious 
than inhibition of either pathway alone. Furthermore, preliminary data with nivolumab in 
combination with ipilimumab have shown promising clinical activity in mCRPC 
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(see Section 1.1.4). Based on these data, this study will provide subjects who are randomized to 
the monotherapy Arms D3 and D4 the option to receive nivolumab in combination with 
ipilimumab in Arm D1 upon BICR-confirmed radiographic progression and provided that such 
crossover treatment is discussed with and approved by the BMS Medical Monitor.
1.1.13
Rationale for Duration of Treatment with Nivolumab plus Ipilimumab
The optimal duration of immunotherapy is an important question and continues to be investigated.  
Clinical trials across different tumors types in the nivolumab and ipilimumab development 
program indicate that most of the responses occur early, with a median time to response of 2-4 
months, and emerging data suggests that benefit can be maintained in the absence of continued 
treatment.  A recent analysis in a melanoma study suggests the majority of patients who 
discontinue nivolumab and/or ipilimumab for toxicity maintain disease control in the absence of 
further treatment.92 Furthermore, a limited duration of ipilimumab, including only 4 induction 
doses, resulted in long term survival in patients with metastatic melanoma, with a sustained plateau 
in survival starting around 2 years after the start of treatment.93
Accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be sufficient 
for long term benefit. CA209003, a dose-escalation cohort expansion trial evaluating the safety 
and clinical activity of nivolumab in patients with previously treated advanced solid tumors 
(including 129 subjects with NSCLC), specified a maximum treatment duration of 2 years.  Among 
16 subjects with non-small cell lung cancer (NSCLC) who discontinued nivolumab after 
completing 2 years of treatment, 12 subjects were alive >5 years and remained progression-free 
without any subsequent therapy. In the CA209003 NSCLC cohort, the overall survival (OS) curve 
begins to plateau after 2 years, with an OS rate of 25% at 2 years and 18% at 3 years.94.These 
survival outcomes are similar to phase 3 studies in previously treated NSCLC, in which nivolumab 
treatment was continued until progression or unacceptable toxicity (2 year OS rates of 23% and 
29%, and 3 year OS rates of 16%-18% for squamous and non-squamous NSCLC respectively).95
Similar results have been reported in clinical studies of pembrolizumab, another PD-1 inhibitor. 
Keynote-010 was a randomized phase 3 trial of pembrolizumab (at either 2 mg/kg or 10 mg/kg 
every 3 weeks) versus docetaxel in subjects with previously treated, PD-L1-positive, advanced 
NSCLC which specified a  maximum treatment duration of 2 years for pembrolizumab. OS was 
significantly longer with both pembrolizumab 2 mg/kg (HR 0.72, p = 0.00017) and pembrolizumab 
10 mg/kg (HR 0.60, p < 0.00001) compared to docetaxel, with an OS plateau developing beyond 
2 years in both pembrolizumab arms. Among 690 patients who received pembrolizumab, 
47 patients completed 2 years of pembrolizumab and stopped treatment. Most were able to 
maintain their response, including those with stable disease, with only 2 patients (4%) having 
confirmed progression after stopping at 2 years.96
Keynote-006 was a randomized phase 3 study of pembrolizumab versus ipilimumab in patients 
with advanced melanoma, which also specified a maximum 2 year duration of pembrolizumab 
treatment. 104 (19%) of 556 patients randomized to pembrolizumab completed 2 years of 
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treatment. With a median follow-up of 9 months after completion of pembrolizumab, the estimated 
risk of progression or death was 9% in these patients.97
Taken together, these data suggest that treatment beyond 2 years is unlikely to confer additional 
clinically meaningful benefit and that the risk of progression after discontinuing treatment at 
2 years is low.
In contrast, a shorter duration of nivolumab of only 1 year was associated with increased risk of 
progression in previously treated patients with NSCLC, suggesting that treatment beyond 1 year 
is likely needed. In CA209153, patients with previously treated advanced NSCLC who completed 
1 year of nivolumab therapy were randomized to either continue or stop treatment, with the option 
of retreatment upon progression. Among 163 patients still on treatment at 1 year and without 
progression, those who were randomized to continue nivolumab had significant improvement in 
progression-free survival (PFS) compared to those who were randomized to stop treatment, with 
median PFS (post-randomization) not reached vs 10.3 months, respectively; HR=0.42 (95% CI, 
0.25 to 0.71). With a median follow-up of 14.9 months post-randomization, there also was a trend 
for patients on continued treatment to live longer (OS HR = 0.63 [95% CI: 0.33, 1.20]). Of note, 
the PFS curves in both groups plateau approximately 1 year after randomization (i.e., 2 years after 
treatment initiation), suggesting that there may be minimal benefit in extending treatment beyond 
a total of 2 years.98
Collectively, these data suggest that there is minimal if any benefit derived from continuing I-O 
treatment beyond two years in advanced tumors. However, even though immunotherapy is well 
tolerated, patients will be at risk for additional toxicity with longer term treatment. Therefore, in 
this study, treatment will be given for a maximum of 2 years from the start of study treatment for 
subjects in Cohort D. 
It is strongly recommended that subjects in Cohorts A, B, and C limit treatment duration with 
immunotherapy treatment for up to 2 years. For subjects in these cohorts who receive 
immunotherapy treatment beyond 2 years, treatment will be given for a maximum of 5 years from 
the start of study treatment.
1.2
Research Hypothesis
Treatment with nivolumab combined with ipilimumab will have clinical activity in subjects with 
metastatic castrate resistant prostate cancer (mCRPC).
1.3
Objectives(s)
1.3.1
Primary Objectives
•
Evaluate objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors 
(RECIST) V1.1 assessed by Blinded Independent Central Review (BICR) in subjects with 
mCRPC and measurable disease at baseline per investigator assessment as entered in the 
interactive web response system (IWRS).
•
Assess Radiographic Progression Free Survival (rPFS) assessed by BICR in all treated subjects
with mCRPC in Cohorts B and C and all randomized subjects with mCRPC in Cohort D using
RECIST V1.1 for soft tissue disease progression and PCWG2 for bone disease progression. 
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1.3.2
Secondary Objectives
•
Assess radiographic/clinical Progression Free Survival (rcPFS, as defined in Section 5.5.3).
•
Assess overall survival (OS).
•
Evaluate PSA response rate (PSA-RR)
•
Determine the safety and tolerability in all treated subjects.
•
Estimate changes in pain as measured by the Brief Pain Inventory-Short Form (BPI-SF)
•
Estimate changes in cancer-related symptoms and quality of life (QoL) using the FACT-P 
questionnaire (Cohort D only)
•
Estimate changes in health status and health utility as measured by the 3-level EQ-5D-3L 
questionnaire
1.4
Product Development Background
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system. An effective immune 
response in this setting is thought to rely on immune surveillance of tumor antigens expressed on 
cancer cells that ultimately results in an adaptive immune response and cancer cell death. 
Meanwhile, tumor progression may depend upon acquisition of traits that allow cancer cells to 
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evade immunosurveillance and escape effective innate and adaptive immune responses.99,100,101
Current immunotherapy efforts attempt to break the apparent tolerance of the immune system to 
tumor cells and antigens by either introducing cancer antigens by therapeutic vaccination or by 
modulating regulatory checkpoints of the immune system.
1.4.1
Mechanism of Action of Nivolumab
PD-1 is a member of the CD28 family of T-cell co-stimulatory receptors that also includes CD28, 
CTLA 4, ICOS, and BTLA.102 PD-1 signaling has been shown to inhibit CD-28-mediated 
upregulation of IL-2, IL-10, IL-13, interferon γ (IFN γ) and Bcl-xL. PD-1 expression also been 
noted to inhibit T cell activation, and expansion of previously activated cells. Evidence for a 
negative regulatory role of PD-1 comes from studies of PD-1 deficient mice, which develop a 
variety of autoimmune phenotypes.103 These results suggest that PD-1 blockade has the potential 
to activate anti-self T-cell responses, but these responses are variable and dependent upon various 
host genetic factors. Thus, PD-1 deficiency or inhibition is not accompanied by a universal loss of 
tolerance to self-antigens.
In vitro, nivolumab binds to PD-1 with high affinity (EC50 0.39-2.62 nM), and inhibits the binding 
of PD-1 to its ligands PD-L1 and PD-L2 (IC50 < 1 nM). BMS-936558 binds specifically to PD-1 
and not to related members of the CD28 family such as CD28, ICOS, CTLA-4 and BTLA. 
Blockade of the PD-1 pathway by nivolumab results in a reproducible enhancement of both 
proliferation and IFN-γ release in the mixed lymphocyte reaction (MLR). Using a CMV 
re stimulation assay with human Peripheral Blood Mononuclear cells (PBMC), the effect of 
nivolumab on antigen specific recall response indicates that nivolumab augmented IFN-γ secretion 
from CMV specific memory T cells in a dose-dependent manner versus isotype-matched control. 
In vivo blockade of PD-1 by a murine analog of nivolumab enhances the anti-tumor immune 
response and result in tumor rejection in several immunocompetent mouse tumor models (MC38, 
SA1/N, and PAN02).104
Immunotherapeutic approaches recently have demonstrated clinical efficacy in several cancer
types, including melanoma, and NSCLC, and RCC.105,106,107,108 Nivolumab (Opdivo®) is 
approved in multiple countries including the US for treatment of previously treated, unresectable 
or metastatic melanoma and previously treated, metastatic NSCLC, and advanced RCC.109
1.4.2
Mechanism of Action of Ipilimumab
CTLA-4, an activation-induced T-cell surface molecule, is a member of the CD28:B7 
immunoglobulin superfamily that competes with CD28 for B7. CTLA-4 mediated signals are 
inhibitory and turn off T cell-dependent immune responses.110,111
Ipilimumab is a fully human monoclonal IgG1κ that binds to the CTLA-4 antigen expressed on a 
subset of T cells from human and nonhuman primates. The proposed mechanism of action for 
ipilimumab is interference of the interaction of CTLA-4 with B7 molecules on APCs, with 
subsequent blockade of the inhibitory modulation of T-cell activation promoted by the CTLA 4/B7 
interaction.
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1.4.3
Nivolumab-plus-Ipilimumab Mechanism of Action
Preclinical and clinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade 
may improve antitumor activity. In vitro combinations of nivolumab plus ipilimumab increase 
IFN-γ production 2- to 7-fold over either agent alone in a mixed lymphocyte reaction. In a murine 
melanoma vaccine model, blockade with either CTLA-4 or PD-1 antibodies increased the 
proportion of CTLA-4- and PD-1-expressing CD4/CD8 tumor-infiltrating T effector cells, and 
dual blockade increased tumor infiltration of T effector cells and decreased intratumoral
T regulatory cells, as compared to either agent alone.112
In the Phase 1 dose escalation Study CA209004, the combination of nivolumab and ipilimumab
has been studied in subjects with unresectable or metastatic melanoma. In this study, a safe dose
level for the combination of ipilimumab and nivolumab was established for the treatment of
advanced melanoma. At this dose level, 3 mg/kg ipilimumab plus 1 mg/kg nivolumab, an ORR of 
53% was observed. This dose level has been approved in subjects with advanced melanoma in the 
US based on the Phase 3 Study CA209067.113
1.4.4
Overview of Nivolumab and Ipilimumab Clinical Pharmacology
The clinical pharmacology profiling of the combination of nivolumab and ipilimumab together 
with an overview of the results of these analyses are summarized below. In addition, the Clinical 
Pharmacology Section of the product labels for ipilimumab and nivolumab, as well as the 
investigational brochures, have additional details.114,115,116,117
1.4.4.1
Population Pharmacokinetics of Nivolumab
The PK, clinical activity, and safety of nivolumab has been assessed in completed and ongoing 
Phase 1, 2, and 3 studies in adult subjects with non-small cell lung cancer (NSCLC), melanoma, 
and renal cell carcinoma (RCC) in addition to other tumor types.118
The PK of nivolumab as monotherapy was characterized by PPK analysis. Nivolumab clearance 
increased with baseline body weight, estimated glomerular filtration (eGFR), and Eastern 
Cooperative Oncology Group (ECOG) performance status > 0. The PPK analysis was performed 
using data from 1908 subjects who received nivolumab from the following studies: nivolumab 
monotherapy data from studies MDX-1106-01, ONO-4538-01, ONO-4538-02, MDX-1106-03, 
CA209010, CA209063, and CA209037. Studies CA209004, CA209069, CA209066, and 
CA209067 provided PK data of nivolumab monotherapy as well as in combination with 
ipilimumab in the target population (advanced melanoma) who received the proposed dosing 
regimens. The data from these studies also allowed for an evaluation of potential drug interactions 
between nivolumab and ipilimumab and of the effect of immunogenicity on clearance. Thus, for 
this analysis, the covariates assessed included ADA status, baseline ECOG status, baseline eGFR, 
baseline body weight (BW), gender and co-administration of ipilimumab.
Co-administration with ipilimumab 3 mg/kg resulted in a modest increase in nivolumab CL of 
35% whereas coadministration with ipilimumab 1 mg/kg did not appear to have an effect on 
nivolumab CL. Presence of anti-nivolumab antibodies increased nivolumab CL by 25%, consistent 
with prior findings. In subjects with an ECOG performance status of > 0, nivolumab CL was 22% 
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higher (based on median values). Male subjects had a median of 12% higher volume of distribution 
of central compartment (VC) than females. Baseline body weight was identified as a significant 
covariate for both CL and VC and the magnitude of the effect of baseline eGFR on CL was not 
considered clinically relevant. The geometric mean CL, Vss, and terminal half-life of nivolumab 
were 9.83 mL/h, 7.62 L, and 24.1 days, respectively. When administered in combination, the CL 
of nivolumab was increased by 35%, whereas there was no effect on the clearance of ipilimumab.
1.4.4.2
Population Pharmacokinetics of Ipilimumab
The PPK of ipilimumab was evaluated using data from 1345 subjects in 4 Phase 2 studies with 
ipilimumab monotherapy (CA184004, CA184007, CA184008, and CA184022), as well as one 
Phase 1 study (CA209004), one Phase 2 study (CA209069) and one Phase 3 study (CA209067) 
with ipilimumab monotherapy and nivolumab in combination with ipilimumab. The ipilimumab 
data from CA209004, CA209069, and CA209067 are included as they provide ipilimumab PK 
samples that were collected in combination with nivolumab in the target population. The data from 
4 ipilimumab monotherapy studies (CA184004, CA184007, CA184008, and CA184022) were 
included in the PPK analysis, to enable the assessment of the potential nivolumab effect on 
ipilimumab PK.
The co-administration of ipilimumab (3 mg/kg) with nivolumab 0.3 mg/kg and nivolumab 
3.0 mg/kg resulted in minimal changes in ipilimumab CL (-7.5% and 11%, respectively); however, 
sample sizes at these doses were small. The CL of ipilimumab coadministered with 1 mg/kg 
nivolumab was estimated to be 1% higher (95% CI: 97.8 - 106) relative to the CL of ipilimumab 
monotherapy, demonstrating that ipilimumab CL is unaffected by co-administration of 1 mg/kg 
nivolumab. Ipilimumab CL was estimated to increase by 6% (95% CI: 96.5 - 115) in the presence 
of ipilimumab ADA, as measured by the drug tolerant (2nd generation) assay. This effect is not 
considered to be statistically significant (95% CI includes 1). Ipilimumab CL and VC increased 
with increasing baseline body weight, and ipilimumab CL increased with increasing baseline LDH.
1.4.4.3
Pharmacokinetics of Nivolumab and Ipilimumab
The PK of nivolumab and ipilimumab, when administered in combination, were characterized by 
summary statistics of observed data from CA209004 and by PPK analyses using serum 
concentration data collected in studies CA209004, CA209069 and CA209067.
A dose-related increase in nivolumab peak and trough concentrations was observed after the first 
dose in Study CA209004. Peak and trough concentrations after the first dose for 1 mg/kg of 
nivolumab in combination with 3 mg/kg of ipilimumab Q3W were in the range of 
18.1 - 21.5 μg/mL and 3.2 - 4.8 μg/mL, respectively. Ipilimumab peak concentrations at 3 mg/kg 
in combination with 1 mg/kg nivolumab after the first dose were in the range of 63.5 - 68.5 μg/mL. 
Ipilimumab trough concentrations at 3 mg/kg in combination with 1 mg/kg nivolumab after the 
first dose were in the range of 9.8 - 11.9 μg/mL.
1.4.5
Safety Summary
1.4.5.1
Nivolumab Safety Summary
Nivolumab has been studied in over 8,600 subjects and is widely approved in multiple indications. 
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Overall, the safety profile of nivolumab monotherapy is manageable and generally consistent 
across completed and ongoing clinical trials, with no maximum tolerated dose (MTD) reached up 
to 10 mg/kg. Most AEs were low-grade (Grades 1 to 2) with relatively few high-grade (Grades 3 
to 4) AEs related to study drug. There was no pattern in the incidence, severity, or causality of AEs 
with respect to nivolumab dose level.
A pattern of immune-related adverse events has been defined, for which management algorithms 
have been developed; these are provided in Appendix 1. Most high-grade events were manageable 
with the use of corticosteroids or hormone replacement therapy (endocrinopathies) as instructed 
in these algorithms. 
For further safety information, please refer to Opdivo® USPI and SmPC. 
1.4.5.2
Ipilimumab Safety Summary
A pooled analysis of 14 phase I-III studies evaluating various doses of ipilimumab in advanced 
melanoma demonstrated that 64.2% of subjects experienced an irAE of any grade.119The majority 
of irAEs were mild-moderate (grade 1-2) with death due to irAEs occurring in <1% of subjects. 
The skin and GI tract were most frequently affected, while hepatic, endocrine, and neurologic 
events were less common.119 In a phase II trial comparing three dose levels of ipilimumab 
(0.3 mg/kg, 3.0 mg/kg, and 10 mg/kg) in subjects who were pretreated for advanced melanoma—
followed by maintenance in subjects achieving an objective response or stable disease—the 
incidence of irAEs was 26%, 56%, and 70%, with an occurrence of grade 3-4 irAEs in 0%, 7%, 
and 25% of subjects, respectively suggesting a dose-response for safety.120
For further safety information with ipilimumab 3 mg/kg in advanced melanoma, including timing 
of onset and resolution of events, please refer to Yervoy® USPI and SmPC.
1.4.5.3
Ipilimumab Safety in Prostate Cancer
A summary of safety observed in the completed Phase 1 and 2 CRPC studies, which used 
ipilimumab as monotherapy or in combination with other therapeutic modalities (ie, docetaxel, 
GVAX) is shown in Table 1.4.5.3-1. Overall, the safety profile of ipilimumab as monotherapy or 
in combination with other treatment modalities in CRPC was characterized by irAEs involving 
skin, GI tract, endocrine tract, and liver, a profile which is consistent with that observed in the 
clinical development program.
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Table 1.4.5.3-1:
Overall Summary of Safety in Completed Phase 1 and 2 CRPC 
Studies of Ipilimumab
Number of Subjects (%)
MDXCTLA4-01a
(N = 14)
MDX010-07b
(N = 44)
MDX010-17c
(N = 28)
Any Drug-related AE
5 (35.7)
33 (75.0)
28 (100.0)
Grade 3 - 4 
NA
26 (59.1)
NA
Most Frequently Reported Drug-related AEs 
Fatigue
0
16 (36.4)
22 (78.6)
Pruritus
2 (14.2)
10 (22.7)
6 (21.4)
Nausea
0
7 (15.9)
8 (28.6)
Rash
2 (14.2)
5 (11.4)
11 (39.3)
Diarrhea
0
3 (6.8)
7 (25.0)
Vomiting
0
3 (6.8)
6 (21.4)
Headache
0
3 (6.8)
7 (25.0)
Anorexia
0
3 (6.8)
6 (21.4)
Pyrexia
--
1 (2.3)
16 (57.1)
Malaise
1 (7.1)
--
6 (21.4)
Influenza-like Illness
0
--
12 (42.9)
Any Serious Adverse Events
6 (42.9)
15 (34.1)
14 (50.0)
Grade 3 - 4
5 (35.7)
15 (34.1)
NA
Any Drug-related Serious Adverse Events
1 (7.1)
7 (15.9)
7 (25.0)
Grade 3 - 4
1 (7.1)
7 (15.9)
NA
Any irAE
1 (7.1)d
24 (54.6)d
5 (17.9)d
Grade 3 - 4
1 (7.1)
7 (15.9)
NA
Any Serious irAE
1 (7.1)
4 (9.1)
NA
Grade 3 - 4
1 (7.1)
NA
NA
Source: CSRs for MDXCTLA4-01,MDX010-07, and preliminary data from MDX010-17 
NA = not available
a Ipilimumab monotherapy
b Data pooled for ipilimumab monotherapy and ipilimumab in combination with docetaxel
c Ipilimumab in combination with GVAX
d Referred to as immune breakthrough events in CSR
The safety profile based on the preliminary data from MDX010-21, A Phase 1/2, Open-label, 
Dose-escalation Study of MDX-010 Administered Every 3 Weeks for 4 Doses in Subjects with 
Metastatic Hormone-Refractory Prostate Cancer is presented in Table 1.4.5.3-2.121 The safety 
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profile in this study was characterized by irAEs involving skin, GI tract, endocrine tract, and liver, 
which is consistent with that observed in the clinical development program.
Table 1.4.5.3-2:
MDX010-21 - Overall Summary of Safety
Parameter
Number (%) of Subjects
3 mg/kg 
N=8
5 mg/kg 
N=6
10 mg/kg 
N=16
3 mg/kg
+ XRT
N=7
10 mg/kg
+ XRT 
N=34
Total
N = 71
Deaths
5 (62.5)
4 (66.7)
7 (43.8)
3 (42.9)
18 (52.9)
37 (52.1)
≤70 days after last 
dose
0
0
0
0
6 (17.6)
6 (8.5)
SAE
3 (37.5)
2 (33.3)
9 (56.3)
2 (28.6)
19 (55.9)
35 (49.3)
Related
2 (25.0)
1 (16.7)
7 (43.8)
2 (28.6)
7 (20.6)
19 (26.8)
AE to DC
2 (25.0)
2 (33.3)
7 (43.8)
3 (42.9)
13 (38.2)
27 (38.0)
Related
2 (25.0)
2 (33.3)
6 (37.5)
3 (42.9)
8 (23.5)
21 (29.6)
AE
8 (100)
6 (100)
16 (100)
6 (85.7)
34 (100)
70 (98.6)
Grade 3-4
2 (25.0)
5 (83.3)
12 (75.0)
3 (42.9)
20 (58.8)
42 (59.2)
Related AE
8 (100)
5 (83.3)
16 (100)
6 (85.7)
29 (85.3)
64 (90.1)
Grade 3-4
2 (25.0)
3 (50.0)
10 (62.5)
3 (42.9)
13 (38.2)
31 (43.7)
irAE
6 (75.0)
5 (83.3)
16 (100)
4 (57.1)
24 (70.6)
55 (77.5)
Grade 3-4
1 (12.5)
3 (50.0)
10 (62.5)
3 (42.9)
6 (17.6)
23 (32.4)
Abbreviations: SAE = serious adverse event; AE = adverse event; DC = discontinuation; irAE = immune-related AE
Ipilimumab, at escalating doses of 3, 5, and 10 mg/kg with and without a single dose of XRT 
administered every 3 weeks up to 4 times was tolerable with a safety profile consistent with that 
demonstrated in previous studies of ipilimumab. Although no DLTs were observed and no MTD 
was reached during the course of the study, rate of AEs showed increase from 3 mg/kg to 
10 mg/kg.121
The phase 3 Study CA184043 evaluated ipilimumab 10 mg/kg monotherapy dose vs. placebo in 
mCRPC.50 The overall safety profile for ipilimumab in these studies was generally consistent with 
the previous Phase 1 and 2 studies of ipilimumab 10 mg/kg monotherapy in prostate cancer. The 
most frequently reported on-study immune-related adverse events of any grade in the ipilimumab 
group were diarrhea, pruritus, rash, colitis, increased aspartate aminotransferase, and increased 
alanine aminotransferase. While less than 2% of fatal adverse events in either treatment group 
were regarded as drug-related, more on-study deaths occurred overall and in the first 5 months in 
the ipilimumab 10 mg/kg group than in the placebo group. 
1.4.5.4
Nivolumab-plus-Ipilimumab Safety Summary
In the Phase 1b, open-label, multi-center, multi-dose, dose-escalation study of nivolumab in 
combination with ipilimumab, study drugs were administered either concurrently (Cohorts 1 
through 3, and Cohort 8) or in a sequenced regimen (Cohorts 6 and 7) in subjects with advanced 
melanoma.38 Each arm in this multi-arm study had an induction phase (ipilimumab dosed 
Q3 weeks x4; nivolumab dosed Q3 weeks x8) and a maintenance phase (ipilimumab dosed 
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Q12 weeks x8; nivolumab dosed Q12 weeks x8). Initial 3 dose-escalation cohorts consisted of 
Cohort 1 (nivolumab 0.3 mg/kg plus ipilimumab 3 mg/kg; n = 14), Cohort 2 (nivolumab 1.0 mg/kg 
plus ipilimumab 3 mg/kg; n = 16) and Cohort 3 (nivolumab 3.0 mg/kg plus ipilimumab 3 mg/kg; 
n = 6).38
Unlike single-agent nivolumab, a dose relationship with toxicity was observed with the 
combination of nivolumab and ipilimumab38. The lowest dose of nivolumab (Cohort 1, 0.3 mg/kg 
with 3 mg/kg ipilimumab) resulted in a lower incidence of Grade 3-4 AEs, SAEs, and AEs leading 
to treatment discontinuation compared with the higher dose cohorts. Treatment with 3 mg/kg 
nivolumab and 3 mg/kg ipilimumab (Cohort 3) resulted in 3 of 6 subjects experiencing DLTs that 
exceeded the protocol-defined MTD. No subjects were enrolled in Cohorts 4 and 5 because the 
maximum tolerated dose (MTD) was exceeded in Cohort 3 and the protocol was amended to 
evaluate a lower dose of ipilimumab (1 mg/kg) in combination with 3 mg/kg nivolumab 
(Cohort 2a). Both Cohort 2 (1 mg/kg nivolumab and 3 mg/kg ipilimumab) and Cohort 2a (3 mg/kg 
nivolumab and 1 mg/kg ipilimumab) were deemed tolerable establishing both dose combinations 
as MTD (2 of 17 and 0 of 16 subjects had DLTs in Cohort 2 and 2a, respectively).38
Treatment with nivolumab in combination with ipilimumab generally resulted in greater 
frequencies of Grade > 3 AEs, SAEs, AEs leading to discontinuation and select AEs than that 
observed with either agent alone; however, no new types of AEs were observed. The overall 
frequency in the pooled Cohorts 1-3 and in Cohort 8 of skin, GI, hepatic and endocrine select AEs 
were greater than either agent alone and the frequency of Grade 3-4 select skin, GI, and hepatic 
AEs was higher than that observed with nivolumab or ipilimumab monotherapy in melanoma 
subjects.38 In contrast, pulmonary and renal select AEs were only slightly higher than observed 
with single-agent nivolumab .The frequency of some Grade 3-4 AEs, notably those related to GI, 
hepatic, and skin, were also increased with combination treatment relative to ipilimumab.38
In study CA209-067, a randomized, double-blind, multicenter, phase 3 trial that was conducted to 
evaluate the safety and efficacy of nivolumab alone or nivolumab combined with ipilimumab in 
comparison with ipilimumab alone in subjects with previously untreated metastatic melanoma, 
treatment-related adverse events of any grade occurred in 82.1% of the subjects in the nivolumab 
group, 95.5% of those in the nivolumab plus ipilimumab group, and 86.2% of those in the 
ipilimumab group.122 The most common adverse events in the nivolumab-plus-ipilimumab group 
were diarrhea (in 44.1% of subjects), fatigue (in 35.1%), and pruritus (in 33.2%).122 The incidence 
of treatment-related adverse events of grade 3 or 4 was also higher in the 
nivolumab-plus-ipilimumab group (55.0%) than in the nivolumab group (16.3%) or the 
ipilimumab group (27.3%).122 Treatment-related adverse events of any grade that led to 
discontinuation of the study drug occurred in 7.7% of the subjects in the nivolumab group, 36.4% 
of those in the nivolumab plus ipilimumab group, and 14.8% of those in the ipilimumab group, 
with the most common events being diarrhea (in 1.9%, 8.3%, and 4.5%, respectively) and colitis 
(in 0.6%, 8.3%, and 7.7%, respectively).122 Grade 3 or 4 diarrhea were higher in the combination 
cohort (2.2% in nivolumab group vs. 9.3% in the nivolumab-plus-ipilimumab group, and 6.1% in 
the ipilimumab group). Similarly colitis (in 0.6%, 7.7%, and 8.7%, respectively), and increased 
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alanine aminotransferase level (in 1.3%, 8.3%, and 1.6%, respectively) were higher in the 
nivolumab-plus-ipilimumab combination arms.122
1.5
Overall Risk/Benefit Assessment
New therapeutic options with the potential to provide durable, long term responses across the 
disease states spectrum of mCRPC are needed. Several lines of evidence, as outlined in 
Section 1.1.2, strongly support the investigation of immunotherapy agents to improve outcomes in 
mCRPC.
Safety and efficacy have been demonstrated with both single agent nivolumab and ipilimumab. 
The combination of dual check-point blockade with both of these agents administered together has 
an efficacy advantage over either single agent alone. Same day sequential administration of 
nivolumab (1 mg/kg) followed by ipilimumab (3 mg/kg) was initially evaluated in 
advanced/metastatic melanoma in 2 studies, the Phase 2 Study CA209069 and the Phase 3 Study 
CA209067, and demonstrated statistically significant and clinically meaningful improvements in 
progression-free survival (PFS) and objective response rate (ORR) compared to nivolumab or 
ipilimumab monotherapy.123,122 and served as the basis for an application to extend the indication 
of Opdivo® to include the use of nivolumab and ipilimumab in combination for the treatment of 
advanced melanoma (United States Packaging Insert [USPI] for nivolumab and Summary of 
Product Characteristics [SmPC] for nivolumab). Subsequently, nivolumab plus ipilimumab has 
also demonstrated clinical activity in several tumor types, including Renal Cell Cancer (RCC)124, 
non-small cell lung cancer (NSCLC)125, Small Cell Lung Cancer (SCLC)126 and gastric cancer127. 
Results to date suggest that the safety profile of nivolumab plus ipilimumab combination therapy 
is consistent with the mechanisms of action of nivolumab and ipilimumab. The nature of the AEs 
is similar to that observed with either agent used as monotherapy; however, both frequency and 
severity of most AEs are increased with the combination. The adverse event profile of nivolumab 
1 mg/kg combined with ipilimumab 3 mg/kg characterized by immune-related toxicities, such as 
diarrhea, rash, pneumonitis, liver toxicity, and endocrinopathies. These events were mostly low 
grade and manageable with well-established treatment algorithms that included the use of 
corticosteroids.
The current melanoma label supports sequential administration of nivolumab and then ipilimumab, 
one administered soon after the other. The recommended dose and schedule is nivolumab 1 mg/kg 
administered as an intravenous infusion over 30 minutes, followed by ipilimumab 3mg/kg 
administered over 90 minutes on the same day, every 3 weeks for four doses. The time in between 
infusions is expected to be approximately 30 minutes but may be more or less depending on the 
situation. The recommended maintenance dose given after the combination has been completed is 
nivolumab, as a single agent, 3 mg/kg, as an intravenous infusion every 2 weeks, until disease 
progression or unacceptable toxicity. However, in this study after completion of the combination 
portion of the study, subjects will receive flat dose 480 mg nivolumab every 4 weeks (Q4W), 
which provides a more convenient dosing regimen for subjects. While 480 mg Q4W is predicted 
to provide greater (approximately 40%) maximum steady state concentrations and lower 
(approximately 15 to 20%) steady state trough concentrations, these exposures are predicted to be 
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within the exposure ranges observed at doses up to 10 mg/kg Q2W used in the Phase 1 nivolumab 
clinical program, and are not considered to put subjects at increased risk. Similar to the nivolumab 
Q2W dosing monotherapy regimen, the exposures predicted following administration of 
nivolumab 480 mg Q4W, are on the flat part of the exposure-response curves for previously 
investigated tumors, melanoma and NSCLC, and are not predicted to affect efficacy. 
1.5.1
Based on these data, nivolumab 480 mg Q4W is expected to have 
similar efficacy and safety profiles to nivolumab 3 mg/kg Q2W.Overall 
Risk/Benefit Assessment for Additional Cohort D
As outlined in Section 1.1, the recent data from Cohorts B and C in CA209650 suggest that 
nivolumab in combination with ipilimumab is an active regimen in patients with mCRPC, with 
potentially greater activity in patients with HRD mutations or higher TMB, but early toxicity was 
the factor which limited the number of combination doses received. Mitigation of severe toxicities 
through alternative combination schedules may help to further improve outcomes, and this 
approach will be explored in the following two arms:
•
Arm D1 will evaluate the combination using a lower dose of ipilimumab (1 mg/kg), but at the 
same frequency used in Part 1 (Q3W). As described earlier, the safety profile and clinical 
activity of Nivolumab 3 mg/kg combined with ipilimumab 1 mg/kg was demonstrated by the 
approval of this regimen in other cancer types. This combination has also shown acceptable 
safety and encouraging efficacy in men with AR-V7-expressing advanced prostate cancer who 
harbor DNA-repair alterations.
•
Since ipilimumab dose of 3 mg/kg may be critical to enhance immune cell infiltration into 
tumors and driving the anti-tumor response, arm D2 will explore the same dose of ipilimumab 
used in Cohorts B and C (3 mg/kg), but at a reduced frequency (Q6W), As described earlier, 
CA209012 supports the rationale to decrease ipilimumab dosing frequency to improve 
tolerability, while maintaining efficacy.
Furthermore, as outlined in Sections 1.1.4 and 1.4.5, ipilimumab monotherapy has demonstrated 
clinical activity and an acceptable safety profile, and previous trials in mCRPC highlight the need 
to identify 
 patients most likely to benefit. Ipilimumab will be evaluated 
in Arm D3 to assess its contribution to the activity of the combination in the chosen population.
Arm D4 will evaluate the standard of care cabazitaxel in the target population and allow for 
comparison with the immunotherapy regimens, 
 
Cabazitaxel has a well-characterized 
AE profile as a cytotoxic chemotherapy, including the potential of neutropenia, anemia, 
thrombocytopenia, diarrhea, nausea and vomiting.
To assure an ongoing favorable risk/benefit assessment for participants enrolled into the present 
study, the following safety measures will be employed throughout the conduct of the study:
•
Early interim reviews of safety and efficacy data will be performed by the Sponsor and 
participating investigators from the Study Steering Committee for Cohort D after the first 
15 treated subjects for each arm have at least 8 weeks of follow-up after first dose and at least 
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one post-baseline tumor assessment in subjects receiving immunotherapy in Arms D1, D2, and 
D3.
•
Rigorous safety monitoring by BMS to ensure participants’ safety including regular and 
systematic review of safety data, close follow-up of reported safety events, and intensive site 
and study investigator training/education on the implementation of the nivolumab and 
ipilimumab toxicity management algorithms 
•
Open-label drug administration of study treatments to allow for prompt and accurate 
assessment of the unique toxicities associated with study treatments
In conclusion, the overall risk-benefit of the proposed study arms is deemed acceptable.
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Council for Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50) and applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to the Sponsor or designee immediately. A 
potential serious breach is defined as a Quality Issue (eg, protocol deviation, etc) that is likely to 
affect, to a significant degree one or more of the following: (1) the physical, safety or mental 
integrity of one or more subjects/participants; (2) the scientific value of the trial (eg, reliability and 
robustness of generated data). Items (1) or (2) can be associated with either GCP Regulation(s) or 
Trial protocol(s).
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The investigator 
or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
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2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives 
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the subject volunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (ie, Global or Local) sample 
informed consent form which will include all elements required by ICH, GCP and applicable 
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
Investigators must:
•
Provide a copy of the consent form and written information about the study in the language in 
which the subject is most proficient prior to clinical study participation. The language must be 
non-technical and easily understood
•
Allow time necessary for subject or subject's legally acceptable representative to inquire about 
the details of the study
•
Obtain an informed consent signed and personally dated by the subject or the subject's legally 
acceptable representative and by the person who conducted the informed consent discussion
•
Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information
If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his or her 
informed consent during the study, consent must additionally be obtained from the subject.
Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal guardian, 
of all pertinent aspects of the study and of any new information relevant to the subject's willingness 
to continue participation in the study. This communication should be documented.
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records.
Subjects unable to give their written consent (eg, subjects with stroke) may only be enrolled in the 
study with the consent of a legally acceptable representative. The subject must also be informed 
about the nature of the study to the extent compatible with his or her understanding, and should 
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this subject become capable, he or she should personally sign and date the consent form as soon 
as possible. The explicit wish of a subject who is unable to give his or her written consent, but who 
is capable of forming an opinion and assessing information to refuse participation in, or to be 
withdrawn from, the clinical study at any time should be considered by the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is a Phase 2 open-label study of nivolumab plus ipilimumab in subjects with metastatic 
castration-resistant prostate cancer (mCRPC). The trial will include 3 treatment cohorts:
Cohort A: Asymptomatic or minimally symptomatic mCRPC subjects who have not been treated 
with and are unable or unwilling to receive second generation hormone therapies or cytotoxic 
chemotherapy in mCRPC setting.
Addendum: Per Revised Protocol 02, Cohort A was discontinued for further enrollment. The 
remainder of Cohort A participants will be allocated to Cohorts B and C in order to have more 
precise efficacy estimates in those arms.
Cohort B: Asymptomatic or minimally symptomatic mCRPC subjects who must have progressed 
after second generation hormone therapies in mCRPC setting and have not been treated with 
cytotoxic chemotherapy in mCRPC setting.
Cohort C: Subjects must have progressed after prior taxane-based cytotoxic chemotherapy in the 
mCRPC setting.
In accordance with Revised Protocol 02, 45 subjects will be treated per treatment Cohorts B and 
C. At least 30 subjects with measurable disease by RECIST V1.1 criteria will be enrolled in each 
cohort. No more than 15 subjects will have non-measurable disease by RECIST V1.1 in each 
cohort.
Subjects will be treated with up to 4 cycles of nivolumab in combination with ipilimumab (Part 1, 
See Section 4.3.1), followed by nivolumab monotherapy (Part 2, Section 4.3.2) until progression
of disease, unacceptable toxicity, or subject withdrawal of consent. In Part 1, a minimum of 1 
combination cycle of nivolumab and ipilimumab is required. Subjects experiencing AEs related 
to combination dose therapy (Part 1) that do not meet dose discontinuation criteria, may proceed 
to nivolumab monotherapy dosing (Part 2) without completing all 4 combination doses, after 
consultation with BMS Medical Monitor, on a case-by-case basis.
Each treatment cycle will be 3 weeks in duration for Part 1. Nivolumab and ipilimumab will be 
dosed every 3 weeks for four doses. After completion of the last combination cycle in Part 1 (ie, 6 
weeks after the last dose of nivolumab plus ipilimumab), subjects will then receive nivolumab 
monotherapy every four weeks for Part 2 until progression of disease, unacceptable toxicity, or 
subject withdrawal of consent. 
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No dose increases or reductions will be allowed for either drug during both the combination 
therapy phase and the nivolumab monotherapy phase.
The study design schematic is presented in Figure 3.1-1.
Figure 3.1-1:
Study Design Schematic Cohorts A, B, and C
In accordance with Revised Protocol 03, additional subjects who have progressed after prior 
docetaxel-containing regimen will be enrolled into Cohort D.
For Cohort D, approximately 259 subjects will be randomized in a 2:2:1:2 ratio to one of the 
following open-label treatment arms: 
•
Arm D1: nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg every 3 weeks for up 
to 4 doses (Cycles 1 to 4), followed by nivolumab 480 mg administered every 4 weeks (Cycle 5 
and beyond). Subjects who are receiving maintenance nivolumab with ongoing disease control
(ongoing CR, PR, or SD) or with radiographic progression per RECIST v1.1/PCWG2 may be 
permitted re-induction with the combination of ipilimumab and nivolumab at their original 
combination dose upon PSA progression or radiographic progression (whichever occurs first), 
as specified in Section 4.3.5. Treatment will continue until disease progression, unacceptable 
toxicity, withdrawal of consent, 2 year maximum treatment duration, or the study ends, 
whichever occurs first.
•
Arm D2: nivolumab 1 mg/kg every 3 weeks plus ipilimumab 3 mg/kg every 2 cycles (ie, every 
6 weeks) for up to 4 ipilimumab doses, followed by nivolumab 480 mg every 4 weeks. Subjects 
who are receiving maintenance nivolumab with ongoing disease control (ongoing CR, PR, or 
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SD) or with radiographic progression per RECIST v1.1/PCWG2 may be permitted re-
induction with the combination of ipilimumab and nivolumab at their original combination 
dose upon PSA progression or radiographic progression (whichever occurs first), as specified 
in Section 4.3.5. Treatment will continue until disease progression, unacceptable toxicity, 
withdrawal of consent, 2 year maximum treatment duration, or the study ends, whichever 
occurs first.
•
Arm D3: ipilimumab 3 mg/kg every 3 weeks for up to 4 doses. Treatment will continue until 
disease progression, unacceptable toxicity, withdrawal of consent, completion of 4 cycles, or 
the study ends, whichever occurs first.
•
Arm D4: Cabazitaxel 20 mg/m2 or 25 mg/m2 (at investigator’s discretion and according to 
country-specific label) every 3 weeks in combination with oral prednisone or prednisolone 
10 mg daily for up to 10 cycles. Treatment will continue until disease progression, 
unacceptable toxicity, withdrawal of consent, completion of 10 cycles of treatment, or the 
study ends, whichever occurs first.
Randomization will be stratified by the presence or absence of measurable disease per investigator 
assessment (measurable disease vs only non-measurable disease) at study entry to ensure treatment 
arms are balanced.
Note: Subjects treated in Arms D3 and D4 who progress on or after treatment may be eligible to 
crossover to Arm D1.
Cohort D will evaluate the above immunotherapy regimens and the standard of care comparator 
cabazitaxel in unselected mCRPC patients. 
 
The study design schematic for the addition of Cohort D is presented in Figure 3.1-2:
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Figure 3.1-2:
Study Design Schematic for Addition of Cohort D
Notes:
a Subjects with investigator-assessed non-measurable disease at baseline will be capped when approximately 105 
subjects are randomized.
b Subjects in Arms D1 and D2 experiencing drug-related AEs with combination dose therapy that do not lead to study 
treatment discontinuation due to toxicity may proceed to nivolumab monotherapy dosing without completing all 
4 combination cycles. Subjects who entered the maintenance period may be permitted re-induction with the 
combination after approval by the BMS medical monitor
c Subjects in Arms D3 and D4 who have progressed on or after treatment have the option to crossover to Arm D1 at 
BICR confirmed disease progression after approval by the BMS medical monitor
d Radiographic progression per RECIST v1.1 or PCWG2 (Section 5.5.3). Treatment beyond investigator-assessed 
RECIST v1.1-defined progression may be considered for subjects meeting criteria according to Section 4.5.4
The study will consist of the following three phases:
Screening Phase:
•
Begins by establishing the subject’s initial eligibility and signing of the informed consent form 
(ICF).
•
Subject is enrolled using the IWRS.
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Treatment Phase:
•
Begins with the cohort assignment call to the IWRS
•
Within 3 calendar days from cohort assignment the subject must receive the first dose of study 
medication (Day 1 of Cycle 1)
•
On-study laboratory assessments (Cycle 2 and beyond) should be drawn within 72 hours prior 
to dosing
•
Adverse event assessments should be documented at each clinic visit
•
•
Study treatment dosing may be delayed for toxicity as described in section 4.5.1
Cohort D : The treatment phase consists of 4 open-label treatment arms (Arm D1, D2, D3, and
D4):
•
Arm D1: nivolumab and ipilimumab are administered every 3 weeks for up to 4 doses, 
followed by nivolumab administered every 4 weeks (Cycle 5 and beyond). The first nivolumab 
dose of 480 mg will be administered 3 weeks after the last combination dose of 
nivolumab/ipilimumab
•
Arm D2: nivolumab is administered every three weeks up to 8 doses. Ipilimumab is 
administered every 6 weeks for up to 4 doses followed by nivolumab administered every 
4 weeks (Cycle 9 and beyond). The first flat dose 480 mg nivolumab will be administered 
3 weeks after the last nivolumab 1 mg/kg dose (and 6 weeks after the last combination dose).
•
Arm D3: ipilimumab is administered every 3 weeks for up to 4 doses
•
Arm D4: Cabazitaxel will be administered every 3 weeks in combination with oral prednisone 
or prednisolone up to 10 cycles.
For Cohorts B and C, tumor assessments are scheduled to be performed every 8 weeks for 6 months 
following treatment initiation and thereafter every 12 weeks until radiographic progression or 
withdrawal of consent.
For Arms D1, D2, D3, and D4, tumor assessments are scheduled to be performed every 8 weeks 
(± 7 days) for 6 months following treatment initiation and thereafter every 12 weeks (± 7 days) 
until radiographic progression has been assessed by the investigator and confirmed by BICR (see 
Section 5.5.3) or withdrawal of consent.
This treatment phase ends when the subject is discontinued from study therapy. 
Optional Re-induction Combination for Cohorts B, C, Arms D1, and D2
Subjects with PSA progression or with radiographic progression per RECIST v1.1/PCWG2
(whichever occurs first) during or after nivolumab monotherapy maintenance may receive 
nivolumab and ipilimumab combination at the same dose levels as assigned at study start and 
follow the same Time and Events schedule, as specified in Section 5.
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Optional Crossover Combination for Arms D3 and D4
Subjects treated in Arms D3 and D4 who demonstrate radiographic progression assessed by the 
investigator and confirmed by BICR during or after treatment may be eligible to receive optional 
crossover nivolumab in combination with ipilimumab (Arm D1) if their case is reviewed with and 
approved by the BMS Medical Monitor:
Subjects must continue to meet all inclusion criteria and all exclusion criteria specified in 
Section 3.3, including criteria related to severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) infection.
Nivolumab 3 mg/kg plus ipilimumab 1 mg/kg Q3W for up to 4 cycles, followed by nivolumab 
480 mg mg/kg Q4W is administered every 4 weeks until disease progression, unacceptable 
toxicity, withdrawal of consent, completion of 2 years of treatment, or the study ends, whichever 
occurs first. At least a 3 week period from last dose of study treatment (ipilimumab or cabazitaxel) 
is required prior to first dose of crossover treatment.
Study assessments are to be collected as outlined in Section 5. A tumor assessment within 28 days 
prior to the first crossover dose is recommended, which can serve as the new baseline by which to 
assess response to nivolumab and ipilimumab. Imaging tumor assessments performed during 
crossover nivolumab should be submitted to the central imaging vendor.
Nivolumab treatment beyond initial radiographic progression defined by RECIST v1.1 (for soft 
tissue lesions) and PCWG2 (for bone lesions) is permitted if the subject has investigator assessed 
clinical benefit and is tolerating the treatment, as specified in Section 4.5.4.
Upon discontinuation of crossover treatment subjects will enter the Follow-Up Phase.
Follow-Up Phase:
•
Begins when the decision to discontinue a subject from study therapy is made (no further 
treatment with study therapy)
•
 
•
Subjects who discontinue treatment for reasons other than disease progression or consent 
withdrawal will continue to have tumor assessments (if clinically feasible) according to the 
schedule in Table 5.1-5 until progression
•
Subjects enrolled in Arms D1, D2, D3, or D4 who discontinue treatment without BICR-
confirmed progression or consent withdrawal will continue to have tumor assessments (if 
clinically feasible) according to the schedule in Table 5.1-5 until radiographic progression has 
been assessed by the investigator and confirmed by BICR.
•
Subjects will be followed for drug-related toxicities until these toxicities resolve, return to 
baseline or are deemed irreversible. All adverse events will be documented for a minimum of 
100 days after last dose
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•
After completion of the first two follow-up visits, subjects will be followed every 3 months for 
survival
•
BMS may request that survival data be collected on all treated subjects in Cohorts B and C, 
and all randomized subjects in Cohort D outside of the protocol defined window as detailed in 
the Time and Events Table (Section 5). At the time of this request, each subject will be 
contacted to determine their survival status unless the subject has withdrawn consent for all 
contact.
•
If exceptional circumstances preclude the continued administration of measures using planned 
modalities, then alternate administration methods may be required after consultation with a 
sponsor or a sponsor’s representative.
Duration of Study for Cohorts A, B, and C: It is expected that the trial will be open to accrual 
for 9 months, with a planned enrollment of 90 subjects. Survival follow-up will continue until 
BMS informs sites to end the study.
The accrual duration is approximately 9 months, assuming a monthly rate of 10 subjects. The 
analysis of the dual primary endpoint of ORR will occur after all the subjects have been followed 
for a total period of approximately 24 weeks, ie, after treatment with a maximum of 4 cycles of 
combination treatment and at least 2 cycles of nivolumab monotherapy treatment. Subjects who 
receive less than 4 cycles of (ie, between 1-3 cycles), will also be included in the analysis after 
they complete 24 weeks of follow-up. 
This will allow sufficient follow up for a stable estimate of best overall response and adequate 
safety follow up. The primary analysis of ORR is expected to occur approximately 15 months after 
the first subject is treated. The analysis of the dual primary endpoint of rPFS will occur after all 
the subjects have been followed up for approximately 12 months since treatment initiation to have 
a stable estimate of one year rPFS.
Additional survival analysis may be conducted for up to 5 years after treatment initiation following 
analysis of the primary endpoint.
Duration of Study for Cohort D: The accrual duration is approximately 24 months for this period.
The analyses of the dual primary endpoints of rPFS and ORR per BICR will occur when around
90% of all randomized subjects have approximately 9 months of minimum follow up, which will 
be a sufficient duration of follow-up for a stable estimate of rPFS and best overall response, as 
well as adequate safety follow up.
Additional long-term survival analysis may be conducted for up to 5 years from the date of 
randomization of the last patient following analysis of the primary endpoint.
3.2
Post Study Access to Therapy
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study treatment. Study treatment will be provided via an 
extension of the study, a rollover study requiring approval by responsible health authority and 
ethics committee or through another mechanism at the discretion of BMS. BMS reserves the right 
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to terminate access to BMS supplied study treatment if any of the following occur: a) the marketing 
application is rejected by responsible health authority; b) the study is terminated due to safety 
concerns; c) the subject can obtain medication from a government sponsored or private health 
program; or d) therapeutic alternatives become available in the local market.
BMS may request that survival data be collected on all treated subjects in Cohorts B and C and all 
randomized subjects in Cohort D outside of the protocol defined window. At the time of this 
request, each subject will be contacted to determine their survival status unless the subject has 
withdrawn consent for all contacts or is lost to follow-up.
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study treatment for the maximum treatment duration 
specified in protocol Section 1.1.13. Study treatment will be provided via an extension of the 
study, a rollover study requiring approval by responsible health authority and ethics committee or 
through another mechanism at the discretion of BMS
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Willing and able to provide informed consent.
2) Target Population
a) Men, 18 years or older
b) ECOG performance status 0-1
c) Histologic confirmation of adenocarcinoma of the prostate
d) Current evidence of metastatic disease documented by either bone lesions on radionuclide 
bone scan and/or soft tissue lesions on CT/MRI. Metastases may be in regional lymph 
nodes (N1 per AJCC staging criteria, 8th edition)128 and/or distant metastases (M1 per 
AJCC staging criteria, 8th edition).
i)
Subjects whose disease spread is limited to regional pelvic lymph nodes (N1M0) must 
have a lymph node measuring at least 2 cm in short axis to be considered eligible.
e) Ongoing androgen deprivation therapy (ADT) with a GnRH analogue or bilateral 
orchiectomy (ie, surgical or medical castration) confirmed by testosterone level 
≤1.73 nmol/L (50 ng/dL) at the screening visit. Castrate levels of testosterone must be 
maintained by surgical or medical means (LHRH/GnRH analogues) throughout the 
conduct of the study
f)
Tumor progression while receiving ADT per PCWG2 criteria and within 6 months prior to 
screening, with at least one of the following:
i)
PSA progression* defined by a minimum of two rising PSA levels with an interval of 
≥1 week between each determination. The PSA value at the Screening visit should be 
≥2 ug/L (2 ng/mL).
*Subjects who received an anti-androgen must have progression after withdrawal 
(≥4 weeks since last flutamide or ≥6 weeks since last bicalutamide or nilutamide).
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ii) Soft tissue disease progression defined by RECIST V1.1. 
iii) Bone disease progression defined by PCWG2 with two or more new lesions on bone 
scan
g) mCRPC subjects will be enrolled into separate cohorts as follows:
i)
Cohort A: Asymptomatic or minimally symptomatic mCRPC subjects. Prior treatment 
with second-generation hormone therapies (eg, enzalutamide, abiraterone) or cytotoxic 
chemotherapy (eg, docetaxel, mitoxantrone) in the mCRPC setting is not allowed. 
Subject’s refusal of or inability to receive treatment with second-generation hormone 
therapies or cytotoxic chemotherapy must be appropriately documented. Prior prostate 
cancer vaccine therapy, radiation therapy, radium 223, anti-androgens (eg, flutamide, 
bicalutamide), ketoconazole and DES or other estrogens, are allowed up to 28 days 
prior to study treatment. Note: bicalumatamide or nilutamide must be discontinued 
within 6 weeks of study treatment. Enrollment discontinued per Revised 
Protocol 02.
ii) Cohort B: Asymptomatic or minimally symptomatic mCRPC subjects who have 
progressed following treatment with at least one second-generation hormone therapies 
(eg, enzalutamide or abiraterone) in the mCRPC setting. Prior cytotoxic chemotherapy 
(eg, docetaxel, mitoxantrone) in the mCRPC setting is not allowed. Prior prostate 
cancer vaccine therapy, radiation therapy, radium-223, anti-androgens (eg, flutamide), 
ketoconazole, and DES or other estrogens, are allowed up to 28 days prior to study 
treatment. Note: bicalutamide or nilutamide must be discontinued within 6 weeks of 
study treatment.
Note: Asymptomatic or minimally symptomatic:
(1) Asymptomatic is defined as BPI-SF item #3 score of 0 to 1
(2) Minimally symptomatic is defined as BPI-SF item #3 score of 2 to 4
Note: Any cancer related pain must not require any opiate analgesics (including codeine 
and dextropropoxyphene) over the 5 day assessment period prior to treatment initiation. 
iii) Cohort C: Subjects must have progressed after prior taxane-based cytotoxic 
chemotherapy in the mCRPC setting.  Ketoconazole, abiraterone, enzalutamide, 
prostate cancer vaccine therapy, radiation therapy, radium-223, anti-androgens 
(eg, flutamide), and DES or other estrogens, are allowed up to 28 days prior to study 
treatment. Note:  bicalutamide or nilutamide must be discontinued within 6 weeks of 
study treatment.
iv) Cohort D: Subjects must have progressed after a prior docetaxel-containing regimen 
and received no more than 2 prior chemotherapy regimens in the metastatic setting. If 
docetaxel was only given in the metastatic castration-sensitive setting, subjects must 
also have progressed following prior treatment with a second generation hormonal 
therapy. Prior second-generation hormonal manipulations (eg, abiraterone acetate,
enzalutamide, apalutamide), ketoconazole, prostate cancer vaccine therapy, 
radium-223, anti-androgens (eg, flutamide), chemotherapy and DES or other estrogens, 
are allowed up to 28 days prior to study treatment.
Note: bicalutamide or nilutamide must be discontinued at least 6 weeks prior to study 
treatment.
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h) Not applicable per Revised Protocol 02.
i)
Anti-androgens (bicalutamide, flutamide, nilutamide) or adrenal androgen production 
inhibitors (aminoglutethamide or ketoconazole) should be discontinued prior to starting 
study therapy:
i)
Subjects with a history of response to an anti-androgen or adrenal androgen production 
inhibitor and subsequent progression while on that anti-androgen should be assessed 
for anti-androgen withdrawal response for 4 weeks (6 weeks for bicalutamide or 
nilutamide), and must demonstrate progression, as described in Inclusion Criterion 2) 
f), off anti-androgen prior to enrollment;
ii) For subjects that have never responded to anti-androgens, observation for 
anti-androgen withdrawal response is not necessary; however, a 2 week washout period 
is required prior to start of study therapy
j)
Subjects already on agents for the management of skeletal-related events (SREs) are 
allowed to continue with anti-bone resorptive therapy that was initiated more than 28 days 
prior to study treatment.
k) Subject Re-enrollment: This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (ie, subject has not been treated). If 
re-enrolled, the subject must be re-consented.
l)
Sufficient tumor samples from either a fresh biopsy (collected during screening period) or 
archival tumor tissue in the form of formalin-fixed paraffin-embedded (FFPE) block or a 
minimum of 15 unstained tumor tissue slides. Archival tumor samples must be obtained 
within 1 year prior to enrollment date, either from a metastatic tumor lesion (preferred) or 
from a primary tumor lesion that has not been previously irradiated. Tumor samples 
collected more than 1 year prior to enrollment date may be acceptable if obtained in the 
metastatic setting and following discussion with and approval by the BMS Medical 
Monitor/designee. Tumor sample may be from core biopsy, punch biopsy, excisional 
biopsy, or surgical specimen. Fine needle aspiration is unacceptable for submission. 
 Central laboratory must confirm receipt of tumor samples prior 
to randomization.
3) Age and Reproductive Status
a) Men ≥18 years of age or minimum age of consent per local regulations
b) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug(s) for a total of 
7 months post-treatment completion
c) Azoospermic males are exempt from contraceptive requirements
Investigators shall counsel male subjects who are sexually active with WOCBP on the importance 
of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall 
advise male subjects who are sexually active with WOCBP on the use of highly effective methods 
of contraception (see Appendix 3). Highly effective methods of contraception have a failure rate 
of < 1% when used consistently and correctly.
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3.3.2
Inclusion Criteria for Crossover Phase for Subjects Originally 
Randomized to Arm D3 or Arm D4 only
1) Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IC approved written informed consent form 
for crossover combination treatment
2) Target Population
a) Subjects previously randomized to Arm D3 or D4 who had histologic confirmation of 
adenocarcinoma of the prostate and evidence of Stage IV disease (as defined by AJCC 
criteria) prior to randomization
b) ECOG performance status 0-1
c) Ongoing androgen deprivation therapy (ADT) with a GnRH analogue or bilateral 
orchiectomy (ie, surgical or medical castration) confirmed by testosterone level 
≤1.73 nmol/L (50 ng/dL) at the screening visit. Castrate levels of testosterone must be 
maintained by surgical or medical means (LHRH/GnRH analogues) throughout the 
conduct of the study
d) Tumor progression per PCWG2 criteria with at least one of the following assessed by the 
investigator and confirmed by BICR:
i)
Soft tissue disease progression defined by RECIST V1.1. Subjects whose disease 
spread is limited to regional pelvic lymph nodes measuring at least 2 cm in short axis 
will be considered eligible
ii) Bone disease progression defined by PCWG2 with two or more new lesions on bone 
scan
e) At least a 3 week period from last dose of study treatment (ipilimumab or cabazitaxel) is 
required prior to first dose of crossover treatment. 
f)
Subjects already on agents for the management of skeletal-related events (SREs) are 
allowed to continue with anti-bone resorptive therapy that was initiated more than 28 days 
prior to study treatment.
3) Age and Reproductive Status
a) Men ≥18 years of age or minimum age of consent per local regulations
b) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug(s) for a total of 
7 months post-treatment completion
c) Azoospermic males are exempt from contraceptive requirements
Investigators shall counsel male subjects who are sexually active with WOCBP on the importance 
of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall 
advise male subjects who are sexually active with WOCBP on the use of highly effective methods 
of contraception (see Appendix 3). Highly effective methods of contraception have a failure rate 
of < 1% when used consistently and correctly.
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3.3.3
Exclusion Criteria
1) Target Disease Exceptions
a) Presence of visceral metastases in liver.
b) Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are 
eligible if these have been treated and there is no magnetic resonance imaging (MRI except 
where contraindicated in which CT scan is acceptable) evidence of progression for at least 
4 weeks after treatment is complete and within 28 days prior to first dose of study drug 
administration. Cases must be discussed with the medical monitor. Brain lesions are not 
considered measurable disease. There must also be no requirement for immunosuppressive 
doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks 
prior to study drug administration.
2) Medical History, Concurrent Diseases and Prior Therapies
a) Subjects must have recovered from the effects of major surgery requiring general 
anesthetic or significant traumatic injury at least 14 days before randomization or treatment 
assignment. 
b) Subjects with an active, known or suspected autoimmune disease. Subjects with type I 
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll
c) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 calendar 
days of start of study treatment. Inhaled or topical steroids, and adrenal replacement steroid 
doses > 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease.
d) Less than 1 month since resolution of ≥ Grade 2 toxicity related to pelvic-targeted therapy 
(eg, radiation enteritis).
e) Prior radiation therapy within 14 days prior to starting study therapy. Any toxicity related 
to prior radiation therapy must have resolved to Grade ≤1 or baseline prior to starting study 
therapy.
f)
Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or 
any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways. 
g) Dementia, altered mental status, or any psychiatric condition that would prohibit the 
understanding or rendering of informed consent or completing quality of life questionnaire
h) Subjects with serious or uncontrolled medical disorders that in the opinion of the 
investigator, would impair the ability of the subject to receive protocol therapy or obscure 
the interpretation of AEs, such as a condition associated with frequent diarrhea
i)
All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must 
have resolved to Grade 1 (NCI CTCAE version 4) or baseline before administration of 
study drug. Subjects with toxicities attributed to prior anti-cancer therapy which are not 
expected to resolve and result in long lasting sequelae, such as peripheral neuropathy after 
platinum based therapy, are permitted to enroll. For Cohort D: Subjects with symptomatic 
peripheral neuropathy grade > 2 are excluded 
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j)
Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed 
at sites where mandated locally
k) Prior malignancy active within the previous 3 years except for locally curable cancers that 
have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder 
cancer, or carcinoma in situ of the breast
l)
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
history of congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements
m) Subjects who have had a history of acute diverticulitis, intra-abdominal abscess, GI 
obstruction and abdominal carcinomatosis which are known risk factors for bowel 
perforation
n) Participants who have received a live/attenuated vaccine within 30 days of first treatment. 
o) For Cohort D: previous treatment with cabazitaxel in the metastatic setting
p) Participants with superscan on Technecium-99m radionuclide bone scans are not eligible 
for the study. Superscan is defined as a bone scan which demonstrates markedly increased 
skeletal radioisotope uptake relative to soft tissues in association with absent or faint renal 
activity (absent kidney sign).
3) Physical and Laboratory Test Findings
a) WBC < 2000/μL
b) Neutrophils < 1500/μL
c) Platelets < 100 x 103/μL
d) Hemoglobin < 9.0 g/dL
e) Serum creatinine >1.5 x ULN or calculated creatinine clearance < 40 mL/min (using the 
Cockcroft-Gault formula)
f)
AST/ALT: > 3.0 x ULN
g) Total bilirubin > 1.5 x ULN 
h) Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of 
virus, eg Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C 
antibody (anti-HCV) positive (except if HCV-RNA negative).
4) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components. 
b) Cohort D: History of severe (> grade 2) hypersensitivity to docetaxel, or polysorbate 80.
5) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated. (Note: under certain specific 
circumstances, and only in countries where local regulations permit, a person who has been 
imprisoned may be included or permitted to continue as a subject. Strict conditions apply 
and Bristol-Myers Squibb approval is required.)
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
c) Sexually active fertile men not using effective birth control if their partners are women of 
child-bearing potential (WOCBP).
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d) Participation in another clinical trial concurrent with this study.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.4
Exclusion Criteria for Crossover Phase for Subjects Originally 
Randomized to Arm D3 or Arm D4 only
1) Target Disease Exceptions
a) Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are 
eligible if these have been treated and there is no magnetic resonance imaging (MRI except 
where contraindicated in which CT scan is acceptable) evidence of progression for at least 
4 weeks after treatment is complete and within 28 days prior to first dose of study drug 
administration. Cases must be discussed with the medical monitor. Brain lesions are not 
considered measurable disease. There must also be no requirement for immunosuppressive 
doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks 
prior to study drug administration.
2) Medical History, Concurrent Diseases and Prior Therapies
a) Subjects must have recovered from the effects of major surgery requiring general 
anesthetic or significant traumatic injury at least 14 days before first dose of nivolumab 
combined with ipilimumab. 
b) Subjects with an active, known or suspected autoimmune disease. Subjects with type I 
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll
c) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 calendar 
days of start of nivolumab combined with ipilimumab. Inhaled or topical steroids, and 
adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in 
the absence of active autoimmune disease.
d) Less than 1 month since resolution of ≥ Grade 2 toxicity related to pelvic-targeted therapy 
(eg, radiation enteritis).
e) Prior radiation therapy within 14 days prior to first dose of nivolumab combined with 
ipilimumab. Any toxicity related to prior radiation therapy must have resolved to Grade ≤1 
or baseline prior to first dose of nivolumab combined with ipilimumab.
f)
For subjects previously randomized to Arm D4, prior treatment with an anti-PD-1, anti-
PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or any other antibody or drug specifically 
targeting T-cell co-stimulation or checkpoint pathways are not allowed. 
g) Dementia, altered mental status, or any psychiatric condition that would prohibit the 
understanding or rendering of informed consent or completing quality of life questionnaire
h) Subjects with serious or uncontrolled medical disorders that in the opinion of the 
investigator, would impair the ability of the subject to receive protocol therapy or obscure 
the interpretation of AEs, such as a condition associated with frequent diarrhea
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i)
All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must 
have resolved to Grade 1 (NCI CTCAE version 4) or baseline before administration of 
nivolumab combined with ipilimumab. Subjects with toxicities attributed to prior anti-
cancer therapy which are not expected to resolve and result in long lasting sequelae, such 
as peripheral neuropathy after platinum based therapy, are permitted to enroll. 
j)
Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed 
at sites where mandated locally
k) Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic 
infection, and/or detectable virus
l)
History of allergy or hypersensitivity to study drug components
m) Prior malignancy active within the previous 3 years except for locally curable cancers that 
have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder 
cancer, or carcinoma in situ of the breast
n) Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
history of congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements
o) Subjects who have had a history of acute diverticulitis, intra-abdominal abscess, GI 
obstruction and abdominal carcinomatosis which are known risk factors for bowel 
perforation
p) Subjects who have received systemic anti-cancer therapy after the last dose of study 
treatment (ipilimumab or cabazitaxel) 
q) If participant has a current or recent SARS-CoV-2 infection, they may be considered 
eligible after meeting all of the following criteria: 
1) At least 10 days (20 days for severe/critical illness) have passed since symptoms first 
appeared or positive reverse transcription polymerase chain reaction (RT-PCR) or viral antigen 
test result, and
2) At least 24 hours have passed since last fever without the use of fever-reducing medications, 
and
3) Acute symptoms (eg, cough, shortness of breath) have resolved and
4) In the opinion of the investigator, there are no coronavirus disease 2019 (COVID-19)-related 
sequelae that may place the participant at a higher risk of receiving investigational treatment, 
and 
5) Negative follow-up SARS-CoV-2 RT-PCR or viral antigen test based on institutional, local,
or regional guidelines
3) Physical and Laboratory Test Findings
a) WBC < 2000/μL
b) Neutrophils < 1500/μL
c) Platelets < 100 x 103/μL
d) Hemoglobin < 9.0 g/dL
e) Serum creatinine >1.5 x ULN or calculated creatinine clearance < 40 mL/min (using the 
Cockcroft-Gault formula)
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f)
AST/ALT: > 3.0 x ULN
g) Total bilirubin > 1.5 x ULN 
h) Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of 
virus, eg Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C 
antibody (anti-HCV) positive (except if HCV-RNA negative).
4) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated. (Note: under certain specific 
circumstances and only in countries where local permissions permit, a person who has been 
imprisoned may be included or permitted to continue as a subject. Strict conditions apply 
and Bristol-Myers Squibb approval is required.)
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
c) Sexually active fertile men not using effective birth control if their partners are women of 
child-bearing potential (WOCBP).
3.3.5
Women of Childbearing Potential
Not Applicable. 
3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments for All Arms
Treatment with any of the following medications are prohibited during the study:
•
Any concurrent non-protocol-specified anti-neoplastic therapy (ie, chemotherapy, hormonal 
therapy other than ADT, immunotherapy, extensive, non-palliative radiation therapy, standard 
or investigational agents for treatment of mCRPC)
•
Any botanical preparation (eg herbal supplements or traditional Chinese medicines) intended 
to treat the disease under study or provide supportive care. Use of marijuana and its derivatives 
for treatment of symptoms related to cancer or cancer treatment are permitted if obtained by 
medical prescription or if its use (even without a medical prescription) has been legalized 
locally. 
3.4.1.1
Prohibited and/or Restricted Treatments on Nivolumab and Ipilimumab
Treatment with any of the following medications are prohibited during treatment with nivolumab 
and/or ipilimumab:
•
Immunosuppressive agents (except to treat a drug-related adverse event) 
•
Systemic corticosteroids > 10 mg daily prednisone equivalent (except as stated in Section 3.4.3
below or to treat a drug-related adverse event). 
•
Any live/attenuated vaccine (eg varicella, zoster, yellow fever, rotavirus, oral polio and 
measles, mumps, rubella (MMR)) during treatment and until 100 days post last dose.
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3.4.1.2
Prohibited and/or Restricted Treatments on Cabazitaxel
Treatment with any of the following medications are prohibited during treatment with cabazitaxel 
(Arm D4)
•
Concomitant administration of strong CYP3A inhibitors (eg, ketoconazole, itraconazole, 
clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, 
voriconazole) should be avoided as an increase of plasma concentrations of cabazitaxel may 
occur.
•
Concomitant administration of strong CYP3A inducers (eg, phenytoin, carbamazepine, 
rifampin, rifabutin, rifapentin, phenobarbital) should be avoided as a decrease of plasma 
concentrations of cabazitaxel may occur. In addition, patients should also refrain from taking 
St. John’s Wort.
•
Concomitant administration of transport proteins of the Organic Anion Transport Polypeptides 
OATP1B1: In vitro, cabazitaxel has also been shown to inhibit the transport proteins of the 
Organic Anion Transport Polypeptides OATP1B1. The risk of interaction with OATP1B1 
substrates (eg, statins, valsartan, repaglinide) is possible, notably during the infusion duration 
(1 hour) and up to 20 minutes after the end of the infusion. A time interval of 12 hours is 
recommended before the infusion and at least 3 hours after the end of infusion before 
administering the OATP1B1 substrates.
Additional information can be found in the cabazitaxel prescribing information.
3.4.2
Other Restrictions and Precautions
Palliative (limited-field) radiation therapy and palliative surgical resection are permitted, if the 
case is discussed with the BMS Medical Monitor or Study Director.
If palliative radiation therapy involves more than one site or if surgery of kyphoplasty to any 
neoplastic lesion is performed, the date of initiation of radiation therapy or date of surgery should 
be reported as the date of clinical progression (Section 5.5.3).
Participants requiring palliative local therapy should be evaluated (by CT/MRI and bone scan if 
clinically indicated) for objective evidence of disease progression prior to the initiation of such 
therapy, particularly if the most recent tumor assessment was more than 4 weeks prior to the 
planned start of local therapy. If progression per PCWG2 is identified prior to the initiation of 
palliative local therapy, then participants must either discontinue study treatment or they must meet 
criteria to continue treatment beyond progression (Section 4.5.4) in order to resume study 
treatment after the completion of palliative local therapy
In cases where palliative radiotherapy is required, nivolumab and ipilimumab dosing should be 
withheld for at least 1 week before, during, and 1 week after radiotherapy. Participants should be 
closely monitored for any potential toxicity during and after receiving radiotherapy, and AEs 
should resolved to Grade ≤1 prior to resuming nivolumab.
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3.4.3
Permitted Therapy
Castrate status must be maintained on study; therefore, subjects who have not had an orchiectomy 
must continue on LHRH/GnRH agonist therapy.
Subjects are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted. A brief (≤3 weeks) course of corticosteroids for prophylaxis 
(eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type 
hypersensitivity reaction caused by a contact allergen) is permitted.
Bisphosphonates and RANK-ligand inhibitors for bone metastases are allowed to be initiated while 
on study as per institutional SOC guidelines.
3.4.4
Other Restrictions and Precautions
It is the local imaging facility̓s responsibility to determine, based on subject attributes 
(eg, allergy history, diabetic history and renal status), the appropriate imaging modality and 
contrast regimen for each subject. Imaging contraindications and contrast risks should be 
considered in this assessment. Subjects with renal insufficiency should be assessed as to whether 
or not they should receive contrast and if so, what type and dose of contrast is appropriate.
Specific to MRI, subjects with severe renal insufficiency (ie, estimated glomerular filtration rate 
(eGFR) < 30 mL/min/1.73 m2) are at increased risk of nephrogenic systemic fibrosis. MRI contrast 
should not be given to this subject population. In addition, subjects are excluded from MRI if they 
have tattoos, metallic implants, pacemakers, etc.
The ultimate decision to perform MRI in an individual subject in this study rests with the site 
radiologist, the investigator and the standard set by the local Ethics Committee.
3.5
Discontinuation of Subjects following any Treatment with Study Drug
The assessment for discontinuation of nivolumab should be made separately from the assessment 
made for discontinuation of ipilimumab. Although there is overlap among the discontinuation 
criteria, if discontinuation criteria are met for ipilimumab but not for nivolumab, treatment with 
nivolumab may continue if ipilimumab is discontinued.
If a participant in any of the nivolumab/ipilimumab combination arms meets criteria for 
discontinuation and investigator is unable to determine whether the event is related to both or one 
study drug, the participant should discontinue both nivolumab and ipilimumab and be taken off 
the treatment phase of the study.
If a subject meets the criteria for discontinuation of ipilimumab but not nivolumab, treatment with 
nivolumab may not resume until the AE has fully resolved and the subject has discontinued 
steroids, if they were required for treatment of the AE. The relationship to ipilimumab should be 
well documented in the source documents. Nivolumab should be resumed at 480 mg every 4 weeks 
starting 6 weeks after the last co-administered dose.
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Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
•
Subject’s request to stop study treatment
•
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the subject
•
Termination of the study by Bristol-Myers Squibb (BMS)
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. Note: Under 
specific circumstances and only in countries where local regulations permit, a participant who 
has been imprisoned may be permitted to continue as a participant. Strict conditions apply and 
BMS approval is required.
•
Additional protocol specified reasons for discontinuation (see Sections 4.5.3 and 4.5.4)
•
Subject meets criteria for radiographic progression by PCWG2 or RECIST v1.1 criteria7
All subjects who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Table 5.1-5.The only exception to this requirement is when a subject 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study treatment is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Follow up after discontinuation of study drug
In this study, overall survival is a key endpoint of the study. Post treatment follow-up is of critical 
importance and is essential to preserving subject safety and the integrity of the study. Subjects who 
discontinue study treatment must continue to be followed for collection of outcome and/or survival 
follow-up data as required and in line with Section 3.1 until death or the conclusion of the study.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study treatment will remain in the study and must continue to 
be followed for protocol specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, if possible. The withdrawal of 
consent should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is from further treatment with study treatment only or also from study procedures 
and/or post treatment study follow-up, and entered on the appropriate CRF page. As vital status 
(whether the subject is alive or dead) is being measured, publicly available information should be 
used to determine vital status only as appropriately directed in accordance with local law.
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3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing status. 
This includes follow-up with persons authorized by the subject as noted above. Lost to follow-up 
is defined by the inability to reach the subject after a minimum of three documented phone calls, 
faxes, or emails as well as lack of response by subject to one registered mail letter. All attempts 
should be documented in the subject’s medical records. If it is determined that the subject has died, 
the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study has 
been included in the subject’s informed consent, then the investigator may use a Sponsor-retained 
third-party representative to assist site staff with obtaining subject’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study. The site staff and 
representative will consult publicly available sources, such as public health registries and 
databases, in order to obtain updated contact information. If after all attempts, the subject remains 
lost to follow-up, then the last known alive date as determined by the investigator should be 
reported and documented in the subject’s medical records.
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4
STUDY TREATMENT
Study treatment includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational [Medicinal] Product (Non-IP/Non-
IMP) and can consist of the following:
Table 4-1:
Study Treatment for CA209650
Product Description / 
Class and Dosage Form
Potency
Primary Packaging
(Volume)/ Label Type
Secondary Packaging
(Qty) /Label Type
Packaging/ 
Appearance
Storage Conditions
(per label)
Nivolumab Solution for 
Injectiona
100 mg (10 mg/mL)
or
40 mg (10 mg/mL)
10 mL per vial/Open 
label
Or
4 mL vial/Open label
5 or 10 vials per carton/ 
Open-label
Or
240 mg kits (2-100 mg 
vials & 1-40 mg vial)
Clear to opalescent 
colorless to pale 
yellow liquid. May 
contain particles
2° to 8°C. Protect from 
light and freezing
Ipilimumab
200 mg (5 mg/mL)
40 mL per vial/Open-
label
4 vials per
carton/Open-label
Clear to opalescent 
colorless to pale 
yellow liquid. May 
contain particles
2° to 8°C. Protect from 
light and freezing
Ipilimumabb
50 mg (5 mg/mL)
10 mL per vial/Open 
label
6 vials per carton/Open-
label
Clear to opalescent 
colorless to pale 
yellow liquid. May 
contain particles
2° to 8°C. Protect from 
light and freezing
Prednisonec
5 mg tablets
Wallet/blister 
card/bottle containing 
tablets/open-label
Wallet card or outer 
carton/open-label
Tablets (appearance 
may vary)
Refer to storage conditions 
on container label.
Cabazitaxel concentrate 
and solvent for solution 
for infusionc
60 mg
Vial/Open-label
Vials in a carton/Open-
label
Vial (various 
configurations 
possible)
Refer to storage conditions 
on container label.
a Nivolumab is labeled as BMS-936558-01 Solution for Injection.
b Ipilimumab 50 mg will be available starting Q3 2022 and may be used in this study.
c Cabazitaxel and prednisone may be obtained by the investigational sites in certain countries as local commercial product (which may be available as a different 
potency/package configuration). Prednisone or prednisolone can be used according to local standards.
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Pre-medications or medications used to treat in infusion reactions should be sourced by the investigative sites if available and 
permitted by local regulations. 
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
In this protocol, investigational products are:
•
Nivolumab
•
Ipilimumab
•
Cabazitaxel
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as 
non-investigational products. In this protocol, non-investigational product is:
•
Prednisone
4.3
Storage and Dispensing
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment
should not be dispensed and BMS must be contacted immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
4.3.1
Arms A, B, and C Part 1 Study Treatment Administration - Nivolumab 
and Ipilimumab Combination Phase (Cycles 1-4)
In the nivolumab plus ipilimumab combination portion, nivolumab is to be administered first. 
Subjects should receive nivolumab at a dose of 1 mg/kg as a 30-minute IV infusion, on Day 1 of 
each treatment cycle every 3 weeks for 4 doses (Cycles 1-4). In Part 1, a minimum of 
1 combination cycle of nivolumab and ipilimumab is required. Subjects experiencing AEs related 
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to combination dose therapy (Part 1) that do not meet dose discontinuation criteria, may proceed 
to nivolumab monotherapy dosing (Part 2) without completing all 4 combination doses, after 
consultation with the Medical Monitor, on a case-by-case basis. 
During Part 1, subjects may be dosed no less than 19 days between doses. If dosing is delayed, 
both nivolumab and ipilimumab must be delayed together. If dosing is resumed after a delay, both 
nivolumab and ipilimumab must be resumed on the same day.
The nivolumab infusion must be promptly followed by a flush of diluent to clear the line of 
nivolumab before starting the ipilimumab infusion.
The second infusion in the combination will always be ipilimumab, and will start after the infusion 
line has been flushed, filters changed and the subject has been observed to ensure no infusion 
reaction has occurred. The time in between infusions is expected to be approximately 30 minutes 
but may be more or less depending on the situation. Subjects should receive ipilimumab at a dose 
of 3 mg/kg as a 30-minute IV infusion, on Day 1 of each treatment cycle every 3 weeks for 4 doses 
(Cycles 1-4). 
Dosing calculations for the combination phase should be based on the body weight assessed at 
screening. It is not necessary to re-calculate subsequent doses if the subject weight is within 10% 
of the weight used to calculate the previous dose. All doses should be rounded to the nearest 
milligram. 
The risk/benefit profile for nivolumab has primarily been investigated using a 60-minute infusion 
and for ipilimumab a 90-minute infusion. Long infusion times place a burden on subjects and 
treatment centers. Establishing that these agents can be safely administered using shorter infusion 
times will diminish some of this burden. Previous clinical studies of nivolumab have used a 
60-minute infusion duration, and for ipilimumab 90-minutes. Both nivolumab and ipilimumab 
have been administered safely at doses ranging up to 10 mg/kg over these treatment durations. 
Overall, infusion reactions including high-grade hypersensitivity reactions have been uncommon 
across multiple clinical studies, and all have been managed by following the safety algorithms. 
Infusion duration of 30 minutes for 3 mg/kg nivolumab (30% of the dose provided at 10 mg/kg) is 
not expected to present any safety concerns compared with the prior experience at 10 mg/kg 
nivolumab dose infused over the 60-minute duration. Similarly, a shortened infusion duration of 
30 minutes for ipilimumab is not expected to present additional safety concerns.129
When given as a single agent, there is a low rate of infusion reactions. The incidence is less than 
1% for ipilimumab (Yervoy® FDA Label) and for nivolumab 3%. In the CA209069 study, in 
which nivolumab and ipilimumab were given sequentially, hypersensitivity/infusion reactions 
occurred at 3.2% for the combination and at 2.2% for ipilimumab. No Grade 3 or Grade 4 
hypersensitivity/infusion reactions were observed in either the combination or single agent 
ipilimumab treatment groups.130
Subjects should be carefully monitored for infusion reactions during nivolumab/ipilimumab 
administration. If an acute infusion reaction is noted, subjects should be managed according to 
Section 4.5.7.
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4.3.2
Arms A, B, and C Part 2 Study Treatment Administration - Nivolumab 
Monotherapy Phase (Cycle 5 and beyond)
Starting 6 weeks after the last co-administered dose in Part 1, subjects will be administered a flat 
dose of 480 mg nivolumab on Day 1 of each 4 week treatment cycle given IV given over 
approximately 30 minutes every 4 weeks (Q4W) until unacceptable toxicity or disease progression.
Subjects may be dosed up to 3 days before or after the scheduled date if necessary. Subsequent 
dosing should be based on the actual date of administration of the previous dose of drug. Every 
effort should be made to adhere to the protocol treatment schedule of administration of nivolumab 
every 4 weeks in the monotherapy phase. In extenuating circumstances in which the subject cannot 
make the dosing schedule within the 3-day window, the BMS Medical Monitor should be 
contacted.
Premedications are not recommended for the first dose of nivolumab monotherapy.
Subjects from Cohorts B and C who entered the maintenance period may be permitted re-induction 
with the combination after approval by the BMS medical monitor (see Section 4.3.5).
4.3.3
Arm D1 Study Treatment Administration - Nivolumab and Ipilimumab 
Subjects randomized to Arm D1 should receive nivolumab 3 mg/kg administered IV over 30 
minutes followed by ipilimumab 1 mg/kg administered IV over 30 minutes on Day 1 of each 
treatment cycle every 3 weeks for 4 doses (Cycles 1 to 4), followed by nivolumab 480 mg 
administered IV over 30 minutes on Day 1 of each treatment cycle every 4 weeks (±3 days) until
progression, unacceptable toxicity, withdrawal of consent, completion of 2 years of treatment, or 
the study ends, whichever occurs first. The first flat dose 480 mg nivolumab will be administered
3 weeks after the last combination dose.
Participants should begin study treatment within 3 calendar days of randomization. During the 
combination portion, subjects may be dosed no less than 19 days between doses. If dosing is 
delayed, both nivolumab and ipilimumab must be delayed together. If dosing is resumed after a 
delay, both nivolumab and ipilimumab must be resumed on the same day.
When study treatments (nivolumab and ipilimumab) are to be administered on the same day, 
nivolumab is to be administered first. Nivolumab infusion must be promptly followed by a flush 
of diluent to clear the line of nivolumab before starting the ipilimumab infusion. The second 
infusion will always be the ipilimumab study treatment and will start after the infusion line has 
been flushed, filters changed and patient has been observed to ensure no infusion reaction has 
occurred.  
During the combination phase, a minimum of 1 combination cycle of nivolumab and ipilimumab 
is required. Subjects experiencing AEs related to combination dose therapy that do not meet dose 
discontinuation criteria, may proceed to nivolumab monotherapy dosing without completing all 4 
combination doses, after consultation with the Medical Monitor, on a case-by-case basis. 
Dosing calculations for the combination phase should be based on the body weight assessed at 
baseline. It is not necessary to re-calculate subsequent doses if the participant weight is within 10% 
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of the weight used to calculate the previous dose. All doses should be rounded up or to the nearest 
milligram per institutional standard.
Premedication for Arm D1 is not recommended for the first dose of nivolumab and ipilimumab.
4.3.4
Arm D2 Study Treatment Administration for Nivolumab and Ipilimumab
Subjects randomized to Arm D2 will receive nivolumab at a dose of 1 mg/kg as a 30-minute IV 
infusion, on Day 1 of each treatment cycle every 3 weeks for 8 cycles (on weeks 1, 4, 7, 10, 13, 
16, 19 and 22) and ipilimumab 3 mg/kg administered IV over 30 minutes every 2 cycles (ie, every 
6 weeks on weeks 1, 7, 13 and 19) for 4 ipilimumab doses, followed by nivolumab 480 mg 
administered IV over 30 minutes on Day 1 of each treatment cycle every 4 weeks (± 3 days) 
starting from cycle 9 (week 25). Treatment will be administered until progression, unacceptable 
toxicity, withdrawal of consent, completion of 2 years of treatment, or the study ends, whichever 
occurs first. The first flat dose 480 mg nivolumab will be administered 3 weeks after the last 
nivolumab 1 mg/kg dose (and 6 weeks after the last combination dose).
Participants should begin study treatment within 3 calendar days of randomization. During the 
combination phase, subjects may be dosed with nivolumab no less than 19 days from the previous 
dose of nivolumab and may be dosed with ipilimumab no less than 37 days from the previous dose 
of ipilimumab. 
When study treatments (nivolumab and ipilimumab) are to be administered on the same day, 
nivolumab is to be administered first. Nivolumab infusion must be promptly followed by a flush 
of diluent to clear the line of nivolumab before starting the ipilimumab infusion. The second 
infusion will always be the ipilimumab study treatment and will start after the infusion line has 
been flushed, filters changed and patient has been observed to ensure no infusion reaction has 
occurred.  
During the combination phase, a minimum of 1 combination cycle of nivolumab and ipilimumab 
is required. Subjects experiencing AEs related to combination dose therapy that do not meet dose 
discontinuation criteria, may proceed to nivolumab monotherapy dosing without completing all 
4 doses of ipilimumab, after consultation with the Medical Monitor, on a case-by-case basis. 
Dosing calculations for the combination phase should be based on the body weight assessed at 
baseline. It is not necessary to re-calculate subsequent doses if the participant weight is within 10% 
of the weight used to calculate the previous dose. All doses should be rounded up or to the nearest 
milligram per institutional standard.
Premedication for Arm D2is not recommended for the first dose of nivolumab and ipilimumab.
4.3.5
Re-Induction of Study Therapy For Subjects in Cohorts B, C, Arms D1 
and D2
Subjects in Cohorts B, C and in Arms D1 and D2 who are receiving maintenance nivolumab with 
ongoing disease control (ongoing CR, PR, or SD) or with radiographic progression per RECIST 
v1.1/PCWG2 may be permitted re-induction with the combination of ipilimumab and nivolumab 
at their original combination dose upon PSA progression or radiographic progression per 
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RECIST v1.1/PCWG2 (whichever occurs first; see Section 5.5.3), and after discussion and 
agreement with BMS Medical Monitor. 
For subjects in Arm D1, the first re-induction combination dosing can start no sooner than 4 weeks 
after the last nivolumab 480 mg dose and no sooner than 12 weeks after the last ipilimumab dose.
For subjects in Arm D2, the first re-induction combination dosing can start no sooner than 8 weeks 
after the last nivolumab 480 mg dose and no sooner than 12 weeks after the last ipilimumab dose.
Pausing nivolumab maintenance dosing is permitted in patients who are planning to receive 
re-induction in Arm D2.
Subjects entering this phase will follow the same Time and Events schedule as outlined in Table 
5.1-2 and Table 5.1-4.
Subjects undergoing re-induction of study therapy should continue to meet eligibility criteria at 
the time study treatment resumes and should not have experienced a toxicity that would require 
permanent discontinuation of study therapy. Subjects will continue to receive study therapy at the 
same dose levels as assigned at study start.
Additional, separate, safety and efficacy summaries will be presented for those subjects who 
reinitiated study therapy.
4.3.6
Arm D3 Study Treatment Administration
Participants should receive ipilimumab at a dose of 3 mg/kg administered IV over 30 minutes on 
Day 1 of each treatment cycle every 3 weeks for 4 doses. Treatment will continue until disease 
progression, unacceptable toxicity, withdrawal of consent, completion of 4 cycles of treatment, or 
the study ends, whichever occurs first.
Participants should begin study treatment within 3 calendar days of randomization. Subjects may 
be dosed with ipilimumab no less than 19 days from the previous dose of ipilimumab.
Dosing calculations should be based on the body weight assessed at baseline. It is not necessary to 
re-calculate subsequent doses if the participant weight is within 10% of the weight used to calculate 
the previous dose. All doses should be rounded up or to the nearest milligram per institutional 
standard.
Premedication for Arm D3 is not recommended for the first dose of ipilimumab.
4.3.7
Arm D4 Study treatment administration - cabazitaxel plus prednisone
The recommended dose of cabazitaxel is 20 mg/m2 or 25 mg/m2 at investigator’s discretion and 
according to country-specific label, administered as a 1 hour intravenous infusion every 3 weeks 
in combination with oral prednisone or prednisolone 10 mg administered daily throughout 
treatment. Since cabazitaxel is extensively metabolized by the liver, patients with mild hepatic 
impairment (total bilirubin >1 to ≤1.5 × ULN or AST >1.5 × ULN) must start cabazitaxel at the 
dose of 20 mg/m2.
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Dosing of cabazitaxel will continue for a maximum of 10 cycles every 3 weeks (± 3 days), until 
progression, unacceptable toxicity, withdrawal of consent, or the study ends, whichever occurs 
first. Participants should begin study treatment within 3 calendar days of randomization.
Dosing calculations of cabazitaxel should be based on the body weight assessed at baseline. It is 
not necessary to re-calculate subsequent doses if the participant weight is within 10% of the weight 
used to calculate the previous dose. All doses should be rounded up or to the nearest milligram per 
institutional standard.
Premedication for cabazitaxel
The recommended premedication regimen should be performed at least 30 minutes prior to each 
administration of cabazitaxel with the following intravenous medicinal products to mitigate the 
risk and severity of hypersensitivity:
•
antihistamine (dexchlorpheniramine 5 mg or diphenhydramine 25 mg or equivalent),
•
corticosteroid (dexamethasone 8 mg or equivalent), and
•
H2 antagonist (ranitidine or equivalent)
The above prophylaxis can be adjusted according to local standards in patients who have 
experienced hypersensitivity reactions not requiring discontinuation.
Antiemetic prophylaxis is recommended and can be given orally or intravenously as per local 
guidelines.
4.3.8
Study Treatment Preparation and Infusion
Separate infusion bags and filters should be used when administering nivolumab and ipilimumab 
on the same day.
For details on prepared study treatment storage, preparation, and administration, please refer to the 
current nivolumab and ipilimumab IBs and/or pharmacy manual.
4.4
Method of Assigning Treatment
CA209650 is an open-label study. After the subject’s initial eligibility is established and informed 
consent has been obtained, the subject must be enrolled into the study by accessing an Interactive 
Response Technologies web-based system (IWRS) to obtain the subject number. Every subject 
that signs the informed consent form must be assigned a subject number in IWRS. Specific 
instructions for using IWRS will be provided to the investigational site in a separate document. 
All participants in Cohort D will be centrally randomized using IWRS. Before the study is initiated, 
each user will receive log in information and directions on how to access the IWRS. The following 
information is required for enrollment:
•
Date that informed consent was obtained
•
Date of birth
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Once enrolled in IWRS, enrolled subjects that have met all eligibility criteria will be ready to be 
assigned treatment through the IWRS. The following information is required for subject first 
treatment:
•
Subject number
•
Date of birth
•
Presence or absence of measureable disease as per RECIST v1.1 at screening
The exact procedures for using the IWRS will be detailed in the IWRS manual.
4.5
Selection and Timing of Dose for Each Subject
The dosing regimen and schedule for Cohorts A, B, and C are detailed in Table 4.5-1 and Table 
4.5-2, respectively. The dosing regimen and schedule for Cohort D is shown in Table 4.5-3.
Table 4.5-1:
Cohorts A, B, and C Dosing Schedule for Part 1 (Cycles 1 through 
4)a
Every 3 weeks dosing
1 cycle = 3 weeks
Cycle 1
Cycle 2
Cycle 3
Cycle 4
All Subjects
Nivolumab 1 mg/kg
Ipilimumab 3 mg/kg
Nivolumab 1 mg/kg
Ipilimumab 3 mg/kg
Nivolumab 1 mg/kg
Ipilimumab 3 mg/kg
Nivolumab 1 mg/kg
Ipilimumab 3 mg/kg
a Minimum of 1 cycle, maximum of 4 combination cycles
The first flat dose 480 mg nivolumab in Part 2 will be administered 6 weeks after the last 
combination dose in Part 1.
Table 4.5-2:
Cohorts A, B, and C Dosing Schedule for Part 2 (Cycles 5 through 
PD)
Every 4 weeks dosing
1 cycle = 4 weeks, Cycle 5 to begin 6 weeks after Cycle 4
Cycle 5 and beyonda
All Subjects
Flat dose 480 mg nivolumab 
a Cycle 6, 7, 8, 9, etc. until disease progression or unacceptable toxicity. In some instances, Part 2 may start after 
Cycle 1, 2 or 3 of Part 1.
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Table 4.5-3:
Cohort D Dosing Schedule
Induction
Maintenance
Arm D1
Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg 
Q3W up to 4 cycles, 
Nivolumab 480 mg Q4W 
Arm D2
Nivolumab 1 mg/kg Q3W (up to 8 doses)+ 
Ipilimumab 3 mg/kg Q6W (up to 4 doses) 
Nivolumab 480 mg Q4W
Arm D3
Ipilimumab 3 mg/kg Q3W up to 4 cycles
Not applicable
Arm D4
Cabazitaxel 20 mg/m2 or 25mg/m2 (at investigator’s discretion and according to country-specific 
label) Q3W + Prednisone 10 mg PO D1-D21* for up to 10 cycles
* Starting dose of cabazitaxel is 20 mg/m2 in patients with mild hepatic impairment (total bilirubin >1 to ≤1.5 × ULN 
or AST >1.5 × ULN) 
There will be no dose escalations of study treatment allowed. Dose reductions are only allowed 
for cabazitaxel.
Doses may be interrupted, delayed, or discontinued depending on how well the subject tolerates 
the treatment. Dosing visits are not skipped, only delayed. The maximum duration of treatment of 
2 years includes any dose interruptions or delays in Cohort D. It is strongly recommended that 
subjects in Cohorts A, B, and C limit treatment duration with immunotherapy treatment for up to 
2 years. For subjects in these cohorts who receive immunotherapy treatment beyond 2 years, 
treatment will be given for a maximum of 5 years from the start of study treatment.
When subjects are treated Q3W, subjects may be dosed no less than 19 days between doses. 
If dosing is delayed, both nivolumab and ipilimumab must be delayed together. If dosing is 
resumed after a delay, both nivolumab and ipilimumab must be resumed on the same day.
During nivolumab monotherapy, subjects may be dosed within a ± 3 day window. 
Subjects experiencing AEs related to combination dose therapy that do not meet dose 
discontinuation criteria, may proceed to nivolumab monotherapy dosing without completing all 4 
combination doses, after consultation with BMS Medical Monitor, on a case-by-case basis 
(Section 4.5.3).
4.5.1
Dose Delay Criteria for Nivolumab and Ipilimumab
Regardless of whether or not the event is attributed to nivolumab or ipilimumab, both study 
treatments must be delayed until treatment can resume. Tumor assessments for all subjects should 
continue as per protocol even if dosing is delayed. During Part 1, both nivolumab and ipilimumab 
should be delayed at the same time.
Nivolumab and ipilimumab administration should be delayed for the following:
•
Any Grade ≥2 non-skin, drug-related adverse event, with the following exception:
−
Grade 2 drug-related fatigue does not require a treatment delay
•
Grade 2 drug-related creatinine, AST, ALT or Total Bilirubin abnormalities 
•
Any Grade 3 skin, drug-related adverse event
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nivolumab 
•
Any Grade 3 drug-related laboratory abnormality (excluding AST, ALT or Total Bilirubin), 
with the following exceptions:
−
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay
−
Grade ≥3 AST, ALT, Total Bilirubin will require dose discontinuation
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication
•
SARS-CoV-2 infection either confirmed or suspected
Subjects who require delay of study treatment should be re-evaluated weekly or more frequently 
if clinically indicated and resume dosing when re-treatment criteria are met.
4.5.2
Criteria to Resume Treatment for Nivolumab and Ipilimumab
Subjects may resume treatment with study treatment when the drug-related AE(s) resolve to 
Grade ≤1 or baseline value, with the following exceptions:
•
Subjects may resume treatment in the presence of Grade 2 fatigue
•
Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity
•
For subjects with Grade 2 AST, ALT, or TBILI elevations, dosing may resume when 
laboratory values return to baseline and management with corticosteroids, if needed, is 
complete
•
Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 4.5.3) should have treatment permanently discontinued
•
Drug-related pulmonary toxicity, diarrhea or colitis must have resolved to baseline before 
treatment is resumed. Subjects with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by BMS Medical Monitor
Subjects with drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment after consultation with the BMS Medical Monitor. Adrenal 
insufficiency requires discontinuation regardless of control with hormone replacement.
4.5.3
Dose Discontinuation for Nivolumab and Ipilimumab
Study treatment (nivolumab or ipilimumab) should be permanently discontinued for the following:
•
Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment 
•
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, or recurs with the following 
exceptions for laboratory abnormalities, diarrhea, colitis, neurologic toxicity, drug-related 
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uveitis, pneumonitis, bronchospasm, hypersensitivity reactions, infusion reactions, and 
endocrinopathies:
−
Grade 3 drug-related diarrhea, colitis, neurologic toxicity, uveitis, pneumonitis, 
bronchospasm, myocarditis, hypersensitivity reactions, or infusion reaction of any duration 
requires discontinuation
−
Grade 3 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement.
−
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
♦Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
♦Any drug-related liver function test (LFT) abnormality that meets the following criteria
requires discontinuation:
o
Grade ≥3 drug-related AST, ALT or Total Bilirubin requires discontinuation*
o
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN
*In most cases of Grade 3 AST or ALT elevation, study treatment(s) will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that warrants 
continuation of study treatment(s), a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
•
Any Grade 4 drug-related adverse event or laboratory abnormality (including but not limited 
to creatinine, AST, ALT, or Total Bilirubin), except for the following events which do not 
require discontinuation:
−
Grade 4 neutropenia ≤7 days
−
Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase
−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset
−
Grade 4 drug-related endocrinopathy adverse events, such as hyper- or hypothyroidism, or 
glucose intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor. Grade 4 drug-related adrenal insufficiency or hypophysitis requires 
discontinuation regardless of control with hormone replacement.
•
Any event that leads to delay in dosing lasting > 8 weeks from the previous dose for Q3W 
dosing cycles , and >10 weeks for Q4W dosing cycles requires discontinuation, with the 
following exceptions:
−
Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events 
are allowed. Prior to re-initiating treatment in a subject with a dosing delay lasting 
> 8 weeks from the previous dose for Q3W dosing cycles and >10 weeks for Q4W dosing 
cycles , the BMS Medical Monitor must be consulted.
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−
Subjects experiencing AEs related to combination dose therapy that do not meet dose 
discontinuation criteria, may proceed to nivolumab monotherapy dosing without 
completing all 4 combination doses, after consultation with BMS Medical Monitor, on a 
case-by-case basis. 
−
Tumor assessments should continue as per protocol even if dosing is delayed. Periodic 
study visits to assess safety and laboratory studies should also continue every 6 weeks or 
more frequently if clinically indicated during such dosing delays.
−
Dosing delays lasting > 8 weeks from the previous dose for Q3W dosing cycles and 
>10 weeks for Q4W dosing cycles that occur for nondrug-related reasons may be allowed 
if approved by the BMS Medical Monitor. Prior to reinitiating treatment in a subject with 
a dosing delay lasting > 8 weeks for Q3W dosing cycles and >10 weeks for Q4W dosing 
cycles, the BMS Medical Monitor must be consulted. 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the subject with continued nivolumab dosing.
4.5.4
Treatment Beyond Disease Progression
Accumulating evidence indicates that some subjects treated with immunotherapy may derive 
clinical benefit despite initial evidence of PD. 
Subjects treated with immunotherapy study treatment(s) will be permitted to continue treatment 
beyond initial radiographic progression defined by RECIST v1.1 (for soft tissue lesions) and 
PCWG2 (for bone lesions) as described in Section 5.5.3. Subjects in Arm D4 may not receive 
treatment beyond progression. Subjects who meet PD criteria as assessed by the investigator may 
continue with study therapy as long as they meet the following criteria (following consultation 
with BMS Medical Monitor):
•
Investigator-assessed clinical benefit
•
Tolerance of study treatment
•
Stable performance status
•
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)
•
Subject provides written informed consent prior to receiving additional nivolumab and 
ipilimumab combination or nivolumab monotherapy treatment. All other elements of the main 
consent including description of reasonably foreseeable risks or discomforts, or other 
alternative treatment options will still apply.
Radiographic assessment/ scan(s) should continue in accordance with the Section 5 Schedule of 
Activities for the duration of the treatment beyond progression and should be submitted to the 
central imaging vendor. The assessment of clinical benefit should be balanced by clinical judgment 
as to whether the subject is clinically deteriorating and unlikely to receive any benefit from 
continued treatment with nivolumab.
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If the investigator feels that the subject continues to achieve clinical benefit by continuing 
treatment, the subject should remain on the trial and continue to receive monitoring according to 
the Time and Events Schedule (Section 5).
For the subjects who continue study therapy beyond progression, further progression is defined as 
follows:
Further disease progression of soft tissue is defined as an additional 10% increase in tumor burden 
with a minimum 5 mm absolute increase from time of initial PD. This includes an increase in the 
sum of diameters of all target lesions and/ or the diameters of new measurable lesions compared 
to the time of initial PD. 
New lesions are considered measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). Any new lesion considered non-measureable at the time of initial progression may 
become measureable and therefore included in the tumor burden if the longest diameter increases 
to at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). In situations where the relative increase in total tumor burden by 10% is solely due to 
inclusion of new lesions which become measurable, these new lesions must demonstrate an 
absolute increase of at least 5 mm.
Further bone disease progression is defined as additional two or more new bone lesions noted on 
bone scans compared to the time of PCWG2-defined progression of bone disease.
Nivolumab-plus-ipilimumab or nivolumab treatment should be discontinued permanently upon 
documentation of further progression.
Confirmed PSA progression alone is not an indication to stop treatment.
4.5.5
Dose Delay, Modification, and Discontinuation for Cabazitaxel
Regardless of whether or not the event is attributed to cabazitaxel, study treatment must be delayed 
until treatment can resume. Tumor assessments for all subjects should continue as per protocol 
even if dosing is delayed. 
Cabazitaxel administration should be delayed for the following:
•
SARS-CoV-2 infection either confirmed or suspected
The cabazitaxel dose will be modified in case of toxicity. Dose modifications are summarized in 
Table 4.5.5-1.
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Table 4.5.5-1:
Dose Modification* and Dose Delay for Cabazitaxel
Toxicity
Grade 2
Grade 3
Grade 4
Neutropenia
If not recovered on D21, 
delay** next infusion until 
recovery to grade ≤1 
(neutrophil ≥1.5 x 109/L).
•
1st 
episode: 
No 
dose 
reduction required.
•
2nd episode; reduce by 
1dose level
No dose reduction if isolated and duration ≤7 days.
If duration more than 7 days or not recovered on D21
Delay** next infusion until ANC ≥1.5 x 109/L and:
•
1st episode: Administer prophylactic G-CSF 
treatment in subsequent cycles.
•
2nd episode or 1st episode despite prophylactic G-
CSF: Reduce dose by 1 dose level.
•
3rd episode or 2nd episode despite prophylactic G-
CSF: Withdraw from study treatment
Febrile neutropenia 
or
neutropenic 
infection 
Not applicable
Delay** next infusion until recovery and ANC ≥1.5 x 
109/L and:
•
1st episode: reduce the dose and administer 
prophylactic G-CSF treatment in subsequent cycles.
•
2nd episode: Withdraw from study treatment
Thrombocytopenia
Delay** next infusion until 
recovery to grade ≤1 (platelets 
≥75 x 109/L).
No dose reduction required.
Delay** infusion until platelets ≥75 x 109/L:
If grade 3 without delay, no dose reduction required.
If grade 4 , or grade 3 with delay
•
1st episode: reduce dose by 1 dose level.
•
2nd episode: reduce dose by 1 more dose level.
•
3rd episode: Withdraw from study treatment in case 
of recurrence
Diarrhea
Delay** next infusion until 
recovery (grade ≤1)
No dose reduction required.
•
1st episode: Reduce dose by 1 dose level. 
•
2nd episode: Reduce dose by 1 more dose level. 
•
3rd episode: Withdraw from study treatment.
Stomatitis
Delay** next infusion until 
recovery (grade ≤1)
No dose reduction required.
•
1st episode: Reduce dose by 1 dose level. 
•
2nd episode: Reduce dose by 1 more dose level. 
•
3rd episode: Withdraw from study treatment.
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Table 4.5.5-1:
Dose Modification* and Dose Delay for Cabazitaxel
Toxicity
Grade 2
Grade 3
Grade 4
Cutaneous 
Reactions
Delay** next infusion until 
recovery (grade ≤1)
No dose reduction required.
Grade 3
Delay** next infusion 
until recovery (grade ≤1):
•
1st episode: Reduce 
dose by 1 dose level.
•
2nd 
episode: 
Withdraw from study 
treatment.
Grade 4
Withdraw from study 
treatment.
Creatinine increase/ 
Creatinine clearance 
decrease
No delay, in case of creatinine > 1 x ULN calculate creatinine clearance on D21:
•
if ≥60 ml/min, no dose modification
•
if clearance ≥40 ml/min and < 60 ml/min, reduce dose by one dose level
•
if clearance <40 ml/min, Withdraw from study treatment.
Neurological 
toxicity***
No delay
Reduce dose by 1 dose level
Stop study treatment.
Bilirubin Elevation 
Delay** until recovery to 
bilirubin ≤1.0 x UNL and 
reduce dose by 1 dose level
Withdraw from study treatment
Transaminases 
Elevation
Delay** until recovery to 
AST/ALT ≤1.5 x UNL and 
reduce dose by 1 dose level
Withdraw from study treatment
Hypersensitivity 
No dose reduction. Follow local 
guidelines for management of 
hypersensitivity due to study 
treatment.
Withdraw from study treatment 
in case of 2nd grade 3 episode.
Withdraw from study treatment
*Dose reduction levels provided in Section 4.5.5.2
**maximum of 2 weeks delay, otherwise the patient will be withdrawn from study treatment, unless otherwise agreed 
between the investigator and the Sponsor on a case-by-case basis
***Including hearing disorders
§Delay infusion by maximum of 2 weeks until recovery to grade ≤1 and apply dose reduction according to worst 
grade observed
4.5.5.1
Other Toxicities for Cabazitaxel
For ≥Grade 3 drug-related AEs except fatigue, local reaction, fluid retention, anemia and other 
toxicities that in the opinion of the investigator are not clinically significant, chemotherapy should 
be held for a maximum of two weeks from the planned date of reinfusion until resolution to 
≤Grade 1, then reinstituted, if medically appropriate. In case of treatment delay greater than 
2 weeks, patient should discontinue study treatment, unless there is strong evidence of clinical 
benefit to justify continuation of dosing with study treatment, and the investigator must discuss 
the rationale with the Sponsor before a decision is taken. A dose reduction of subsequent doses 
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will be left to the investigator’s judgment. These patients will be withdrawn from study treatment 
if >2 dose reductions are needed.
4.5.5.2
Dose Reduction for cabazitaxel
Cabazitaxel dose can be reduced when necessary as described in following sections. The dose, 
which has been reduced for toxicity, must not be re-escalated. Up to a maximum of 2 dose 
reductions will be allowed per patient. If a third dose reduction is required per the modifications 
below, the patient should discontinue study treatment.
Table 4.5.5.2-1:
Dose reduction levels for cabazitaxel
Dose reduction levels for cabazitaxel
Starting dose (mg/m²)
1st Dose Reduction
2nd Dose Reduction
Cabazitaxel
20
15
12
Cabazitaxel
25
20
15
Note: Starting dose is 20 mg/m2 or 25 mg/m2 at investigator’s discretion and according to country-specific label;
participants with hepatic impairment must start cabazitaxel at the dose of 20 mg/m2).
4.5.5.3
Special Precautions for Cabazitaxel
1) Risk of neutropenia: Neutropenia is the most common adverse reaction of cabazitaxel. 
Monitoring of complete blood counts is essential on a weekly basis during cycle 1 and before 
each treatment cycle thereafter so that the dose can be adjusted, if needed. Patients treated with 
cabazitaxel may receive prophylactic G-CSF as per current institutional guidelines, to reduce 
the risk or manage neutropenia complications.
2) Primary prophylaxis with G-CSF should be considered in patients with high-risk clinical 
features (age >65 years, poor performance status, previous episodes of febrile neutropenia, 
extensive prior radiation ports, poor nutritional status, or other serious comorbidities) that 
predispose them to increased complications from prolonged neutropenia.
3) Gastrointestinal disorders: Symptoms such as abdominal pain and tenderness, fever, persistent 
constipation, diarrhea, with or without neutropenia, may be early manifestations of serious 
gastrointestinal toxicity and should be evaluated and treated promptly. 
4) Nausea, vomiting and severe diarrhea, at times, may occur. Deaths related to diarrhea and 
electrolyte imbalance occurred in the randomized clinical trials. Intensive measures may be 
required for severe diarrhea and electrolyte imbalance. Antiemetic prophylaxis is 
recommended. Treat patients with rehydration, antidiarrheal or antiemetic medications as 
needed.
4.5.5.4
Prednisone Dose Modifications and Dose Delays 
Prednisone or prednisolone doses should not be delayed or modified or stopped (unless there is a 
contraindication to continue, the decision will be left to the investigator’s discretion). If prednisone 
or prednisolone is stopped, the patient will continue cabazitaxel treatment in the absence of major 
toxicity, disease progression, or any other discontinuation criteria as defined in Section 4.5.5.
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4.5.5.5
Criteria to Resume Study Treatment following SARS-CoV-2 Infection
Participants with SARS-CoV-2 infection (either confirmed or suspected) may resume treatment 
after all of the following:
1) at least 10 days (20 days for severe/critical illness) have passed since symptoms first appeared 
or positive test result (eg, RT-PCR or viral antigen)
2) resolution of acute symptoms (including at least 24 hours has passed since last fever without 
fever reducing medications)
3) evaluation by the investigator with confirmation that there are no sequelae that would place 
the participant at a higher risk of receiving investigational treatment 
4) consultation by the Medical Monitor. For suspected cases, treatment may also resume if SARS-
CoV-2 infection is ruled-out and other criteria to resume treatment are met.
4.5.6
Management Algorithms for Immuno-Oncology Agents
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab and ipilimumab are considered immuno-
oncology agents in this protocol. Early recognition and management of AEs associated with 
immuno-oncology agents may mitigate severe toxicity. Management Algorithms have been 
developed to assist investigators in assessing and managing the following groups of AEs:
•
Gastrointestinal
•
Renal
•
Pulmonary
•
Hepatic
•
Endocrinopathy
•
Skin
•
Neurological
•
Myocarditis
The above algorithms are found in the Appendix 1 of this protocol.
4.5.7
Treatment of Related Infusion Reactions
4.5.7.1
Nivolumab and Ipilimumab Treatment of Related Infusion Reactions
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, they are 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypotension, hypertension, bronchospasm, or other allergic-like reactions. All 
Grade 3 or 4 infusion reactions should be reported within 24 hours to the study medical monitor 
and reported as an SAE if it meets the criteria. Infusion reactions should be graded according to 
NCI CTCAE (Version 4.0) guidelines.
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Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention not 
indicated):
•
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab and/or ipilimumab administrations.
For Grade 2 symptoms: (moderate reaction required therapy or infusion interruption but responds 
promptly to symptomatic treatment (eg, antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids); prophylactic medications indicated for 
≤24 hours):
•
Stop the study treatment infusion, begin an IV infusion of normal saline, and treat the subject 
with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg; remain at bedside and monitor subject until resolution of symptoms. Corticosteroid 
and/or bronchodilator therapy may also be administered as appropriate. If the infusion is 
interrupted, then restart the infusion at 50% of the original infusion rate when symptoms 
resolve; if no further complications ensue after 30 minutes, the rate may be increased to 100% 
of the original infusion rate. Monitor subject closely. If symptoms recur, then no further study
treatment will be administered at that visit
•
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before nivolumab and/or ipilimumab infusions. If 
necessary, corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae (eg, renal impairment, 
pulmonary infiltrates). Grade 4: Life-threatening; pressor or ventilatory support indicated):
•
Immediately discontinue infusion of study treatment. Begin an IV infusion of normal saline 
and treat the subject as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored until 
the Investigator is comfortable that the symptoms will not recur. Study treatment will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor subject until recovery of the 
symptoms
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In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
4.5.7.2
Hypersensitivity Reactions for Cabazitaxel
All patients should be pre-medicated prior to the initiation of the infusion of cabazitaxel (see 
Section 4.5.5).
Patients should be observed closely for hypersensitivity reactions especially during the first and 
second infusions. Hypersensitivity reactions may occur within a few minutes following the 
initiation of the infusion of cabazitaxel, thus facilities and equipment for the treatment of 
hypotension and bronchospasm should be available. Severe reactions can occur and may include 
generalized rash/erythema, hypotension and bronchospasm. Severe hypersensitivity reactions 
require immediate discontinuation of cabazitaxel and appropriate therapy.
4.6
Blinding/Unblinding
This is an Open-label study, blinding procedures are not applicable.
4.7
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and electronic case report form (eCRF).
4.8
Return of Study Treatment
For this study, IP (those supplied by BMS, a vendor or sourced by the investigator) such as partially 
used study treatment containers, vials and syringes may be destroyed on site. 
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:
•
On-site disposal practices must not expose humans to risks from the drug
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances
•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
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If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of IP provided by BMS (or its vendors).
4.9
Retained Samples for Bioavailability/Bioequivalence
At the time of receipt of the investigational product by the investigator or designee’s, BMS will 
specify the appropriate number of containers or units to select for retention, the conditions of 
sample storage, required duration of sample retention, and provisions for returning or disposing of 
the investigational product. When samples are selected, containers or units should be placed in 
packaging with a tamper evident seal provided by BMS. Package labeling should clearly identify 
the contents as bioavailability/bioequivalence (BA/BE) samples and state that the investigational 
product should be stored in the restricted area with limited access.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline (CA209650) for All Treatment Arms (Cohorts A, B, C, and D)
Procedure
Screening Visit
Notes
Eligibility Assessments
Informed Consent
X
Prior to any screening procedures. Contact IWRS to obtain study subject number. Study allows for 
re-enrollment of a subject that has discontinued the study as a pre-treatment failure. If re-enrolled, 
the subject must be re-consented and assigned a new subject number from IWRS.
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening and confirmed prior to first 
treatment. See Section 3.3.
BPI-SF
X
Within 14 days prior to first dose. To be completed for all participants and must be performed to 
establish eligibility in Cohort B participants. (See Section 3.3.1)
FACT-P (Cohort D only)
X
Within 14 days prior to first dose.
EQ-5D-3L
X
Within 14 days prior to first dose.
Medical History
X
Includes clinical stage and Gleason score at diagnosis 
Prior Cancer Therapy
X
Details and dates of prior therapy including all hormonal therapies.
ECOG Performance Score
X
Within 14 days prior to first dose. See Appendix 2 for ECOG Performance Status scale
Safety Assessments
Physical Examination
X
Within 14 days prior to first dose
Vital Signs
X
Including BP, HR, and temperature. Obtain vital signs at screening visit and within 72 hours prior 
to first dose.
Physical Measurements 
X
Height and Weight 
Assessment of Signs and Symptoms
X
Within 14 days prior to first dose
ECG
X
Within 14 days prior to first dose
Adverse Events Assessment
X
All SAEs, including SAEs associated with SARS-CoV-2 infection collected from time of consent. 
Non-serious AEs associated with SARS-CoV-2 infection, collected from time of consent.
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Table 5.1-1:
Screening Procedural Outline (CA209650) for All Treatment Arms (Cohorts A, B, C, and D)
Procedure
Screening Visit
Notes
Concomitant Medication Collection
X
Within 14 days prior to first dose
Laboratory Tests
X
On site/local complete blood count (CBC) w/differential, Chemistry panel including: LDH, AST, 
ALT, ALP, T-Bili, blood urea nitrogen (BUN) or serum urea level, creatinine, phosphate, Ca, Na, 
K, Cl, glucose, albumin, amylase, lipase, PTT, PT, and INR within 14 days prior to randomization 
(Cohort D) and first dose for other Cohorts.
Endocrine panel (TSH, Free T4, Free T3), Hep B/C (HBV HBsAG, HCV antibody or HCV RNA), 
within 28 days prior to randomization (Cohort D) and first dose for other Cohorts.
PSA
X
To be performed by local lab up to 6 weeks prior to randomization (Cohort D) and first dose for 
other Cohorts.
Testosterone 
X
To be performed by local lab up to 6 weeks prior to randomization (Cohort D) and first dose for 
other Cohorts. 
Efficacy Assessment
Screening/Baseline Tumor 
Assessment
X
Contrast enhanced CT of the Chest, CT/MRI scan of the abdomen, pelvis, and any clinically 
indicated sites, and radionuclide bone scan within 28 days prior to first dose.
MRI of the brain without and with contrast is required for participants with known or suspected 
brain metastases, unless participant has completed an imaging study of the brain within 30 days of 
study treatment administration.
CT of the brain without and with contrast can be performed if MRI is contraindicated.
For the assessment of bone lesions, a Technecium99m (Tech99m) bone scan is the preferred 
imaging modality. If Tech99m is unavailable, a full body CT/MRI should be performed as 
described in Section 5.5.2
Images will be collected and held centrally for potential future independent review. See Section 
5.5.
Protocol Amendment No.: 05
Date:01-Dec-2021
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6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab 
Table 5.1-1:
Screening Procedural Outline (CA209650) for All Treatment Arms (Cohorts A, B, C, and D)
Procedure
Screening Visit
Notes
IWRS
IWRS call or website entry
X
Website entry must be made to IWRS for subject number assignment at the time informed consent 
is obtained.
Cohort Assignment
X
Website entry to IWRS prior to first dose for cohort assignment. 
IWRS Drug Vial Assignment
X
Within 3 working days from vial assignment, the subject must receive the dose of study 
medication.
Protocol Amendment No.: 05
Date:01-Dec-2021
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6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab 
Table 5.1-2:
On Treatment Part 1: Sequential Treatment with Nivolumab and Ipilimumab Procedural Outline 
(CA209650) - Cohorts A, B, and C
Procedure
For Part 1, Study Treatment
Every 3 Weeks for Cycles 1-4 
(Cohorts A, B and C)
Notes
Cycle 1, 2, 3, 4
(Day 1)
Safety Assessments
Targeted Physical Examination
X
To be performed only as clinically indicated within 72 hours prior to dosing
Vital Signs
X
Including BP, HR, and Temperature
Physical Measurements 
X
Weight within 72 hours prior to dosing
Adverse Event Assessment
Continuously
Assessed using NCI CTCAE v. 4. All AEs, including those associated with 
SARS-CoV-2 infection, must be collected continuously during the treatment 
period.
SAE Assessment
Continuously
Assessed using NCI CTCAE v. 4. All SAEs, including those associated with 
SARS-CoV-2 infection, must be collected continuously during the treatment 
period. 
Review of Concomitant Medication
X
Laboratory Tests
X 
Within 72 hours prior to each dose.
All safety labs to be performed also at the conclusion of Part 1 (~week 12).
On site/local CBC w/differential, ALT, AST, ALP T-Bili, BUN or serum urea 
level, creatinine, calcium, phosphate, Na, K, Cl, LDH, glucose, albumin, 
amylase, lipase; PTT, PT, and INR
Thyroid function testing (TSH with reflexive fT3 and fT4) is to be done every 
3 weeks (following each sequential combination dose infusion) for on-
treatment Part 1 phase (ie, during the period of same day sequential dosing 
with nivolumab 1 mg/kg followed by ipilimumab 3 mg/kg), then every 
8 weeks for subjects receiving nivolumab at 480 mg q4w
Note: Safety Laboratory tests do not need to be repeated on C1D1 if 
screening labs were performed within 14 days prior to first dose.
Protocol Amendment No.: 05
Date:01-Dec-2021
101
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Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab 
Table 5.1-2:
On Treatment Part 1: Sequential Treatment with Nivolumab and Ipilimumab Procedural Outline 
(CA209650) - Cohorts A, B, and C
Procedure
For Part 1, Study Treatment
Every 3 Weeks for Cycles 1-4 
(Cohorts A, B and C)
Notes
Cycle 1, 2, 3, 4
(Day 1)
ECOG Performance Status
X
Refer to Appendix 2
PSA
X
Performed locally D1 (prior to treatment) and every 6 weeks (± 3 calendar 
days) thereafter. Can be performed at conclusion of Part 1~ week 12. 
Efficacy Assessment
Body Imaging
X
Contrast enhanced CT of the chest, CT/MRI of the abdomen, pelvis, and all 
other known and/or suspected sites of disease should occur every 8 weeks 
(±7 days) from first dose regardless of treatment schedule for first 6 months. 
Protocol Amendment No.: 05
Date:01-Dec-2021
102
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Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab 
Table 5.1-2:
On Treatment Part 1: Sequential Treatment with Nivolumab and Ipilimumab Procedural Outline 
(CA209650) - Cohorts A, B, and C
Procedure
For Part 1, Study Treatment
Every 3 Weeks for Cycles 1-4 
(Cohorts A, B and C)
Notes
Cycle 1, 2, 3, 4
(Day 1)
After that, it will switch to every 12 weeks (±7 days) regardless of treatment 
schedule until disease progression is documented or treatment is discontinued 
(whichever occurs later). See Section 5.5.3.
Use same imaging method as was used at screening/baseline. 
Images will be collected and held centrally for retrospective independent 
review. See Section 5.5.
Brain Imaging
X
Participants with a history of brain metastasis or symptoms should have a 
surveillance MRI study per standard of care (approximately every 12 weeks), 
or sooner if clinically indicated. CT of the brain without and with contrast 
can be performed if MRI is contraindicated.
Tc99m based radionuclide bone scan
X
Every 8 weeks (±7 days) from first dose regardless of treatment schedule for 
first 6 months. After that, it will switch to every 12 weeks (±7 days) 
regardless of treatment schedule until disease progression is documented (and 
confirmed if needed) or treatment is discontinued (whichever occurs later). 
Evidence of progressive disease as per PCWG2. See Section 5.5.3. 
Use same imaging method as was used at screening baseline or as described 
in Section 5.5.2.
Images will be collected and held centrally for retrospective independent 
review. (See Section 5.5).
Outcomes Research Assessments
BPI-SF
X
Subject must be informed of treatment assignment prior to first post-
randomization assessment. Each assessment should be completed at the start 
of the clinic visit prior to dosing and other study assessments.
EQ-5D-3L
X
Protocol Amendment No.: 05
Date:01-Dec-2021
103
6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab 
Table 5.1-2:
On Treatment Part 1: Sequential Treatment with Nivolumab and Ipilimumab Procedural Outline 
(CA209650) - Cohorts A, B, and C
Procedure
For Part 1, Study Treatment
Every 3 Weeks for Cycles 1-4 
(Cohorts A, B and C)
Notes
Cycle 1, 2, 3, 4
(Day 1)
Clinical Drug Supplies
IWRS Drug Vial Assignment
X
Within 72 hours prior to dosing
Administer Study Treatment
X
A minimum of one combination cycle is required.
Protocol Amendment No.: 05
Date:01-Dec-2021
104
6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab 
Table 5.1-3:
On Treatment Part 2: Nivolumab Monotherapy Phase Procedural Outline for Cohorts A, B, and C
(CA209650)
Procedure
For Part 2, Study Treatment
is
Administered Every 4 Weeks
(Cohorts A, B and C)
Notes
Cycle 5 will begin 6 weeks after Cycle 4 starts
Cycle 5 and beyond
(Day 1)
Safety Assessments
Targeted Physical Examination
X
To be performed only as clinically indicated within 72 hours prior to dosing
Vital Signs
X
Including BP, HR, and Temperature
Adverse Event Assessment
Continuously
Assessed using NCI CTCAE v. 4. All SAEs, including those associated with 
SARS-CoV-2 infection, must be collected continuously during the treatment 
period.
SAE Assessment
Continuously
Assessed using NCI CTCAE v. 4. All SAEs, including those associated with 
SARS-CoV-2 infection, must be collected continuously during the treatment 
period.
Review of Concomitant Medication
X
Laboratory Tests
X
On site/local complete blood count (CBC) w/differential, Chemistry panel 
including: LDH, AST, ALT, ALP, T-Bili, blood urea nitrogen (BUN) or serum 
urea level, creatinine, calcium, phosphate, Na, K, Cl, glucose, albumin, amylase 
lipase; PTT, PT, and INR.
Thyroid function testing (TSH with reflexive fT3 and fT4) is to be performed 
every 8 weeks (start at Cycle 5, ~week 16) for subjects receiving nivolumab 
maintenance therapy.
Physical measurements (including 
ECOG Performance Status)
X
Weight and ECOG Performance status within 72 hours prior to dosing
Protocol Amendment No.: 05
Date:01-Dec-2021
105
6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab 
Table 5.1-3:
On Treatment Part 2: Nivolumab Monotherapy Phase Procedural Outline for Cohorts A, B, and C
(CA209650)
Procedure
For Part 2, Study Treatment
is
Administered Every 4 Weeks
(Cohorts A, B and C)
Notes
Cycle 5 will begin 6 weeks after Cycle 4 starts
Cycle 5 and beyond
(Day 1)
PSA
X
Performed locally at start of Cycle 6 (~week 20) and then every 8 weeks 
(± 3 calendar days) thereafter until radiographic progression or the start of 
subsequent systemic cancer therapy, whichever occurs later. PSA evaluation 
beyond radiographic progression or the start of subsequent systemic cancer 
therapy to confirm PSA response or PSA progression should be performed as 
needed.
Testosterone
X
Performed locally at start of Cycle 7 (~week 24), followed by Cycle 10 
(~week 36) and then every 12 weeks thereafter to correspond with nivolumab
monotherapy dosing.
Protocol Amendment No.: 05
Date:01-Dec-2021
106
6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab 
Table 5.1-3:
On Treatment Part 2: Nivolumab Monotherapy Phase Procedural Outline for Cohorts A, B, and C
(CA209650)
Procedure
For Part 2, Study Treatment
is
Administered Every 4 Weeks
(Cohorts A, B and C)
Notes
Cycle 5 will begin 6 weeks after Cycle 4 starts
Cycle 5 and beyond
(Day 1)
Efficacy Assessment
Body Imaging
X
Contrast enhanced CT of the chest, CT/MRI of the abdomen, pelvis, and all 
other known and/or suspected sites of disease should occur every 8 weeks 
(±7 days) from first dose regardless of treatment schedule for first 6 months. 
After that, it will switch to every 12 weeks (±7 days) regardless of treatment 
schedule until disease progression assessed by investigator or treatment is 
discontinued (whichever occurs later). Evidence of progressive disease as per 
PCWG2.See Section 5.5.3.
Use same imaging method as was used at screening baseline or as described in 
Section 5.5.2.
Images will be collected and held centrally for retrospective independent 
review. (See Section 5.5.)
Brain Imaging
X
Participants with a history of brain metastasis or symptoms should have 
surveillance MRIs per standard of care (approximately every 12 weeks) or 
sooner if clinically indicated. CT of the brain without and with contrast can be 
performed if MRI is contraindicated
Tc99m based radionuclide bone scan
X
Every 8 weeks (±7 days) from first dose regardless of treatment schedule for 
first 6 months. After that, it will switch to every 12 weeks (±7 days) regardless 
of treatment schedule until disease progression is documented (and confirmed if 
needed) or treatment is discontinued (whichever occurs later). 
Evidence of progressive disease as per PCWG2. See Section 5.5.3.
Use same imaging method as was used at screening baseline or as described in 
Section 5.5.2
Images will be collected and held centrally for retrospective independent 
review. (See Section 5.5.)
Protocol Amendment No.: 05
Date:01-Dec-2021
107
6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab 
Table 5.1-3:
On Treatment Part 2: Nivolumab Monotherapy Phase Procedural Outline for Cohorts A, B, and C
(CA209650)
Procedure
For Part 2, Study Treatment
is
Administered Every 4 Weeks
(Cohorts A, B and C)
Notes
Cycle 5 will begin 6 weeks after Cycle 4 starts
Cycle 5 and beyond
(Day 1)
Clinical Drug Supplies
IWRS Drug Vial Assignment
X
Within 72 hours prior to dosing
Administer Study Treatment
X
See Section 4.3.2.
Outcomes Research Assessments
BPI-SF
X
Each assessment should be completed at the start of the clinic visit prior to 
dosing and other study assessments.
EQ-5D-3L
X
Protocol Amendment No.: 05
Date:01-Dec-2021
108
6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab 
Table 5.1-4:
On Treatment Procedural Outline (CA209650) for Cohort D
Procedure
Cycle 1 Day 1 
and each 
subsequent cycle 
(C1D1)
Notes
Safety Assessments
Targeted Physical Examination
X
To be performed only as clinically indicated within 72 hours prior to dosing
Vital Signs
X
Including BP, HR, and Temperature
Physical Measurements 
X
Weight within 72 hours prior to dosing
Adverse Event Assessment
Continuously
Assessed using NCI CTCAE v. 4. All AEs, including those associated with SARS-CoV-2 
infection, must be collected continuously during the treatment period.
SAE Assessment
Continuously
Assessed using NCI CTCAE v. 4. All SAEs, including those associated with SARS-CoV-2 
infection, must be collected continuously during the treatment period. 
Review of Concomitant Medication
X
Laboratory Tests
X 
Within 72 hours prior to each dose.
On site/local CBC w/differential, ALT, AST, ALP T-Bili, BUN or serum urea level, creatinine, 
calcium, phosphate, Na, K, Cl, LDH, glucose, albumin, amylase and, lipase. Subjects receiving 
cabazitaxel must have weekly on site/local CBC w/differential during first cycle. 
Thyroid function testing (TSH with reflexive fT3 and fT4) is to be done every 3 weeks for Q3W
dosing cycles, then every 8 weeks for subjects receiving nivolumab at 480 mg q4w dosing cycles.
Note: Safety Laboratory tests do not need to be repeated on C1D1 if screening labs were 
performed within 14 days prior to first dose.
Protocol Amendment No.: 05
Date:01-Dec-2021
109
6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab 
Table 5.1-4:
On Treatment Procedural Outline (CA209650) for Cohort D
Procedure
Cycle 1 Day 1 
and each 
subsequent cycle 
(C1D1)
Notes
ECOG Performance Status
X
Refer to Appendix 2
PSA
X
Performed locally Day 1 of C1 to C5 (within 72 hours prior to treatment), then Day1 of every 
odd-numbered cycle (C7, C9, C11, etc) [within 72 hours prior to treatment]. Participants who 
discontinue study treatment without documented radiographic progression will continue to have 
PSA performed every 8 weeks (± 7 days) until radiographic progression or the start of subsequent 
systemic cancer therapy, whichever occurs later. 
PSA evaluation beyond radiographic progression or the start of subsequent systemic cancer 
therapy to confirm PSA response or PSA progression should be performed as needed
Protocol Amendment No.: 05
Date:01-Dec-2021
110
6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab 
Table 5.1-4:
On Treatment Procedural Outline (CA209650) for Cohort D
Procedure
Cycle 1 Day 1 
and each 
subsequent cycle 
(C1D1)
Notes
Efficacy Assessment
Body Imaging
X
Contrast enhanced CT of the chest, CT/MRI of the abdomen, pelvis, and all other known and/or 
suspected sites of disease should occur every 8 weeks (±7 days) from first dose regardless of 
treatment schedule for first 6 months. After that, it will switch to every 12 weeks (±7 days) 
regardless of treatment schedule until disease progression is assessed by investigator and 
confirmed by BICR or treatment is discontinued (whichever occurs later). See Section 5.5.3. Use 
same imaging method as was used at screening/baseline. 
Brain Imaging
X
Participants with a history of brain metastasis or symptoms should have surveillance MRIs per 
standard of care (approximately every 12 weeks) or sooner if clinically indicated. CT of the brain 
without and with contrast can be performed if MRI is contraindicated
Tc99m based radionuclide bone scan
X
Every 8 weeks (±7 days) from first dose regardless of treatment schedule for first 6 months. After 
that, it will switch to every 12 weeks (±7 days) regardless of treatment schedule until disease 
progression is assessed by the investigator and confirmed by BICR or treatment is discontinued 
(whichever occurs later). Evidence of progressive disease as per PCWG2. See Section 5.5.3. 
Use same imaging method as was used at screening baseline or as described in Section 5.5.2.
Outcomes Research Assessments
BPI-SF
X
Subject must be informed of treatment assignment prior to first post-randomization assessment. 
Each assessment should be completed at the start of the clinic visit prior to dosing and other study 
assessments.
FACT-P
X
EQ-5D-3L
X
Healthcare Utilization
X
Healthcare resource utilization data will be collected at each visit by study site staff using the 
case report form (CRF).
Protocol Amendment No.: 05
Date:01-Dec-2021
111
6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab 
Table 5.1-4:
On Treatment Procedural Outline (CA209650) for Cohort D
Procedure
Cycle 1 Day 1 
and each 
subsequent cycle 
(C1D1)
Notes
Clinical Drug Supplies
IWRS Drug Vial Assignment
X
Within 72 hours prior to dosing
Administer Study Treatment
X
See Section 3.1 for Crossover Treatment.
See Section 4.3.5 for Re-induction Treatment. 
•
For subjects in Arm D1, the first re-induction combination dosing can start no sooner than 
4 weeks after the last nivolumab 480 mg dose and no sooner than 12 weeks after the last 
ipilimumab dose.
•
For subjects in Arm D1, the first re-induction combination dosing can start no sooner than 
8 weeks after the last nivolumab 480 mg dose and no sooner than 12 weeks after the last 
ipilimumab dose. Pausing nivolumab maintenance dosing is permitted in patients who are 
planning to receive re-induction in Arm D2.
Protocol Amendment No.: 05
Date:01-Dec-2021
112
6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab 
Table 5.1-5:
Follow-up Assessments (CA209650) for All Treatment Arms (Cohorts A, B, C, and D)
Procedure
Follow Upa, 
Visits X1 and X2
Survivalb,
Follow-up
Visits
Notes
Safety Assessments
Targeted Physical Examination
X
To assess for potential late emergent study treatment related issues.
Adverse Event Assessments
X
X
Assessed using NCI CTCAE v. 4. All AEs, including those associated with 
SARS-CoV-2 infection, must be collected continuously during the treatment 
period and for a minimum of 100 days following discontinuation of study 
treatment.
Participants will be followed for all SAEs, non-serious AEs of special interest, 
and all AEs (SAEs and non-serious AEs) associated with confirmed or 
suspected SARS-CoV-2 infection until resolution, the condition stabilizes, the 
event is otherwise explained, the event is deemed irreversible, the participant is 
lost to follow-up (as defined in Section 3.6.2), or for suspected cases, until 
SARS-CoV-2 infection is ruled-out.
SAE Assessment
X
X
Assessed using NCI CTCAE v. 4. All SAEs, including those associated with 
SARS-CoV-2 infection, must be collected continuously during the treatment 
period and for a minimum of 100 days following discontinuation of study 
treatment.
Participants will be followed for all SAEs, non-serious AEs of special interest, 
and all AEs (SAEs and non-serious AEs) associated with confirmed or 
suspected SARS-CoV-2 infection until resolution, the condition stabilizes, the 
event is otherwise explained, the event is deemed irreversible, the participant is 
lost to follow-up (as defined in Section 3.6.2), or for suspected cases, until 
SARS-CoV-2 infection is ruled-out.
Laboratory Tests
X
On site/local CBC w/differential, LFTs, BUN, creatinine, amylase, lipase and 
TSH (+ reflex Free T4 and Free T3) for X1, repeat at X2 if study treatment
related toxicity persists.
PSA
X
PSA to be collected every 8 weeks (± 7 days) in follow up until radiographic 
disease progression or the start of subsequent systemic cancer therapy, 
whichever occurs later. PSA evaluation beyond radiographic progression or the 
start of subsequent systemic cancer therapy to confirm PSA response or PSA 
progression should be performed as needed.
Protocol Amendment No.: 05
Date:01-Dec-2021
113
6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab 
Table 5.1-5:
Follow-up Assessments (CA209650) for All Treatment Arms (Cohorts A, B, C, and D)
Procedure
Follow Upa, 
Visits X1 and X2
Survivalb,
Follow-up
Visits
Notes
Review of Concomitant Medications
X
Survival Status
Collection of Subject Status and 
Subsequent Therapy Information
X
X
Every 3 months, Survival Follow up Visits may be accomplished by visit or 
phone contact, or email to include subsequent anti-cancer therapy and OS 
status. 
Additional subsequent cancer therapy details such as regimen, setting of the 
regimen, line of therapy, start date and end date of each regimen, best response 
to the regimen and date of progression after second line therapy will be 
collected.
Efficacy Assessments
Body Imaging
See Notes 
Only for subjects without radiographic progression on study therapy.
If progression is not recorded during the treatment phase (ie, subjects who 
discontinue for toxicity), contrast enhanced CT of the chest, CT/MRI of the 
abdomen, pelvis, and all other known and/or suspected sites of disease should 
occur every 8 weeks (± 7 days) for the first 6 months and then every 12 weeks 
(± 7 days) thereafter until disease progression is documented.
Use same imaging method as was used at screening/baseline.
Protocol Amendment No.: 05
Date:01-Dec-2021
114
6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab 
Table 5.1-5:
Follow-up Assessments (CA209650) for All Treatment Arms (Cohorts A, B, C, and D)
Procedure
Follow Upa, 
Visits X1 and X2
Survivalb,
Follow-up
Visits
Notes
For Cohorts A, B, and C, images will be collected and held centrally for 
retrospective independent review. (See Section 5.5).
For Cohort D, images will be collected and reviewed by BICR prospectively on 
a rolling basis and must continue until radiographic progression has been 
assessed by investigator and confirmed by BICR.
Brain Imaging
See Notes 
Participants with a history of brain metastasis or symptoms should have 
surveillance MRIs per standard of care (approximately every 12 weeks) or 
sooner if clinically indicated. CT of the brain without and with contrast can be 
performed if MRI is contraindicated.
Tc99mm based radionuclide bone 
Scan
See Notes
If progression is not recorded during the treatment phase (ie, subjects who 
discontinue for toxicity), bone scan should be completed every 8 weeks 
(± 7 days) for the first 6 months and then every 12 weeks (± 7 days) thereafter 
until disease progression is documented (and confirmed if needed).
For Cohorts A, B, and C: Images will be collected and held centrally for 
retrospective independent review. (See Section 5.5).
For Cohort D, Images will be collected and reviewed by BICR prospectively on 
a rolling basis and must continue until radiographic progression has been 
assessed by investigator and confirmed by BICR.
Outcomes Research Assessments
BPI-SF
X
Follow-up visits 1 and 2 only
FACT-P (Cohort D only)
X
Follow-up visits 1 and 2 only
FACT-P PCS (Cohort D only)
X
For survival follow-up visits, only the Prostate Cancer Subscale (PCS) portion 
of the FACT-P should be administered.  Can be administered by telephone if 
needed.
Protocol Amendment No.: 05
Date:01-Dec-2021
115
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Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab 
Table 5.1-5:
Follow-up Assessments (CA209650) for All Treatment Arms (Cohorts A, B, C, and D)
Procedure
Follow Upa, 
Visits X1 and X2
Survivalb,
Follow-up
Visits
Notes
EQ-5D-3L
X
X
Follow-up visits 1 and 2 and every 3 months for the first 12 months then every 
6 months thereafter for the survival follow-up visits. For survival visits, can be 
administered by telephone if needed.
Healthcare Utilization (Cohort D 
only)
X
X
Healthcare resource utilization data will be collected at each visit by study site 
staff using the case report form (CRF).
a X visits occur as follows - X1 = 30 days from the last dose (± 7 days) or coincide with the date of discontinuation (± 7 days) if date of discontinuation is greater 
than 37 days after last dose, X2 = 84 days (± 7 days) from follow-up visit 1. Follow up visits X1 and X2 will occur only after patient completes all study 
treatment.
b Y Survival visits = every 3 months from X2 (± 7 days).
Protocol Amendment No.: 05
Date:01-Dec-2021
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930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab 
5.2
Re-Testing During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments within any single Screening period 
will be permitted (in addition to any parameters that require a confirmatory value). 
Any new result will override the previous result (ie, the most current result prior to treatment) and 
is the value by which study inclusion will be assessed, as it represents the subject’s most current, 
clinical state.
5.3
Study Materials
•
NCI CTCAE version 4
•
BMS-936558 (nivolumab) IB
•
Ipilimumab IB
•
Pharmacy Manual
•
Laboratory manuals for collection
 
•
Site manual for operation of IWRS, including enrollment worksheets
•
Manual for entry of local laboratory data
•
Pregnancy surveillance forms (for WOCBP partners of study subjects)
•
RECIST v1.1 pocket guide
•
Patient reported outcomes questionnaires: BPI-SF, FACT-P, and EQ-5D-3L
5.4
Safety Assessments
At screening, a medical history will be obtained to capture relevant underlying conditions. The 
screening examinations should include weight, height, ECOG Performance Status, blood pressure 
(BP), heart rate (HR), and temperature. Screening assessments should be performed within 
28 calendar days prior to first treatment or as indicated in Schedule of Assessments Table.
Screening local laboratory assessments should be done within 14 calendar days prior to first 
treatment and are to include: CBC with differential, Chemistry panel including LFTs (ALT, AST, 
total bilirubin, alkaline phosphatase), BUN or serum urea level, creatinine, Ca, Na, K, Cl, 
phosphate, LDH, glucose, albumin, amylase, lipase, PTT, PT, and INR.
The following screening local laboratory assessments should be done within 28 calendar days prior 
to first treatment: thyroid panel including TSH, free T3, and free T4 and Hepatitis B and C testing 
(HBV sAg and HCV Ab or HCV RNA).
While on-study the following local laboratory assessments are to be done within 72 hours prior to
each dose: CBC with differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN 
or serum urea level, creatinine, Ca, Na, K, Cl, phosphate, LDH, glucose, albumin, amylase, and
lipase.
For Cohorts A, B, and C; PTT, PT, and INR are to be done within 72 hours prior to each dose; and 
thyroid function testing (TSH with reflexive fT3 and fT4) is to be done every 3 weeks (following 
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each sequential combination dose infusion) for on-treatment Part 1 phase (ie, during the period of 
same day sequential dosing with nivolumab 1 mg/kg followed by ipilimumab 3 mg/kg), then every 
8 weeks for subjects receiving nivolumab at 480 mg q4w.
For Cohort D, thyroid function testing (TSH with reflexive fT3 and fT4) is to be done every 
3 weeks for Q3W dosing cycles, then every 8 weeks for subjects receiving nivolumab at 480 mg 
q4w dosing cycles.
Subjects will be evaluated for safety if they have received any study treatment. Toxicity 
assessments will be continuous during the treatment phase as well as during the first two safety 
follow-up visits. Once subjects reach the survival follow-up phase, either in-person visits or 
documented telephone calls/email correspondence to assess the subject’s status are acceptable.
Adverse events and laboratory values will be graded according to the NCI-CTCAE version 4.
The start and stop time of the study therapy infusions and any interruptions or infusion rate 
reductions should be documented.
Physical examinations are to be performed as clinically indicated. If there are any new or 
worsening clinically significant changes since the last exam, report changes on the appropriate 
non-serious or serious adverse event page.
On treatment local laboratory assessments are to be completed within 3 calendar days prior to 
dosing.
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
induced liver enzyme evaluations) will be monitored during the follow-up phase via on site/local 
labs until all study treatment related toxicities resolve, return to baseline, or are deemed 
irreversible.
If a subject shows pulmonary-related signs (hypoxia, fever) or symptoms (eg, dyspnea, cough, 
fever) consistent with possible pulmonary adverse events, the subject should be immediately 
evaluated to rule out pulmonary toxicity, according to the suspected pulmonary toxicity 
management algorithm in the BMS-936558 (nivolumab) Investigator Brochure and in Appendix 1 
of this protocol.
Some of the assessments referred to in this section may not be captured as data in the eCRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
5.4.1
Imaging Assessment for the Study
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per
standard medical/clinical judgment. Images will be submitted to a central imaging vendor and may 
undergo BICR at any time during the study. Prior to scanning first participant, sites should be 
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qualified and understand the image acquisition guidelines and submission process as outlined in 
the CA209650 Imaging Manual provided by the central imaging vendor.
Tumor assessments at other timepoints may be performed if clinically indicated and should be 
submitted to the central imaging vendor as soon as possible. Unscheduled CT/MRI should be 
submitted to central imaging vendor. X-rays that clearly demonstrate interval progression of 
disease (for example, unequivocal lesions that are unmistakably new since the prior CT/MRI)
should be submitted to central imaging vendor. Otherwise, X-rays do not need to be submitted 
centrally. 
5.5
Efficacy Assessments
Study evaluations will take place in accordance with the flow charts in Section 5.1. Baseline 
assessments should be performed within 28 calendar days prior to first treatment utilizing CT or 
MRI and radionuclide bone scan. In addition to chest, abdomen, pelvis, and brain, all known sites 
of disease should be assessed at baseline. 
Subjects who cannot receive CT IV contrast should be imaged by MRI of abdomen/pelvis with IV 
contrast and CT of chest without contrast. 
Subsequent assessments should include chest, abdomen, and pelvis, and all known sites of disease 
should use the same imaging method as was used at baseline.
Subjects who cannot receive either CT or MRI contrast can be monitored by CT of chest, abdomen, 
and pelvis without IV contrast. 
To ensure a uniform tumor assessment (TA) schedule, regular radiological imaging (eg, MRI/CT 
of chest, abdomen, pelvis, plus other nodal disease as applicable, and bone scans) will be 
performed for all subjects at Screening, and thereafter for tumor response beginning 8 weeks 
(± 7 days) from first treatment and continuing every 8 weeks (± 7 days) for the first 6 months from 
first treatment, and every 12 weeks (± 7 days) thereafter.  Cohorts A, B, and C will continue scans
until radiographic disease progression is documented by the investigator or treatment is 
discontinued (whichever occurs later). Cohort D will have scans performed until radiographic 
progression has been assessed by the investigator and is confirmed by BICR or treatment is 
discontinued (whichever occurs later).
All disease progression should be evaluated per Table 5.5.3-1.
Subjects that enter Follow-up phase without documented PD will have tumor assessments as 
specified in Table 5.1-5.
For all treated subjects in Cohorts A, B, C, and for all randomized subjects in Cohort D, scans will 
be collected and held by a centralized imaging core laboratory for review by independent 
radiologists using RECIST v1.1 and PCWG2 (for bone disease progression) criteria. Scans will be 
centrally reviewed by BICR retrospectively for Cohorts A, B, and C, and prospectively on a rolling 
basis for Cohort D.
For subjects with measurable disease, tumor assessments for ongoing study treatment decisions 
will be completed by the investigator using RECIST v1.1 criteria.
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5.5.1
Primary Efficacy Endpoints
The dual primary endpoints are overall response rate (ORR) by RECIST v1.1 for subjects with 
measurable disease and radiographic progression-free survival (rPFS) assessed by BICR for all 
subjects as detailed in Table 5.5.3-1. BICR assessment will be performed retrospectively in 
Cohorts A, B, and C, and prospectively in Cohort D.
Objective response rate (ORR) is defined as the proportion of subjects who had confirmed 
complete or partial best overall response (BOR) among treated subjects with measurable disease 
at baseline In all subjects, radiographic progression-free survival (rPFS) is defined as the time 
between the date of first treatment and the first date of documented radiographic progression or 
death due to any cause, whichever occurs first.
The consensus guidelines of the Response Evaluation Criteria in Solid Tumors, version 1.1 
(RECIST v1.1) and the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) have been 
taken into consideration for the determination of radiographic disease progression assessment. 
Radiographic disease progression is defined by RECIST v1.1 for soft tissue disease, or by PCWG2 
for bone lesions demonstrated on Tc99m based radionuclide bone scans.
If exceptional circumstances preclude the continued administration of measures using planned 
modalities, then alternate administration methods may be required after consultation with a 
sponsor or a sponsor’s representative.
5.5.2
Method of Tumor Response Assessment
All target and non-target sites of disease identified on the baseline bone scan, CT or MRI studies 
should be reassessed with the same imaging modality at subsequent assessments. If, due to a 
radioisotope shortage, your imaging facility is unable to perform a Technetium-99m (Tech-99m) 
bone scan at a protocol-specified time point, then the following scanning options may be used:
•
Full body CT
•
Full body MRI
If an alternate imaging modality must be used, the following guidelines should be followed:
•
If a methodology other than a Tech-99m bone scan is used for a baseline or post-baseline 
assessment, then that same methodology must be used at all subsequent assessment time points, 
regardless of the availability of Tech-99m.
•
If a Tech-99m bone scan assessment reveals an unconfirmed progression and your imaging 
facility indicates that Tech-99m may not be available 6 or more weeks later for the 
confirmatory follow-up scan, then an additional full body scan using an alternate methodology 
should be performed at first progression in order to ensure that the same scanning methodology 
will be available at both time points. 
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5.5.3
Disease Progression Criteria
At each disease assessment, progression (PD) will be determined using the criteria in Table 5.5.3-
1 and Table 5.5.3-2. These criteria are based on RECIST v1.1 for soft tissue lesions and PCWG2 
for bone lesions and PSA measurements. 
For Cohort D participants, sites should submit all scans to the central imaging vendor on a rolling 
basis, throughout the duration of the study. BICR of scans will occur on a rolling basis, blinded to 
treatment arm, clinical data, and investigator assessment of submitted scans. When progression 
per RECIST v1.1 criteria for soft tissue lesions and PCWG2 for bone lesions is assessed by the 
investigator, the site will inform the central imaging vendor, in order for BICR assessment of 
progression to be performed. The BICR will be completed and the results provided to the site as 
specified in the imaging vendor documents, provided there are no pending imaging queries to the 
site. All details on the timelines and associated process requirements will be outlined in the 
CA209650 Imaging Manual.  
Cohort D participants whose progression is not confirmed by the BICR will be required to continue 
tumor assessments (if clinically feasible) according to the protocol-specified schedule, or sooner 
if clinically indicated. Also, if Cohort D participants discontinue treatment without radiographic 
progression, tumor assessments will continue according to the protocolspecified schedule, as 
noted in the Schedule of Activities, until progression has been confirmed by BICR or treatment is 
discontinued, whichever occurs later.
All study treatment decisions will be based on the investigator’s assessment of tumor images and 
not on the BICR assessment.
Radiographic Progression in soft tissue lesions (Target lesions, Non-target (non-bone) lesions) 
and Bone lesions are described in Table 5.5.3-1 below:
Table 5.5.3-1:
Definition of Radiographic Progression per protocol
Parameter
Unconfirmed Progression
Confirmed Progression
Date of 
Progression
Soft tissue 
lesions (target, 
non-target) 
measurements
per RECIST v1.1
(CT or MRI)
Progression of soft tissue lesions 
(target, non-target, new lesions) 
per RECIST v1.1 (CT or MRI)
Not applicable. RECIST v1.1 does not 
require confirmation
Date of 
progression
per 
RECIST v1.
1
Bone lesions on 
radionuclide 
bone scan per 
PCWG2
Appearance of ≥2 new lesions at 
the week 8 bone scan* as
compared to baseline bone scan 
Persistence of the 2 lesions noted on 
week 8 bone scan* 
AND
Appearance of ≥2 new lesions on the 
next bone scan obtained at least 6 weeks 
after unconfirmed progression identified 
(≥week 14)
Date of 
unconfirmed 
progression
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Table 5.5.3-1:
Definition of Radiographic Progression per protocol
Parameter
Unconfirmed Progression
Confirmed Progression
Date of 
Progression
If week 8 bone scan* does not 
demonstrate ≥2 new lesions as 
compared to baseline bone scan, 
appearance of ≥2 new lesions on 
any bone scan performed after 
week 8 bone scan* as compared 
to the week 8 bone scan* 
Not Applicable
Date of 
unconfirmed 
progression
*If the bone scan at Week 8 was not performed, use the first post-baseline bone scan performed after Week 8 instead
PSA progression: For participants with an initial PSA decline from baseline, the date of PSA 
progression is the date that an increase of 25% or more and an absolute increase of 2 ng/mL or 
more from the nadir are documented and confirmed by a second consecutive PSA value at least 
3 weeks later. For participants with no PSA decline from baseline, the date of PSA progression is 
the date that an increase of 25% or more and an absolute increase of 2 ng/mL or more from baseline 
are documented at or beyond Week 13. 
PSA progression alone is not an indication to stop treatment. Rather, subjects must discontinue 
treatment upon radiographic progression per RECIST v1.1 criteria for soft tissue disease and/or 
PCWG2 criteria for bone disease (see Table 5.5.3-1 above).
Participant who discontinue treatment without documented radiographic progression will continue 
to have PSA performed every 8weeks (± 7 days) until radiographic progression or the start of 
subsequent systemic cancer therapy, whichever occurs last. PSA evaluation beyond radiographic 
progression or the start of subsequent systemic cancer therapy to confirm PSA response or PSA 
progression should be performed as needed.
Table 5.5.3-2:
Definition of Disease Progression by PSA (per PCWG2) and 
Clinical Progression
Parameter
Unconfirmed Progression
Confirmed 
Progression
Date of 
Progression
PSA
Initial PSA decline from baseline: 
≥25% increase and ≥2 ng/ml increase above 
the nadir ≥week 13
Confirmed by a second 
consecutive PSA value 
at least 3 weeks later
Date of 
unconfirmed 
progression
No PSA decline from baseline:
≥25% increase and ≥2 ng/ml increase above 
the baseline ≥week 13 
Not applicable
Date of 
unconfirmed 
progression
Clinical 
Progression
Need for palliative radiation therapy involving more than one site, 
OR
Date of palliative 
radiation therapy, 
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Table 5.5.3-2:
Definition of Disease Progression by PSA (per PCWG2) and 
Clinical Progression
Parameter
Unconfirmed Progression
Confirmed 
Progression
Date of 
Progression
Surgery of kyphoplasty to any neoplastic lesion, OR
Cancer-associated clinical deterioration as determined by the treating 
physician
surgery or clinical 
deterioration
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5.8
Outcomes Research Assessments
The evaluation of patient-reported outcomes is an increasingly important aspect of clinical efficacy 
in oncology trials. Such data provide an understanding of the impact of treatment from the 
participant’s perspective and offer insights into patient experience that may not be captured 
through physician reporting. Additionally, generic health-related quality of life measures provide 
data needed for calculating utility values to inform health economic models.
For Cohort D, participants will be asked to complete the Brief Pain Inventory - Short Form 
(BPI-SF), The Functional Assessment Of Cancer Therapy - Prostate Cancer (FACT-P), and the 
3-level version of the EuroQol Group’s EQ-5D (EQ-5D-3L) in the participant’s preferred language 
when available. The assessments will be given at screening, before any clinical activities are 
performed during on-study clinic visits, and at designated visits during the follow-up phase. For 
Cohorts A, B, and C, the FACT-P will not be administered at any timepoint. Before administering 
the first patient-reported assessment after randomization, the Investigator should confirm that the 
participant is aware of their treatment assignment. If exceptional circumstances preclude the 
continued administration of measures using planned modalities, then alternate administration 
methods may be required after consultation with a sponsor or a sponsor’s representative.
5.8.1
The Brief Pain Inventory - Short Form
The BPI-SF133 measures both pain severity and functional interference caused by pain through the 
use of a numerical rating scale. Subjects rate the severity of their pain at its ‘‘worst,’’ ‘‘least,’’ and 
‘‘average’’ in the last 24 hours using an 11-point numerical rating scale with anchors of ‘‘no pain’’ 
and ‘‘pain as bad as you can imagine.’’ They are also asked to rate their pain at the time they 
complete the BPI-SF. Using an 11-point numerical rating scale with anchors of ‘‘does not 
interfere’’ and ‘‘completely interferes,’’ the BPI-SF similarly assesses to what extent pain 
interferes with mood, walking, general activity, work, relations with others, sleep, and enjoyment 
of life. The BPI-SF also asks subjects to mark the location of their pain on a body drawing and 
includes additional questions regarding pain treatment and the extent of pain relief. The original 
instrument on which the BPI-SF is based, The Wisconsin Brief Pain Questionnaire, was developed 
and validated in oncology subjects with the following four tumor types: breast, prostate, colorectal, 
and gynecological.134 The BPI-SF has been validated in cancer subjects in several countries with 
psychometrically validated translations in over 25 countries.
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5.8.2
The Functional Assessment Of Cancer Therapy - Prostate Cancer 
(FACT-P)
The FACT-P is a multidimensional, self-report QoL instrument specifically designed for use with 
prostate cancer patients.135 It consists of 27 core items, the Functional Assessment of Cancer 
Therapy - General (FACT-G) questionnaire, which assesses patient function in 4 domains: 
Physical, Social/Family, Emotional, and Functional well-being, which is further supplemented by 
the Prostate Cancer Subscale (PCS), 12 disease-specific items to assess for prostate-related 
symptoms. Each item is rated on a 0 (Not at all) to 4 (Very much) Likert type scale, and then 
combined to produce subscale scores for each domain, a Trial Outcome Index (TOI) which is based 
on the Physical and Functional well-being scales and the PCS as well as a total score which ranges 
from 0 to 156. Higher scores represent better QoL.
5.8.3
The 3-level EQ-5D-3L
The EQ-5D-3L136 is a standardized instrument used to measure self-reports of health status and 
functioning. The instrument’s descriptive system consists of 5 dimensions: mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels, reflecting 
"no health problems," "moderate health problems," and "extreme health problems." A dimension 
for which there are no problems is said to be at level 1, while a dimension for which there are 
extreme problems is said to be at level 3. Thus, the vectors 11111 and 33333 represent the best 
health state and the worst health state, respectively, described by the EQ-5D-3L. Altogether, the 
instrument describes 35 = 243 health states. Empirically derived weights can be applied to an 
individual’s responses to the EQ-5D-3L descriptive system to generate an index measuring the 
value to society of his or her current health. Such preference-weighting systems have been 
developed for Japan, UK, US, Spain, Germany, and numerous other populations. In addition, the 
EQ-5D-3L includes a visual analog scale (VAS) that allows respondents to rate their own current 
health on a 100-point scale ranging from “best imaginable” to “worst imaginable” health.
5.9
Additional Research Collection
Additional research collections are mandatory for all participants, except where prohibited by local 
laws or regulations, ethics committees or where a waiver is provided by the BMS Study Director. 
Where one or more of these exceptions occurs, participation in the additional research collection 
should be encouraged but will not be a condition of overall study participation, and subjects may 
opt out of the collection. This protocol will include residual sample storage for additional research 
(AR).
This collection for additional research is intended to expand the translational R&D capability at 
Bristol-Myers Squibb, and will support as yet undefined research aims that will advance our 
understanding of disease and options for treatment. It may also be used to support health authority 
requests for analysis, and advancement of pharmacodiagnostic development to better target drugs 
to the right subjects. This may also include genetic/genomic exploration aimed at exploring disease 
pathways, progression and response to treatment etc. 
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All requests for access to samples or data for additional research will be vetted through a diverse 
committee of the study sponsor’s senior leaders in Research and Development to ensure the 
research supports appropriate and well-defined scientific research activities.
•
Additionally, residual blood and tissue collections will also be retained by the BMS 
Biorepository 
 at a BMS approved third party storage management facility 
for additional research purposes
•
Additional research samples will be retained for 15 years or the maximum allowed by 
applicable law. No additional sampling is required for residual collections
Further details of sample collection and processing will be provided to the site in the procedure 
manual.
5.10
Health Economics OR Medical Resource Utilization and Health 
Economics
Healthcare resource utilization data will be collected for all randomized participants in Cohort D 
using an internal CRF developed for use in previous trials. The form, which is completed by study 
staff, records information about hospital admissions, including the number of days spent in various 
wards and discharge diagnosis, and non-protocol specified visits related to study therapy, including 
date of visit, reason for visit, and type of visit. The healthcare resource utilization data will be used 
to support subsequent economic evaluations.
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study treatment and 
that does not necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of study treatment, whether or not considered related to 
the study treatment.
The causal relationship to study treatment is determined by a physician and should be used to 
assess all adverse events (AE). The causal relationship can be one of the following:
•
Related: There is a reasonable causal relationship between study treatment administration and 
the AE.
•
Not related: There is not a reasonable causal relationship between study treatment 
administration and the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
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Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which were 
exacerbated by the induction of autoimmunity. Information supporting the assessment will be 
collected on the participant’s case report form.
Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/EC and FDA 
Code of Federal Regulations 21 CFR Parts 312 and 320.
Events Meeting the AE Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or results 
from other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical and 
scientific judgment of the investigator. Note that abnormal lab tests or other safety assessments 
should only be reported as AEs if the final diagnosis is not available. Once the final diagnosis 
is known, the reported term should be updated to be the diagnosis.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose, as a verbatim term (as reported by the investigator), 
should not be reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae and 
should specify "intentional overdose" as the verbatim term
Events NOT Meeting the AE Definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital).
6.1
Serious Adverse Events
DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.
A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that at any dose:
•
results in death
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•
is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
•
requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE
below)
•
results in persistent or significant disability/incapacity
•
is a congenital anomaly/birth defect
•
is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
treatment is an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 6.1.1
for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported) (see Section 6.1.1 for reporting details).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
−
a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)
−
elective surgery, planned prior to signing consent
−
admissions as per protocol for a planned medical/surgical procedure
−
routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)
−
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
−
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)
−
Admission for administration of anticancer therapy in the absence of any other SAEs 
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EVALUATING AES AND SAES
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study intervention administration will be 
considered and investigated.
•
The investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, 
for marketed products, in his/her assessment.
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study treatment, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period 
and within 100 days of the last dose of study treatment. 
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study treatment, but is potentially related 
to the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship must be specified in the narrative section of the SAE Report Form.
All SAEs associated with confirmed or suspected SARS-CoV-2 infection must be collected from 
the date of the participant’s written consent until 100 days following discontinuation of dosing.
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SAEs, whether related or not related to study treatment, and pregnancies must be reported to BMS 
(or designee) within 24 hours of awareness of the event. SAEs must be recorded on the SAE Report 
Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). The required 
method for SAE data reporting collection is through the eCRF. The paper SAE/pregnancy 
surveillance forms are only intended as a back-up option when the eCRF system is not functioning.
When paper forms are used, the original paper forms are to remain on site. In this case, the paper 
forms are to be transmitted via email or confirmed facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. In the event the electronic system is unavailable for transmission, 
paper forms must be used and submitted immediately. When paper forms are used, the original 
paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study treatment or if new information 
becomes available, the SAE report must be updated and submitted within 24 hours to BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, non-serious AEs of special interest, and AEs (SAEs and 
non-serious AEs) associated with confirmed or suspected SARS-CoV-2 infection will be followed 
until resolution, the condition stabilizes, the event is otherwise explained, the event is deemed 
irreversible, the participant is lost to follow-up (as defined in Section 3.6.2) or for suspected cases, 
until SARS-CoV-2 infection is ruled-out.
All SAEs must be followed to resolution or stabilization.
BMS will be reporting adverse events to regulatory authorities and ethics committees according to 
local applicable laws including European Directive 2001/20/EC and FDA Code of Federal 
Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected Serious Adverse 
Reaction) is a subset of SAEs and will be reported to the appropriate regulatory authorities and 
investigators following local and global guidelines and requirements.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
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6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information (with the exception of non-serious AEs related to 
SARS-CoV-2 infection) should begin at initiation of study treatment. Nonserious AE information 
should also be collected from the start of a placebo lead-in period or other observational period 
intended to establish a baseline status for the subjects. 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study treatment and for those present at the end of study 
treatment as appropriate. All identified nonserious AEs must be recorded and described on the 
nonserious AE page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that 
are reported/identified during the course of the study.
All nonserious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following discontinuation 
of study treatment. 
All non-serious AEs associated with confirmed or suspected SARS-CoV-2 infection must be 
collected from the date of the participant’s written consent until 100 days following 
discontinuation of dosing. Every adverse event must be assessed by the investigator with regard to 
whether it is considered immune-mediated. For events which are potentially immune-mediated, 
additional information will be collected on the subject’s case report form.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form as appropriate. Paper forms are only intended as a back-up option when 
the electronic system is not functioning.
•
Any laboratory test result that is clinically significant or meets the definition of an SAE
•
Any laboratory test result abnormality that required the subject to have study treatment
discontinued or interrupted
•
Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
Not applicable.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for BMS to collect any pregnancy surveillance information from the 
female partner, the female partner must sign an informed consent form for disclosure of this 
information. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
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6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered of both excessive and specifically important.
All occurrences of overdose must be reported as SAEs (see Section 6.1.1 for reporting details). 
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
Potential drug induced liver injury is defined as: 
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase)
AND
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic
6.7
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly.
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
No Data Monitoring Committee is planned
A Study Steering Committee (consisting of selected participating investigators) will meet regularly 
to advise BMS regarding study-related issues, including safety concerns.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
Sample size determination for Cohorts B and C:
Approximately 90 subjects with mCRPC will be enrolled and treated in 2 cohorts, subjects who
must have progressed after second-generation hormone therapies but have not received cytotoxic 
chemotherapy, and subjects who have progressed following cytotoxic chemotherapy (Cohorts B 
and C, respectively). Each cohort will consist of 30 or more subjects with measurable disease at 
baseline per RECIST v1.1 and no more than 15 with non-measurable disease. 
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This open-label Phase 2 study is not designed to statistically test specific hypotheses. Therefore,
the sample size is not based on statistical power calculations, but the size in each cohort is 
calculated using the observed objective response rate among treated subjects with measurable 
disease at baseline. 
Sample size determination for Cohort D:
Approximately 259 subjects with mCRPC, previously treated with docetaxel, will be randomized
and treated in Cohort D. These 259 subjects will be randomized between 4 arms in a 2:2:1:2 ratio
(74, 74, 37, and 74 subjects in Arm D1, D2, D3, and D4, respectively) and stratified by 
presence/absence of measurable disease by RECIST v1.1 per investigator assessment. Subjects 
with non-measurable disease at baseline by RECIST v1.1 per investigator assessment will be 
capped when approximately 105 subjects are randomized so that the remaining 154 subjects (44, 
44, 22, and 44 subjects in Arm D1, D2, D3, and D4, respectively) will be with measurable disease 
at baseline. 
Because this open-label phase 2 study is not designed to statistically test specific hypotheses, the 
sample size of Cohort D is not based on statistical power calculations. 
 
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•
 
8.1.1
Populations for Analyses
•
Enrolled Subjects: All subjects who signed an informed consent form and were registered 
into the IWRS.
•
Treated Subjects: All enrolled subjects who received any dose of study therapy (nivolumab 
or ipilimumab). This is primary dataset for analysis of study conduct, study population, 
efficacy, exposure, safety, and outcome research analysis for Cohorts A, B, and C.
•
Treated Subjects in Part 2: All treated subjects who received at least one dose of study 
medication in the nivolumab flat dose monotherapy phase (Part 2) for Cohorts A, B, and C.
•
Randomized Subjects: All subjects who are randomized to any treatment group in Cohort D.
This is the population for the analysis of demography, protocol deviations, baseline 
characteristics, efficacy analysis, and outcome research analysis.
•
Treated Subjects in Cohort D: All enrolled subjects who received any dose of study therapy 
in Cohort D. This is the primary population for exposure and safety analyses.
•
Response Evaluable Subjects: For Cohorts B and C, all treated subjects who had measurable 
disease at baseline per RECIST v1.1.
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8.2
Endpoints
8.2.1
Dual Primary Endpoints
Objective Response Rate (ORR)
In Cohorts B and C, objective response rate (ORR) is defined as the proportion of subjects who 
had confirmed complete or partial best overall response (BOR) among treated subjects with 
measurable disease at baseline. In Cohort D, ORR is defined as the proportion of subjects who had 
confirmed complete or partial BOR among randomized subjects with measurable disease at 
baseline by RECIST v1.1 per investigator assessment as entered in IWRS. For Cohorts B and C, 
the BOR is assessed by BICR (BICR assessment will be performed retrospectively in Cohorts A, 
B, and C, and prospectively in Cohort D) and is recorded between the date of treatment initiation 
and the date of objectively documented progression per RECIST v1.1 or the date of subsequent 
systemic anti-cancer therapy, whichever occurs first. For Cohort D, the BOR is assessed by BICR 
and is recorded between the date of randomization and the date of objectively documented 
progression per RECIST v1.1 or the date of subsequent systemic anti-cancer therapy, whichever 
occurs first. For subjects without documented progression or subsequent therapy, all available 
response assessments will contribute to the BOR assessment. Tumor assessments are scheduled to 
be performed every 8 weeks (± 7 days) for 6 months since treatment initiation and thereafter every 
12 weeks (± 7 days). In Cohorts A, B, and C, tumor assessments continue until radiographic disease 
progression is documented by the investigator or treatment is discontinued (whichever occurs 
later). In Cohort D, tumor assessments continue until radiographic progression is documented by 
the investigator and confirmed by BICR or treatment is discontinued (whichever occurs later).
Radiographic Progression-Free Survival
The following progressive diseases will be collected and documented as assessed as noted below:
•
Radiographic progression per BICR assessment
1) Bone disease progression by PCWG2 
2) Non-bone soft tissue disease progression by RECIST v1.1 
•
Clinical progression per investigator assessment
1) Need for palliative radiation therapy involving more than one site, OR
2) Surgery of kyphoplasty to any neoplastic lesion, OR 
3) Cancer-associated clinical deterioration as determined by the treating physician.
The following censoring rules will be used to define PFS endpoints for analysis. 
i.
Subjects who did not progress or die will be censored on the date of their last evaluable 
tumor assessment (ie, bone scan, CT, MRI).
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ii.
Subjects who did not have any on study tumor assessments and did not die will be censored 
on their date of first treatment if they are in Cohorts B and C, and will be censored on their 
date of randomization if they are in Cohort D.
iii.
Subjects who receive subsequent systemic anti-cancer therapy prior to progression (or 
death) will be censored.
In Cohorts B and C, the radiographic progression-free survival (rPFS) is defined as the time 
between the date of first treatment and the first date of documented progression per BICR 
(radiographic a-b) or death due to any cause, whichever occurs first. In Cohort D, the radiographic 
progression-free survival (rPFS) is defined as the time between the date of randomization and the 
first date of documented progression per BICR (radiographic a-b) or death due to any cause, 
whichever occurs first. The censoring rules (i-ii) will be applied for primary analyses; as shown 
above in type of progressive disease and censoring rule. In addition, rPFS with censoring 
subsequent therapy will also be defined for a sensitivity analysis, ie, the censoring rules (i-iii) will 
be applied.
8.2.2
Secondary Endpoint(s)
Radiographic/Clinical Progression-Free Survival
In Cohorts B and C, the radiographic/clinical progression-free survival (rcPFS) is defined as the 
time between the date of first treatment and the first date of documented progression (radiographic 
a-b; clinical c-e) or death due to any cause, whichever occurs first. In Cohort D, rcPFS is defined 
as the time between the date of randomization and the first date of documented progression 
(radiographic a-b; clinical c-e) or death due to any cause, whichever occurs first. The censoring 
rules (i-ii) and (i-iii) will be applied, respectively (ie, without and with censoring for subsequent 
therapy); see type of progressive disease and censoring rule in Section 8.2.1.
Overall Survival
In Cohorts B and C, , overall survival (OS) is defined as the time from first treatment to the date of 
death from any cause. In Cohort D, overall survival (OS) is defined as the time from randomization 
to the date of death from any cause. For subjects who are alive, their survival time will be censored 
at the last known alive date. Overall survival will be censored for subjects at the date of first 
treatment if they had no follow-up.
Safety and Tolerability
Overall safety and tolerability will be measured by the incidence of adverse events, serious adverse 
events, adverse events leading to discontinuation, immune mediated adverse events, deaths, 
laboratory abnormalities and changes from baseline.
Outcomes Research Assessments
The endpoints of changes pain as measured by BPI-SF, changes in cancer-related symptoms and 
quality of life (QoL) using the FACT-P questionnaire, and changes in health status and health 
utility as measured by the EQ-5D-3L questionnaire are described in Section 8.2.9. The analysis of 
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QoL will be based on all treated subjects for Cohorts B and C and on all randomized subjects for 
Cohort D.
PSA response rate
PSA response rate (PSA-RR) is the proportion of participants with a 50% or greater decrease in 
PSA from baseline to the lowest post-baseline PSA result. A second consecutive value obtained 3 
or more weeks later is required to confirm the PSA response. PSA response will be calculated for 
all participants with PSA values at baseline and at least one post baseline assessment. The analysis 
of PSA-RR will be based on all treated subjects with PSA values at baseline and at least one post-
baseline assessment for Cohorts B and C, and on all randomized subjects for Cohort D with PSA 
values at baseline and at least one post-baseline assessment.
 
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8.2.4
Demographics and Baseline Characteristics
For Cohorts A, B and C, demographics and baseline characteristics will be summarized by cohort 
and total for all treated subjects, using descriptive statistics. For Cohort D, similar analyes will be 
repeated by treatment group and total for all randomized subjects.
8.2.5
Efficacy Analyses
For Cohorts B and C, all efficacy analyses will be performed by cohort (ie, Cohorts B and C) as 
applicable to either (i) subjects with investigator-assessed measurable disease by RECIST v1.1 
and/or (ii) total number of subjects within each cohort. All efficacy data for treated subjects in 
Cohort A, if any, will be listed. For Cohort D, efficacy analysis will be performed by treatment 
arm for all randomized subjects.
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For the dual primary endpoint of ORR, estimated rates and corresponding 95% exact CIs will be 
calculated using the Clopper-Pearson method for all treated subjects with measurable disease at 
baseline per RECIST v1.1 in Cohorts B and C and for all randomized subjects with measurable 
disease at baseline per RECIST v1.1 per investigator assessment as entered in IWRS in Cohort D. 
In Cohorts B and C, estimated odds ratios and differences and corresponding 95% CIs between 
cohorts will be calculated for descriptive purpose. In Cohort D, sensitivity analysis of ORR may 
also be performed for all randomized subjects with measurable disease at baseline as entered in 
the CRF if the discrepancy rate is higher than 5%.
For time to event endpoints (eg, rPFS, rcPFS, and OS), medians and rates at months 6 and 12 and 
corresponding 95% CIs will be estimated for each cohort via the Kaplan-Meier methodology for 
all treated subjects in Cohorts B and C, and similar analyses will be done for each treatment arm
for all randomized subjects in Cohort D. Kaplan-Meier plots will be presented for each cohort for 
Cohorts B and C; similarly, Kaplan-Meier plots will be displayed by treatment arm for all 
randomized subjects in Cohort D. Note that these analyses will be stratified by the stratification 
factor when these are conducted for Cohort D. 
Estimate of PSA-RR and corresponding 2-sided exact 95% CI using the Clopper-Pearson method 
will be performed on all treated subjects with PSA values at baseline and at least one post-baseline 
assessment for Cohorts B and C; similar analysis will be done for each treatment arm in Cohort D
with PSA values at baseline and at least one post-baseline assessment. Note that this analysis will 
be stratified by the stratification factor when conducted for Cohort D.
For all treated subjects with measurable disease at baseline in Cohorts B and C,
 will be 
summarized by cohort for subjects with a BOR of PR or CR using the Kaplan-Meier methodology. 
Median values, along with two-sided 95% CIs will also be calculated. Summary statistics of 
 
will be provided by cohort for subjects with a BOR of CR or PR. For all randomized subjects with
measurable disease at baseline by RECIST v1.1 per investigator assessment as entered in IWRS
in Cohort D, similar
 and 
analyses will be repeated by treatment arm.
8.2.6
Safety Analyses
For Cohorts A, B, and C, all the safety analyses will be performed by cohort and total (including 
treated subjects in Cohort A) for all treated subjects. Descriptive statistics of safety will be 
presented using the NCI CTCAE v4 by cohort and total. All AEs, drug-related AEs, SAEs and 
drug-related SAEs will be tabulated using the worst grade per NCI CTCAE v 4 by system organ 
class and preferred term. On-study lab parameters including hematology, coagulation, chemistry, 
liver function, thyroid, adrenal and renal function will be summarized using worse grade by NCI 
CTCAE v 4. In addition, immune mediated adverse events incident rate is defined as the proportion 
subjects with any grade adverse events among subjects treated by each cohort and total. Events 
reported from the first dose and up to and including 100 days following the last dose of study 
treatment could be included in estimating this incidence rate. For Cohort D, similar safety analyses 
will be repeated by treatment arm for all treated subjects.
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8.2.10
Other Analyses
Methodology for other analyses including 
 summary of other questionnaires 
will be described in the statistical analysis plan.
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9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. If a deviation or change to a protocol is implemented to eliminate an 
immediate hazard(s) prior to obtaining relevant approval/favorable opinion(s), the deviation or 
change will be submitted as soon as possible to:
•
IRB/IEC 
•
Regulatory Authority(ies), if applicable by local regulations per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority, must be sent to BMS. If an 
amendment substantially alters the study design or increases the potential risk to the subject: (1) the 
consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan.
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable.
In addition, the study may be evaluated by BMS or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to BMS or designee.
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9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original.
9.2
Records
9.2.1
Records Retention
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS or designee prior to destroying 
any records associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee.
9.2.2
Study Treatment Records
Records for IP (whether supplied by BMS, its vendors, or the site) must substantiate IP integrity 
and traceability from receipt, preparation, administration, and through destruction or return. 
Records must be made available for review at the request of BMS/designee or a Health Authority.
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If...
Then...
Supplied by BMS
(or its vendors):
•
and guidelines and should include:
•
amount received and placed in storage area
•
amount currently in storage area
•
label identification number or batch number
•
amount dispensed to and returned by each subject, including unique subject 
identifiers
•
amount transferred to another area/site for dispensing or storage
•
nonstudy disposition (eg, lost, wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for bioavailability/bioequivalence, if applicable 
•
dates and initials of person responsible for Investigational Product 
dispensing/accountability, as per the Delegation of Authority Form.
Sourced by site, and not 
supplied by BMS or its 
vendors (examples 
include IP sourced from 
the sites stock or 
commercial supply, or a 
specialty pharmacy)
The investigator or designee accepts responsibility for documenting traceability and 
study treatment integrity in accordance with requirements applicable under law and 
the SOPs/standards of the sourcing pharmacy.
These records should include:
•
label identification number or batch number 
•
amount dispensed to and returned by each subject, including unique subject 
identifiers
•
dates and initials of person responsible for Investigational Product 
dispensing/accountability, as per the Delegation of Authority Form.
BMS or designee will provide forms to facilitate inventory control if the investigational site does 
not have an established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively. If 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor of designee. 
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The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task. For electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool. The investigator must retain a copy of the CRFs including 
records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals.
9.3
Dissemination of Clinical Study Data
In order to benefit potential study participants, patients, healthcare providers and researchers, and 
to help BMS honor its commitments to study participants, BMS will make information about 
clinical research studies and a summary of their results available to the public as per regulatory 
and BMS requirements. BMS will post study information on local, national, or regional databases 
in compliance with national and international standards for disclosure. BMS may also voluntarily 
disclose information to applicable databases.
9.4
Clinical Study Report
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:
•
External Principal Investigator designated at protocol development
•
National Coordinating Investigator 
•
Study Steering Committee chair or their designee
•
Subject recruitment (eg, among the top quartile of enrollers)
•
Involvement in trial design
•
Regional representation (eg, among top quartile of enrollers from a specified region or country)
•
Other criteria (as determined by the study team)
9.5
SCIENTIFIC PUBLICATIONS
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTAg) governing [Study site or Investigator] participation in 
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the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTAg.
Scientific Publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors.  No public presentation or publication of any interim results may be made by any 
principal investigator, sub-investigator or any other member of the study staff without the prior 
written consent of the Sponsor.  
Authorship of publications at BMS is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant 
contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for 
authorship:
1) Substantial intellectual contribution to the conception or design of the work; or the acquisition 
of data (ie, evaluable subjects with quality data), analysis, or interpretation of data for the work 
(eg, problem solving, advice, evaluation, insights and conclusion); AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Those who make the most significant contributions, as defined above, will be considered by BMS 
for authorship of the primary publication. Sub-investigators will generally not be considered for 
authorship in the primary publication. Geographic representation will also be considered.  
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant contributions 
to the work. For secondary analyses and related publications, author list and author order may vary 
from primary to reflect additional contributions.
For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions.
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10
GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
Complete Abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all study drugs. 
This also means that abstinence is the preferred and usual lifestyle of the 
patient. This does not mean periodic abstinence (eg, calendar, ovulation, 
symptothermal, profession of abstinence for entry into a clinical trial, post-
ovulation methods) and withdrawal, which are not acceptable methods of 
contraception. Women must continue to have pregnancy tests. Acceptable 
alternate methods of highly or less effective contraception’s must be 
discussed in the event that the subject chooses to forego complete abstinence.
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11
LIST OF ABBREVIATIONS
Term
Definition
ADT
androgen deprivation therapy 
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AT
aminotransaminases
BA/BE
bioavailability/bioequivalence
BICR
Blinded Independent Central Review
BID, bid
bis in die, twice daily
BMS
Bristol-Myers Squibb
BOR
best overall response
BP
blood pressure
BPI-SF
Brief Pain Inventory-Short Form
BUN
blood urea nitrogen
C
Celsius
Cavgss
average concentration
CBC
complete blood count
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
cm
centimeter
Cmaxss, CMAX
maximum observed concentration
Cmin1,Cminss
trough observed concentration
CNS
Central nervous system
COVID-19
coronavirus disease 2019
CRC
Colorectal cancer
CrCL
Creatinine clearance
CR
Complete response
CRF
Case Report Form, paper or electronic
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Term
Definition
CRPC
castration resistant prostate cancer
CSR
clinical study report
CT
computerized tomography
CTA
Clinical trial agreement
CTCAE
Common Terminology Criteria for Adverse Events
D/C
discontinue
DES
diethylstilbestrol
DILI
drug induced liver injury
dL
deciliter
DLT
Dose Limiting Toxicity
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eg
exempli gratia (for example)
eGFR
estimated glomerular filtration 
EQ-5D-3L
3-level EuroQol Five Dimensions questionnaire
EMR/EHR
electronic medical/health records
FDA
Food and Drug Administration
g
Gram
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GI
gastrointestinal
GnRH/LHRH
gonadotropin-releasing hormone/luteinizing hormone-releasing hormone
h
hour
HA
Health Authority
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
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Term
Definition
HIPAA
Health Insurance Portability and Accountability Act of 1996
HIV
Human Immunodeficiency Virus
HR
heart rate
HRPC
hormone-refractory prostate cancer
IB
Investigator Brochure 
ICF
Informed consent form
ICH
International Council of Harmonisation 
Ie
id est (that is)
IEC
Independent Ethics Committee
IMAE
Immune-mediated adverse events
IMP/IP
investigational medicinal products/investigational product
IND
Investigational New Drug Exemption
INR
international normalized ratio
I-O
Immuno-oncology
IRB
Institutional Review Board
IWRS
Interactive Web Response System
IV
Intravenous
kg
kilogram
L
liter
LDH
lactate dehydrogenase
mAb
monoclonal antibody
mCRPC
metastatic castration-resistant prostate cancer
mg
milligram
Mg++
Magnesium
min
Minute
mL
Milliliter
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
μg
Microgram
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Term
Definition
N
number of subjects or observations
Na+
Sodium
N/A
not applicable
NCCN
National Comprehensive Cancer Network
ng
Nanogram
NSCLC
Non small cell lung cancer
ORR
Objective response rate
OS
Overall survival
PAP
Prostatic acid phosphatase
PBMC
Peripheral Blood Mononuclear Cells
PCWG2
Prostate Cancer Working Group
PD
Pharmacodynamics; progressive disease
PD-1/PD-L1
Programmed cell death protein 1/Programmed death-ligand 1
PFS
Progression free survival
PK
Pharmacokinetics
PO
per os (by mouth route of administration)
PPK
population pharmacokinetic
PR
Partial response
PSA
prostate-specific antigen
PSA-RR
prostate-specific antigen response rate
PSMA
prostate-specific membrane antigen
PT
prothrombin time
PTT
partial thromboplastin time
QC
quality control
QD, qd
quaque die, once daily
QoL
quality of life
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
rPFS
radiographic Progression Free Survival
RT
radiation therapy
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Term
Definition
RT-PCR
reverse transcription polymerase chain reaction
SAE
serious adverse event
SCLC
Small cell lung cancer
SD
stable disease
SmPC
Summary of Product Characteristics
SOC
Standard of care
SOP
Standard Operating Procedures
SRE
skeletal-related events
Subj
Subject
SUSAR
Suspected, Unexpected Serious Adverse Reaction
t
Temperature
T
Time
TAA
tumor-associated antigens
Treg
Regulatory t-cells
USPI
United States Packaging Insert
VAS
Visual analogue scale
Vss/F (or Vss)
apparent volume of distribution at steady state
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
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12
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14 Petrylak DP, Tangen CM, Maha PH, et al. Docetaxel and Estramustine compared with 
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21 Kiniwa Y, Miyahara Y, Wang HY, Peng W, Peng Wheeler TM, et al. CD8+ Foxp3 +regulatory 
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22 Arlen PM, Mohebtash M, Madan RA, Gulley JL. Promising novel immunotherapies and 
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26 Kantoff PW, Schuetz TJ, Blumenstein BA, Glode LM, Bilhartz DL, Wyand M, et al. Overall 
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Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, 
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28 Small EJ, Schellhammer PF, Higano CS, et al. Placebo-Controlled Phase III Trial of 
Immunologic Therapy with Sipuleucel-T (APC8015) in Subjects with Metastatic, 
Asymptomatic Hormone Refractory Prostate Cancer. J Clin Oncol 2006 24: 3089-3094.
29 Small EJ, Fong L. Developing immunotherapy as legitimate therapy for subjects with prostate 
cancer. J Clin Oncol. 2010;28:1085-1098.
30 Antonarakis ES, Drake CG. Current status of immunological therapies for prostate cancer. 
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31 Drake CG. Prostate cancer as a model for tumour immunotherapy. Nat Rev Immunol. 
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36 Roden AC, Moser MT, Tri SD, Mercader M, Kuntz SM, Dong H, et al. Augmentation of T 
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37 Drake CG, Doody AD, Mihalyo MA, Huang CT, Kelleher E, Ravi S, et al. Androgen ablation 
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38 Clinical Study Report: Study No. CA209004. A Phase 1b, Open- Label, Multicenter, 
Multidose, Dose-Escalation Study of MDX-1106 (BMS-936558) in Combination with 
Ipilimumab (BMS-734016) in Subjects with Unresectable Stage III or Stage IV Malignant 
Melanoma. Bristol-Myers Squibb Company; 2014. Document Control No. 930082868.
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39 Curran MA, Montalvo W, Yagita H, et al. PD-1 and CTLA-4 combination blockade expands 
infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. 
PNAS 2010; 107: 4275-80.
40 Safety and clinical activity of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in 
combination with ipilimumab in subjects (pts) with advanced melanoma (MEL). Jedd D. 
Wolchok, Harriet M. Kluger, Margaret K. Callahan et al. J Clin Oncol 31, 2013 (suppl; abstr 
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41 Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, et al. Combined Nivolumab and Ipilimumab 
or Monotherapy in Untreated Melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. doi: 
10.1056/NEJMoa1504030. Epub 2015 May 31.
42 Small, E. J., N. S. Tchekmedyian, B. I. Rini, L. Fong, I. Lowy, and J. P. Allison. 2007. A pilot 
trial of CTLA-4 blockade with human anti-CTLA-4 in subjects with hormone-refractory 
prostate cancer. Clin. Cancer Res. 13:1810–1815.
43 Is there a role for immune checkpoint blockade with ipilimumab in prostate cancer? Cha E1, 
Small EJ. Cancer Med. 2013 Apr;2(2):243-52. doi: 10.1002/cam4.64. Epub 2013 Feb 24.
44 Tollefson, M. K., R. J. Karnes, and R. H. Thompson, et al. 2010. A randomized phase II study 
of ipilimumab with androgen ablation compared with androgen ablation alone in subjects with 
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50 Lancet Oncol. 2014 Jun;15(7):700-12. doi: 10.1016/S1470-2045(14)70189-5. Epub 2014 May 
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63 J Clin Oncol. 2008 Mar 1;26(7):1148-59. doi: 10.1200/JCO.2007.12.4487. Design and end 
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90 James ND, de Bono JS, Spears MR, et al. Abiraterone for Prostate Cancer Not Previously 
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91 J Clin Oncol. 2011 Sep 20;29(27):3695-704. JCO.2011.35.8648. Epub 2011 Aug 22. End 
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104 Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 
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8583)
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120 Wolchok J, Neyns B, Linette G, et al. Ipilimumab monotherapy in subjects with previously 
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APPENDIX 1
MANAGEMENT ALGORITHMS
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
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BMS-936558
nivolumab
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CA209650
BMS-936558
nivolumab
Protocol Amendment No.: 05
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CA209650
BMS-936558
nivolumab
Protocol Amendment No.: 05
Date:01-Dec-2021
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CA209650
BMS-936558
nivolumab
APPENDIX 2
PERFORMANCE STATUS SCALES - ECOG
ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair
5
Dead
Source: Oken MM, Creech RH, Tomey DC, Horton J, Davis TE, McFadden ET, and Carbone PP. Toxicity and 
Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-655.
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BMS-936558
nivolumab
APPENDIX 3
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
•
Premenarchal
•
Premenopausal female with 1 of the following:
−
Documented hysterectomy
−
Documented bilateral salpingectomy
−
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
−
A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 
45 years in the absence of other biological or physiological causes. In addition, females 
under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level 
> 40 mIU/mL to confirm menopause.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as 5 months after the end of study 
treatment.*
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a
•
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 
−
oral 
−
intravaginal 
−
transdermal 
•
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
−
oral 
−
injectable 
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Highly Effective Methods That Are User Independent 
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb
•
Hormonal methods of contraception including oral contraceptive pills containing a 
combination of estrogen and progesterone, vaginal ring, injectables, implants and 
intrauterine hormone-releasing system (IUS)c
•
Intrauterine device (IUD)c
•
Bilateral tubal occlusion
•
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
•
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
•
It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
•
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 
•
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence that 
the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative methods 
of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Unacceptable Methods of Contraception*
•
Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously
•
Diaphragm with spermicide
•
Cervical cap with spermicide
•
Vaginal Sponge with spermicide
•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
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•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal (coitus interruptus).
•
Spermicide only
•
Lactation amenorrhea method (LAM)
* Local laws and regulations may require use of alternative and/or additional contraception 
methods.
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.
•
Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.
•
Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 7 months after the end of study treatment.
•
Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 7 months after the end of 
treatment in the male participant.
•
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 7 months after the end of study treatment. 
•
Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of study treatment.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 6.4 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting.
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BMS-936558
nivolumab
APPENDIX 4
COUNTRY SPECIFIC REQUIREMENTS
1
COUNTRY SPECIFIC REQUIREMENTS
1.1
Germany
Original language
Country-specific language
Section 5 Schedule of Activities
Table 5.1-1 Screening Procedural 
Outline, Laboratory Tests
Add “HIV” to the list of laboratory tests
Section 3.3.3 Exclusion Criteria,
Exclusion criterion 2 j)
“Known history of testing positive for human immunodeficiency virus
(HIV) or known acquired immunodeficiencysyndrome (AIDS)”to be
replaced with “Positive test for HIV”.
Section 5.4
Safety Assessments
The following screening local laboratory assessments should be done 
within 28 calendar days prior to first treatment: thyroid panel including 
TSH, free T3, and free T4 and Hepatitis B and C testing (HBV sAg and 
HCV Ab or HCV RNA), and HIV..
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BMS-936558
nivolumab
APPENDIX 5
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for the Revised Protocol 04, 26-Mar-2020
The purpose of this revision is to modify the maximum tumor sample age from 5 years to 1 year.
The study will allow submission of tumor samples obtained more than 1 year prior to enrollment 
if collected in the metastatic setting and if approved by the BMS Medical Monitor/designee. 
Recent prostate cancer studies evaluating tumor biology across different settings have found that 
the frequencies of individual genetic alterations increase as the disease progresses, suggesting that 
tumor samples collected in the localized disease setting may not reflect the tumor biology at the 
time of study treatment. In addition, Revised Protocol 04 allows starting dose of cabazitaxel of 
20 mg/m2 to align with cabazitaxel labeling, clarifies the population for analyses in 
Cohort D-Part 1, clarifies the exclusion criteria for prior pelvic radiotherapy, incorporates updated 
nivolumab clinical program protocol standards, and makes minor clarifications for consistency 
throughout the document. Where applicable, sections in the synopsis have been updated to align 
with the protocol section changes listed below.
Summary of key changes of Revised Protocol 04
Section Number & Title
Description of Change
Brief Rationale
Global changes
Replaced ‘Amendment 02’ with ‘Revised 
Protocol 02’.
The mention of Amendment 02 
was an error and was corrected 
to reference Revised Protocol 02
Where applicable “study drug” was 
updated to “study treatment”.
Revised to align with the most 
recent language for BMS studies
Where applicable “co-primary endpoint(s)” 
was changed to “dual primary endpoint(s)”.
To comply with HA’s guidance 
on the definition of multiple 
endpoints
Section 1.3.1, Primary 
Objectives, bullet item 2
Revised bullet item 2. (Text changes are 
underlined).
•
Assess Radiographic Progression Free 
Survival (rPFS) assessed by BICR in all 
treated subjects with mCRPC in Cohort B, 
C, D - Part 2 period and all randomized
subjects with mCRPC in Cohort D - Part 1 
period using RECIST V1.1 for soft tissue 
disease progression and PCWG2 for bone 
disease progression.
To clarify that the population for 
analyses in Cohort D-Part 1 are 
all ‘randomized subjects’ since 
the study design is randomized.
Section 1.5.1, Overall 
Risk/Benefit Assessment for 
Additional Cohort D, bullet 
item 3
Revised bullet item 3. (Text changes are 
underlined).
•
Early interim reviews of safety and 
efficacy data will be performed by the 
Sponsor and participating investigators 
from the Study Steering Committee for 
Cohort D after the first 15 treated subjects 
for each arm have at least 8 weeks of 
follow-up after first dose and at least one 
post-baseline tumor assessment in subjects 
To add the Study Steering 
Committee for Cohort D.
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BMS-936558
nivolumab
Summary of key changes of Revised Protocol 04
Section Number & Title
Description of Change
Brief Rationale
receiving immunotherapy in Arms D1, D2, 
and D3.
Section 2.1, Good Clinical 
Practice
Revised paragraph 3 regarding potential 
breaches.
Revised to align with the most 
recent language for BMS 
studies.
Section 3.1, Study Design and 
Duration, bullet items 1 and 2 
were revised
Bullet items 1 and 2 were revised. (Text 
changes are underlined).
•
Arm D1: nivolumab 3 mg/kg in 
combination with ipilimumab 1 mg/kg 
every 3 weeks for up to 4 doses 
(Cycles 1 to 4), followed by nivolumab 
480 mg administered every 4 weeks 
(Cycle 5 and beyond). Subjects who are
receiving maintenance nivolumab with 
ongoing disease control (ongoing CR, 
PR, or SD) or with radiographic 
progression per RECIST 1.1/PCWG2
may be permitted re-induction with the 
combination 
of 
ipilimumab 
and 
nivolumab at their original combination 
dose 
upon 
PSA 
progression
or 
radiographic progression (whichever 
occurs 
first), 
as 
specified 
in 
Section 4.3.5. Treatment will continue 
until disease progression, unacceptable 
toxicity, withdrawal of consent, 2 year 
maximum treatment duration, or the 
study ends, whichever occurs first.
•
Arm D2: nivolumab 1 mg/kg every 
3 weeks plus ipilimumab 3 mg/kg every 
2 cycles (ie, every 6 weeks) for up to 
4 ipilimumab 
doses, 
followed 
by 
nivolumab 480 mg every 4 weeks. 
Subjects 
who 
are 
receiving 
maintenance nivolumab with ongoing 
disease control (ongoing CR, PR, or 
SD) or with radiographic progression 
per RECIST 1.1/PCWG2
may be 
permitted 
re-induction 
with 
the 
combination 
of 
ipilimumab 
and 
nivolumab at their original combination 
dose 
upon 
PSA 
progression
or 
radiographic progression (whichever 
occurs 
first), 
as 
specified 
in 
Section 4.3.5. Treatment will continue 
until disease progression, unacceptable 
toxicity, withdrawal of consent, 2 year 
maximum treatment duration, or the 
study ends, whichever occurs first.
To allow re-induction in patients 
with radiographic progression 
before PSA progression
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BMS-936558
nivolumab
Summary of key changes of Revised Protocol 04
Section Number & Title
Description of Change
Brief Rationale
Section 3.1, Study Design and 
Duration, bullet item 4
Bullet item4 was revised. (Text changes are 
underlined).
•
Arm D4: Cabazitaxel 20 mg/m2 or
25 mg/m2 (at investigator’s discretion
and according to country-specific label)
every 3 weeks in combination with oral 
prednisone or prednisolone 10 mg daily 
for up to 10 cycles. Treatment will 
continue until disease progression, 
unacceptable toxicity, withdrawal of 
consent, completion of 10 cycles of 
treatment, or the study ends, whichever 
occurs first.
To align with cabazitaxel 
product label.
Section 3.1, Study Design and 
Duration, third paragraph 
below bulleted list
The third paragraph below bulleted list 
was revised. (Text changes are 
underlined):
Cohort D-Part 1 will evaluate the above 
immunotherapy regimens and the standard 
of care comparator cabazitaxel in 
unselected mCRPC patients. 
 
Figure 3.1-2, Study Design 
Schematic addition of Cohort 
D-Part 1
Revised cabazitaxel dose for Arm D4.
To align with cabazitaxel 
product label.
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BMS-936558
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Summary of key changes of Revised Protocol 04
Section Number & Title
Description of Change
Brief Rationale
Section 3.1, Study Design and 
Duration, Treatment Phase
Previously:
For Arms D1, D2, D3, and D4, tumor 
assessments are scheduled to be performed 
every 8 weeks for 6 months following 
treatment initiation and thereafter every 12 
weeks until radiographic progression has 
been assessed by the investigator and 
confirmed by BICR (see Section 5.5.3) or 
withdrawal of consent.
Revised:
For Arms D1, D2, D3, and D4, tumor 
assessments are scheduled to be performed 
every 8 weeks (±7  days) for 6 months 
following treatment initiation and thereafter 
every 12 weeks (± 7 days) until 
radiographic progression has been assessed 
by the investigator and confirmed by BICR 
(see Section 5.5.3) or withdrawal of 
consent.
Specify window for tumor 
assessments.
Section 3.1, Study Design and 
Duration, Optional 
Re-induction Combination for 
Cohorts B, C, Arms D1, and 
D2
Revised first paragraph. (Text changes are 
underlined):
Subjects with PSA progression or with 
radiographic progression per RECIST 
1.1/PCWG2 (whichever occurs first) during 
or after nivolumab monotherapy 
maintenance may receive nivolumab and 
ipilimumab combination at the same dose 
levels as assigned at study start and follow 
the same Time and Events schedule, as 
specified in Section 5.
To allow re-induction in patients 
with radiographic progression 
before PSA progression
Section 3.1, Study Design and 
Duration, Follow-Up Phase,
Bullet item 7, sentence 1
Revised bullet item 7, sentence 1 (Text 
changes are underlined). 
•
BMS may request that survival data be 
collected on all treated subjects in Cohort 
B, C, D - Part 2 period and all randomized 
subjects in Cohort D - Part 1 period outside 
of the protocol defined window as detailed 
in the Time and Events Table (Section 5). 
At the time of this request, each subject 
will be contacted to determine their 
survival status unless the subject has 
withdrawn consent for all contact.
To clarify that the population for 
analyses in Cohort D-Part 1 are 
all ‘randomized subjects’ since 
the study design is randomized.
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Summary of key changes of Revised Protocol 04
Section Number & Title
Description of Change
Brief Rationale
Section 3.2, Post Study Access 
to Therapy, paragraph 2, 
sentence 1.
Revised paragraph 2, sentence 1 (Text 
changes are underlined). 
BMS may request that survival data be 
collected on all treated subjects in Cohort 
B, C, D - Part 2 period and all randomized 
subjects in Cohort D - Part 1 period outside 
of the protocol defined window.
To clarify that the population for 
analyses in Cohort D-Part 1 are 
all ‘randomized subjects’ since 
the study design is randomized.
Section 3.3.1, Inclusion 
Criteria Criterion 2) Target 
Population, item d)
Previously:
d) Evidence of Stage IV disease (as defined 
by AJCC criteria) on previous bone, CT, 
and/or MRI scan
Revised:
d) Current evidence of metastatic disease 
documented by either bone lesions on 
radionuclide bone scan and/or soft tissue 
lesions on CT/MRI. Metastases may be in 
regional lymph nodes (N1 per AJCC 
staging criteria, 8th edition) and/or distant 
metastases (M1 per AJCC staging criteria, 
8th edition).
i) Subjects whose disease spread is limited 
to regional pelvic lymph nodes (N1M0) 
must have a lymph node measuring at least 
2 cm in short axis to be considered eligible.
Clarified patient eligibility.
Section 3.3.1, Inclusion 
Criteria Criterion 2) Target 
Population, f)
Revised criterion 2) Target Population, f) 
(Text changes are underlined)
f) Tumor progression while receiving ADT 
per PCWG2 criteria and within 6 months 
prior to screening, with at least one of the 
following:
Clarified patient eligibility.
Section 3.3.1, Inclusion 
Criteria Criterion 2) Target 
Population, f), ii)
Revised this item to remove the sentence:
“Subjects whose disease spread is limited 
to regional pelvic lymph nodes (N1M0) 
must have a lymph node measuring at least 
2 cm in short axis to be considered 
eligible.”
This sentence was moved to item 
d), i).
Section 3.3.1, Inclusion 
Criteria Criterion 2) Target 
Population, criterion g) iv)
Revised criterion g) iv). (Text changes are 
shown as strike through or underlined).
iv) Cohort D: Subjects must have 
progressed after a prior docetaxel-
containing regimen and received no more 
than 2 prior chemotherapy regimens in the 
metastatic setting. If docetaxel was only 
given in the metastatic castration-sensitive 
setting, subjects must also have progressed 
following prior treatment with a second 
generation hormonal therapy. Prior second-
generation hormonal manipulations (eg, 
Revised to clarify washout 
period for prior chemotherapy.
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Summary of key changes of Revised Protocol 04
Section Number & Title
Description of Change
Brief Rationale
abiraterone acetate, enzalutamide, 
apalutamide), ketoconazole, prostate cancer 
vaccine therapy, radiation therapy, 
radium-223, anti-androgens (eg, flutamide), 
chemotherapy and DES or other estrogens, 
are allowed up to 28 days prior to study 
treatment.
Section 3.3.1, Inclusion 
Criteria Criterion 2) Target 
Population, criterion l
Revised criterion l). (Text changes are 
underlined):
l) Sufficient tumor samples from either a 
fresh biopsy (collected during screening 
period) or archival tumor tissue in the form 
of formalin-fixed paraffin-embedded 
(FFPE) block or a minimum of 
15 unstained tumor tissue slides. Archival 
tumor samples must be obtained within 1 
year prior to enrollment date, either from a 
metastatic tumor lesion (preferred) or from 
a primary tumor lesion that has not been 
previously irradiated. Tumor samples 
collected more than 1 year prior to 
enrollment date may be acceptable if 
obtained in the metastatic setting and 
following discussion with and approval by 
the BMS Medical Monitor/designee.
Tumor sample may be from core biopsy, 
punch biopsy, excisional biopsy, or surgical 
specimen. Fine needle aspiration is 
unacceptable for submission. 
 
 Central 
laboratory must confirm receipt of tumor 
samples prior to randomization.
Revised to restrict the age of 
tumor samples to 1 year, but to 
allow submission of tumor 
samples obtained more than 1 
year prior to enrollment if 
collected in the metastatic setting 
and if approved by the Sponsor.
Section 3.3.3, Exclusion 
Criteria, Criterion 2, Medical 
History, Concurrent Diseases 
and Prior Therapies
Criterion d) was revised. (Text changes are 
underlined).
d) Less than 1 month since resolution of 
≥Grade 2 toxicity related to pelvic-targeted 
therapy (eg, radiation enteritis).
Revised to exclude participants 
who are less than 1 month since 
resolution of ≥ Grade 2 toxicity 
related to pelvic-targeted therapy
Section 3.3.3, Exclusion 
Criteria, Criterion 2, Medical 
History, Concurrent Diseases 
and Prior Therapies
Criterion e) was revised. (Text changes are 
underlined).
e) Prior radiation therapy within 14 days 
prior to starting study therapy. Any toxicity 
related to prior radiation therapy must have 
resolved to Grade ≤1 or baseline prior to 
starting study therapy.
Revised to clarify washout from 
prior radiation therapy (RT) and 
exclusion of subjects based on 
resolution of RT-related 
toxicities.
Section 3.3.3, Exclusion 
Criteria, Criterion 2, Medical 
History, Concurrent Diseases 
and Prior Therapies
Revised criterion o). (Text changes are 
underlined).
o) For Cohort D: previous treatment with 
cabazitaxel in the metastatic setting
To clarify that previous 
treatment with cabazitaxel is an 
exclusion criteria only if it was 
received in the metastatic 
setting.
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Summary of key changes of Revised Protocol 04
Section Number & Title
Description of Change
Brief Rationale
Section 3.3.3, Exclusion 
Criteria, Criterion 5) Other 
Exclusion Criteria
Revised criterion a). (Text changes are 
underlined).
a) Prisoners or subjects who are 
involuntarily incarcerated. (Note: under 
certain specific circumstances, and only in 
countries where local regulations permit, a 
person who has been imprisoned may be 
included or permitted to continue as a 
subject. Strict conditions apply and Bristol-
Myers Squibb approval is required.)
Revised to align with the most 
recent language for BMS 
studies.
Section 3.3.4, Exclusion 
Criteria for Crossover Phase 
for Subjects Originally 
Randomized to Arm D3 or 
Arm D4 only, 7) Medical 
History, Concurrent Diseases 
and Prior Therapies
Revised criterion d). (Text changes are 
underlined).
d) Less than 1 month since resolution of 
≥ Grade 2 toxicity related to pelvic-targeted 
therapy (eg, radiation enteritis).
Revised to exclude participants 
who are less than 1 month since 
resolution of ≥ Grade 2 toxicity 
related to pelvic-targeted 
therapy.
Section 3.3.4, Exclusion 
Criteria for Crossover Phase 
for Subjects Originally 
Randomized to Arm D3 or 
Arm D4 only, 7) Medical 
History, Concurrent Diseases 
and Prior Therapies; item e)
Revised criterion e). (Text changes are 
underlined).
e) Prior radiation therapy within 14 days 
prior to first dose of nivolumab combined 
with ipilimumab. Any toxicity related to 
prior radiation therapy must have resolved 
to Grade ≤1 or baseline prior to first dose 
of nivolumab combined with ipilimumab.
Revised to clarify washout from 
prior radiation therapy (RT) and 
exclusion of subjects based on 
resolution of RT-related 
toxicities.
Section 3.3.4, Exclusion 
Criteria for Crossover Phase 
for Subjects Originally 
Randomized to Arm D3 or 
Arm D4 only, 7) Medical 
History, Concurrent Diseases 
and Prior Therapies; item p
Added criterion p)
p)
Subjects who have received systemic 
anti-cancer therapy after the last dose of 
study treatment (ipilimumab or cabazitaxel)
To clarify that no systemic anti-
cancer therapy is allowed 
between main treatment and 
crossover treatment
Section 3.4.2, Other 
Restrictions and Precautions
Revised first paragraph.
Previously:
Palliative (limited-field) radiation therapy 
and 
palliative 
surgical 
resection 
are 
permitted, if the following criteria are met:
1)
The subject will be considered to have 
progressed at the time of palliative 
therapy and must meet criteria to 
continue 
with 
treatment 
beyond 
progression (Section 4.5.4).
2)
The case is discussed with the BMS 
Medical Monitor or Study Director.
Revised:
Palliative (limited-field) radiation therapy 
and palliative surgical resection are 
To align with Table 5.5.3-2: on 
when local therapy is considered 
clinical progression.
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Summary of key changes of Revised Protocol 04
Section Number & Title
Description of Change
Brief Rationale
permitted, if the case is discussed with the 
BMS Medical Monitor or Study Director.
Section 3.5, Discontinuation of 
Subjects following any 
Treatment with Study Drug
Added a note to bullet item 4.
Added a note to bullet item 4. (Text 
changes are underlined).
Loss of ability to freely provide consent 
through imprisonment or involuntarily 
incarceration for treatment of either a 
psychiatric or physical (eg, infectious 
disease) illness. Note: Under specific 
circumstances and only in countries where 
local regulations permit, a participant who 
has been imprisoned may be permitted to 
continue as a participant. Strict conditions 
apply and BMS approval is required.
Alignment with current BMS 
standards for studies using 
nivolumab.
Section 3.5, Discontinuation of 
Subjects following any 
Treatment with Study Drug
Revised last bullet item.
Previously:
•
Subject meets criteria for confirmed 
progression 
(radiographic 
and/or 
clinical) by PCWG2 or RECIST 1.1
criteria.
Revised:
•
Subject meets criteria for radiographic
progression by PCWG2 or RECIST 1.1
criteria.
To clarify that patients with 
radiographic progression by 
PCWG2 or RECIST 1.1 must 
discontinue treatment. 
Requirement to discontinue for 
clinical progression was 
removed.
Section 4, Study Treatment, 
Table 4-1, Study Treatment for 
CA209650
Corrected potency for prednisone and 
cabazitaxel.
Per Administrative Letter 02.
Section 4.3.1, Arms A, B, and 
C Part 1 Study Treatment
Administration - Nivolumab 
and Ipilimumab Combination 
Phase (Cycles 1-4)
In paragraph 3, the text “saline flush” was 
revised to “flush of diluent.”
Alignment with current BMS 
standards for studies using 
nivolumab.
Section 4.3.5, Re-Induction of 
Study Therapy For Subjects in 
Cohorts B, C, Arms D1 and 
D2
Revised first paragraph and added 2 
paragraphs. (Text changes are shown as 
strike through or underlined).
Subjects in Cohorts B, C and in Arms D1 
and D2 who are receiving maintenance 
nivolumab and achieved initial with 
ongoing disease control (ongoing CR, PR, 
or SD) during the combination period or
with radiographic progression per RECIST 
1.1/PCWG2 may be permitted re-induction 
with the combination of ipilimumab and 
nivolumab at their original combination 
dose upon PSA progression as or 
radiographic progression per RECIST 
1.1/PCWG2 (whichever occurs first; see 
Section 5.5.3), and after discussion and 
agreement with BMS Medical Monitor.  
To allow re-induction in patients 
with radiographic progression 
before PSA progression and 
define timing of starting the first 
re-induction combination dosing
Protocol Amendment No.: 05
Date:01-Dec-2021
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v


Clinical Protocol
CA209650
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 04
Section Number & Title
Description of Change
Brief Rationale
For subjects in Arm D1, the first 
re-induction combination dosing can start 
no sooner than 4 weeks after the last 
nivolumab 480 mg dose and no sooner than 
12 weeks after the last ipilimumab dose.
For subjects in Arm D2, the first 
re-induction combination dosing can start 
no sooner than 8 weeks after the last 
nivolumab 480 mg dose and no sooner than 
12 weeks after the last ipilimumab dose. 
Pausing nivolumab maintenance dosing is 
permitted in patients who are planning to 
receive re-induction in Arm D2,
Section 4.3.7, Arm D4 Study 
treatment administration -
cabazitaxel plus prednisone; 
and Table 4.5-3, Cohort D 
Dosing Schedule, row Arm D4
Revised dose of cabazitaxel to include “or 
20 mg/m2 at investigator’s discretion and 
according to country-specific label”.
To align with cabazitaxel 
product label.
Section 4.4, Method of 
Assigning Treatment
Removed bullet item requiring “M Stage at 
screening” from the second bulleted list.
To align with IWRS 
Table 4.5-3, Cohort D Dosing 
Schedule, footnote
Revised footnote for starting dose of 
cabazitaxel for patients with mild hepatic 
impairment.
To align with cabazitaxel 
product label.
Section 4.5.3 Dose 
Discontinuation for Nivolumab 
and Ipilimumab
Revised first dashed item under bullet 2 to 
include ‘myocarditis.”
Alignment with current BMS 
standards for studies using 
nivolumab.
Section 4.5.3 Dose 
Discontinuation for Nivolumab 
and Ipilimumab
Revised fourth dashed item under bullet 3 
to add statement regarding adrenal 
insufficiency requiring discontinuation.
To align with section 4.5.2 
mandating discontinuation for 
adrenal insufficiency.
Section 4.5.4, Treatment 
Beyond Disease Progression
Revised Paragraph 5 and 6. Replaced “by 
RECIST 1.1” with “of soft tissue”. 
To clarify that the rules for 
determining further progression 
do not follow RECIST 1.1 for 
soft tissue.
Section 4.5.5.1, Other 
Toxicities for Cabazitaxel
Added the following sentence.
In case of treatment delay greater than 
2 weeks, patient should discontinue study 
treatment, unless there is strong evidence of 
clinical benefit to justify continuation of 
dosing with study treatment, and the 
investigator must discuss the rationale with 
the Sponsor before a decision is taken.
To allow more flexibility in case 
a dose delay > 2 weeks is needed 
for cabazitaxel.
Protocol Amendment No.: 05
Date:01-Dec-2021
200
6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 04
Section Number & Title
Description of Change
Brief Rationale
Table 4.5.5.2-1: Dose 
reduction levels for cabazitaxel
Revised the table footnote to include 
“20 mg/m2 or” for the starting dose of 
cabazitaxel for subjects with mild hepatic 
impairment.
To align with cabazitaxel 
product label.
Section 4.5.6, Management 
Algorithms for Immuno-
Oncology Agents
Added myocarditis to the bullet list of 
management algorithms.
Alignment with most recent 
nivolumab IB.
Table 5.1-1, Screening 
Procedural Outline 
(CA209650) for All Treatment 
Arms (Cohorts A, B, C, and D)
Updated table notes for laboratory, PSA, 
and Testosterone tests.
For consistency with study 
assessments.
Table 5.1-4, On Treatment 
Procedural Outline 
(CA209650) for Cohort D, 
Safety Assessments
Laboratory Test row, Notes column, 
deleted statement regarding all safety labs, 
deleted PTT, PT, and INR assessments, and 
revised language for thyroid function 
testing.
Removed inclusion of tests 
specific to Cohorts A, B, and C, 
and clarified laboratory tests 
specific to Cohort D.
Table 5.1-4, On Treatment 
Procedural Outline 
(CA209650) for Cohort D, 
Safety Assessments
PSA row. Clarified that PSA testing should 
be performed within 72 hours.
Specify window for PSA testing.
Table 5.1-4, On Treatment 
Procedural Outline 
(CA209650) for Cohort D,
Clinical Drug Supplies
Administer Study Treatment row, Notes 
column: Added the following bullet items 
under Re-Induction Treatment:
•
For subjects in Arm D1, the first 
re-induction combination dosing can 
start no sooner than 4 weeks after the 
last nivolumab 480 mg dose and no 
sooner than 12 weeks after the last 
ipilimumab dose.
•
For subjects in Arm D1, the first 
re-induction combination dosing can 
start no sooner than 8 weeks after the 
last nivolumab 480 mg dose and no 
sooner than 12 weeks after the last 
ipilimumab dose. Pausing nivolumab 
maintenance dosing is permitted in 
patients who are planning to receive 
re-induction in Arm D2
To define the timing of starting 
the first re-induction 
combination dosing.
Protocol Amendment No.: 05
Date:01-Dec-2021
201
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930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 04
Section Number & Title
Description of Change
Brief Rationale
Table 5.1-5, Follow-up 
Assessments (CA209650) for 
All Treatment Arms (Cohorts 
A, B, C, and D)
PSA row. Provided ±7 day window for 
PSA collection.
Specify window for PSA testing.
Body Imaging row: Provided ±7 day 
window for body imaging.
Specify window for body 
imaging.
Tc99mm based radionuclide bone Scan
row: Provided ±7 day window for bone 
scan.
Specify window for bone scan.
Section 5.4, Safety 
Assessments
Updated to text reflect Safety Assessment 
and Procedures tables.
Align with Flow Chart/Time and 
Events Schedule.
Section 5.5, Efficacy 
Assessments, paragraph 8
Revised paragraph 8. (Text changes are 
underlined).
For all treated subjects in Cohorts A, B, C, 
and Cohort D-Part 2 period and for all 
randomized subjects in Cohort D-Part 1 
period, scans will be collected and held by 
a centralized imaging core laboratory for 
review by independent radiologists using 
RECIST 1.1 and PCWG2 (for bone disease 
progression) criteria. Scans will be 
centrally reviewed by BICR retrospectively 
for Cohorts A, B, and C, and prospectively 
on a rolling basis for Cohort D. 
To clarify that scans will be 
collected and reviewed for all 
‘randomized subjects’ in Cohort 
D-Part 1.
Section 5.5.3, Disease 
Progression Criteria
Revised paragraph 2. (Text changes are 
shown as strike through or underlined).
PSA progression alone is not an indication 
to stop treatment. In addition Rather, 
subjects must also meet discontinue 
treatment upon radiographic progression by
per RECIST 1.1 criteria for measurable soft 
tissue disease and/or PCWG2 criteria for 
bone disease (see Table 5.5.3-1 above) 
and/or criteria for clinical progression (see 
below).
For consistency with the 
protocol where discontinuation 
is only mandated for 
radiographic progression.
Protocol Amendment No.: 05
Date:01-Dec-2021
202
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Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 04
Section Number & Title
Description of Change
Brief Rationale
Protocol Amendment No.: 05
Date:01-Dec-2021
203
6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 04
Section Number & Title
Description of Change
Brief Rationale
Section 6, Adverse Events
Added criteria for meeting or not meeting 
AE definition.
Revised to align with the most 
recent language for BMS 
studies.
Protocol Amendment No.: 05
Date:01-Dec-2021
204
6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 04
Section Number & Title
Description of Change
Brief Rationale
Section 6.1, Serious Adverse 
Events
Added definition of an SAE and text for 
evaluating AEs and SAEs.
Revised to align with the most 
recent language for BMS 
studies.
Section 6.1.1, Serious Adverse 
Event Collection and 
Reporting
Revised text regarding SAE collection, and 
reporting, and follow-up of AEs and SAEs.
Revised to align with the most 
recent language for BMS 
studies.
Section 7, Data Monitoring 
Committee and Other External 
Committees
Revised to include a Study Steering 
Committee. 
To advise BMS regarding study-
related issues.
Section 8.2, Endpoints
Revised this section.
To clarify that the population for 
analyses in Cohort D-Part 1 are 
all ‘randomized subjects’ since 
the study design is randomized.
Section 8.2.5, Efficacy 
Analyses, revised second 
paragraph
Revised second paragraph. (Text changes 
are underlined).
For the dual primary endpoint of ORR, 
estimated rates and corresponding 95% 
exact CIs will be calculated using the 
Clopper-Pearson method for all treated 
subjects with measurable disease at 
baseline per RECIST 1.1 in Cohort B, C, D 
- Part 2 period and all randomized subjects
with measurable disease at baseline per 
RECIST 1.1 in Cohort D - Part 1 period. 
Estimated odds ratios and differences and 
corresponding 95% CIs between cohorts 
will be calculated for descriptive purpose.
To comply with HA’s guidance 
on the definition of multiple 
endpoints
Section 8.2.9, Outcomes 
Research Analyses
Updated this section. (Text changes are 
underlined).
Analyses of BPI-SF, FACT-P, and EQ-5D-
3L data will be performed by cohort in all 
treated subjects in Cohort A, B, C, (BPI-SF 
and EQ-5D-3L only) and Cohort D-Part 2 
period and in all randomized subjects in 
Cohort D-Part 1 period who have an 
assessment at baseline (Day 1, assessment 
To clarify analyses for each 
cohort.
Protocol Amendment No.: 05
Date:01-Dec-2021
205
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930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 04
Section Number & Title
Description of Change
Brief Rationale
prior to administration of drug on day of 
first dose) and at least 1 other assessment 
while on treatment. Questionnaire 
completion rate, defined as the proportion 
of questionnaires actually received out of 
the expected number, will be calculated and 
summarized at each assessment point.
Section 8.2.9.2, Change in 
Cancer-Related Symptoms and 
Quality of Life
Revised paragraph 1. (Text changes are 
shown as underline or strike-through).
Unless otherwise specified, the analysis of 
FACT-P will be performed in all treated 
subjects in Cohort D-Part 2 period and in 
all randomized subjects in Cohort D-Part 1 
period who have an assessment at baseline 
and at least one or more post-baseline 
assessments. The following descriptive 
analyses will be conducted: performed in 
all treated subjects
To clarify that FACT-P is only 
implemented with Cohort D.
Section 8.2.9.3, Change in 
Health Status and Health 
Utility
Revised paragraph 1. (Text changes are 
underlined).
EQ-5D-3L data will be described by cohort 
for all treated subjects in Cohort A, B, C, 
and Cohort D-Part 2 period and for all 
randomized subjects in Cohort D-Part 1 
period in the following ways:
To clarify analyses for each 
cohort.
Section 9.3, Clinical Study 
Report and Publications
Split this section into 2 sections. Revised 
text regarding Signatory Investigator for 
the Clinical Study Report. Added content 
regarding Scientific Publications.
Revised to align with the most 
recent language for BMS 
studies.
Section 9.4, Scientific 
Publications
New Section.
Revised to align with the most 
recent language for BMS 
studies.
Protocol Amendment No.: 05
Date:01-Dec-2021
206
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Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 04
Section Number & Title
Description of Change
Brief Rationale
Appendix 1, Management 
Algorithms
Management algorithms have been updated 
including new algorithm for myocarditis 
Alignment with current BMS 
standards for studies using 
nivolumab.
All
Minor formatting and 
typographical/editorial corrections.
Minor, therefore not 
summarized.
Overall Rationale for the Revised Protocol 03, 21-Feb-2019
Recent data from Cohorts B and C in CA209650 suggest that nivolumab in combination with 
ipilimumab is an active regimen in patients with mCRPC, with potentially greater activity in 
patients with HRD mutations or higher TMB, but early toxicity limited the number of combination 
doses received. This global Revised Protocol 03 introduces the addition of Cohort D containing 4 
open-label treatment arms. These arms (Arm D1 and D2) include 2 different dosing schedules of 
nivolumab in combination with ipilimumab to identify a dose combination which reduces toxicity 
and increases the potential clinical benefit from the dual checkpoint inhibition. The 3rd arm (Arm 
D3) evaluates ipilimumab monotherapy to assess its contribution to the activity of the combination, 
and the 4th arm (D4) reference arm evaluates SOC cabazitaxel to allow for comparison with the 
immunotherapy regimens,
 
 
 
In addition, this revised protocol introduces optional re-induction for subjects entered the 
maintenance period, incorporates language to define PSA response and progression according to 
PCWG2, incorporates updated nivolumab clinical program protocol standards, and makes minor 
clarifications for consistency throughout the protocol document.
Summary of key changes of Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
Synopsis
Section 1.3.1 Primary Objectives
Section 3.1 Study Design and 
Duration
Blinded independent central review 
(BICR) was added for retrospective 
analysis for Cohorts A, B, and C and 
prospective analysis for Cohort D
Tumor assessments generally 
will be verified by central 
reviewers blinded to study 
treatments to minimize 
assessment bias.
Protocol Amendment No.: 05
Date:01-Dec-2021
207
6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
Section 5.5.3 Disease Progression 
Criteria
Synopsis, Secondary Objectives  
Section 1.3.2 Secondary Objectives
Section 5.5.3 Disease Progression 
Criteria
Table 5.5.3-2 Definition of Disease 
Progression by PSA (per PCWG2) 
and Clinical Progression
Objective added to evaluate PSA 
response rate (PSA-RR) 
 
 
To assess PSA response rate 
which is an important 
measure of efficacy outcomes 
in prostate cancer clinical 
trials as recommended by 
PCWG2. 
Synopsis, Secondary Objectives 
Section 1.3.2 Secondary Objectives
Objective added to estimate changes in 
cancer-related symptoms and quality of 
life (QoL) using the FACT-P 
questionnaire (Cohort D only)
Patient-reported outcomes 
will provide a better 
understanding of the clinical 
efficacy and the impact of 
treatment from the 
participant’s perspective.
Synopsis Study Design for Cohort D
Section 3.1 Study Design and 
Duration
Section 4.3.2 Arms A, B, and C Part 2 
Study Drug Administration -
Nivolumab Monotherapy Phase 
(Cycle 5 and beyond)
Section 4.3.5 Re-Induction of Study 
Therapy For Subjects in Cohorts B, C, 
Arms D1 and D2
Subjects from Cohorts B and C who 
entered the maintenance period may be 
permitted re-induction with the 
combination upon PSA progression and 
after approval by the BMS medical 
monitor.
As a result of the recent data 
from Cohorts B and C 
showing promising clinical 
activity in mCRPC, subjects 
from Arms D3 and D4 have 
the option to receive 
nivolumab in combination 
with ipilimumab upon 
documented radiographic 
progression.
Synopsis Study Design for Cohort D
Section 1.1.12 Rationale for Optional 
Crossover Combination for 
Monotherapy Arms (Arm D3 and D4)
Section 3.1.1 Crossover Phase for 
Subjects Originally Randomized to 
Arm D3 or Arm D4only
Additional design information and 
rationale for crossover during treatment 
phase were added.
Combined blockade of both 
PD-1 and CTLA-4 has 
proven more efficacious than 
inhibition of either pathway 
alone. Preliminary data with 
nivolumab in combination 
with ipilimumab have shown 
promising clinical activity in 
mCRPC. Therefore, 
participants on monotherapy 
Arms D3 and D4 may receive 
nivolumab in combination 
with ipilimumab upon BICR 
progression and medical 
monitor approval.
Protocol Amendment No.: 05
Date:01-Dec-2021
208
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Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
Synopsis
Section 3.1 Study Design and 
Duration
Section 4.3.5 Re-Induction of Study 
Therapy For Subjects in Cohorts B, C, 
Arms D1 and D2
Subjects in Arm D1 and D2 may be 
permitted re-induction with the 
combination of ipilimumab and 
nivolumab at their original combination 
dose upon PSA progression.
Subjects who entered the 
maintenance period may be 
permitted re-induction with 
the combination after 
approval by the BMS 
medical monitor.
Synopsis
Section 1.1.13 Rationale for Duration 
of Treatment with Nivolumab plus 
Ipilimumab
A treatment duration with 
immunotherapy treatment limit of 2 
years is strongly recommended that 
subjects in Arms A, B, and C. 
Accumulating data suggest 
that 2 years of PD-1 
checkpoint inhibitor 
treatment may be sufficient 
for long term benefit.  
Synopsis
Study Drug Table
Table 4-1 Study Drugs for CA209650
Section 4.1 Investigational Product
Section 4.2 Non Investigational 
Product
Sections and tables were updated with 
new study drugs, cabazitaxel and 
prednisone.
Updated language aligns with 
new study design 
Section 1.1.6 Rationale to Support 
Dose and Schedule Selection in 
Cohort D
Supportive data for safety and clinical 
activity of Cohort D were added. 
Provides safety and clinical 
activity of study drugs in 
Cohort D
Section 1.5.1 Overall Risk/Benefit 
Assessment for Additional Cohort D
Section added to provide overall 
risk/benefit assessment for additional 
Cohort D
Section added to provide 
overall risk/benefit 
assessment of new study 
design.
Protocol Amendment No.: 05
Date:01-Dec-2021
209
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Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
Section 3.4.1 Prohibited and/or 
Restricted Treatments for All Arms
Section 3.4.1.1 Prohibited and/or 
Restricted Treatments on Nivolumab 
and Ipilimumab
Updated language for prohibited 
botanical preparations was added. 
Updated language for prohibited 
vaccines was added. 
Updated language added to 
align with program standards 
for safety.
Section 3.4.1.2 Prohibited and/or 
Restricted Treatments on Cabazitaxel
Updated language for prohibited 
treatments 
Updated language for 
prohibited treatments with 
change of study design 
Section 3.4.2 Other Restrictions and 
Precautions
Additional information for the use of 
palliative radiation therapy was added 
Updated language provides 
clarity
Section 4.3.3 Arm D1 Study Drug 
Administration - Nivolumab and 
Ipilimumab
Section 4.3.4 Arm D2 Study Drug 
Administration for Nivolumab and 
Ipilimumab
Section 4.3.5 Re-Induction of Study 
Therapy For Subjects in Cohorts B, C, 
Arms D1 and D2
Section 4.3.6 Arm D3 Study Drug 
Administration
Section 4.3.7 Arm D4 Study drug 
administration - cabazitaxel plus 
prednisone
Storage and dispensing information for 
investigational drugs and non-
investigational drugs added
Storage and dispensing 
information added with 
change of study design
Section 4.5.5 Dose delay, 
modification, and discontinuation for 
cabazitaxel
Section 4.5.5.1 Other Toxicities for 
Cabazitaxel
Section 4.5.5.2 Dose Reduction for 
cabazitaxel 
Section 4.5.5.3
Special Precautions 
for Cabazitaxel
ection 4.5. Hypersensitivity reactions 
for cabazitaxel
Dose delay, modification, 
discontinuation, toxicities, dose 
reductions, and precautions for 
cabazitaxel added
Sections for cabazitaxel 
added with change in study 
design
Section 4.5.5.4 Prednisone Dose 
Modifications and Dose Delays
Prednisone dose modifications and 
dose delays added
Sections for prednisone 
added with change in study 
design
Protocol Amendment No.: 05
Date:01-Dec-2021
210
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930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
Table 5.1-1: Screening Procedural 
Outline (CA209650) for All 
Treatment Arms (Cohorts A, B, C, 
and D)
Table 5.1-2:
On Treatment Part I: 
Sequential Treatment with Nivolumab 
and Ipilimumab Procedural Outline 
(CA209650) - Arms A, B, and C
Table 5.1-5: Follow-up Assessments 
(CA209650) for All Treatment Arms 
(Cohorts A, B, C, and D)
Updated BPI-SF, FACT-P and EQ-5D-
3L schedule in time and events 
schedule.
PRO instruments added to 
study to assess patient’s 
symptoms, signs, or an aspect 
of functioning directly related 
to disease status.
Table 5.1-2:
On Treatment Part I: 
Sequential Treatment with Nivolumab 
and Ipilimumab Procedural Outline 
(CA209650) - Arms A, B, and C
BPI-SF and EQ-5D-3L added to time 
and events schedule.
PRO instruments added to 
study to assess patient’s 
symptoms, signs, or an aspect 
of functioning directly related 
to disease status.
Table 5.1-1 Screening Procedural 
Outline (CA209650) for All 
Treatment Arms (Cohorts A, B, C, 
and D)
Table 5.1-2 On Treatment Part I: 
Sequential Treatment with Nivolumab 
and Ipilimumab Procedural Outline 
(CA209650) - Arms A, B, and C
Table 5.1-3 On Treatment Part 2: 
Nivolumab Monotherapy Phase 
Procedural Outline (CA209650)
Table 5.1-5 Follow-up Assessments 
(CA209650) for All Treatment Arms 
(Cohorts A, B, C, and D)
Section 5.4.1 Imaging Assessment for 
the Study
Updated imaging language
Aligns with standard imaging 
language
Table 5.1-3:On Treatment Part 2: 
Nivolumab Monotherapy Phase 
Procedural Outline (CA209650)
Table 5.1-5: Follow-up Assessments 
(CA209650) for All Treatment Arms 
(Cohorts A, B, C, and D)
Updated PSA collection and response 
assessment
To assess PSA response rate 
which is an important 
measure of efficacy outcomes 
in prostate cancer clinical 
trials as recommended by 
PCWG2.
Table 5.1-4:On Treatment Procedural 
Outline (CA209650) for Cohort D
Cohort D table added with change in 
study design
Cohort D table added with 
change in study design
Table 5.1-5: Follow-up Assessments 
(CA209650) for All Treatment Arms 
(Cohorts A, B, C, and D)
Added healthcare utilization
New endpoint added with 
change in study design.
Protocol Amendment No.: 05
Date:01-Dec-2021
211
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930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
Section 5.8 Outcomes Research 
Assessments
Updated outcomes assessments 
collection for Cohort D
PRO instruments and 
analyses added to study to 
assess patient’s symptoms, 
signs, or an aspect of 
functioning directly related to 
disease status.
Section 5.10 Health Economics OR 
Medical Resource Utilization and 
Health Economics
Added HCRU  collection for Cohort D
HCRU collection updated 
with change in study design
Section 8.1 Sample Size 
Determination
Section 8.1.1 Populations for 
Analyses
Section 8.2 Endpoints
Section 8.2.9 Outcomes Research 
Analyses
Statistical section updated 
Statistical section updated 
with change in study design
Overall Rationale for the Revised Protocol 02, 28-Aug-2017
The purpose of this amendment is to discontinue randomization and enrollment into Cohort A. 
This discontinuation reflects the changing landscape of metastatic castration resistant prostate 
cancer (mCRPC) management whereby use of second generation hormonal therapies is preferred 
as the initial intervention in the pre-chemotherapy metastatic prostate cancer setting. This trial will 
now include 2 cohorts, Cohorts B and C.
Protocol Amendment No.: 05
Date:01-Dec-2021
212
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Approved
930104999
6.0
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Approved
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v


Clinical Protocol
CA209650
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Title Page
Updated the name and contact 
information of the Medical Monitor
Administrative change
Synopsis - Secondary Objectives; 
Synopsis - Study Design; Section 
1.1.5 Rationale to Support 
Nivolumab plus Ipilimumab Dose 
and Schedule Selection; Section 
1.3.2 Secondary Objectives; Section 
1.5 Overall Risk/Benefit 
Assessment; Section 3.1 Study 
Design and Duration;
 
Replaced “recurrence of disease” with 
“progression of disease” as a reason for 
treatment discontinuation. 
To accurately reflect 
nivolumab program standards 
Synopsis, Study Design; Section 1 
Introduction; Section 3.1 Study 
Design and Duration; Section 8.1 
Sample Size Determination
Notified that Cohort A enrollment is 
discontinued per Amendment 02.
Discontinuation of Cohort A 
enrollment due to slow 
accrual and changing 
treatment landscape for 
metastatic CRPC
Synopsis, Study Design and 
Statistical Considerations - Sample 
Size; Section 3.1 Study Design and 
Duration
Revised the number of subjects to be 
treated in Cohorts B and C from 30 to 45. 
Revised the numbers of participants 
required to have measurable (≥30 
subjects) or non-measurable disease (≤15 
subjects) based on a 2-cohort study 
design
To reflect discontinuation of 
Cohort A enrollment
Synopsis, Study Design; Section 3.1 
Figure 3.1-1 Study Design 
Schematic
Updated study schematic to reflect 
discontinuation of Cohort A and revised 
the numbers of subjects allocated to 
Cohorts B and C
To reflect discontinuation of 
Cohort A enrollment
Synopsis, Study Population: Key 
Inclusion Criteria; Section 3.3.1 
Inclusion Criteria, Criterion 2(g)
Deleted note (ii) regarding window for 
bone pain palliation by radiation therapy
To remove a redundancy 
with exclusion criterion 2(e)
Synopsis, Study Population: Key 
Inclusion Criteria; Section 3.3.1 
Inclusion Criteria, Criterion 2(c)
Clarified that adenocarcinoma of the 
prostate confirmed by histology is 
mandatory for inclusion
To indicate the precise type 
of adenocarcinoma required 
for inclusion. 
Synopsis, Statistical Analyses; 
Section 8.3.2 Efficacy Analyses; 
Section 8.3.6 Outcomes Research 
Analyses
Stated that efficacy and outcomes 
research analyses will be performed by 
cohort only, not combined
To reflect the change in 
statistical priorities
Section 1.1.9 Rationale for 
Evaluating Chemotherapy-Naive, 
Second Generation Hormone 
Therapy-Naive, Asymptomatic or 
Minimally Symptomatic Metastatic 
CPRC Subjects (Cohort A Subjects)
Added Addendum to describe changes in 
the treatment landscape for 
chemotherapy-naive and hormone 
therapy-naive mCRPC patients, resulting 
in the decision to discontinue Cohort A 
enrollment
To substantiate the decision 
to discontinue Cohort A 
enrollment
Protocol Amendment No.: 05
Date:01-Dec-2021
213
6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Section 3.3.1 Inclusion Criteria 
2(g)i, 2(h)
Criteria 2(g)i and 2(h) not applicable per 
Amendment 02
To reflect discontinuation of 
Cohort A enrollment
Section 3.3.1 Inclusion Criteria, 
Criteria 2(g)ii
Bicalutamide discontinuation required 
within 6 weeks of study treatment.
To clarify prior treatment 
window permitted prior to 
first dose
Section 3.3.1, Inclusion Criteria, 
Criteria 4(e)
Removed requirement for female lab 
values
Not applicable for male only 
study
Section 3.4.1 Prohibited and/or 
Restricted Treatments
Prior systemic therapy to be discontinued 
within 4 weeks of Day 1 visit, and 
bicalutamide or nilutamide within 6 
weeks of Day 1 visit. Added treatment 
window for concurrent neoplastic therapy 
administration.
To clarify prior treatment 
windows permitted prior to 
first dose
Section 3.5 Discontinuation of 
Subjects following any Treatment 
with Study Drug
For subjects with AE related to 
ipilimumab who discontinue ipilimumab 
treatment, inserted a paragraph after 
second paragraph describing requirement 
to delay nivolumab treatment until AE 
has resolved, and conditions for resuming 
nivolumab treatment.
To clarify conditions for 
continuation of nivolumab 
treatment after 
discontinuation of 
ipilimumab 
Section 4.5.1 Dose Delay Criteria
Clarified that, during Part 1, nivolumab 
and ipilimumab should be discontinued if 
AE meeting criteria for dose delay is 
reported, regardless of causality
To correct a typographical 
error from “discontinued” to 
“delayed” in first paragraph
Section 4.5.3 Dose Discontinuation
Modified (increased) duration of dose 
delays due to Grade 3 AST or ALT 
elevations allowed prior to treatment 
discontinuation for Parts 1 and 2
To update conditions for 
discontinuation based on 
AST/ALT AEs.
Section 5.1 Flow Chart/Time and 
Events Schedule, Table 5.1-1 
Screening Procedural Outline
For Laboratory Tests, required 
hematology/blood chemistry testing to be 
performed within 14 days prior to first 
dose 
To provide a time limitation 
for obtaining 
hematology/blood chemistry 
test results prior to first dose
Section 5.1 Flow Chart/Time and 
Events Schedule, Table 5.1-1 
Screening Procedural Outline
Added phosphate to screening labs
To be consistent with Section 
5.4
Section 5.1 Flow Chart/Time and 
Events Schedule, Table 5.1-2 On 
Treatment Part I: Sequential 
Treatment with Nivolumab and 
Ipilimumab Procedural Outline
For Laboratory Tests, noted that repeated 
laboratory tests were not necessary if 
screening labs were performed within 14 
days prior to first dose
To clarify the conditions for 
requiring repeat laboratory 
assessments prior to first 
dose
Section 5.1 Flow Chart/Time and 
Events Schedule, Table 5.1-2 On 
Treatment Part I: Sequential 
Treatment with Nivolumab and 
Ipilimumab Procedural Outline; 
Table 5.1-3 On Treatment Part 2: 
For Efficacy Assessment CT/MRI and 
Tc99m based bone scans, specified that 
scans are to be performed until 
documented disease progression or 
treatment discontinuation, whichever 
occurs later
To clarify conditions for 
stopping efficacy 
assessments
Protocol Amendment No.: 05
Date:01-Dec-2021
214
6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Nivolumab Monotherapy Phase 
Procedural Outline; Table 5.1-4 
Follow-up Assessments
Section 5.1 Flow Chart/Time and 
Events Schedule, Table 5.1-3 On 
Treatment Part 2: Nivolumab 
Monotherapy Phase Procedural 
Outline; Table 5.1-4 Follow-up 
Assessments
Added SAE assessments
To be consistent with Part 1 
and AE reporting 
requirements
Section 5.4, Safety Assessments
Added reference to Schedule of 
Assessment table to determine time 
windows of screening procedures, and 
added albumin, amylase, and lipase to on 
study assessments.
To clarify time windows of 
screening procedures and 
provide consistency with 
Schedule of Assessments
Section 5.5.3 Disease Progression 
Criteria, Table 5.5.3-1 Definition of 
Radiographic Progression per 
protocol 
In the case of unconfirmed progression 
for soft tissue lesion measurements, 
deleted the requirement for this to occur ≥
Week 14
To align with RECIST 1.1
Section 5.5.3 Disease Progression 
Criteria, Table 5.5.3-2 Definition of 
disease Progression by PSA (per 
PCWG2) and Clinical Progression; 
Section 8.2.1 Co-Primary Endpoints 
(under Radiographic Progression-
Free Survival)
Specified that any one of the 3 definitions 
of Clinical Deterioration is applicable
To clarify that any one of the 
3 definitions of Clinical 
Deterioration is applicable 
Protocol Amendment No.: 05
Date:01-Dec-2021
215
6.0
Approved
930104999
6.0
v
Approved
1.0
v


Clinical Protocol
CA209650
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
specifically circulating tumor DNA 
(ctDNA) 
Section 8.2.1 Co-Primary 
Endpoint(s) - Radiographic 
Progression-Free Survival (rPFS)
Revised the definition of clinical 
progression in the context of rPFS such 
that only one of 3 criteria need to be met
To align with RECIST 1.1 
Section 8.3.2 Efficacy Analyses
Stated that efficacy analyses for all 
treatment-assigned subjects (by cohort 
only) will be performed for Cohorts B 
and C only; these data will be listed for 
all treated subjects in Cohort A.
To reflect discontinuation of 
Cohort A enrollment
Section 8.3.3 Safety Analyses
Stated that safety analyses will be 
performed for all treated subjects in 
Cohorts B and C only and that these data 
will be listed for all treated subjects in 
Cohort A
To reflect change in 
statistical priorities and 
discontinuation of Cohort A 
enrollment
Section 11, List of Abbreviations
Added additional abbreviations included 
in the protocol and removed abbreviations 
that are not referenced
To reflect current language 
used in protocol
Appendix 3 Women of Child-
Bearing Potential Definitions and 
Methods of Contraception
Updated appendix to provide more 
complete list of methods of contraception 
and to clarify definitions.
To align with nivolumab 
program standards
Protocol Amendment No.: 05
Date:01-Dec-2021
216
6.0
Approved
930104999
6.0
v
Approved
1.0
v