Conditions: Advanced Tumors
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 83
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of BMS-986158 in subjects with select advanced cancers

Detailed description:

Arms:
arm 1: Patients treated at various doses and schedules arm 2: Patients treated at selected doses and schdules

Interventions: intervention 1: BMS-986158 intervention 2: Nivolumab
Intervention descriptions: intervention 1: Specified dose on specified days intervention 2: Specified dose on specified days

Protocol document:
Prot_000.pdf: 
Official Title of Study: 
A Phase I/IIa Trial With BMS-986158, a Small Molecule Inhibitor of the Bromodomain and 
Extra-Terminal (BET) Proteins, as Monotherapy or in Combination with Nivolumab in Subjects 
with Selected Advanced Solid Tumors or Hematologic Malignancies 
 
 
NCT Number: NCT02419417   
 
Document Date (Date in which document was last revised): 18 Mar 2019 


Page:
1
Protocol Number:
CA011001
IND Number:
124734
Ex-US
Non-IND
EUDRACT Number
2015-000324-29
Date:
02-Mar-2015
Revised Date:
18-Mar-2019
CLINICAL PROTOCOL CA011001
A Phase I/IIa Trial With BMS-986158, a Small Molecule Inhibitor of the Bromodomain and 
Extra-Terminal (BET) Proteins, as Monotherapy or in Combination with Nivolumab in Subjects 
with Selected Advanced Solid Tumors or Hematologic Malignancies
Revised Protocol Number: 07
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organization will participate in and/or the performance of the proposed BMS-sponsored 
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within your organization or to your independent ethics committee(s). Any other use, 
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CA011001
BMS-986158
BET Inhibitor
Revised Protocol No.: 07
Date: 18-Mar-2019
2
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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CA011001
BMS-986158
BET Inhibitor
Revised Protocol No.: 07
Date: 18-Mar-2019
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 07
18-Mar-2019
Identifies the dose and schedule for Part 2 and updates the study design 
for Part 2. Includes revisions to rationales, inclusion/exclusion criteria, 
T&E tables, sample collection tables and statistics; minor typographical 
edits, and an update to Appendix 4 RECIST 1.1.
 
Revised Protocol 06
17-Jul-2018
Updates schedules for mandatory biopsies during Part 2, updates imaging 
requirements for tumor assessments; updates inclusion criteria for 
subjects with NSCLC, corrects dose-limiting toxicity period for Part 2, 
updates schedules for PK sample collections, includes language to allow 
for release of IRT codes to facilitate ongoing data review, and added 
PROSTATE CANCER WORKING GROUP 3 (PCWG3) appendix.
Revised Protocol 05
01-Mar-2018
Incorporates Administrative Letter 04 and the following changes:1) 
clarify the acceptable prior lines of therapy for participants with Non-
Small Cell Lung Cancer (NSCLC) in Part 2; 2) update Exclusion Criteria 
for subjects participating in Part 2; and 3)  provide updated contraception 
and protection requirements based on recent non-clinical reproductive 
toxicology study. Study design elements including time and events 
schedules, sample collections, laboratory analyses and additional safety 
measures have been added to align with these changes.
Administrative 
Letter 04
13-Oct-2017
Revised Protocol 04
06-Sep-2017
Adds nivolumab to Part 2 escalation phase and updates to biomarker 
driven study design with additional tumor types added. Includes 
revisions to rationales, inclusion/exclusion criteria, T&E table, sample 
collection tables and statistics; and minor typographical edits.
Revised Protocol 03
12-Apr-2016
Incorporates Amendment 05
Amendment 05
12-Apr-2016
Removes Parts 1B & 2B and pertaining language from the protocol;
incorporates revisions to the inclusion/exclusion criteria, T&E table, and 
minor typographical edits.
Revised Protocol 02
03-Mar-2016
Incorporates Amendment 04
Amendment 04
03-Mar-2016
Incorporates new dosing regimens, revisions to the inclusion/exclusion 
criteria, T&E table and minor typographical edits
Revised Protocol 01
10-Aug-2015
Incorporates Amendment 01
Amendment 01
10-Aug-2015
Incorporates revisions to the inclusion/exclusion criteria, T&E table, and
minor typographical edits
Original Protocol
02-Mar-2015
Not applicable
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CA011001
BMS-986158
BET Inhibitor
OVERALL RATIONALE FOR REVISED PROTOCOL 07:
The purpose of this revised protocol is 1) To specify the doses and schedule selected for Part 2; 2) 
To describe changes in study design for Part 2, including limiting the initial enrollment into Part 2 
to subjects with a subset of tumor types and making enrollment to therapy with BMS-986158 in 
combination with nivolumab contingent upon evaluation of data obtained from subjects treated 
with monotherapy; 3) To indicate that subjects with castration-resistant prostate cancer are eligible 
only if they can provide a biopsy sample; 4) To update overdose language to conform to current 
BMS standards; and 5) To update Appendix 4 to reflect BMS modifications to RECIST 1.1. Study 
design elements including time and events schedules, sample collections, laboratory analyses and 
additional safety measures have been modified to align with these changes. Additionally, where 
applicable, sections in the synopsis have been updated to align with the protocol section changes 
listed below.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 07
Section Number and Title
Description of Change
Brief Rationale
Selection of doses and schedule for Part 2
Section 1.1.5 Rationale for Dose 
and Schedule: BMS-986158
The estimate for the projected 
human dose has been changed to 
2 mg/day.
The estimate was changed based on 
human PK
Section 1.1.5 Rationale for Dose 
and Schedule: BMS-986158
Added a rationale for selection of 
Schedule A 
To provide justification for 
selection of schedule for Part 2
Section 1.1.5 Rationale for Dose 
and Schedule: Nivolumab
Added text indicating that Schedule 
A will be used for combination 
therapy with nivolumab.
To indicate the dosing schedule 
selected for combination therapy
Section 1.1.13 Rationale for 
Inclusion of Adolescent Subjects 
Modified text to indicate that 
Schedule A was selected for Part 2 
and to indicate the doses selected 
for adolescents
To indicate the dose and schedule 
selected for adolescents
Section 1.4.4.1 Pharmacokinetics of 
BMS-986158
Added 4.5 mg as the highest dose 
tested
To reflect the most recent data 
available for BMS-986158
Section 3.3.2 Exclusion Criteria
New exclusion criterion 
2-g Weight of < 40 kg
Insufficient data to support 
enrollment of patients <40 kg
Section 5.5 Pharmacokinetic 
Assessments
Updated description of PK analysis; 
Removed PK specimen collection 
tables for Part 2 Schedules B and C; 
Updated Table 5.5.1-4 (PK sample 
collection for Part 2 Schedule A) 
To reflect changes in study design 
and selection of Schedule A for Part 
2
Selection of Tumor Types for Initial Enrollment into Part 2
Section 1.1.7: Rationale for 
Evaluating BMS-986158 in an 
Initial Monotherapy Expansion 
Cohort
This is a new section that has been 
added to provide a rationale for 
initial enrollment of subjects with a 
limited subset of tumor types.
To provide a rationale for the 
change in study design
Revised Protocol No.: 07
Date: 18-Mar-2019
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 07
Section Number and Title
Description of Change
Brief Rationale
Section 1.1.8: Rationale for 
Genetically Defined Tumor 
Cohorts: Amplifications
Added a rationale for including 
subjects with MYC amplifications 
in CRPC and non-GC-DLBCL 
tumor types.
Added text indicating which tumor 
types will be enrolled as part of the 
initial expansion and which will be 
enrolled as part of the subsequent 
expansion in Part 2. 
To reflect changes in Part 2 study 
design
Section 1.1.9: Rationale for 
Specific Patient Populations
Added a rationale for inclusion of 
subjects with non-GC-DLBCL. 
To provide a rationale for inclusion 
of non-GC-DLBCL patients
Section 1.1.9: Rationale for 
Specific Patient Populations
Described preliminary results of 
treatment of a CRPC patient with 
OTX015/MK-8628. 
To provide a rationale for inclusion 
of CRPC patients
Section 1.1.13: Rationale for 
Inclusion of Adolescent Subjects
Added tumor types from which 
adolescent subjects may be 
enrolled. 
To align with study design change 
Section 1.5 Overall Risk/Benefit
Described preliminary results from
a study using another BET 
inhibitor, CPI-0610.
To provide further rationale for 
enrollment of specific tumor types
Section 3.3.1 Inclusion Criteria
Inclusion Criterion 2-a-ix-3: Added 
the following text: Abiraterone but 
not enzalutamide may be continued 
during the study.
Inclusion Criterion 2-a-ix-4: Added 
the following new criterion: 
Detected MYC amplification in 
tumor cells (with or without AR 
amplification) 
To clarify inclusion criteria for 
subjects with CRPC
Section 3.3.1 Inclusion Criteria
Inclusion Criterion 2-a-xiii: Added 
the following text: “DHL” 
Inclusion Criterion 2-a-xiii-4: 
Added the following new criterion: 
“IHC confirmed CD 10-, BCL6-
DLBCL, or CD10-, BCL6+ and 
MUM1+ DLBCL. Gene expression 
profile may also be used to confirm 
a diagnosis of non-GC-DLBC.”
To add subjects with non-GC 
DLBCL as eligible for enrollment
To remove mandatory enrollment to therapy with BMS-986158 in combination with nivolumab in Part 2
Section 1.1.2 Rationale for 
combining BMS-986158 with 
Nivolumab
Added examples from the literature  
illustrating both proinflammatory 
and anti-inflammatory actions of 
BET inhibitors.
Contradictory findings in the 
literature provide a rationale for 
deferring combination therapy until 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 07
Section Number and Title
Description of Change
Brief Rationale
the effects of BMS-986158 
monotherapy have been evaluated.
 
Section 1.2 Research Hypothesis
Changed “monotherapy or in 
combination with nivolumab” to 
“monotherapy and/or in 
combination with nivolumab.”
To indicate that combination
therapy will only be pursued after 
an assessment of data obtained 
from monotherapy
Section 4.1 Investigational Product
Added: “BMS-986158 combination 
with nivolumab will only be 
pursued on review of safety 
information and the totality of data 
obtained from BMS-986158 
monotherapy in Parts 1 and 2.”
To indicate that combination 
therapy will only be pursued after 
an assessment of data obtained 
from monotherapy
Overall Study Design
Section 1.3 Objectives
Modified primary objectives for 
Parts 1 and 2: there is now one 
primary objective for all 
monotherapy and a second primary 
objective for combination therapy 
Modified all objectives that refer to 
combination therapy to indicate that 
these objectives will only be 
evaluated if combination is 
pursued.
To reflect the changes in study 
design
Section 3.1 Study Design and 
Duration
Updated description of overall 
study design, Part 2 study design, 
and sample size.
Updated Figure 3.1-1 Study 
Overview and Figure 3.1-2 
Expansion Cohort.
To reflect changes in study design
Revised Protocol No.: 07
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BMS-986158
BET Inhibitor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 07
Section Number and Title
Description of Change
Brief Rationale
Section 3.1.2 Dose Expansion (Part 
2)
Updated text describing the study 
design for Part 2.
To reflect changes in study design
Section 3.1.2.1 Safety Evaluation 
Phase of BMS-986158 
Monotherapy
Changed section title from “Parallel 
and Sequential Evaluation of 
Monotherapy and Combination 
Therapy” To “Safety Evaluation 
Phase of BMS-986158 
Monotherapy
Removed section contents unrelated 
to safety.
To better describe the contents of 
this section
Section 3.1.2.3 Safety Evaluation in 
Adolescents
Updated text describing the study 
design for Part 2.
To reflect changes in study design
Section 3.1.2.4 BMS-986158 
Monotherapy and in Combination 
with Nivolumab Dose Expansion--
Number of Participants
Added the text “Number of 
Participants” to the section title
Updated Table 3.1.2.4-1 Planned 
Sample Size.  
Updated sample size text.
To reflect change in study design
Section 3.6 Treatment Beyond 
Progression
Updated section to indicate that 
subjects receiving BMS-986158 
monotherapy are not eligible for 
treatment beyond progression.
Evidence supporting the 
continuation of BMS-986158 
monotherapy beyond progression is 
lacking.
Section 8.1 Sample Size 
Determination
Updated section.
To reflect changes in study design
Other changes
Section 1.1.9: Rationale for 
Specific Patient Populations
Section 1.5 Overall Risk/Benefit 
Assessment
Changed OTX-015 to OTX-
015/MK-8626
To provide both names used in the 
literature
Section 1.1.9: Rationale for 
Specific Patient Populations
Changed “therapies that maintain a 
castrate state” to “abiraterone but 
Enzalutamide is a moderate-to-
strong inducer of CYP enzymes. 
Because BMS-986158 is a CYP3A 
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BMS-986158
BET Inhibitor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 07
Section Number and Title
Description of Change
Brief Rationale
not enzalutamide to maintain a 
castrate state.”
substrate, enzalutamide is excluded 
in subjects with CRPC.
Section 1.1.13: Rationale for 
Inclusion of Adolescent Subjects
Updated number of subjects treated 
with BMS-986158.
To reflect the most recent data 
available for BMS-986158
Section 1.4.3.5 Pharmacokinetic 
Drug Interactions
Removed text describing BMS-
986158 as an OATP3 substrate.
Due to inconsistencies in preclinical 
data 
Section 1.4.4 Clinical 
Pharmacology and Safety
Updated number of subjects treated 
and AE information to reflect the 
December 2018 data cut from 
CA011001.
To reflect the most recent data 
available for BMS-986158
Section 1.5 Overall Risk/Benefit 
Assessment
Updated safety information to 
reflect the December 2018 data cut 
from CA011001
To reflect the most recent data 
available for BMS-986158
Section 3.3.1 Inclusion Criteria
Updated Inclusion Criterion 1-a-i 
Inclusion Criterion 2-d: the text 
“only be eligible” has been added
To ensure evaluable biopsies are 
collected from all subjects
Section 4.6 Blinding/Unblinding
Removed text indicating Sponsor 
may access IRT treatment codes 
prior to database lock
Part 2 is open-label
Section 5.1 Flow Chart/Time and 
Events Schedule
Table 5.1-1 (Screening): Added 
PSA screening for CRPC patients 
added; mandatory archival tumor 
samples if pretreatment tumor 
samples not available or sufficient. 
Table 5.1-3 and Table 5.1-4 (Part 1 
Schedule B and C): Targeted 
Physical Exam, Physical 
Measurement, Vital Signs may be 
omitted on Day 8, D8 laboratory 
tests may be performed at local 
labs, and tumor assessments should 
occur every 12 weeks  for subjects 
who have been on study for ≥1 
year. 
Table 5.1-5 (Part 2): added PSA 
screening for CRPC patients; 
 
.
To simplify visit scheduling for 
subjects in Part 1 Schedules B and 
C who have been on study for >1 
year and to reflect changes in study 
design for Part 2.
Section 5.3.2 Laboratory Test 
Assessments
Added PSA screening for CRPC 
subjects.
To conform with PCWG3 
assessment of  subjects with CRPC
Section 6.1.1 Serious Adverse 
Event Collection and Reporting
Added SAE reporting period for 
combination therapy
To align with current reporting 
standards for nivolumab
Section 6.5 Overdose
Updated section.
To align with current BMS 
standards
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Date: 18-Mar-2019
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BMS-986158
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 07
Section Number and Title
Description of Change
Brief Rationale
Appendix 4 RECIST 1.1
Updated appendix 
To align with current BMS 
standards
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CA011001
BMS-986158
BET Inhibitor
SYNOPSIS
Clinical Protocol CA011001
Protocol Title: A Phase I/IIa Trial with BMS-986158, a Small Molecule Inhibitor of the Bromodomain and Extra-
Terminal (BET) Proteins, as Monotherapy or in Combination with Nivolumab in Subjects with Selected Advanced 
Solid Tumors or Hematologic Malignancies
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): BMS-986158 is formulated as a hard gelatin capsule 
 to be administered by oral route. Nivolumab is formulated as a solution for injection. 
Part 1 (BMS-986158 monotherapy dose escalation with Schedules A, B, and C enrolling at different dosing 
schedules, See Figure 1). Schedule A enrolled first. Each subject in Schedules A, B and C is administered a single 
dose of BMS-986158 on Cycle 1 Day 1 and no additional doses are administered until Cycle 2 Day 1. For subjects in 
Schedule A on Cycle 2 Day 1, which must be within approximately 7 days of the Cycle 1 Day 1 dose administration, 
and on each subsequent cycle, subjects receive once daily dosing for 5 consecutive days of each week, followed by a 
2-day rest period, on a 28-day cycle. For subjects in Schedule B on Cycle 2 Day 1, which must be within approximately
7 days of the Cycle 1 Day 1 dose administration, and on each subsequent cycle, subjects receive once daily dosing for 
14 consecutive days, followed by a 7-day rest period, on a 21-day cycle. For subjects in Schedule C on Cycle 2 Day 1, 
which must be within approximately 7 days of the Cycle 1 Day 1 dose administration, and on each subsequent cycle, 
subjects receive once daily dosing for 7 consecutive days, followed by a 14-day rest period, on a 21-day cycle. In 
Part 1, the continuous dosing Schedule A enrolled first. Subjects may continue to receive treatment in all 3 dose 
schedules until disease progression, unacceptable adverse events (AEs) or withdrawal of consent.
Part 2 expansion (BMS-986158 monotherapy and/or in combination therapy with nivolumab, See Figure 1). In 
Part 2, Schedule A (QD dosing for 5 consecutive days on with 2 days off each week of a 28-day cycle) for BMS-
986158 administration has been selected for expansion of the 4.5 mg dose, which will be administered for 2 weeks 
(10 doses) followed by 3.75 mg for the remainder of the treatment period, as agreed upon between the 
Sponsor/Medical Monitor and investigators considering safety, PK
 data generated 
during Part 1. This dosing and schedule will be evaluated for up to 2 years in adult and adolescent subjects. Adults 
and adolescent subjects weighing ≥40 kg will be administered a flat dose of BMS-986158. Using Schedule A and a 
dosage of 4.5 mg for a 2-week loading period followed by 3.75 mg for the remainder of the treatment period, BMS-
986158 will be tested as monotherapy and potentially in combination with nivolumab. If pursued, nivolumab will be 
administered as a flat dose of 480 mg Q4W. Adolescent subjects will receive nivolumab at 6 mg/kg up to a maximum 
of 480 mg for Schedule A with the same frequency of administration as adults.
Study Phase:  Phase I/IIa
Research Hypothesis: There is no formal primary research hypothesis for this study to be statistically tested. It is 
anticipated that BMS-986158 as monotherapy and/or in combination with nivolumab (i pursued) will demonstrate 
adequate safety and tolerability at pharmacologically relevant doses, so as to permit further clinical development (at 
a recommended dose range).
Objectives:  
Primary
•
To assess the safety and tolerability and to assess the dose limiting toxicities (DLTs), maximum tolerated dose 
(MTD), and recommended Phase 2 dose (RP2D) of BMS-986158 as monotherapy for subjects with selected 
advanced solid tumors and hematologic malignancies.
•
If combination with nivolumab is pursued, to assess the safety and tolerability at the RP2D of BMS-986158 in 
combination with nivolumab and to assess the DLT for subjects with advanced solid tumors and hematologic 
malignancies.
Secondary
•
To assess the preliminary antitumor activity of BMS-986158 monotherapy and, if pursued, in combination with 
nivolumab as measured by objective response rate (ORR), and response duration based on response evaluation 
Revised Protocol No.: 07
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BMS-986158
BET Inhibitor
criteria in solid tumors using criteria from RECIST v1.1, prostate cancers using PCWG3 criteria, or hematologic 
malignancies using criteria from Lugano 2014.
•
To characterize pharmacokinetics of BMS-986158 and metabolite in monotherapy and, if pursued, in combination 
with nivolumab.
•
To assess the dose-response and exposure-response effect of BMS-986158 monotherapy on the ECG (QT 
interval).
Study Design:  This is a Phase I/IIa, open-label study of BMS-986158 administered as monotherapy and, if pursued,
in combination with nivolumab to subjects with selected advanced solid tumors and hematologic malignancies. The 
study will be conducted in two parts: a dose escalation phase (Part 1) and a dose expansion phase (Part 2). Schematics
of the study are provided in Figure 1 and Figure 2.
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BMS-986158
BET Inhibitor
Figure 1:
Study Overview
Abbreviations: BL = Burkitt’s lymphoma; CRPC = castrate-resistant prostate cancer; DHL = double-hit lymphoma; ES = Ewing sarcoma; NEPC = neuroendocrine 
prostate cancer; NMC = NUT-midline carcinoma; NSCLC = non-small cell lung cancer; OC = ovarian cancer; RCC = renal cell carcinoma; Res = response; SOC 
= standard of care; TNBC = triple negative breast cancer; UCS = uterine carcinosarcoma; UM = uveal melanoma; Non-GC-DLBCL = Non-germinal center diffuse 
large B-cell lymphoma.
*Up to 45 subjects with a limited set of tumor types will be enrolled in the Initial Expansion. Subsequent enrollment of subjects with an expanded set of tumor 
types within and across groups (eg, fusion proteins, BRD amplifications, MYC amplifications, AR amplifications, or mutations)as part of the Subsequent Expansion 
will depend on the totality of data obtained from subjects in the Initial Expansion. If combination therapy with nivolumab is pursued, subjects with any listed tumor 
type will be eligible.
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BMS-986158
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Figure 2:
Expansion Cohorts
Part 1 consists of the dose escalation phase with BMS-986158 administered as monotherapy.
Part 2 consists of cohort expansions in solid tumors and hematologic malignancies (BMS-986158 monotherapy and 
potentially in combination with nivolumab). Treatment in Part 2 will be initiated when the MTD or maximum 
administered dose (MAD) if no MTD is reached and dose schedule(s) from Part 1 has been determined. Schedule A 
(QD dosing for 5 consecutive days of each week, followed by a 2-day rest period, on a 28-day cycle) has been chosen 
for expansion after starting with 4.5 mg for a 2-week loading period (5 days on/2 days off) followed by the same 
schedule at a reduced dose level of 3.75 mg for all subjects. The schedule and dosage were chosen based on safety, 
PK
 data generated during Part 1.
Part 1: Selection of Dose Levels
The first cohort of subjects in Schedule A received a starting dose level of 0.75 mg daily for 5 consecutive days per 
week beginning at Cycle 2. Dose escalation for each subsequent cohort of subjects is guided by the incidence of AEs 
for which no clear alternative cause is identified, as graded by National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03) in the first 32-35 days of dosing (DLT evaluation 
period) of Schedule A, and the first 35 days of dosing (DLT evaluation period) of Schedules B and C. Dose escalation 
will be in increments of 100% above the previous dose level until the first occurrence of any of the following toxicities 
that have no alternate cause: any DLT (as described in Section 4.5.1), any ≥Grade 2 toxicities with the following 
exceptions: Grade 2 fatigue, Grade 2 alopecia. 
Once one or more of the above identified DLTs occurs, a modified Fibonacci dose escalation schema will be employed 
for any subsequent dose escalations at that schedule, with increments of 67%, 50%, 40%, and 33%. Any further dose 
escalations will be 33%. In addition, dose modification could also include changes in the dosing interval (e.g. twice 
weekly), based on available safety and PK data.
Intermediate dose levels may be evaluated if agreed upon by the Sponsor/Medical Monitor and investigators. The next 
dose level will not exceed 100% of the prior dose level or the dose increment per the modified Fibonacci dose 
escalation schema.
Part 1: Dose Escalation Decision Rules
Enrollment in dose escalation and selection of the maximum tolerated dose (MTD) will adhere to a modified Toxicity 
Probability Interval (mTPI) design. The design provides a simple algorithm for decisions on escalation, expanding at 
the same dose level, and de-escalation, depending on the number of observed toxicities after each dose level cohort 
(see Figure 3). The mTPI method utilizes a target toxicity (DLT) rate and equivalence interval (EI) to guide decisions 
on escalation after each cohort and to estimate the MTD. For this study the target DLT rate is 27% and the EI is 
25%-29%.
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Dose escalation decisions starting with the first dose cohort will be guided by the cumulative number of subjects who 
are DLT evaluable and who experience a DLT in the DLT evaluation period for all arms (Figure 3). If no DLTs are 
observed in the first dose cohort, 3-4 subjects will be enrolled at the next dose level. If 1 DLT is observed in 3 or 4 
evaluable subjects, this dose level will be expanded by enrolling another cohort of 3-4 at the same dose level. If 2 of 
3 or 3 of 4 subjects are observed with DLTs, the next cohort will be enrolled at the lower dose level. Additional 
decisions are shown in Figure 3. If a decision to treat more subjects at a given dose level is suggested by the mTPI 
algorithm when there are already at least 13 DLT evaluable subjects treated at the same dose level, a need for further 
enrollment in the dose escalation phase will be determined by the Sponsor. These same rules will be applied to 
Schedules B and C. A total of approximately 30 DLT evaluable subjects is expected to be treated per schedule with a 
total of 90 planned across schedules for the dose escalation phase.
Decisions to escalate, add more subjects to the current dose level, de-escalate (with options to re-escalate), or de-
escalate and declare the current dose as unacceptable (exceeding the MTD), will be based on the rate of DLTs in 
evaluable subjects within the 32 to 35-day DLT evaluation period for Part 1 Schedule A and within the 35-day DLT 
evaluation period for Part 1 Schedules B and C. At least 3 DLT-evaluable subjects treated at each dose level are 
required to enable a decision. To account for subjects who may not be able to complete the DLT evaluation period, 
for reasons other than a DLT, or may not be evaluable for DLT, a fourth subject may be enrolled at this dose level, 
following agreement between the investigator and Sponsor/Medical Monitor. Subjects must receive at least 16 of the 
21 planned doses in Schedule A of Part 1, 17 of the 22 planned doses in Schedule B of Part 1, or 12 of the 15 planned 
doses in Schedule C of Part 1, during the DLT evaluation period to be considered evaluable for dose escalation 
decisions. Subjects who developed a DLT during the DLT period are considered evaluable regardless of the number 
of received doses. Subjects with insufficient data to establish safety during the DLT evaluation period at the dose level
tested may be replaced upon agreement of the Sponsor/Medical Monitor and investigators.
There will be no intrasubject dose escalation of BMS-986158.
Figure 3 shows examples of scenarios guiding decisions that may be encountered during dose escalation with respect 
to the number of DLT evaluable subjects and the number of subjects with a DLT. In addition to escalation or expansion 
decisions, dose re-escalation is permitted as per Figure 3 after a decision to de-escalate is made, except when a dose 
level has been identified as exceeding the MTD. Therefore, a dose level could be revisited multiple times under the 
mTPI design.
Figure 3:
Monotherapy Dose Escalation Decision Guide
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Part 1A: MTD Determination
At the end of dose escalation, the MTD or MAD for each evaluated dosing schedule (Schedules A, B, and C) will be 
selected as the dose with the smaller difference between estimated toxicity and the target DLT rate (27%), among the 
dose levels used, with an isotonic regression model of the accumulated DLT data based on the mTPI design (Appendix 
1).
Dose Limiting Toxicity for Part 1
For the purpose of guiding dose escalation decisions, DLTs are defined separately in Protocol Section 4.5.1 and will 
be determined based on the incidence, intensity, and duration of AEs for which no clear alternative cause is identified. 
The DLT evaluation period will be within 32 to 35 days (depending on the exact day of the start of Cycle 2) of initiation 
of study therapy for Schedule A and 35 days for Schedules B and C in Part 1. The DLT period for safety assessment 
of BMS-986158 and nivolumab combination therapy in Part 2 will match the DLT period for the selected schedule in 
Part 1 (ie, 32 to 35 days for Schedule A and 35 days for Schedules B and C). AEs will be graded according to NCI 
CTCAE v4.03. For the purposes of subject management, DLTs will lead to dose interruptions regardless of the cycle 
in which a DLT occurs. AEs occurring after the above defined DLT evaluation period will be considered for the 
purposes of defining the RP2D, upon agreement between the Sponsor/Medical Monitor and investigators, if they are 
determined to have no clear alternative cause and are not related to disease progression.
Part 2: Dose Expansion
Treatment in Part 2 can be initiated before Part 1 is completed and when the MTD, or maximum administered dose 
(MAD) if no MTD is reached for Part 1, has been determined. Schedule A (QD dosing for 5 consecutive days of each 
week, followed by a 2-day rest period for a 28-day cycle) has been chosen for dosing in expansion to be implemented 
as follows: The initial dose level of BMS-986158 selected for Part 2 is 4.5 mg with a loading period of 2 weeks
(10 doses or half a cycle) with subsequent lower dose of 3.75 mg for the duration of study treatment for each subject.
Further dose modification at the subject level is permitted below the dose level of 3.75 mg depending on the observed 
toxicity and tolerability.
The dose and schedule were selected upon agreement between the Sponsor/Medical Monitor and investigators, 
considering safety, PK
 data generated during Part 1. Adult and adolescent subjects 
weighing ≥40 kg will be administered a flat dose of BMS-986158. 
BMS-986158 will be evaluated in expansion as monotherapy; initially in up to 45 subjects with tumors harboring 
specific genetic alterations including fusion proteins (NUT-midline carcinoma [NMC], double-hit lymphoma [DHL]), 
BRD amplifications (triple negative breast cancer [TNBC]), MYC amplifications (non-germinal center diffuse large 
B-cell lymphoma [non-GC DLBCL]) and AR amplification (castrate resistant prostate cancer [CRPC]).
 
 
 
 
Depending on the safety, 
preliminary efficacy, tolerability
in these initial cohorts, a subsequent set of monotherapy cohorts in up to 
126 subjects with tumor types already evaluated in the initial expansion cohort as well additional tumor types within 
and across groups of specific genetic alterations may be enrolled. Categories of genetic alterations and tumors under 
consideration for subsequent enrollment include fusion proteins (NMC, DHL, Ewing sarcoma [ES] and Burkitt’s 
lymphoma [BL]), BRD amplifications (triple negative breast cancer [TNBC], ovarian cancer [OC] and neuroendocrine 
prostate cancer [NEPC]), MYC amplifications (Non-GC DLBCL, uterine carcinosarcoma [UCS], OC), AR 
amplification (CRPC) and mutations (renal cell carcinoma [RCC], non-small cell lung cancer [NSCLC] and uveal 
melanoma [UM]).
The decision to assign new cohorts of subjects to BMS-986158 plus nivolumab combination therapy will be made 
after review of preliminary efficacy, 
 and other available data obtained from both Initial and 
Subsequent monotherapy expansion subjects upon agreement between the Sponsor/Medical Monitor and 
investigators. If combination therapy of BMS-986158 and nivolumab is pursued, subjects may be enrolled with any 
of the tumors types listed in Figure 1.
In Part 2, subjects who have progressive disease after receiving BMS-986158 in combination with nivolumab may 
have the option of continuing on treatment with the combination, if combination therapy is pursued. Subjects who 
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have progressive disease after receiving BMS-986158 monotherapy will not have the option of continuing on 
treatment with BMS-986158 monotherapy or receiving BMS-986158 in combination with of nivolumab.
Clinical safety monitoring of subjects treated with BMS-986158 monotherapy enrolled in Part 2 of the study will be 
the same as conducted during the dose escalation portion. During Part 2, if in a given tumor cohort the combined 
incidence of study drug-related AEs that require dose modification exceeds 29% (of treated subjects), then further 
enrollment to that arm may be interrupted and the findings will be discussed between the Sponsor/Medical Monitor 
and investigators. An agreement will be reached as to whether a lower dose level or an alternate dose schedule of 
BMS-986158 should be examined, or whether any additional treatment guidelines should be implemented prior to 
enrollment of additional subjects on study.
If pursued, the safety of the selected BMS-986158 dose when given in combination with nivolumab within the dose 
expansion phase will be evaluated by monitoring DLTs in the first 6 to 12 subjects treated across different tumor 
cohorts receiving combination therapy. The DLT period in Part 2 will be 28 days, which excludes a 7-day single dose 
period in Part 1 (Cycle 1) to allow appropriate comparison. Once the selected dose of BMS-986158 in combination 
with nivolumab is deemed safe based on the DLT evaluation, the dose expansion will continue as planned in all 
cohorts. The guidance for assessing the DLT-related safety and overall safety will be similar to that used in the 
monotherapy cohorts. The DLT safety monitoring during the dose evaluation phase including potential decision to de-
escalate to a lower dose will be based on the mTPI-2 design with target toxicity (DLT) rate of 29% (-2%, +4%).
Duration of Study: The overall duration of the study is expected to be approximately 4 years from the time of the first 
visit of the first subject to the required survival follow-up of the last subject enrolled. Subjects may discontinue 
treatment due to disease progression, unacceptable AEs, or withdrawal of consent. Dependent upon treatment, the 
Clinical Follow-up visits will occur approximately 30 days (for subjects who receive monotherapy) and 60 and 
100 days (for subjects who receive combination therapy) after the subject discontinues study treatment. For subjects 
in partial response (PR) or complete response (CR) who discontinue treatment for AEs, tumor assessments will be 
performed every 12 weeks for the first year then every 6 months for the second year. If a subject discontinues treatment 
due to an AE, the subject should be seen in Clinical Follow-up every 30 days until the AEs either resolved to baseline
or Grade 1, stabilized, or been deemed irreversible. After completing the Clinical Follow-up Period, subjects will 
continue on to a Survival Follow-up Period. 
 
 
 
The end of the study will occur after the last treated subject completes their Clinical Follow-up, unless 
if a subject discontinues prematurely.
Number of Subjects: The planned sample size consists of up to approximately 90 subjects for Part 1 and up to 
approximately 327 subjects for Part 2 for a total of up to approximately 417 subjects in the entire study.
Study Population: The study population will include adult men and women who are at least 18 years of age and 
adolescents ≥12 years of age who meet the study eligibility criteria. Adult subjects must have histologic/cytologic 
confirmation of one of the following malignancies to be eligible: OC, TNBC, NSCLC, RCC, UM, UCS, NEPC, CRPC, 
NMC, ES, BL, DHL, or non GC-DLBCL. Adolescent subjects must have histologic/cytologic confirmation of NMC, 
ES, or BL. At least one (1) site of measurable disease as defined by RECIST v1.1 for solid tumors, Lugano 2014 
criteria for lymphomas, or PCWG3 for prostate cancers is mandatory. Additionally, in order to be eligible for 
enrollment to Part 1 of the study, all subjects must have either an archival tumor tissue block or at least twenty (20) 
unstained cut slides identified and available, and consent to provide this archival tissue. Acquisition of adequate pre-
treatment tumor tissue is mandatory for adult subjects in this study. Subjects who do not have archival tissue available 
may consent to a pre-treatment fresh tumor biopsy to be eligible for this study if it can be performed at acceptable 
clinical risk as judged by the investigator and if it does not include a target lesion or a lesion in an area treated with 
prior radiation therapy. All adult subjects enrolled in Part 2 must have tumor lesions that can be biopsied or collected 
via core needle at acceptable clinical risk (as judged by the investigator) at baseline (pre-treatment), during treatment, 
and end of treatment (EOT) in case of PD. 
Women of childbearing potential (WOCBP) must not be nursing or pregnant and must be using an acceptable method 
of contraception for at least 4 weeks before dosing and for 5 months following the last dose of study drug. WOCBP 
must have a negative pregnancy test within 24 hours prior to dosing with study medication. Male participants who are 
sexually active with a WOCBP should also use an adequate method(s) of contraception, irrespective of vasectomy 
status or partner’s pregnancy status, for up to 7 months following the last dose of study drug.
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Study Drug: includes Investigational [Medicinal] Products (IP/IMP) as listed:
BMS-986158 is formulated as a hard gelatin capsule 
 
 to be administered by oral route. 
Nivolumab is formulated as a solution for injection.
Study Drug for BMS-986158
Medication 
Potency 
IP/Non-IP 
BMS- 986158
0.25 mg and 2 mg
IP
Nivolumab
100 mg/vial (10 mg/mL)
IP
Study Assessments:  
Safety Outcome Measures: AEs will be assessed continuously during the study and for 30 days after the last treatment
of BMS-986158 monotherapy and 100 days post discontinuation of combination therapy. AEs will be coded using the 
most current version of MedDRA and reviewed for potential significance and importance. AEs will be evaluated 
according to the NCI CTCAE v4.03. Subjects should be followed until all treatment related AEs have recovered to 
baseline, or are deemed irreversible by the investigator. Safety assessments will be based on medical review of AE
reports and the results of vital sign measurements, ECGs, physical examinations, and clinical laboratory tests.
Efficacy Measures: Disease assessment with computed tomography (CT) and/or magnetic resonance imaging (MRI)
(solid tumors and lymphoma) or fluorodeoxyglucose - positron emission tomography (hematologic malignancies, 
when standard of care [SOC]), as appropriate, will be performed at baseline. Disease assessment will occur every 
8-9 weeks ±1 week from the start of study therapy. Disease assessment at other time points may be performed at the 
discretion of the investigator. Tumor assessments will continue until disease progression or until subjects withdraw 
from the study. Tumor responses will be determined as defined by RECIST v1.1 criteria for solid tumors. For 
hematologic malignancies, responses will be based on the Lugano 2014 Classification for Initial Evaluation, Staging, 
and Response for Hodgkin Lymphoma. For prostate cancers (CRPC and NEPC), responses will be defined based on 
PCWG3. At the Sponsor’s discretion, scans and measurements may be reviewed by independent radiologists using 
RECIST v1.1, Lugano 2014, or PCWG3 criteria at a later date, or at any time during the study.
Pharmacokinetic Measures: Pharmacokinetic parameters for BMS-986158 (Cmax, Tmax, AUC(TAU), and 
AUC(0-T); single dose only if data permits: T-HALF, AUC(INF), CLT/F, Vz/F; multiple dose only: Cmin, Ctau, 
Ctrough, Accumulation Index (AI) and T-HALFeff), will be derived from parent (BMS-986158) and metabolite 
plasma concentration versus time data.  In addition the metabolite to parent ratios adjusted for molecular weight (MR) 
will be calculated for Cmax, AUC(0-T), AUC(INF) and AUC(TAU).
 
 
 
 
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Statistical Considerations:
Sample Size:  
Dose Escalation: In the dose escalation part of the study for monotherapy Part 1, the sample size per dose level cannot 
be precisely determined and will depend on observed DLTs and the decision rules of the mTPI design. Between 3 and 
up to 13 DLT evaluable subjects may be enrolled to a given dose level, based on the decision guide by the mTPI 
design. Treating additional subjects beyond the 13 that are DLT evaluable at a dose level would be unlikely to alter 
the decision specified by the mTPI algorithm. A total of approximately 30 subjects is expected to be treated per 
schedule, with a total of 90 planned across schedules for the dose escalation phase. More subjects may be added at a 
specific schedule if additional dose levels need to be evaluated. Similarly, fewer than 30 subjects may be needed for 
a different schedule if a smaller number of dose levels are evaluated. 
Cohort Expansion:
During this part of the study, the efficacy signal assessment will start with initial monotherapy cohorts. This 
assessment will be guided by a Fleming 2-stage design, to provide the option for early evaluation and planning based 
on an initial efficacy signal. The sample sizes for each cohort are calculated based on assumptions of true (target) and 
historic ORR for each tumor type. A 2-stage design provides criteria for the option to stop early for futility, and an 
understanding of an early signal of preliminary, strong antitumor activity. Approximately 5 to 9 subjects will be treated 
in each of the cohorts, based on the Fleming (optimal) design criteria; Enrollment may continue after the initial 
5 subjects to ensure that sufficient subjects are evaluable (eg, with tumor scans) or in case of early drop outs. There 
will be no stopping due to an efficacy signal. 
In summary, approximately up to 45 subjects are expected to be treated across the Initial monotherapy cohorts, with 
approximately 5 to 9 subjects per cohort. Based on the totality of data obtained from Initial monotherapy cohorts, up 
to 126 subjects may be enrolled in Subsequent monotherapy cohorts with an expanded set of tumor types within and 
across groups.
If the combination of BMS-986158 with nivolumab is pursued, safety will be evaluated across the tumor types in the 
first 6 to 12 evaluable subjects who receive combination therapy based on the DLT observed. The mTPI-2 design with 
DLT target of 29% (-2%, +4%) will be used to guide decisions in this setting, including potential de-escalation to a 
lower dose of BMS-986158 in combination with nivolumab, if warranted by the observed results. 
The above sample sizes are based on the assumption that the selected RP2D is deemed safe in combination therapy. 
If a lower dose level must be evaluated in combination therapy, an additional 6 to 12 subjects may be enrolled to 
assess safety of BMS-986158 prior to fully expanding in combination therapy.
The potential total for expansion will be approximately up to 201 subjects if only monotherapy is pursued, and 
approximately up to 327 subjects if all planned expansion cohort subjects in monotherapy and combination therapy 
groups are pursued. 
Endpoints:  
Primary Endpoints: Incidence of AEs at their worst grade, serious adverse events (SAEs) at their worst grade, AEs 
leading to discontinuations, deaths, and frequency of laboratory test toxicity grade shifting from baseline. Safety will 
be evaluated from the time that the subject signs the informed consent and for up to 30 days and 100 days after the 
last dose of BMS-986158 monotherapy or if pursued, BMS-986158 in combination with nivolumab, respectively, or 
until resolution of any AE for which alternative causes could not be identified resolve to ≤Grade 1 or baseline or until 
the event has stabilized, whichever is longer.
Pharmacokinetics: Select PK parameters including Cmax, Cmin, Tmax, AUC (TAU), AUC(0-T), will be derived 
from parent (BMS-986158) and metabolite plasma concentration versus time data for all schedules. In addition 
parameters specific to single dose only, if data permits, (T-HALF, AUC(INF), CLT/F, Vz/F) or multiple dose only 
(Cmin, Ctau, Ctrough, AI and T-HALFeff) will be calculated derived from parent (BMS-986158) and metabolite 
plasma concentration versus time data. The metabolite to parent ratios (MR) will also be calculated for Cmax, AUC(0-
T), AUC(INF) and AUC(TAU).
 
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Efficacy: ORR, Duration of response (DOR), progression-free survival, and Progression Free Survival Rate (PFSR) 
at select times are efficacy endpoints. ORR is defined as the total number of subjects whose best overall response 
(BOR) is either a CR or PR, divided by the total number of subjects in the population of interest.
ECG: Changes in QTcF (ΔQTcF) from baseline at selected times following monotherapy treatment with 
BMS-986158 and association measures of QTc changes with BMS-986158 PK exposure.
Analyses:
Safety Analyses: All recorded AEs will be listed and tabulated by system organ class, preferred term and treatment. 
Vital signs and clinical laboratory test results will be listed and summarized by treatment. Any significant physical
examination findings and clinical laboratory results will be listed. ECG readings by the investigator will be 
summarized, and abnormalities, if present, will be listed. Safety data may also be presented in adolescent participants 
based on data availability.
Efficacy Analyses: Efficacy results will be presented by tumor type, dose level, dosing schedule and/or regimen. 
Individual BOR, DOR and PFS using RECIST v1.1 criteria for solid tumors, Lugano 2014 criteria for hematologic 
malignancies, or PCWG3 for prostate cancers will be listed. BOR outcomes and ORR will be tabulated by dose/dose 
regimen and across doses for each tumor. For ORR, 95% confidence intervals will be calculated based on the 
Clopper-Pearson method. The median DOR (mDOR) for responders and median PFS will be estimated by Kaplan-
Meier (K-M) methodology. PFS rates (e.g. at 24 weeks) will be similarly estimated, based on K-M methodology, with 
confidence intervals based on the Greenwood formula and tabulated for each tumor. Individual changes in the tumor 
burden versus time will be presented graphically by dose level/study arm/dose regimen within a tumor type. 
 
ECG Analyses: For subjects with serial ECG measurements and time-matched PK following monotherapy treatment 
with BMS-986158, changes in the QTcF (ΔQTcF), ECG intervals QRS, and PR, and in heart rate (ΔHR) will be 
tabulated by treatment and study day. Frequency distributions of max QTcF values, max ΔQTcF, max QRS, max PR, 
and max heart rate in pre-specified categories will be tabulated by treatment. Scatter plots of heart rate, ΔHR, QTc, 
and ΔQTcF, vs time-matched BMS-986158 concentrations will be provided. A concentration-response effect of 
BMS-986158 on QTcF may be assessed by a linear mixed effects regression model for ΔQTcF on PK, by study day, 
as well as pooled across days.
Pharmacokinetic Analyses: PK parameters for BMS-986158 will be calculated using noncompartmental analysis. 
Summary statistics will be tabulated for the PK parameters by dose level, dose regimen, and study cycle/day for each 
schedule. To describe the dependency on dose, scatter plots of Cmax and AUC(0-T), AUC(TAU), versus dose will be 
provided on indicated study cycle for each dose regimen.
 
 Geometric means and coefficients of variation (CV%) will be reported for Cmax, AUC, Cmin, Ctau, 
Ctrough, CLT/F, Vz/F, AI, T-HALFeff and MR; Medians and ranges will be reported for Tmax; means and Standard 
Deviations will be reported for T-Half. PK data may also be summarized separately for adolescent participants 
depending on data availability. 
 
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Interim Analysis: Because of the exploratory nature of the early phase study, data emerging from each dose level, 
treatment arm, or each part of the study will be examined prior to the final lock of the study database for timely 
decisions such as dose level or dose schedule selection, early termination of the study or publications. Analyses will 
only consist of listings, summaries, and graphs of the available data. In addition, modeling of PK (e.g. exploration of 
exposure-response and simulations) or key safety data may be utilized to inform dose level or dose schedule selection 
for subsequent parts of the study, as data permits. No formal inferences requiring any adjustment to statistical 
significance level will be performed, or adjustment for multiplicity.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR REVISED PROTOCOL 07: ..................................... 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 07 ......................... 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Study Rationale ................................................................................................. 
1.1.1 Rationale for targeting bromodomains for cancer therapy ..................... 
1.1.2 Rationale for combining BMS-986158 with Nivolumab .......................... 
1.1.3 Rationale for targeting PD-1 ................................................................... 
1.1.4 Preclinical studies with BMS-986158 ...................................................... 
1.1.5 Rationale for Dose and Schedule ............................................................. 
1.1.6 Rationale for Monotherapy Dose Escalation Design and Combination 
Safety Monitoring. ....................................................................................... 
1.1.7 Rationale for Evaluating BMS-986158 in an Initial Monotherapy 
Expansion Cohort ....................................................................................... 
1.1.8 Rationale for Genetically Defined Tumor Groups................................... 
1.1.9 Rationale for Tumor Specific Patient Populations .................................. 
1.1.12 Rationale for QTc Objective .................................................................. 
1.1.13 Rationale for Inclusion of Adolescent Subjects ..................................... 
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 Pharmacology .......................................................................................... 
1.4.2 Toxicity ..................................................................................................... 
1.4.3 Preclinical Metabolism and Pharmacokinetics ....................................... 
1.4.3.1 Absorption ....................................................................................... 
1.4.3.2 Distribution ..................................................................................... 
1.4.3.3 Metabolism ...................................................................................... 
1.4.3.4 Excretion ......................................................................................... 
1.4.3.5 Pharmacokinetic Drug Interactions ............................................... 
1.4.4 Clinical Pharmacology and Safety .......................................................... 
1.4.4.1 Pharmacokinetics of BMS-986158 ................................................. 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
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3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.1.1 Monotherapy Dose Escalation (Part 1) ................................................... 
3.1.2 Dose Expansion (Part 2) .......................................................................... 
3.1.2.1 Safety Evaluation Phase of BMS-986158 Monotherapy Expansion
...............................................................................................................
3.1.2.2 Safety Evaluation Phase of BMS-986158 Combination with 
Nivolumab ............................................................................................. 
3.1.2.3 Safety Evaluation in Adolescents .................................................... 
3.1.2.4 BMS-986158 Monotherapy and in Combination with Nivolumab 
Dose Expansion--Number of Subjects .................................................. 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Treatment Beyond Progression ......................................................................... 
3.7 Post Study Drug Follow-up .............................................................................. 
3.7.1 Withdrawal of Consent ............................................................................ 
3.7.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage and Dispensing..................................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.5.1 Dose Limiting Toxicities .......................................................................... 
4.5.2 Guidelines for Dose Modifications .......................................................... 
4.5.3 Management of Diarrhea for BMS-986158 ............................................. 
4.5.4 Management Algorithms for Immuno-oncology Agents .......................... 
4.6 Blinding/Unblinding ......................................................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction of Study Drug ................................................................................ 
4.9 Return of Study Drug ........................................................................................ 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening ..................................................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Imaging Assessment for the Study............................................................ 
5.3.2 Laboratory Test Assessments ................................................................... 
5.4 Efficacy Assessments ........................................................................................ 
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5.4.1 Primary Efficacy Assessment ................................................................... 
5.4.2 Secondary Efficacy Assessments .............................................................. 
5.5 Pharmacokinetic Assessments .......................................................................... 
5.5.1 Pharmacokinetics 
: Collection 
and Processing ............................................................................................ 
5.5.2 Pharmacokinetic Sample Analyses .......................................................... 
5.5.4 Labeling and Shipping of Biological Samples ......................................... 
5.6 Biomarker Assessments .................................................................................... 
5.7 Outcomes Research Assessments ..................................................................... 
5.9 Results of Central Assessments ........................................................................ 
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 ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
8.3.2.1 Efficacy ........................................................................................... 
8.3.2.2 Pharmacokinetics ............................................................................ 
8.3.2.4 ECG/QTc......................................................................................... 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
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8.4.5 ECG Analyses .......................................................................................... 
8.4.7 Outcomes Research Analyses .................................................................. 
8.5 Interim Analyses ............................................................................................... 
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 .................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
12 REFERENCES ........................................................................................................ 
APPENDIX 1 DOSE ESCALATION ALGORITHM BASED ON MODIFIED 
TOXICITY PROBABILITY INTERVAL (MTPI) DESIGN ................................ 
APPENDIX 2 SIMULATION OF MTPI VS 3 + 3 DOSE ESCALATION DESIGNS 
WITH 6 DOSE LEVELS ........................................................................................ 
APPENDIX 3 CYP3A4 GUIDANCE .......................................................................... 
APPENDIX 4 RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) 
 ........................ 
APPENDIX 5 ECOG PERFORMANCE STATUS ..................................................... 
APPENDIX 6 NYHA CLASSIFICATION .................................................................. 
APPENDIX 8 SIMULATION OF MTPI-2 VS 3+3 DOSE ESCALATION DESIGNS 
WITH 2 DOSE LEVELS ........................................................................................ 
APPENDIX 9 LUGANO 2014 CLASSIFICATION FOR INITIAL EVALUATION, 
STAGING, AND RESPONSE FOR HODGKIN LYMPHOMA ........................... 
APPENDIX 10 MANAGEMENT ALGORITHMS FOR IMMUNO-ONCOLOGY 
AGENTS ................................................................................................................. 
APPENDIX 11 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
APPENDIX 12 PROSTATE CANCER WORKING GROUP 3 (PCWG3) 
GUIDELINES (WITH MODIFIED RESPONSE EVALUATION CRITERIA IN 
SOLID TUMORS (RECIST) CRITERIA FOR SOFT TISSUE LESION 
ASSESSMENT) ...................................................................................................... 
APPENDIX 13 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ...... 
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1
INTRODUCTION AND STUDY RATIONALE
Patients with relapsed or refractory hematologic and solid tumors have a very poor prognosis1. 
Despite advances in multimodal therapy, increases in overall survival (OS) in these patient 
populations have been limited. The unmet need resides in the lack of effective treatments to deliver 
long term survival, hence the need to test compounds that have novel mechanisms of action in 
clinical studies. This study is focused on BMS-986158, a novel epigenetic drug candidate with 
direct antitumor effects and immunomodulatory functions, which may be further augmented by 
nivolumab.
1.1
Study Rationale
1.1.1
Rationale for targeting bromodomains for cancer therapy
The bromodomain and extra-terminal (BET) family of adaptor proteins is comprised of 4 members 
(BRD2, BRD3, BRD4, and BRDT), each of which contain two conserved N-terminal 
bromodomains (BD1 and BD2) and an extra terminal (ET) protein interaction motif.2,3
Bromodomain-mediated interactions with acetylated chromatin result in the localization of BET 
proteins to discrete chromosome regions, where they recruit additional regulatory complexes to 
influence gene transcription.4,5,6 BRD4 is dysregulated by chromosomal translocation to form in-
frame fusions with the NUT (nuclear protein in testis) gene in NUT-midline carcinoma (NMC);7
it is also overexpressed in many solid tumors. Early BET inhibitors, JQ1 and I-BET, demonstrated 
therapeutic effects in multiple tumor models of hematologic malignancies8,9 including multiple 
myeloma (MM),10 as well as in solid tumors.11 The therapeutic activity of BET inhibitors in 
hematologic malignancies correlates with transcriptional suppression of key proto-oncogenes, 
including MYC and BCL2.12,13 c-MYC is the most frequently amplified oncogene and is 
deregulated in 40% to 70% of all cancers;14 however, efforts to target MYC inhibition have not 
been successful to date.15,16
BET inhibitors have the potential to provide an effective strategy for targeting the MYC oncogene 
in the treatment of cancer.9 Examination of BRD4 occupancy at genes whose transcription is 
highly sensitive to JQ1, led to the observation that BRD4 (and potentially other BET family 
members) localizes to the core promoter regions of many oncogenes.17 Additionally, BRD4 is 
enriched in enhancer regions, leading to high expression levels of many growth promoting genes, 
in addition to MYC.17 Recent studies demonstrated that key lineage-specific survival genes are 
regulated by these super-enhancer regions.18 These enhancers are considerably larger than typical 
gene enhancer regions and are densely populated by transcription factors, leading to strong 
activation of gene transcription. Super-enhancers are present in the loci of key oncogenic drivers. 
BRD4 is particularly enriched in these critical control regions suggesting that inhibition of the 
bromodomain activity of BRD4 will lead to transcriptional repression of these key oncogenic 
drivers.17,18 The greater sensitivity of super-enhancers to perturbation by BRD4 inhibition may 
explain why cancer cells are specifically sensitive to BRD4 inhibition despite ubiquitous BRD4 
expression in a wide range of cells. Because tumor cells are frequently highly reliant on high 
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oncogene expression for survival, selective disruption of super-enhancers by a BET inhibitor may 
represent an effective strategy for the treatment of multiple tumor types with an acceptable safety 
profile.
Preclinical studies using in vitro and in vivo models of various cancer types demonstrated that 
sensitivity to BET inhibition is higher in tumor cells harboring genetic abnormalities, including 
gene amplifications (eg, BRD, MYC, or androgen receptor [AR] gene),19,20,21,22 mutations (eg, 
Gnaq/11, KRAS, or SWI/SNF),23,24 and translocations (eg, MYC, BCL2/6, or BRD3/4).25,26,27
These findings warrant further clinical investigations to understand whether the selected genetic 
abnormalities can be used as biomarkers for sensitivity of the tumors to treatment with BET 
inhibitors.
1.1.2
Rationale for combining BMS-986158 with Nivolumab
BET proteins are important in the control of networks of genes, and depending on the context, 
function as co-activators or co-repressors regulating expression of approximately 3,000 genes. 
BET inhibitors disrupt the binding interface between the bromodomain and the acteylated lysine 
groups resulting in pleotropic effects. Several BET inhibitors are currently under investigation as 
anticancer, anti-inflammatory, and immunomodulatory agents changing a whole field of new 
epigenetically targeted therapeutics.28
Cooperative interactions between BET inhibitors and PD-1 inhibitors may involve different 
molecular pathways. Inflammatory cytokines, including IFNγ, are expressed within the tumor
microenvironment and upregulate PD-L1 levels contributing to immunosuppression.29,30
Induction of PD-L1 expression in tumor cells, as a downstream effect of canonical IFNγ signaling, 
is BRD4-dependent.25 In some tumors, BET inhibitors reduce IFNγ-mediated PD-L1 induction 
via inhibition of NF-κB activity.31,32 In mixed lineage leukemia (MLL)-rearranged acute myeloid 
leukemia (AML) cells, BET inhibition does not induce PD-L1 downregulation,25 suggesting that 
the effect of BET inhibitors on PD-L1 expression is not universal and is likely cell-context 
dependent. JQ1, a BET inhibitor, has been reported to interfere with the production of both pro-
inflammatory (IL-12 and TNF) and anti-inflammatory (IL-10 and TGF-β) cytokines from dendritic 
cells, with lower mRNA expression of IL-12 and TNF but higher expression of IL-10 and TGF-β. 
At the same time, JQ1 reduced monocyte-derived dendritic cell maturation and T cell 
proliferation.33 This finding supports that JQ1 and possibly other BET inhibitors such as BMS-
986158 may have immunosuppressive activity in some contexts.34 However, studies in animal 
models demonstrated that targeted inhibition of the PD-1/PD-L1 axis by combining anti-PD-1 
antibodies and the BET inhibitor JQ1 resulted in synergistic responses in mice bearing MYC-
driven lymphomas.25 These contradictory findings highlight the need to define the effect of BMS-
986158 on the immune system before exploring the combination of BMS-986158 with anti-PD-1 
agents such as nivolumab. Clinical development of this combination regimen may provide 
additional options for patients who are currently not effectively treated with anti-PD-1 
monotherapy. 
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1.1.3
Rationale for targeting PD-1
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 result in immune responses and cancer cell death. Meanwhile, tumor 
progression may depend upon acquisition of traits that allow cancer cells to evade 
immunosurveillance and escape effective innate and adaptive immune responses.35,36,37 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. T-cell stimulation is a complex process 
involving the integration of numerous positive as well as negative co-stimulatory signals in 
addition to antigen recognition by the T-cell receptor.38 Collectively, these signals govern the 
balance between T-cell activation and tolerance.
Programmed cell death protein 1 (PD-1) is a member of the CD28 family of T-cell co-stimulatory 
receptors.39 PD-1 signaling has been shown to inhibit CD28-mediated upregulation of IL-2, IL-
10, IL-13, interferon-γ (IFN-γ), and Bcl-xL. PD-1 expression has 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.40 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 (BMS-936558) binds specifically to PD-1 with high affinity and inhibits the 
binding of PD-1 to its ligands, programmed cell death-ligand 1 (PD-L1) and programmed cell 
death-ligand 2 (PD-L2). In vivo blockade of PD-1 by a murine analog of nivolumab enhances the 
antitumor immune response and result in tumor rejection in several immunocompetent mouse 
tumor models (MC38, SA1/N, and PAN02).41
Clinical studies have been conducted to evaluate safety and efficacy of nivolumab across various 
tumor types. Nivolumab has been approved as treatment for melanoma, non-small cell lung cancer 
(NSCLC, both nonsquamous and squamous histologies), head and neck cancer, renal cell 
carcinoma (RCC), bladder cancer, Hodgkin’s lymphoma, and mismatch repair deficient and 
microsatellite instability-high (MSI-H) colorectal cancer in the US and other countries, and is 
being evaluated extensively across a wide range of other solid tumors and hematological 
malignancies.42,43
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1.1.4
Preclinical studies with BMS-986158
BMS-986158 has been tested against a wide-array of cancer cell lines and has demonstrated potent 
cytotoxicity against multiple hematologic and solid tumors. Many of the most sensitive cancer 
types are driven by c-MYC including MM, AML and small cell lung carcinoma (SCLC). The on-
target mechanism of BMS-986158 is evidenced by its inhibition of c-MYC expression in the 
JJN3R MM cell line at the same potency (IC50 = 0.8 nM) as its targeted cytotoxicity potency 
(IC50 = 4 nM). Two other hematologic cell lines, known to be driven by c-MYC, MOLM-13 and 
OCI-AML3, demonstrated sensitivity with IC50 of 1.7 and 0.7 nM, respectively.
In a panel of 30 human lung cancer cell lines, BMS-986158 demonstrated potent and selective 
cytotoxic activity (IC50 <10 nM) in 8 lines, intermediate activity (IC50 = 10-100 nM) in 4, and 
low activity in 18 (IC50 >100 nM). Six of the 8 highly sensitive cell lines were SCLC, further 
re-enforcing the potential importance of c-MYC in the mechanism of action (MOA) of 
BMS-986158 BET inhibition.
BMS-986158 was evaluated in a panel of patient-derived xenografts (PDX) in mice. The dose of 
BMS-986158 (1.6 mg/kg administered BID, 5-days-on-2-days-off for two cycles) was 2-3-fold 
below its maximum tolerated dose (MTD) in mice (MTD range: 5-10 mg/kg QDx10; 
3.2-4.8 mg/kg BIDx10). BMS-986158 demonstrated antitumor activity (tumor growth inhibition 
[TGI] > 70%) in 8 of 19 (42%) of the PDX models tested. The excellent potency of BMS-986158 
against hematologic cancer cell lines in vitro was also reflected in vivo in tumor xenografts in 
mice; each demonstrated robust sensitivity to BMS-986158 at low, well-tolerated doses. In an 
ovarian cancer (OC) PDX model that was determined to have amplification of the BRD4 gene, 
tumor regression was observed during the dosing period (TGI = 126%) suggesting that tumors 
with BRD4 amplification may be particularly sensitive to BET inhibition. Analysis of human 
TCGA data also shows that approximately 27% of ovarian tumors of serous histology that are 
BRCA 1/2 wildtype are also have BRD4 amplification.
1.1.5
Rationale for Dose and Schedule
BMS-986158
In the pivotal 1-month oral toxicity studies of BMS-986158, the highest non-severely toxic dose 
(HNSTD) in dogs was 0.15 mg/kg. The MTD in rats was 0.25 mg/kg. The dog was considered the 
most appropriate species for calculation of the maximum recommended starting dose (MRSD)
because a nontolerated dose was attained in dog but not rat and the toxicity profile was similar in 
both species. The starting dose of 0.75 mg/day was selected based upon the human equivalent dose 
(HED; scaled by body-surface area) of the HNSTD in dogs (the more sensitive species between 
dogs and rats) with a safety factor of 1/6 (see Section 1.4.2 for details). The projected human 
efficacious dose is estimated to be 2 mg/day based on the observed human pharmacokinetics (PK) 
and a projected human efficacious concentration of 46 ng/mL. This concentration is derived from 
the minimal efficacious concentration (MEC) established in a mouse xenograft model and 
corrected for protein binding differences between species. As a patient’s disease pathophysiology 
differs from preclinical animal tumor models, the human efficacious dose will be determined and 
confirmed in clinical studies. 
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To assure safety of human subjects, the initial dose of BMS-986158 tested in this study was 
0.75 mg/day. Part 1 of this study also evaluates different administration schedules: monotherapy 
given 5 consecutive days on with 2 days off each week of a 4-week cycle (Schedule A of Part 1); 
monotherapy given 14 consecutive days on with 7 days off of a 3-week cycle (Schedule B of Part 
1); and monotherapy given 7 days on and 14 days off of a 3-week cycle (Schedule C of Part 1). 
The rationale for the 3 schedules is based on the human half-life of 39 hours. Schedule A 
effectively provides continuous drug exposure, while Schedules B and C provide intermittent 
exposure with a break to allow for platelet recovery as needed at higher doses in human trials of 
other compounds in this class.44,45,46,47
For Part 2, Schedule A, has been selected considering the safety, 
 
and PK obtained during Part 1 (see Section 3.1.2.1). Preliminary analysis of Part 1 showed that 
Schedule A provided continuous drug exposure with a tolerated safety profile at selected doses 
above the projected efficacious dose and resulted in sustained targeted gene expression 
modulation. BMS-986158 will be administered at a starting dose of 4.5 mg for 2 weeks (10 doses) 
followed by 3.75 mg for the remainder of treatment. A higher dose of 4.5 mg will ensure initial 
maximal suppression of key oncogenes 
. The 
subsequent reduction in dose is expected to maintain this gene suppression without compromising 
tolerability and to mitigate the potential risk for dose interruptions and dose delays. Further dose 
reduction is permitted beyond the dose de-escalation to 3.75 mg depending on toxicity and 
tolerability observed in each subject (see guidelines for dose modification in Section 4.5.2).
In addition to adult subjects, adolescent subjects will be included in Part 2 and dosage rationale 
for these subjects is discussed in Section 1.1.13.
Depending on safety, PK and the totality of data obtained from Part 2, Schedule A with BMS-
986158 monotherapy, subjects may also be enrolled in Schedules B or C upon agreement between 
investigators and the Sponsor/Medical Monitor.
Nivolumab
Nivolumab has been extensively studied in a number of tumor types with body weight normalized 
dosing (mg/kg), and a dose of 3 mg/kg has been approved to be used as monotherapy.42,43
Population pharmacokinetic (PPK) analyses showed that the PK of nivolumab is linear with 
dose-proportional exposures over a dose range of 0.1 to 10 mg/kg, similar across tumor types. To 
evaluate the impact of a flat dosing regimen on the safety and efficacy of nivolumab, simulations 
were performed using the previously developed, well-characterized PPK model. Based on the 
simulation results, the range of systemic exposures of nivolumab resulting from either a 3-mg/kg 
dose or 360 mg every 3 weeks (Q3W) or 480 mg every 4 weeks (Q4W) flat doses is similar. The 
dosage regimen for nivolumab for the currently approved indications in the US (RCC, metastatic
melanoma and NSCLC) has been modified to 240 mg IV every 2 weeks (Q2W) based on FDA 
approval of the dosing regimen on 13-Sep-2016.
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 
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relatively flat.42,43 Taken together, the PK, safety, and efficacy data indicate that the safety and 
efficacy profile of 360 mg Q3W or 480 mg Q4W nivolumab will be similar to that of 3 mg/kg 
Q2W nivolumab. Based on these results, a flat dose of 360 mg Q3W or 480 mg Q4W is 
recommended for further investigation in adult subjects. A total body-weight dose of 4.5 mg/kg 
Q3W up to a maximum of 360 mg or 6 mg/kg Q4W up to a maximum of 480 mg is recommended 
for adolescent subjects. 
The decision to pursue combination therapy with nivolumab will be made depending on 
 
 
safety 
and PK results obtained during Part 2 monotherapy. If combination with nivolumab is pursued, 
Schedule A (5 days on/2 days off for a 4-week cycle) will be used to dose BMS-986158 with a flat 
dose of 480 mg Q4W nivolumab. The dosage in adolescent subjects is discussed in Section 1.1.13
1.1.6
Rationale for Monotherapy Dose Escalation Design and Combination 
Safety Monitoring. 
The increment in the dose levels used in monotherapy dose escalation, especially in the first 
schedule tested (Schedule A), is guided by the modified Fibonacci to help mitigate the potential 
risk inherent in the steep dose/toxicity curve and/or the low therapeutic index seen in preclinical 
studies. Dose escalation decisions will utilize a modified toxicity probability interval (mTPI) 
design.48 Rationale for selection of an mTPI over a 3+3 design includes a more accurate 
determination of MTD, greater flexibility in cohort size, and that it allows de-escalation and re-
escalation to a previously tried dose. The design provides a simple dose escalation decision 
algorithm (Appendix 1), and in addition to the higher accuracy of MTD selection, it treats fewer 
subjects at suboptimal doses, as seen by simulations described in Appendix 2.
If pursued, the safety monitoring of the selected BMS-986158 dose in combination with nivolumab 
based on dose limiting toxicities (DLTs) will be guided within the mTPI framework using the more 
recently available mTPI-2 methodology and taking into account prior information on the safety of 
monotherapy for nivolumab and BMS-986158 related AEs observed so far. The mTPI-2 design 
provides better operating characteristics over the 3+3 method (Appendix 8) and has improved 
performance over the original mTPI design, as it was developed to mitigate some suboptimal 
decisions by the original mTPI design and to provide a more efficient safety evaluation than the 
mTPI.49
1.1.7
Rationale for Evaluating BMS-986158 in an Initial Monotherapy 
Expansion Cohort
The number of subjects and types of tumors initially enrolled in the Part 2 expansion will be limited 
to initially focus on tumor types where the greatest signal of activity is expected, based on 
published preclinical and clinical data.143,50 Preliminary antitumor activity will be assessed in 
subjects enrolled during the Initial Expansion, to inform subsequent expansion. 
 
 
 
 
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1.1.8
Rationale for Genetically Defined Tumor Groups
Drug development strategies in oncology continue to evolve with the advent of histology-agnostic 
biomarkers correlating with the clinical activity of targeted anticancer drugs. For example, recent 
breakthrough findings led to accelerated approval of pembrolizumab for the treatment of adult and 
pediatric patients with various solid tumors bearing MSI-H or mismatch repair deficiency.51,52
Another success of such an approach is a development of larotrectinib, a selective TRK tyrosine 
kinase inhibitor that demonstrated histology-agnostic efficacy in patients with TRK fusion-
positive cancers.53 Thus, in the light of these novel strategies, tumors with genetic rearrangements 
that engage molecular pathways regulated by BRD proteins, including gene translocations, 
mutations, or amplifications, have been selected for Part 2 of this study to identify early clinical 
activity in these preselected patient populations. The results of this study may help to understand 
whether the activity of BMS-986158 depends on specific genetic alterations observed in selected 
histologies or may be tumor agnostic.
Translocations
Chromosomal translocations may lead to the formation of fusion proteins with oncogenic 
properties. Examples of these genetic abnormalities include BRD3,4-NUT fusion (in 75% of cases 
of NMC), EWS/FLI1 fusion (in 85% of cases of Ewing sarcoma [ES]), and IGH/L-MYC and IGH-
BCL-2/6 fusions (in Burkitt’s lymphoma [BL] and double-hit lymphoma [DHL]).
•
NMC: BRD3 or BRD4, as partners in the BRD3,4-NUT fusion protein, directly contribute to 
malignant transformation by interfering with cell differentiation,54,55 and BET inhibitors have 
been shown to suppress tumor growth in preclinical models as well as in patients.26,46,56,57
•
ES: BRD proteins function as epigenetic readers regulating
the expression of 
EWS/FLI1.58,59,60,61,62 BET inhibitors downregulate EWS/FLI1 expression and interfere with 
tumor cell viability, proliferation, and growth in animal models.27,63
•
Lymphomas: Pathogenesis of Burkitt’s lymphoma (BL) is driven by translocation of 
MYC,64,65 and DHL by translocation of both MYC and BLC2 or BCL6.66 The expression of 
formed IGH/L-MYC and IGH-BCL-2 fusion proteins is regulated by the BET family,9,67,68
and BET inhibitors arrested tumor cell growth in vitro as well as in xenograft models.9,25,69
Detection of these fusion proteins is required for diagnosis and is a routine clinical practice. 
Initially, only subjects with NMC carrying BRD3,4-NUT fusion will be selected to participate in 
Part 2. Subjects with other fusion proteins may be eligible to participate in Part 2 of this study as 
part of the Subsequent Expansion based on review of the totality of data obtained from subjects in 
the Initial Expansion in Part 2 (see Section 3.1.2).
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Mutations
SWI/SNF functions as a tumor suppressing complex and mutations in subunits contribute to 
malignant transformation.70 The KRAS protein is required for signaling in normal cells, and the 
mutation of a KRAS gene contributes to the development of many cancers. Similarly, Gnaq and 
Gnaq/11 mediate the intracellular signal transduction pathway, and mutations in these genes lead 
to oncogenesis.
•
Renal cell carcinoma (RCC): Approximately 40% of patients with RCC harbor mutations 
within the SWI/SNF complex, including ARID1A, ARID1B, SMARCA4, SMARCA2, 
SMARCB1, ARID2, PBRM1 (BAF180) ,71 and BET inhibitors induced RCC cell apoptosis 
and repressed tumor growth in vitro and in vivo.23
•
Non-small cell lung cancer (NSCLC): BMS-986158 suppressed proliferation of NSCLC cell 
lines with SWI/SNF mutations (BMS, data on file). In vitro and in vivo antitumor activity of 
other BET inhibitors has also been reported in NSCLC cells harboring KRAS mutations, 
although this effect was abrogated by concurrent alterations of LKB1, also known as STK11.72
According to TCGA database, 30% of patients with NSCLC harbor SWI/SNF mutations, and 
15% harbor KRAS mutations of which approximately 75% express wild type LKB1. 
•
Uveal melanoma (UM): BET inhibitor demonstrated cytotoxic activity in UM cells carrying 
Gnaq/11 mutations and inhibited tumor growth in xenograft models.24
Mutations in SWI/SNF complex, KRAS, and Gnaq/11 will be detected in tumor biopsies using the 
 diagnostic platform. Mutations in SWI/SNF complex, KRAS, and 
Gnaq/11 will be detected in tumor biopsies using the 
 diagnostic 
platform. Subjects with tumors carrying these mutations may be eligible to participate in Part 2 of 
this study as part of the Subsequent Expansion based on review of the totality of data obtained 
from subjects in the Initial Expansion in Part 2 (see Section 3.1.2 and Figure 3.1-1). 
Amplifications
•
BRD: In patients with OC, BRD amplification is associated with worse overall survival.19
BRD gene amplification correlates with overexpression of BRD RNA (TCGA database) and 
is necessary for proliferation and survival of some tumor cell types, including OC20 and triple 
negative breast cancer (TNBC).21 Blocking hyperactivity of BRD proteins with a BET 
inhibitor results in growth inhibition of xenografts obtained from patients with OC19 and from 
patients with TNBC.21,73,74 Approximately 43% of patients with TNBC, 55% of patients with 
neuroendocrine prostate cancer (NEPC), and 17% of patients with OC harbor BRD4 
amplifications (TCGA database). 
•
MYC: Forty-one percent of patients with castration-resistant prostate cancer (CRPC) and 47% 
of OC patients harbor MYC amplifications (TCGA database). BET inhibition results in 
reduced MYC expression and inhibition of tumor growth in PDX models with high MYC 
expression and inhibition of AR signaling.75 High frequency of MYC amplification
(approximately 30%) has also been observed in patients with uterine carcinosarcoma (UCS; 
TCGA database). Also, the non-germinal center subtype of diffuse large B-cell lymphoma 
(non-GC-DLBCL) is often associated with MYC (and BCL2) overexpression.76 A recent 
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Phase I study of a BET inhibitor in patients with relapsed and refractory lymphoma reported 
objective clinical responses in the non-GC-DLBCL subtype, in particular in patients with 
activated B cell (ABC)-DLBCL.77
•
AR: Among other genetic abnormalities sensitive to BET regulation is AR amplification.22 AR 
promotes ligand-independent prostate cancer (PC) progression through c-MYC upregulation.78
BET inhibitors decreased MYC levels and proliferation viability of CRPC cells, and inhibited 
growth of PC xenografts.22 Approximately 67% of CRPC patients harbor AR amplification, 
and 25% to 30% harbor both MYC and AR amplifications (TCGA database). 
BRD, MYC, and AR amplifications will be detected in tumor biopsies using 
 
 diagnostic platform. Subjects with TNBC, non-GC-DLBCL and CRPC with any of these gene 
amplifications/overexpressions will be eligible to participate in Part 2 as part of the Initial 
Expansion. Subjects with other tumors with these amplifications may be eligible to participate in 
Part 2 of this study as part of the Subsequent Expansion based on review of the totality of data 
obtained from all subjects in the Initial Expansion in Part 2 (see Section 3.1.2 and Figure 3.1-1).
1.1.9
Rationale for Tumor Specific Patient Populations
NMC: NMC is a rare and aggressive tumor that has a lethal clinical course and no established 
treatment algorithms.79 In the absence of guidelines, combinations of different drugs (actinomycin 
D, alkylating agent, anthracycline, vinca-alkaloid, VP-16, platinum compounds, taxane agents, 
5-FU, and cytarabine) have been used as first line (1L) therapy for NMC. On current therapies, 
patients die of disease with median overall survival (OS) time of 9.7 months from the time of 
diagnosis.80 While several complete response (CR) cases following 1L therapy have been reported, 
the majority of patients relapse with a median time to progression of 9.3 months.81 Only 
8 survivors have been reported to date, and all received surgery in combination with chemotherapy 
or radiation.80 Since the vast majority of NMC cases remain refractory to conventional therapy 
with no 2L options, efforts have been made to develop novel targeted therapeutics. In 75% of 
cases, NUT (NUTM1) is fused to BRD3 or BRD4 forming a fusion protein that drives oncogenic 
transformation.82 Thus, BET inhibitors may directly interfere with molecular mechanisms 
mediating NMC pathogenesis. In a recent study, 3 of 10 subjects treated with OTX015/MK-8628
achieved (partial response) PR or stable disease (SD),83 although the genetic rearrangements in 
responders versus non-responders have not been reported. Because survival with current therapies 
has been dependent on the possibility of surgical resection, subjects with unresectable NMC
harboring BRD3-NUT and BRD4-NUT fusions, regardless of prior treatments, will be eligible to 
participate in this study. 
ES: There is a consensus for the ES treatment pathway that VDC/IE interval compression
chemotherapy is recommended for 1L therapy.84,85 Local control includes surgery and radiation. 
Most ES relapses (approximately 80%) occur within 2 years of the initial diagnosis.86,87
Chemotherapy is generally recommended for all recurrent ES patients; however, the outcomes 
remain poor. A combination of irinotecan and temozolomide is the first option after relapse, 
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primarily because of the favorable toxicity profile. The combined response (CR+PR) rate on this 
regimen is 53%, and progression-free survival (PFS) at 4 months is approximately 60%. Another 
regimen is cyclophosphamide and topotecan, and responses to this therapy were correlated with 
the relapse interval, with no responses when the disease was progressing on prior therapy and with 
a response rate of approximately 50% when 2 years had passed between the prior therapy and the 
initiation of therapy. The intensification of conventional therapy or even myeloablative 
chemotherapy with hematopioetic stem cell transplant (HSCT) has not been reported to be 
advantageous. In the relapse setting, the response or disease stabilization after all these therapies 
with median postrecurrence survival ranges from 9 to 17 months dependent on the extent of 
disease. Thus, the development of novel therapeutic approaches is warranted. ES is associated with 
translocation of EWS and FLI1 genes resulting in a chimeric fusion transcript EWS/FLI1 in 85% 
of cases.58 EWS/FLI1 fusion protein acts as a transcription factor and drives ES cell proliferation 
and survival by inducing a panel of genes, including GLI159,60 and MYC,61,62 and BET inhibitors 
have been shown to downregulate EWS/FLi1 expression.63 Thus, ES patients harboring the 
EWS/FLI1 fusion that progressed after 1L therapy will be eligible to participate in this study.
BL: While BL is among the therapeutic successes in oncology, the optimal initial therapy for BL 
has not been clearly defined given the paucity of randomized studies and the fact that different, 
modern BL regimens can all achieve good results.88 Several chemotherapy regimens have been 
successfully tested, including CODOX-M/IVAC,89
LMB
89,90
R-Hyper-CVAD,91
and 
others88,92,93,94 with CR rates up to 95% and 5-year OS in 70% of patients. Incidence of relapse or 
refractory disease is approximately 10%, and current results in refractory/relapsed BL are 
extremely poor.88 For relapsed or refractory BL in patients who have not received prior cytarabine, 
regimens such as dexamethasone plus cytarabine plus cisplatin or etoposide plus 
methylprednisolone plus cytarabine plus cisplatin may be considered. Gemcitabine-based 
regimens, such as gemcitabine, dexamethasone, and cisplatin, are an option for patients who have 
received cytarabine. Unfortunately, the vast majority of patients will not respond to additional 
chemotherapy. Responders are referred for high-dose chemotherapy and HSCT, with a reported 
5-year OS of only 21% and 18% for autologous and allogeneic HSCT, respectively.95 The salvage 
treatment of relapsed or refractory BL is usually unsuccessful. Median survival for patients with 
progressive disease (PD) or early relapse is 5 months,96 and no long-term disease-free survivors
after BL relapse have been reported.88,97 Therefore, novel therapies are needed for this patient 
population. BL is driven by MYC translocation and formation of an IGH-MYC fusion with the 
IGH,98,99 and importantly, translocated MYC locus harbors super enhancers that are sensitive to 
BET inhibition.100 In preclinical studies, treatment with the BET inhibitor JQ1 resulted in a 45% 
tumor volume reduction in Raji cell xenografts as compared to control.9 In combination with a 
PD-L1 inhibitor, JQ1 treatment resulted in 100% CR in mice with Eμ-MYC lymphoma,25
supporting further studies. Therefore, patients with BL that relapsed or are refractory to 1L therapy 
will be eligible to participate in this study. 
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DHL and non-GC-DLBCL: DHL and non-GC-DLBCL are highly aggressive disease subsets of 
DLBCL with very poor clinical outcomes and the standard of care (SOC) has not been established
for DHL.101,102 Patients are treated with various chemotherapy regimens, including R-CHOP, 
R-EPOCH, HyperCVAD, and CODOX-MIVAC as 1L therapy. Retrospective analysis across 
different studies demonstrated an approximately 57% CR rate for DHL.103,104 DHL and non-GC-
DLBCL are associated with advanced age, therefore, regimens such as CODOX-M/IVAC and 
HyperCVAD/MA, which are poorly tolerated in elderly patients, are not appropriate for the 
majority of these patients, whereas R-EPOCH has been suggested as appropriate for most patients 
with DHL.105 Overall, the outcome of patients with DHL or non-GC-DLBCL treated with 
conventional chemotherapy is often poor because, despite the response rate, the majority of 
patients will experience disease progression after standard treatment with PFS of approximately 
9 months and median OS of 15 months.104,106,107 Regimens used in relapsed/refractory DHL 
include R-DHAP, R-ESHAP, R-GDP, and R-ICE. However, none of these traditional 
chemoimmunotherapy regimens produced a significant rate of complete or sustained remissions
with a 3-year OS rate from the time of first progression of 7% and median OS of 
8 months.94,104,108,109 Overall, the optimal approach to DHL and non-GC-DLBCL is unknown, 
and developing optimal therapeutics for DHL and non-GC-DLBCL represents a great unmet 
clinical need.110,111 DHL is characterized by translocation of both MYC and BCL2 (IGH-MYC
and IGH-BCL2), and both fusion proteins expressed on BRD4-loaded superenhancers may be 
directly targeted by BET inhibitors.100,112 Non-GC-DLBCL is characterized by MYC (and BCL2) 
overexpression, which may be also be targeted by BET inhibitors. Indeed, in combination with 
other agents (eg, bortezomib, YM-155, or chemotherapy), JQ1 kills DHL cells in vitro.69 Another 
BET inhibitor, GS-5829, in combination with venetoclax resulted in broader activity in a DLBCL 
cell line with greater activity correlating with higher MYC protein levels compared with either 
agent alone.113 Thus, subjects with DHL or non-GC-DLBCL that relapsed or are refractory to 1L
therapy will be eligible for enrollment in the Initial Expansion in Part 2 of this study.
OC: Platinum-containing compounds are recommended as 1L therapy for patients with OC and 
may be repeated as long as the disease remains platinum sensitive. Platinum refractory disease 
(RD) is defined as disease progression during the last line of platinum therapy or within 4 weeks 
from the last platinum dose, and platinum-resistant disease is defined by a platinum free interval 
(time from last platinum-based chemotherapy to recurrence) of > 1 and < 6 months.114 A majority 
(80%) of patients with advanced disease experience a recurrence within 5 years from diagnosis, 
with 70% of them relapsing within 18 months.115 Among patients affected by recurrent disease, 
approximately 23% are platinum resistant, with 5.3% presenting as RD.116 When single agents 
like topotecan, paclitaxel, gemcitabine, or pegylated liposomal doxorubicin are used, the PFS 
across different studies is approximately 5 months with OS approximately 15 months.117 Recently 
revised National Comprehensive Cancer Network (NCCN) guidelines recommend the following 
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combination regimens for patients with platinum-resistant recurrent OC: paclitaxel plus 
bevacizumab, liposomal doxorubicin plus bevacizumab, and topotecan plus bevacizumab.118 A 
combination of bevacizumab with chemotherapy agents resulted in improved PFS of 6.7 months 
with median OS of 16.6 months.119 The poly ADP ribose polymerase (PARP) inhibitor, rucaparib,
has been recently approved as a single agent for patients with advanced OC harboring BRCA 
mutations with PFS of 12.8 months.120,121 Another PARP inhibitor (olaparib) has also been 
approved for patients with BRCA-mutated progressive OC, and olaparib and niraparib have been 
approved in the maintenance setting (ongoing complete or partial response to platinum-based 
chemotherapy). Palliative chemotherapy has been shown only to reduce symptoms in patients with 
platinum-resistant disease without improving the outcomes.115,122 Since agents available for 
patients with platinum-resistant and refractory OC provide only temporary benefit,119 novel
therapeutic approaches are needed.123 Increased BRD levels are associated with worse PFS and 
OS in patients with OC,19 and BRD4 is necessary for proliferation and survival of OC cells20
providing a basis for testing BET inhibitors in patients harboring BET amplifications. 
Furthermore, BET inhibitor JQ1 inhibited OC tumor growth with high MYC expression in PDX 
models.20 Therefore, subjects with platinum-resistant OC harboring BET and/or MYC 
amplifications will be eligible to participate in this study; subjects with platinum-resistant OC with 
BET and/or MYC amplifications and coexisting BRCA1 or BRCA2 mutations will be eligible 
after treatment with a PARP inhibitor, if available. 
TNBC: For local disease, surgery and radiotherapy are preferred as 1L therapy. Although, based 
on NCCN and the European Society for Medical Oncology guidelines, there is no SOC therapy 
identified as the treatment of choice specifically for TNBC, alkylator plus anthracycline plus 
taxane-based chemotherapy backbone are frequently used for early stage systemic 
treatment.124,125,126 Approximately 30% of patients achieve CR with 5-year disease-free survival 
of 57% and 5-year OS of 70%.127 Approximately 36% of patients experience recurrence after the 
front line neoadjuvant therapy with 25% developing distant metastasis. Survival duration of 
patients with metastatic TNBC is approximately 15 months.128 Patients with BRCA1 or BRCA2 
mutations (30% of TNBC patients) have above average platinum sensitivity.129 In patients with 
metastatic 1L or 2L TNBC treated with carboplatin or docetaxel, objective response rates (ORRs)
were observed in 31.4% in the carboplatin arm and 35.6% in the docetaxel arm. The median PFS 
was 3.1 months in the carboplatin arm and 4.5 months in the docetaxel arm with a median OS of 
12.4 months and 12.3 months, respectively. Carboplatin demonstrated significantly increased 
activity vs docetaxel in BRCA-carriers. ORR was 68% with carboplatin and 33% with docetaxel. 
In BRCA-negative patients, ORRs were not significantly different at 28.1% with carboplatin and 
36.6% with docetaxel. Despite the high ORR to carboplatin, responses were short in both 
subgroups: BRCA-positive patients had a median PFS of 6.8 months compared with 3.1 months 
in patients with nonmutated BRCA-receiving carboplatin. For patients with metastatic cancer, 
sequential single agents are preferred, including taxanes, topoisomerase II inhibitors, platinum-
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based drugs, vinca alkaloids, and other antitubulins and antimetabolites, although toxicity profiles 
should be considered.126,130 Despite these therapeutic approaches, TNBC remains a lethal disease, 
thus novel therapeutic approaches are needed. Approximately 34% of TNBC patients harbor BRD 
amplifications resulting in increased levels of BRD proteins, which control growth and 
proliferation of cancer cells.21 BET inhibitors JQ1 and OTX015/MK-8628 inhibit TNBC 
proliferation in vitro and in vivo73,74 providing a scientific rationale for testing the effects of BET 
inhibitors in patients with TNBC harboring BRD amplifications. Thus, subjects with TNBC 
positive for BRD amplification that progressed after at least 1 therapy in the recurrent/metastatic 
setting will be eligible to participate in either Part 1 or 2 of this study. 
CRPC: Most PC-related deaths are results of mCRPC, which progresses and metastasizes after 
surgical or medical castration.131 NCCN guidelines recommend use of Sipuleucel-T as 1L therapy 
in patients with asymptomatic or minimally symptomatic mCRPC. Docetaxel represents the 
current 1L therapy for symptomatic CRPC patients, and Radium-223 can be used as 1L therapy in 
patients who are not candidates for docetaxel.132 Time-to-treatment failure in patients treated with 
docetaxel is approximately 5 months.133 Abiraterone or enzalutamide can be used as 2L therapy
in patients who progressed on docetaxel, and mitoxantrone and prednisone can used for 
palliation.132 Patients with metastatic disease progressing after docetaxel treated with abiraterone 
acetate plus prednisone achieved median 5.6 months PFS compared to 3.6 months in patients 
treated with prednisone alone.134 In patients with mCRPC who progressed on docetaxel, treatment 
with enzalutamide resulted in median PFS of 8.3 months compared with 2.9 months on placebo.135
Different guidelines are provided by the European Association of Urology: based on the 
performance status, symptoms, comorbidities, and extent of disease, the choice of 1L treatment 
includes abiraterone, cabazitaxel, docetaxel, enzalutamide, Radium 223, and sipuleucel-T. When 
used as 1L therapy in mCRPC patients, abiraterone plus prednisone treatment resulted in PFS of 
16.5 months compared with 8.2 months for prednisone alone.136 The options for 2L therapy are 
affected by the treatment chosen as 1L therapy: if either abiraterone or enzalutamide were used as 
1L therapy, docetaxel would be offered next; if docetaxel was used as 1L therapy, cabazitaxel, 
abiraterone plus prednisone, or enzalutamide can be used in patients who had progressed after or 
during docetaxel-based chemotherapy.137 It is also recommended that patients who develop 
CRPC, despite castrate levels of testosterone, should be maintained in a castrate state 
indefinitely.138 However, regardless of treatment, life expectancy for CRPC patients is only 15 to 
20 months.137,139,140,141,142 Thus, there is an urgent need to develop novel drugs targeting 
alternative pathways.138 Recent studies have shown that BET inhibitors inhibited growth of CRPC 
in vitro and in vivo, and AR overexpressing cells are more sensitive to BRD inhibitors.22
OTX015/MK-8628, in a Phase I monotherapy, dose-escalation study, demonstrated clinical 
activity in an unselected population of advanced solid cancer. One patient with CRPC was reported 
to have an unconfirmed PR; no details of genetic amplification were given.143 Therefore, subjects
with metastatic CRPC positive for AR amplification that progressed on or after treatment with a 
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taxane and with an androgen pathway antagonist (eg, abiraterone or enzalutamide) will be eligible 
to participate in either Part 1 or 2 of this study, and will be permitted to continue abiraterone but 
not enzalutamide to maintain a castrate state.
NEPC: Radical prostatectomy (RP) and radiation therapy (RT) combined with chemotherapy are 
commonly used as 1L therapy for localized NEPC.144,145 Metastatic disease is identified in 64% 
of cases at diagnosis with median survival of 8.5 months.145,131 Neither RP nor RT improve 
survival in metastatic patients.145. Currently available data suggest that chemo-radiotherapy 
provides maximal benefit in metastatic patients with ORR of 61%, however, prognosis is poor 
regardless of histologic subtype and administered treatment due to quick progression (PFS of 
5.8 months) and OS of 10.5 months 131,146. Current 1L treatment generally entails platinum-based 
chemotherapy.147,148 Pure small cell carcinoma is frequently treated with platinum plus etoposide 
combinations, and mixed NEPC is frequently treated with docetaxel.147 However, the duration of 
response is transient with a median survival of less than 12 months.147 In a recent study, patients 
were treated with cisplatin plus etoposide after disease progression on a carboplatin plus docetaxel 
regimen, with median OS of 16 months. The trial results suggest that continued platinum-based 
chemotherapy with the addition of etoposide may be a 2L therapy option in patients with NEPC 
who experience disease progression on platinum plus taxane combinations.149 However, others 
recommend this regimen for palliative purposes due to high toxicity rates.150,151,152 Other 
regimens, such as a combination of estrogen and somatostatin analogues, provided symptomatic 
responses in patients who were refractory to conventional therapy.153 Palliative benefit of clinical 
symptom control was also shown for the combination of cyclophosphamide and mitoxantrone with 
34.5% ORR and 7.5 months PFS.154,155 Given the poor outcomes with current options,144,150,156
studies are needed to identify novel targeted therapies.147 Approximately 23% of patients with 
NEPC harbor BRD4 amplifications,71 and the inhibitory effect of BET inhibitor JQ1 on growth of 
neuroendocrine tumors in preclinical models has been reported.157 Thus, subjects with metastatic 
NEPC harboring BRD amplifications that relapsed or is refractory to 1L therapy will be eligible 
to participate in this study. 
UCS: Per NCCN guidelines, carcinosarcoma is now considered and treated as high-grade 
carcinoma. For UCS, NCCN guidelines include complete surgical staging followed by systemic 
chemotherapy including ifosfamide/paclitaxel or cisplatin/ifosfamide combinations as 1L
therapy.158 Gynecologic Cancer Intergroup also considers a carboplatin/paclitaxel combination.159
However, due to the high rate of recurrent tumors (40% to 60%) and the low median OS of 16 to 
40 months post-diagnosis, UCS has a poor prognosis.160 In persistent or recurrent disease, several 
drugs or combinations (including gemcitabine/docetaxel, thalidomide, imatinib, and sorafenib) 
have been tested as 2L therapy with no success.161,162,163,164 For example, patients with recurrent 
disease who had previously failed 1 regimen of chemotherapy were treated with gemcitabine and 
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docetaxel with 0% CR, 8.3% PR, and 33.3% SD with PFS of 1.8 months and OS of 4.9 months.161
Due to the aggressive nature of this disease, rarity, and limited therapeutic options in the 
relapsed/refractory stage, optimal management of UCS is still not established and novel 
therapeutic approaches are needed.165 Approximately 41% of patients with UCS harbor MYC
amplifications, and BET inhibitors downregulate NF-κB activity that is required for 
TGF-β-mediated oncogenic signaling in UCS.166,167 Thus, subjects with UCS harboring MYC
amplifications that relapsed or is refractory to 1L therapy will be eligible to participate in this 
study. 
NSCLC: Per NCCN guidelines, 1L treatment largely depends on the stage and histology of 
NSCLC and includes surgery, radiation, and systemic therapy (eg cisplatin-based chemotherapy 
combined with other regimens, including etoposide, docetaxel, bevacizumab, etc). For metastatic 
disease, treatment decisions are also based on molecular profiling of tumors (ie, testing EGFR, 
ALK, ROS1, BRAF, and PD-L1), which allows the use of targeted therapies as 1L treatment. The 
2L treatment options for patients who progress on 1L therapy include systemic therapies (eg, 
docetaxel, gemcitabine, and ramucirumab/docetaxel) and immune checkpoint inhibitors (eg, 
nivolumab, pembrolizumab, and atezolizumab). Patients on 2L docetaxel- or pemetrexed-based 
chemotherapy and erlotinib achieve ORR of approximately 8% to 10%, PFS of 4 months, and
median OS of 8 to 10 months, whereas PD-1/PD-L1 inhibitors have shown to prolong OS in 
pretreated patients.168,169 Patients with 2L squamous-cell NSCLC treated with nivolumab or 
docetaxel achieve ORR of 20% or 9%, PFS of 3.5 months or 2.8 months, and OS of 9.2 months or 
6.0 months, respectively.170 In a similar setting, patients with nonsquamous-cell NSCLC treated 
with nivolumab or docetaxel achieved ORR of 19% or 12%, PFS of 2.3 months or 4.2 months, and 
OS of 12.2 months or 9.4 months, respectively.170 Nevertheless, NSCLC remains a lethal disease,
and there is a need to investigate novel therapies. In pre-clinical studies, BET inhibitor JQ1 exerts 
in vitro and in vivo antitumor efficacy in a subset of NSCLC cells harboring KRAS mutation; 
however, the activity of JQ1 in mutant KRAS NSCLC is abrogated by concurrent alteration or 
genetic knockdown of LKB1.171 In addition, BMS-986158 inhibits proliferation of NSCLC cell 
lines with SWI/SNF mutations (BMS, data on file). Thus, subjects with NSCLC harboring 
mutations in the SWI/SNF complex or KRAS mutation with wild type LKB1 that progressed on 
or after 2L therapy will be eligible to participate in this study.
RCC: Surgical resection remains an effective therapy for clinically localized RCC. Patients with 
advanced or stage IV RCC can also be treated with surgery if present with a solitary site of 
metastasis or solitary recurrence after nephrectomy. For patients with metastatic RCC (mRCC), 
the prognosis remains poor and median OS ranges from 7.8 to 43.2 months depending on the 
adverse factor profiling. Treatment for relapsed or Stage IV disease and surgically unresectable 
mRCC is challenging.172 For clear cell histology, 1L options include cytokine therapy (eg,
interleukin-2 [IL-2] and IFN) and targeted therapy (eg, pazopanib, sunitinib, and temsirolimus). 
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These drugs showed modest or no improvement in survival and high levels of toxicity. For 
example, frontline treatment of patients with bevacizumab or interferon alpha resulted in PFS of 
10.2 months versus 5.4 months, respectively, with marginal changes in OS (23.3 months versus 
21.3 months, respectively).173 In similar settings, pazopanib provided 9.2 months PFS compared 
to 4.2 months with best supportive care.174 As 2L therapy, NCCN recommends checkpoint 
inhibitors (eg, nivolumab) and anti-VEGF/ VEGFR therapy in addition to cytokines and kinase 
inhibitors.175,176,177 In patients with prior cytokine treatment, sorafenib treatment resulted in 
5.5 months PFS (compared with 2.8 months for placebo) and 19.3 months OS (compared to 
15.5 months for placebo).178 The best PFS outcome in the 2L setting was observed for lenvatinib,
with patients achieving 14.6 months PFS compared with 5.5 months on everolimus.179 Because
metastatic RCC remains a lethal disease and SOC has not been established, there is a need to 
investigate novel therapeutic approaches.176,180,181,182 Preclinical studies demonstrated that BET 
inhibitor JQ1 suppressed RCC cell proliferation, induced cell apoptosis in vitro, and repressed 
tumor growth in vivo.23 Notably, SWI/SNF and BET family function as co-regulators of gene 
transcription machinery.183 Approximately 50% of patients carry mutations within the SWI/SNF 
complex.71 Thus, subjects with metastatic RCC harboring mutations within the SWI/SNF complex 
that relapsed or is refractory to 2L therapy will be eligible to participate in this study.
UM: NCCN guidelines do not provide a recommendation for UM treatment.184 Currently, local 
1L treatment options include transpupillary thermotherapy, photodynamic therapy, plaque 
radiotherapy, and proton beam radiotherapy for small and medium tumors. For more advanced 
tumors, enucleation and orbital exenteration are used as 1L treatment options. However, 50% of 
patients treated locally will develop metastatic disease, with OS approximately 13.4 months and 
only 8% surviving for 2 years. Several therapies have been tested as 2L treatment, including 
dacarbazine, BCG, systemic interferon, selumetinib, and fotemustine but have not reported 
promising results.185,186,187,188,189 For example, patients with metastatic disease have been treated 
with the combination of dacarbazine and treosulfan with ORR 0%, median PFS of 12 weeks and 
median OS of 30 weeks.186 In another study, patients with metastatic disease were treated with 
selumetinib or chemotherapy with PFS of 15.9 weeks and 7 weeks, and ORR 49% and 0%, 
respectively.189 A number of clinical studies are currently in progress evaluating safety and 
efficacy of potential 1L and 2L therapies, including sunitinib, valproic acid, dacarbazine/INFα-2b, 
crizotinib, and ipilimumab, and results have yet to be reported.190,191 For patients with systemic 
metastasis, observation is usually chosen because metastatic UM is resistant to treatment, and there 
is no evidence that current treatment is able to extend survival.192,193 Because half of patients will 
develop fatal metastatic disease, there is an urgent need to develop novel therapeutic options.191,192
Preclinical studies demonstrated that the BET inhibitor JQ1 has cytotoxic activity in cells carrying 
Gnaq/11 mutations, and inhibits tumor growth in xenografts with Gnaq-mutant UM cells.24
According to the TCGA database, 85% of patients with UM harbor Gnaq/11 mutations. Thus, 
subjects with unresectable or metastatic UM harboring Gnaq/11 mutations regardless of prior 
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number of therapies (including treatment-naive subjects) will be eligible to participate in this 
study. 
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1.1.12
Rationale for QTc Objective
In this study, the effect of BMS-986158 on the QT interval will be evaluated. Preclinical 
evaluations did not identify a signal indicating that BMS-986158 may increase the QT interval or 
affect cardiac conduction. Similar to other drugs in this class, the likelihood BMS-986158 directly 
or indirectly affects QTc intervals is low. Despite the low risk, such evaluation is required during 
the development of a therapeutic agent and the design of this study treating subjects across several
doses is well suited for this type of evaluation. Serial electrocardiograms (ECGs) (reviewed by a 
central laboratory) will be collected with matching PK samples from all subjects in dose escalation 
and at least 20 subjects treated at the MTD or an alternative selected dose in the dose expansion 
monotherapy cohorts. 
1.1.13
Rationale for Inclusion of Adolescent Subjects
Exclusion of adolescent subjects from adult trials may slow the investigation of novel therapies in 
adolescent subjects and delay the delivery of novel efficacious drugs to this patient population. 
Thus, it has been recommended to consider adolescent subjects for tumor type- and molecular 
target-appropriate adult oncology trials.202
At the time of the clinical cutoff day 21-Dec-2018, BMS-986158 was administered to a total of 
81 subjects with various advanced cancers, including rare diseases such as NMC and ES. Some of 
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these cancers, such as NMC, affect both children and adults. While NMC was initially thought to 
be a childhood cancer, recent studies have shown that it affects people of all ages with 30% of new 
cases reported in pediatric patients.80 Similar to adult patients, NMC is highly lethal in children 
and adolescent patients with an average of 10 months survival time, despite intensive 
therapies.203,80 Thus, there is an unmet medical need for new therapeutic approaches for patients 
with NMC across all ages. During the dose escalation part of this study, 1 subject with NMC with 
BRD3-NUT rearrangement responded to 2 mg BMS-986158 treatment by reaching stable disease, 
characterized by 15% reduction in tumor burden and improved clinical symptoms, including 
reduced pain. The duration of stable disease in this subject was 9 months. 
ES is a rare disease in adults and mostly affects children and adolescents, with a peak of incidence 
around 15 years.204 Clinically, most pediatric patients present with lesions arising from the bone, 
whereas more than 50% of lesions in adults occur in the soft tissue.205 Early observations 
suggested an adverse prognosis for patients of older age,206 whereas recent findings report no 
effect of age on OS.207 The lower dose intensity of chemotherapy used to treat adults was discussed 
as a possible factor.205 Currently, the treatment of adult patients follows the same principles as for 
ES in the pediatric age group.208,209 Approximately 20% to 25% of ES patients are diagnosed with 
metastatic disease, and with current multimodality treatments, including chemotherapy and 
radiation, 5-year survival in this patient population is less than 20%.209 During the dose escalation 
part of this study, 1 subject with ES responded to BMS-986158 treatment with improved clinical 
symptoms, including reduced pain and increased overall activity. This observation supports 
previously published findings that BET inhibitors may affect survival of ES cells in preclinical 
models.63
During the dose expansion part of this study, BMS-986158 will initially be tested in subjects with 
TNBC, CRPC, DHL, non-GC-DLBCL, NMC and possibly other advanced cancers, including UM, 
RCC, NSCLC, and BL in the Subsequent Expansion. Except for BL, these cancers are rare in 
children.204,210,211,212,213 BL is the most common (approximately 46%) non-Hodgkin’s lymphoma
in children and adolescents in western countries, and rare in adults with approximately 1,200 cases
per year in the US.214,215 A recent study reported that 5-year relative survival in BL for children, 
adults, and the elderly were 90.4%, 47.8%, and 28.9%, respectively. Some predictors of poor 
outcome were shared among all age groups, such as multiple primary tumor sites and advanced 
stage disease.216 It was suggested that older patients have inferior outcomes compared with 
younger patients due to the low intensity therapy, and one of the ways to reduce treatment burden, 
especially in elderly patients, might be the use of targeted therapy approaches.214,215 In both adults 
and children, relapse occurs infrequently but is characterized by a poor prognosis. Pediatric 
patients who relapse or progress have chemotherapy-resistant disease and can rarely be 
cured.217,218,219 In adults, relapsed or refractory BL treated with salvage therapy resulted in median 
OS of 2.8 months.220 Because patient numbers are low, there are no randomized trials comparing 
different relapse regimens. These results provide rationale for development of alternative treatment 
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approaches focusing on targeted therapy to circumvent chemotherapy-resistant disease by 
providing alternative therapeutic targets across different ages. 
Current experience with BMS-986158 (see Section 1.4.4 and the Investigator’s Brochure for 
details) did not identify drug-related adverse events (AEs) that warrant exclusion of adolescent
subjects from this study. Thus, the balance of benefit to risk may be favorable in adolescent 
subjects with advanced cancers and poor treatment options. Therefore, adolescent subjects with 
NMC, BL, or ES will be eligible to participate in this study. Additional indications will be allowed 
at the discretion of the Sponsor if the tumor contains similar genetic abnormalities sensitive to 
regulation by the BET family proteins. 
Rationale for Adolescent Dose
BMS-986158
Analysis of available PK data indicates dose proportionality and a linear relationship between 
exposure and body size, allowing for appropriate scaling of dose to younger subjects using 
allometric scaling of clearance and volume. Current experience with BMS-986158 demonstrates
that tested doses are safe in adult subjects. To provide an additional margin of safety, the lower 
limit of enrollment will be 12 years of age. By 6 years of age, developmental processes related to 
drug disposition are typically complete, and body weight is the main factor differentiating pediatric 
and adult drug exposures.221,222,223 The PK results suggest that BMS-986158 exposure in 
adolescent subjects ≥40 kg could be similar to adults at the same dose level. Therefore, adolescent 
subjects ≥40 kg will be administered the same doses as adults and receive a starting dose of 4.5 mg 
for 2 weeks (10 doses) followed by 3.75 mg for the remainder of treatment in Schedule A. Due to 
the limited PK data collected in Part 1, only adolescents ≥40 kg will be enrolled in Part 2. By 
enrolling subjects ≥40 kg, it is expected that around 50% of adolescents will be eligible.
Nivolumab
Flat doses of nivolumab, 360 mg Q3W or 480 mg Q4W, have been shown to be safe and 
efficacious in adult subjects. In adolescent subjects, 6 mg/kg dose Q4W up to a maximum of 
480 mg will be used for the Schedule A dose expansion. The combination of BMS-986158 with 
nivolumab will only be pursued if results of the effect of BMS-986158 monotherapy in the tumor 
microenvironment is favorable for the combination.
1.2
Research Hypothesis 
There is no formal primary research hypothesis for this study to be statistically tested. It is 
anticipated that BMS-986158 as monotherapy and/or in combination with nivolumab will 
demonstrate adequate safety and tolerability at pharmacologically relevant doses, so as to permit 
further clinical development (at a recommended dose range).
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1.3
Objectives(s)
1.3.1
Primary Objectives
•
To assess the safety and tolerability and to assess the DLTs, MTD, and recommended Phase 2
dose (RP2D) of BMS-986158 as monotherapy for subjects with advanced solid tumors and 
hematologic malignancies.
•
If combination with nivolumab is pursued, to assess the safety and tolerability at the RP2D of 
BMS-986158 in combination with nivolumab and to assess the DLT for subjects with advanced 
solid tumors and hematologic malignancies.
1.3.2
Secondary Objectives
•
To assess the preliminary antitumor activity of BMS-986158 monotherapy and, if pursued, in 
combination with nivolumab as measured by ORR, and response duration based on response 
evaluation criteria in solid tumors using criteria from RECIST v1.1 (Appendix 4), prostate 
cancers using PCWG3 (Appendix 12) criteria, or hematologic malignancies using criteria from 
Lugano 2014 (Appendix 9).
•
To characterize PK of BMS-986158 and metabolite in monotherapy and, if pursued, in 
combination with nivolumab.
•
To assess the dose-response and exposure-response effect of BMS-986158 monotherapy on 
the ECG (QT interval).
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1.4
Product Development Background
1.4.1
Pharmacology
Please refer to the Investigator’s Brochure.
1.4.2
Toxicity
BMS-986158 is an inhibitor of the BET reader of acetylated lysine residues on histone tails. The 
safety profile of BMS-986158 was established in 1-month intermittent dose (5 days on/2 days off; 
4 cycles) oral toxicity studies in rats and dogs. The dog data were used to calculate the MRSD for 
first-in-human clinical studies because a nontolerated dose was attained in the dog but not the rat 
and the toxicity profiles were considered similar in both species.
In the pivotal 1-month oral study in rats,224 BMS-986158 was administered by gavage at 0, 0.05, 
0.15, or 0.25 mg/kg, followed by a 3-week treatment-free recovery period. In addition to standard 
toxicologic and toxicokinetic endpoints, pharmacodynamic blood biomarkers (mRNA) were 
assessed. BMS-986158 was clinically tolerated at doses ≤0.25 mg/kg. There were no BMS-
986158-related effects on physical (including neurologic and respiratory evaluations) or 
ophthalmologic examinations. Additionally, there was no increase in micronuclei frequency at 
≤0.25 mg/kg indicating that BMS-986158 was not genotoxic in the blood micronucleus assay.
BMS-986158-related clinical signs occurred only at the high dose of 0.25 mg/kg beginning on 
Day 7 and included sporadic incidences of chromorhinorrhea, scant feces, and soiling. Transient,
minimal mean body-weight losses at ≥0.15 (≤1.8%; females only) from Days 1 to 4 and reduced 
body-weight gain resulted in lower mean body weights (1.7% to 7.5% lower than controls) on 
Day 25. BMS-986158-related transient decreases in mean food consumption occurred in males at
≥0.05 mg/kg and in females at doses ≥0.15 mg/kg. These clinical findings were considered 
nonadverse due to their low small magnitude or transient nature. 
BMS-986158-related hematology changes were observed at all doses and those considered notable 
or toxicologically relevant included decreased white blood cells (0.75 to 0.84× control), 
lymphocytes (0.74 to 0.85×), and eosinophils (0.54 to 0.61×) and decreased platelets (0.49 to 
0.88×)
with increased mean platelet volume
(1.07 to 1.08×). At ≥0.15 mg/kg, 
BMS-986158-related changes included decreased reticulocytes (0.33 to 0.76×); increased red cell 
distribution width (1.06 to 1.28×) and mean cell volume (1.04×) and decreased mean cell 
hemoglobin concentration (0.96 to 0.97×); and decreased segmented neutrophils, monocytes, and 
basophils (0.48 to 0.77×). At 0.25 mg/kg, additional findings included decreases in red blood cells
(RBCs) and hemoglobin (0.92 to 0.93×). The hematology changes were attributed to bone marrow 
toxicity (with correlative decreased cellularity of the bone marrow; see below) or regenerative 
responses of the bone marrow to platelet and reticulocyte decreases.
BMS-986158-related decreases in size and weight of the thymus and spleen with lymphoid 
depletion noted in both organs were observed generally at ≥0.15 mg/kg.
The primary BMS-986158-related microscopic changes at all doses included: 1) minimal to 
moderate bone marrow hypocellularity and minimal lymphoid depletion in the mesenteric or 
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mandibular (≥0.15 mg/kg) lymph nodes accompanied by minimally increased macrophage 
infiltration in the mesenteric lymph nodes at 0.25 mg/kg; 2) minimal epithelial single-cell necrosis 
in various segments of the gastrointestinal tract; and 3) minimal to mild degeneration of the 
mammary gland in males. At the high dose of 0.25 mg/kg, additional microscopic findings 
included: 1) minimal lymphoid single-cell necrosis in the thymus, 2) minimal decreases in Paneth-
cell granules in the jejunum; and 3) minimal erosions, hemorrhage, and mixed-cell or neutrophilic 
infiltration of the glandular mucosa of stomach.
Day 1 biomarker results at approximately 4 hours after dosing suggested that inhibition of BET 
pathway resulted in transcriptional modulation including: 1) increases in HEX1M1 and 2) 
decreases in ZMYND8 and MYC. These generally expected pharmacodynamic biomarker results 
confirmed that BMS-986158 binds and inhibits bromodomains in rats.
BMS-986158-related adverse target organ effects in rats were dose dependent and occurred in the 
bone marrow, lymphoid tissues, and gastrointestinal tract, were generally more prominent or 
severe in females than in males (correlating with higher systemic exposures in females at ≥
0.15 mg/kg), and were reversible or partially reversible following a 3-week post-dose recovery. 
The MTD was the high dose of 0.25 mg/kg (area under the concentration-time curve 
[AUC] ≤72.2 ng•h/mL, and a no-observed-adverse-effect level (NOAEL) was not identified.
In the pivotal 1-month oral study in dogs,225 BMS-986158 was administered in gelatin capsules at
0, 0.07, 0.15, or 0.25 mg/kg, followed by a 3-week treatment-free recovery period. In addition to 
standard toxicologic and toxicokinetic endpoints, pharmacodynamic blood biomarkers (mRNA) 
were assessed. BMS-986158 was clinically tolerated at doses ≤0.15 mg/kg. There were no 
BMS-86158-related clinical signs; no physical, ophthalmologic, or electrocardiographic findings; 
and no effects on food consumption, arterial oxygen saturation, coagulation, or urinalysis 
parameters at ≤0.15 mg/kg. At a dose of 0.25 mg/kg, severe clinical toxicity resulted in early 
euthanasia of all males and 1 female after 2 cycles of treatment (10 doses). Dosing was 
discontinued in the remaining 4 female dogs at 0.25 mg/kg. The poor condition of these dogs was 
attributed to pharmacologically mediated bone-marrow and gastrointestinal toxicities. 
At 0.15 mg/kg, minimal body-weight loss (4%) occurred in 1 male over the course of the study. 
At 0.25 mg/kg, an increased incidence of sporadic fecal changes (mucous, red, dark, black, blood 
or scant) began on Day 5 and progressed to include: moderate to severe thrombocytopenia, reduced 
to no food consumption, dehydration, hunched posture, ulceration (mouth and perianal area), 
hemorrhage (gums), increased body temperature, and body-weight loss in males (6.7% compared 
to 1% loss in controls) through Day 11.
BMS-986158-related findings at all doses were dose related in incidence and/or severity and 
included: 1) minimal to moderate seminiferous tubule degeneration in testes with decreased testes 
weights absolute 14% to 20% at ≤0.15 mg/kg; no organ weight data were available at 0.25 mg/kg 
due to unscheduled euthanasia); 2) minimal to moderate cell debris in the epididymides; and 3) 
minimal to marked bone-marrow hypocellularity. Decreases in spleen weights (15% to 39%) were 
noted at ≤0.15 mg/kg without any microscopic correlates. 
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At ≥0.15 mg/kg, additional BMS-986158-related findings that were generally dose related in 
incidence and/or severity included: 1) decreased platelet counts (0.10 to 0.82× most recent pretest)
beginning on Day 7; 2) minimal to severe enteropathy of the small and/or large intestines that was 
characterized by 1 or more of the following: decreased numbers of goblet cells, crypt/gland 
dilatation, abscesses, and increased mitotic activity, flattening, increased basophilia and/or single-
cell necrosis of crypt/gland enterocytes; and/or villous atrophy 3) minimal to mild epithelial cell 
necrosis, secretory depletion, and marked hypospermia (at 0.15 mg/kg only) in the epididymides; 
4) minimal to moderate RBCs in the sinuses of mesenteric lymph nodes that was a consequence 
of intestinal hemorrhage; 5) increased incidence and severity of lymphoid depletion (mild to 
severe) in the thymus; and 6) minimal to moderate lymphoid depletion in the mandibular lymph 
nodes in males.
At the severely toxic dose of 0.25 mg/kg, additional BMS-986158-related findings included: 1) 
decreased reticulocytes (0.05 to 0.42× most recent pretest) with corresponding decreases in red 
cell distribution width (0.88 to 0.96×); 2) decreased eosinophils (≤ 0.41×) and lymphocytes
(0.16 to 0.41×); 3) mild hemorrhage or acute inflammation in the lungs and pericardium in males; 
4) minimal to marked erosions or ulcerations in the oral cavity, tongue, esophagus, stomach
(pylorus), and intestines; 5) moderate hemorrhage and/or severe hematomas in the oral cavity and 
tongue in males; 6) minimal to mild acute inflammation in the esophagus in males; 7) mild 
hemorrhage in the serosa of the stomach and capsular surface of the spleen and surrounding 
adipose tissue; 8) mild hemorrhage and/or minimal to moderate single-cell necrosis of 
lymphocytes (in Peyer’s patches) in the small intestines; 9) minimal to moderate lymphoid 
depletion in the mesenteric lymph nodes and spleen in males; and 10) minimal pancreatic acinar 
cell necrosis with mild hemorrhage in 1 male.
In general, the decreased circulating reticulocytes, platelets, lymphocytes, and eosinophils were 
attributable to bone marrow and lymphoid toxicities and correlated microscopically with bone 
marrow hypocellularity and cellular depletion in lymphoid tissues. Hemorrhage and hematomas 
in multiple tissues at 0.25 mg/kg with corresponding necropsy findings of dark, brown-black, or 
red discoloration were related to the moderate to severe thrombocytopenia associated with bone 
marrow toxicity. Mucosal erosions and ulceration in the gastrointestinal (GI) tract were
consequences of BMS-986158-related enteropathy that was considered to be pharmacologically 
mediated because suppression of the BET protein BRD4 is known to affect intestinal epithelial 
cell lineage differentiation and reduce stem cell numbers.226 The degenerative changes in the testes 
with227 reduced testicular weights were considered to be pharmacologically mediated as the testes-
specific BET protein BRDT is critical in male germ cell differentiation.
On Day 1, blood pharmacodynamic biomarker results at 4 hours post dose indicated generally 
dose-dependent increases (up to approximately 3× control) in the gene expression markers 
HEXIM1 and MKNK2 and decreases (down to approximately 0.2× control) in ZMYND8 and 
MYC expression at all doses of BMS-986158. At 24 hours postdose (Day 1), gene expression 
parameters generally returned to control levels with the exception of the ZMYND8 gene marker 
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at 0.25 mg/kg. Transcriptional modulation of these biomarkers confirms that BMS-986158 binds 
and inhibits bromodomains in dogs.
BMS-986158-related changes observed during or after the 3-week recovery period included: 1) 
dose-related minimal to severe seminiferous tubule degeneration at 0.07 and 0.15 mg/kg with 
decreased testes weights (absolute: 26% to 48%) and a correlative bilateral decrease in testes size 
in 1 male at 0.15 mg/kg; and 2) minimal to mild increases in cell debris, minimal to marked
secretory depletion, and moderate hypospermia (0.15 mg/kg only) in the epididymides. The 
absence of recovery for the testes and epididymal changes was expected given that a full 
spermatogenic cycle in the dog requires 8-9 weeks. Additional findings at 0.25 mg/kg included: 
1) an increase in reticulocytes (3.49× most recent pretest) and a corresponding increase in red cell 
distribution width (1.17×) in 1 female on Day 35 that was likely a regenerative response to bone-
marrow toxicity during the dosing phase; and 2) small increases in serum blood urea nitrogen 
(1.44×), creatinine (1.52×), and phosphorus (1.57×) in 1 female on Day 26
The primary target organs in dogs were the bone marrow with associated hematology changes and 
testes/epididymides at all doses and the gastrointestinal tract and lymphoid tissues at doses ≥0.15 
mg/kg. A dose of 0.15 mg/kg (AUC[0-T] 106 ng•h/mL) was considered the HNSTD for this study
and a NOAEL was not identified.
Telemeterized rats demonstrated mild increased heart rate (HR) (~50 bpm) and minimal decreased 
blood pressure (BP) (~5-10 mmHg) when administered BMS-986158 at 0.5 or 1 mg/kg (AUC[0-
24h] ≤220 ng•h/mL; maximum observed concentration [Cmax] ≤32 ng/mL).228 These effects 
were not dose related. Evaluations of potential BMS-986158-related effects on the cardiovascular 
nervous, and respiratory systems were conducted as part of the pivotal repeat-dose toxicity studies 
in rats (nervous, respiratory) and dogs (cardiovascular, nervous, respiratory).224,225 There were no 
clear BMS-986158-related effects on these systems in these studies after 1-month repeat dosing 
(5 days on/ 2 days off; 20 doses total) at ≤0.25 mg/kg in rats (AUC ≤72.2 ng•h/mL; Cmax ≤13.8 
ng/mL) and ≤0.15 mg/kg in dogs (AUC ≤106 ng•h/mL; Cmax ≤19.5 ng/mL).
The potential effects of BMS-986158 on embryo-fetal development were evaluated in an expanded 
dose range-finding study in pregnant rats.229 BMS-986158 was administered daily by oral gavage 
to timed-mated female rats at 0, 0.05, 0.15, or 0.5 mg/kg from Gestation Days (GD) 6 through 16, 
the period of organogenesis in this species. BMS-986158 was embryolethal at all tested doses. 
Specifically, there were profound post-implantation losses (manifested mainly as early 
resorptions) at all tested doses, 63.6% at 0.05 mg/kg/day and 100% at ≥ 0.15 mg/kg/day. 
Additionally, in surviving fetuses at 0.05 mg/kg/day, the mean body weight was reduced (28% 
less than controls) and malformations (affecting tail, anus, and/or viscera) occurred in 4 of 43 
(9.3%) fetuses from 2 of 8 (25%) litters. Based on the results from a previous rat toxicity 
study,230maternal AUC values at the lowest observed adverse effect level (LOAEL) of 0.05 
mg/kg/day are expected to be 0.002× human exposures following a single dose of 0.75 mg 
(AUCINF 4.102 μg•h/mL). Increased postimplantation loss has been reported in mouse embryos 
with BRD2 gene knocked out231 or nullizygous for BRD4.232Moreover, in BRD4 heterozygous 
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mice, prenatal and postnatal growth retardations, malformations of the eyes and bones, and other 
pathological abnormalities were noted.232 Therefore, the developmental toxicity observed in litters 
of BMS-986158-treated dams is consistent with the pharmacological action of BMS-986158.
BMS-986158 was negative for mutagenicity (exploratory bacterial-reverse mutation and in vitro 
clastogenicity).233,234 BMS-986158 was not genotoxic in an oral rat micronucleus assay following 
intermittent (5 days of dosing followed by a 2-day dosing holiday) dosing for 2 weeks (2 cycles)
at doses ≤0.25 mg/kg.224
BMS-986158 was not phototoxic in rats administered single oral doses ≤ 1 mg/kg (Cmax ≤ 86.5 
ng/mL and AUC ≤ 379 ng•h/mL).235
BMS-986158 had no meaningful interaction with a broad spectrum of in vitro pharmacologic 
receptors, transporters, ion channels, nuclear hormone receptors, or enzymes at 5 μg/mL.236 In 
subsequent patch-clamp assays, (hERG, calcium, and sodium channels), BMS-986158 produced 
a mild to moderate inhibition of cardiac hERG/IK2 potassium channel (≤51.9% at ≤15 μg/mL), 
SCN5A sodium channel (25.3% to 31.1% at 5.0 μg/mL), and L-type calcium channel (41.7% at 
5.0 μg/mL).237 The in vitro concentrations (up to 15 μg/mL) of BMS-986158 evaluated are 
substantially higher (2083 to 125,000×) than the free Cmax in humans at the starting and ending 
Phase 1 doses.
In conclusion, the nonclinical toxicity profile of BMS-986158 has been well characterized and it 
supports first-in-human dosing in cancer patients.
1.4.3
Preclinical Metabolism and Pharmacokinetics
This section summarizes the data available from a series of in vitro and in vivo PK and metabolism 
studies that were conducted with BMS-986158 in mice, rats, dogs, and monkeys.
1.4.3.1
Absorption
The permeability coefficient (Pc) of BMS-986158 was high in both the Caco-2 cell assay (A-to-B 
Pc: 176 nm/sec, B-to-A Pc: 436 nm/sec) and parallel artificial membrane permeability assay (704 
nm/sec at pH 7.4), indicating high membrane permeability. After oral administration of BMS-
986158, the time of peak plasma concentration (Tmax) ranged from 1 to 3.7 hours in mice, rats, 
dogs and monkeys. The absolute oral bioavailability (F) from a solution formulation was ~100% 
(mouse), 47% (rat), 59% (dog), and 16% (monkey). After intravenous (IV) administration, the 
apparent elimination half-life (T-HALF) of BMS-986158 was 1.9, 4.2, 5.6 and 2.0 hours for mice, 
rats, dogs, and monkeys, respectively. 
The total plasma clearance (CLTp) of BMS-986158 was 12, 41, 15 and 32 (mL/min/kg) in mice, 
rats, dogs, and monkeys, respectively. 
BMS-986158 exhibited an efflux ratio (B-to-A Pc vs. A-to-B Pc) of ~3 at a nominal concentration 
of 3 μM, suggesting that BMS-986158 is likely a substrate of efflux transporter(s) such as 
P-glycoprotein (P-gp) and BCRP. However, based on the existing animal data, efflux transporters 
do not appear to limit the oral absorption of BMS-986158 to a meaningful extent. 
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The compound exhibited pH-dependent oral absorption in rats. Coadministration of famotidine 
(25 mg/kg) reduced, the Cmax and AUC of BMS-986158 (20 mg/kg administered-orally as a 
microsuspension), by 46% and 55%, respectively. However, this may represent the worst-case 
scenario, as the projected clinical dose and exposure are much lower than that used in the rat study.
1.4.3.2
Distribution
The steady-state volumes of distribution of BMS-986158 in mice, rats, dogs, and monkeys were
1.9, 4.3, 5.3, and 4.2 L/kg, respectively. 
At 10 μM, BMS-986158 was 96.1 ± 0.1% bound to human serum proteins and 84.2 to 90.2% 
bound to the serum proteins of the animal species studied. Consistent with the difference in protein 
binding between humans and animal species, the blood-to-plasma concentration ratio of 
BMS-986158 was low (0.57 ± 0.002) in humans, whereas it was close to unity in animal species. 
The blood-to-plasma concentration ratio of BMS-986158 was about 0.99, 1.08, 1.19, and 1.15 in 
mouse, rat, dog, and monkey, respectively. These results suggested that the compound was 
distributed evenly between blood cells and plasma in preclinical species, but not in humans.
1.4.3.3
Metabolism
The metabolic stability of BMS-986158 in human liver microsomes was lower than that in rat liver 
microsomes, but similar to that in dog and monkey liver microsomes (predicted intrinsic hepatic 
clearance [CLint] = 10 mL/min/kg in humans, 12 to 72 mL/min/kg in animals).
Because no quantitative assays were available for most of the metabolites except for Met5 
(BMT-161485), no discussion of the relative abundance is possible, other than for parent drug and 
BMT-161485.
Overall, BMS-986158 was found to be relatively metabolically stable in vitro and in vivo in the 
animal species tested, except for monkey which exhibited relatively faster turnover in vitro than 
in vivo. Several metabolites were detected in hepatocyte incubates and in plasma of rat, dog, and 
monkey. General routes of biotransformation of BMS-986158 included:
•
Mono-oxidation at the methyl of the triazole to form Met5 (BMT-161485)
•
Glucuronidation at the tertiary alcohol moiety to form Met4
•
Mono-oxidation on the benzyl tetrahydropyran moiety to form Met6, Met7
•
Mono-oxidation on other parts of the molecule to form Met3, Met12
•
Further oxidation of Met5 to form Met8, Met9
•
Glucuronidation of Met5, Met6, Met7 to form Met2, Met10, Met11
•
Multiple oxidation to form Met1, Met13
The major in vitro oxidative metabolite for BMS-986158 in dog, monkey, and human was 
BMT-161485, accounting for ~75% of total metabolites in human hepatocytes. In rodents, 
however, Met6 and Met7 were the major oxidative metabolites. In monkey liver microsomes, 
BMT-161485 was further oxidized to Met8 and Met9. Met4 was high in monkey and rat 
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hepatocytes, but was minor in human hepatocytes (~20% of total metabolites). Met4 was not 
presented in dog hepatocytes. In rat hepatocytes, major metabolites also included Met10/Met11. 
No glutathione adducts were detected in incubations supplemented with glutathione. There was no 
human metabolite that was not formed in nonclinical species.
In vivo, BMS-986158 was detected in all 3 animal species as the major circulating drug-related 
component. BMT-161485 was the major circulating metabolite in dogs and monkeys but not in 
rats. Met1 and Met3 were detected in dogs and monkeys, and Met6 and Met7 were detected in 
rats. Overall, the in vivo circulating metabolite profiles were consistent with in vitro profiles.
1.4.3.4
Excretion
Following a single 0.1-mg/kg IV dose of BMS-986158 to dogs, the fraction of dose recovered as 
unchanged BMS-986158 in the urine over 48 hours was < 1%, demonstrating that renal clearance 
is not a meaningful systemic clearance pathway for BMS-986158 in dogs.
1.4.3.5
Pharmacokinetic Drug Interactions
In vitro metabolic reaction phenotyping studies, using individually expressed recombinant human 
cytochrome P450 (CYP) enzymes, demonstrated that the oxidative metabolism of BMS-986158 
was primarily mediated by CYP3A4 (66%) and CYP3A5 (23%). Furthermore, reaction 
phenotyping studies with recombinant human uridine diphosphate glucuronosyltransferase (UGT) 
enzymes demonstrated that the glucuronidation of BMS-986158 is primarily mediated via 
UGT1A4, with minor contribution by UGT2B17. These data suggest that the potential exists for 
drug-drug interactions if BMS-986158 is co-administered with an inhibitor or inducer of these 
enzymes.
Inhibition of CYP enzymes by BMS-986158 in human liver microsomes was minimal (IC50 > 40 
μM), except for CYP2C9 (IC50 = 8.4 μM). The IC50 for recombinant hUGT1A1 was 3 μM. In 
addition, BMS-986158 (up to 40 μM) neither transactivated the human pregnane-X receptor nor 
induced CYP3A4, CYP2B6, or CYP1A2 mRNA expression and activity in cryopreserved primary 
human hepatocytes. Therefore, the DDI potential of BMS-986158 as an inhibitor of metabolic 
enzymes and transporters is minimal, based on the currently projected therapeutic dose and 
exposure (Cmax 0.082 μM at 11 mg once-a-day).
1.4.4
Clinical Pharmacology and Safety
The current study is a first-in-human study. 
At the time of the clinical data cutoff date of 21-Dec-2018, a total of 81 subjects had received at 
least 1 dose of BMS-986158 in Part 1 of the study under Schedule A, Schedule B or Schedule C. 
Each subject was administered a single dose of BMS-986158 on Cycle 1 Day 1 (4- to 7-day cycle), 
and no additional doses were administered until Cycle 2 Day 1. On Cycle 2 Day 1 and each 
subsequent cycle, subjects in Schedule A received once daily (QD) dosing for 5 consecutive days, 
followed by a 2-day rest period repeated weekly on a 28-day cycle. Subjects in Schedule B 
received QD dosing for 14 consecutive days, followed by a 7-day rest period on a 21-day cycle 
and subjects in Schedule C received QD dosing for 7 consecutive days, followed by a 14-day rest 
period on a 21-day cycle. In Schedule A, a total of 44 subjects have received QD dosing of 0.75 mg 
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(n=5), 1.25 mg (n=4), 2 mg (n=13), 3 mg (n=10), or 4.5 mg (n=12) BMS-986158. In Schedule B, 
8 subjects have received QD dosing of 2 mg (n=4), 3 mg (n=4). In Schedule C, 29 subjects have 
received QD dosing of 2 mg (n=6), 3 mg (n=12) or 4.5 mg (n=11) BMS-986158. All clinical data 
are preliminary and subject to change. 
As of 21-Dec-2018, a total of 79 subjects (97.5%) experienced at least 1 AE. The most frequent 
AEs (occurring in ≥20% of subjects) were diarrhea (49 [60.5%] subjects), nausea (43 [53.1%] 
subjects), fatigue (41 [50.6%] subjects), decreased appetite (34 [42.0%] subjects), vomiting (34
[42.0%] subjects), thrombocytopenia (32 [39.5%] subjects), dyspnoea (23 [28.4%] subjects), 
anemia (19 [23.5%] subjects), constipation (19 [23.5%] subjects), and cough (17 [21.0%] 
subjects). A total of 49 subjects (60.5%) experienced Grade 3 to 4 AEs. Five subjects (6.2%) 
experienced Grade 5 AEs, all assessed by both Sponsor and investigator to be not related to 
BMS-986158.
Adverse events evaluated as related to BMS-986158 were experienced by 59 of 81 subjects 
(72.8%). Thirty-four subjects (42%) experienced diarrhea with none experiencing Grade 3 to 4 
diarrhea. Thirty subjects (37%) experienced treatment-related thrombocytopenia including 
17 subjects (21.0%) with either Grade 3 or 4 events. Thirteen subjects (16%) were reported to have 
nausea, including 1 (1.2%) Grade 3 nausea. Other Grade 3 to 4 treatment-related AEs include 
anemia (3 [3.7%] subjects), vomiting, fatigue, increased bilirubin (2 [2.5%] subjects each), and 
neutropenia and vertigo (1 [1.2%] subject each). There were no treatment-related AE’s of Grade 5 
reported.
No treatment-related deaths have been reported in any treatment cohort of Study CA011-001. Nine 
deaths were reported in participants treated with BMS-986158 monotherapy within 30 days of last 
dose. Of the 9 deaths, 8 deaths were reported as secondary to disease and 1 due to cerebrovascular 
accident; all of which were considered not related to BMS-986158 treatment.
A total of 68 subjects were discontinued from study treatment due to disease progression.
A detailed description of BMS-986158 safety is provided in the IB.
1.4.4.1
Pharmacokinetics of BMS-986158
BMS-986158
Interim noncompartmental PK analyses were conducted on BMS-986158 (parent) and 
BMT-161485 (metabolite) using samples from the monotherapy portion of the study
administration of 0.75, 1.25, 2, 3, and 4.5 mg oral doses of BMS-986158 following single and 
multiple doses using nominal time and examining continuous and intermittent schedules 
(Schedules A and C, respectively).
Interim PK results indicate that BMS-986158 is moderately to rapidly absorbed (Tmax range: 
0.5 to 4 hours) following single dose administration at doses of 0.75 to 4.5 mg. The exposure 
within the dose range examined appears to increase with increasing dose. From these multiple 
dosing data, a peak to trough ratio of approximately 2.4 and an accumulation index of 
approximately 1.97 were determined. The inter- and intra-subject variability was from low to high. 
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PK parameters of BMS-986158 using nominal sample times show that the overall exposure was 
significantly higher than predicted. This higher than predicted human exposure may have resulted 
from, and is consistent with a lower than anticipated clearance and increased serum protein binding 
in humans. Preclinical determinations of human serum protein binding indicated a 3.9% free 
fraction for BMS-986158. Interim data from ex vivo plasma samples collected from the 6 subjects 
at the 2 mg dose on this study showed mean free drug fractions of 0.1% to 0.2% with small to 
moderate intra- and inter-subject variability that were not concentration dependent. It is postulated 
that the unexpectedly low free fraction resulted in the low clearance. 
The metabolite (BMT-161485) exhibited a similar terminal phase elimination as the parent drug, 
suggesting formation rate limited PK of BMT-161485. Plasma concentrations of metabolite were 
low relative to the plasma concentration of the parent drug with exposure ratios less than 30%. The 
metabolite has potency that is approximately 10-fold weaker than the parent drug.
Preclinical data suggests that BMS-986158 is metabolized in the liver by CYP3A4 mediated 
oxidation to a hydroxylated metabolite; it also undergoes glucuronidation. BMS-986158 is a 
substrate of CYP3A4 and an inhibitor of P-gp and transporters. 
1.5
Overall Risk/Benefit Assessment
Many cancers are driven by MYC pathway and BRD4 super enhancer activation, providing a solid 
rationale for the trial of BET inhibitors as suppressors of BRD4 and MYC in multiple tumor 
types.9,15 Preclinical studies have linked repression of MYC and other oncogenes to tumor cell 
death and tumor regression in both solid tumors and hematologic cancer models, following BET 
inhibition.8,9,10,BRD4 amplification and overexpression has been correlated with adverse 
prognostic information.19
Sixteen other BET inhibitors have entered Phase 1/2 clinical trials, and 24 studies focused on solid 
tumors and hematological malignancies are recruiting patients or are completed as listed in 
clinicaltrials.gov.
Results from most studies have not been reported. Preliminary clinical data is available on the 
OTX-015/MK-8628 Phase 1 study in leukemia which shows that no DLTs were observed in 28
evaluable subjects with AML, ALL, and refractory anemia (RA) through dose level (DL) 5 (120 
mg QD). At DL6 (160 mg QD), MTD was exceeded with 1 patient experiencing grade 3 diarrhea 
and another grade 3 fatigue and anorexia.44 The main toxicities were non-cumulative grade 
1-2 gastrointestinal events (6 patients diarrhea, 3 dysgueusia, 3 abdominal pain, 3 nausea, 
1 anorexia), hyperglycemia (3 patients), coagulation factor VII decrease (6 patients) and direct 
bilirubin increase (3 patients) (two latter AEs asymptomatic). These toxicities were mainly 
observed at QD doses above 80 mg and with 40 mg BID. Clinically relevant activity was reported 
in 5 AML patients treated at 10, 40 and 80 mg, including one sustained CR from cycle 4 to cycle
12 (40 mg QD) and one CR with incomplete platelet recovery (CRp) from cycle 2 to cycle 5 (80 
mg QD).44 Preliminary clinical data is also available on OTX015/MK-8628 Ph 1 study in Non-
Leukemic Hematologic Malignancies.45 In this study, 37 non-leukemic patients (18 diffuse large 
B-cell lymphoma [DLBCL], 9 other lymphomas, 10 myeloma) were treated over 5 dose levels, 33 
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of whom were evaluable for DLT. No DLTs were observed through DL4 (80 mg QD). Reversible 
grade 4 thrombocytopenia was the DLT at DL4 BID (40 mg x2) and 120 mg QD continuous.
Sixteen patients experienced Grade 3-4 thrombocytopenia and 3 patients had grade 3-4 
neutropenia. Grade 3 non-hematologic toxicities were diarrhea, vomiting, hyperglycemia, and 
hypernatremia (1 patient each). Other toxicities were non-cumulative grade 1-2 gastrointestinal 
events (8 patients with diarrhea, 3 dysgueusia, 2 vomiting, 1 nausea, 1 anorexia, 1 abdominal pain), 
hyperglycemia (7 patients), skin rash (3 patients), asymptomatic coagulation factor VII decrease 
(2 patients), and direct bilirubin increase (1 patient). Clinically relevant activity was reported in 
6 patients treated from 40 to 120 mg, including one CR (120 mg, 17+ weeks [wks]) and 1 PR 
(80 mg, 28 wks), both in DLBCL patients failing 3-4 prior therapy lines, and both with clinical 
benefit. Four other patients (two with DLBCL, one follicular, and one lymphoplasmacytic 
lymphoma) had minor tumor shrinkage with clinical benefit (40 mg, 36+ wks; 80 mg, 14 wks; 120 
mg 15 wks; 120 mg, 17 wks). Similarly, a study using another BET inhibitor, CPI-0610, as
monotherapy reported objective clinical responses in 5 of 36 subjects with relapsed or refractory 
DLBCL, specifically in T cell/histocyte-rich and activated B-cell subtypes. Of note was 1 CR and 
2 PR in subjects with ABC-DLBCL, 1 PR in follicular lymphoma, and 1 PR in T-cell histocyte 
rich lymphoma.77
The initial assessment of the risk of side effects of BMS-986158 in clinical trials was based on
data from nonclinical toxicology studies in rats and dogs. Those studies primarily demonstrated
the expected toxicity profile of BET inhibition, with most toxicity shown in the highly proliferative 
cell populations of the bone marrow and gastrointestinal tract. An additional toxicity observed in 
the rat but not dog was mammary gland atrophy in males. An additional toxicity observed in the 
dog but not rat was testicular degeneration. An additional toxicity finding observed in pregnant 
rats demonstrated embryolethality and teratogenicity. A detailed description of these toxicities is 
provided in Section 1.4.2 and in the Investigational Brochure. The GI and bone marrow toxicities 
were reversible upon discontinuation of the drug.
The nonclinical toxicity profile was used to determine the starting dose and to develop appropriate 
exclusion criteria, contraception measures for male and female participants, and safety monitoring 
for this study. In addition to frequent complete blood counts (CBCs) and chemistry (including liver 
enzyme) tests, because of the potential effect of immune system repression, subjects with viral 
infection (Human immunodeficiency virus [HIV], Hepatitis B or C) are excluded and lymphocyte 
numbers are monitored regularly. Immunoglobulin levels are also followed routinely to evaluate 
the potential need for supplementation. Although the nonclinical in vitro and in vivo assessments 
have not demonstrated any cardiovascular liability, electrocardiograms (ECG) are being monitored 
frequently. Subjects will be evaluated frequently by physical exam; their weights are being closely 
monitored, and they are being assessed for the development of diarrhea or other anticipated GI 
symptoms. Guidelines for the management of diarrhea are provided in Section 4.5.3. 
As of the data cutoff date on 21-Dec-2018, preliminary clinical data from the first-in-human 
CA011001 monotherapy study in subjects with advanced solid tumors have demonstrated that 
BMS-986158 has an acceptable toxicity profile in 81 subjects treated at all dose levels in Schedule 
A (0.75, 1.25, 2, 3, and 4.5 mg), Schedule B (2 and 3 mg) and Schedule C (2, 3, and 4.5 mg). All 
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observed toxicities in the GI or hematopoietic system reversed spontaneously or upon drug 
withdrawal. To date, the cumulative human safety data are consistent with the non-clinical
assessment of toxicity in rats and dogs and support the continued clinical exploration of BMS-
986158 for the treatment of a variety of malignancies. 
Although BMS-986158 does not demonstrate evidence of genotoxicity, perturbation of cellular 
differentiation pathways may contribute to development of cancer. Subjects are informed of the 
potential risk, and are carefully evaluated by the investigators throughout the study. Subjects are 
counseled on appropriate contraceptive measures, while on study and for at least 3 months after 
the last dose of BMS-986158. Additionally, subjects are informed of the potential risks to 
reproductive organs and the option of sperm or egg banking discussed, if appropriate.
The frequent safety assessments are utilized by the Sponsor/Medical Monitor and investigators to 
determine whether dose modification, additional safety measures, or termination of the study is 
required at any time. Thorough evaluation of the above-described safety monitoring procedures 
and of AEs and serious adverse events (SAEs) are reviewed on an ongoing basis by the Sponsor’s 
Medical Monitor and Global Pharmacovigilance and Epidemiology representatives to monitor for 
any safety signals or trends.
As BMS-986158 is an experimental agent, it is possible that unforeseen, unknown, or 
unanticipated reactions may occur. Five serious, unexpected serious adverse events have been 
reported with BMS-986158; 4 of them were assessed to be related to study drug. Two subjects 
experienced Grade 4 thrombocytopenia, 1 subject experienced Grade 3 vertigo and another subject 
experienced myocardial infarction. One subject experienced anemia, which was assessed not to be 
related to BMS-986158.
However, based on the nonclinical safety and toxicity profile of BMS-986158 observed with tested 
doses in Schedules A, B, and C, the potential safety risks are expected to be minimized, following 
the planned cautious dose escalation scheme. An urgent need exists for new therapies for subjects 
with advanced cancer that has progressed or not responded to other treatments. Pharmacologically-
active dosing has been achieved at the 4.5 mg dose level in Schedule A. Thus, there may be 
potential benefits to study subjects with BMS-986158 monotherapy treatment. In addition, based 
upon potential synergistic effect,25 a combination of BMS-986158 with nivolumab may provide 
potential additional benefit but will be pursued only after the effects of BMS-986158 on the tumor 
microenvironment have been characterized. Furthermore, the substantial nonclinical efficacy 
profile (see Section 1.4.2) and the growing evidence for MYC and BRD4 targeting in many human 
cancers (see Section 1.1.3), indicates that the balance of benefit to risk is likely to be favorable for 
study subjects.
This study may allow the characterization of the safety and clinical activity of nivolumab in 
combination with BMS-986158 depending on the information obtained in the monotherapy dose 
expansion cohorts and provide an estimate of the clinical benefit as measured by ORR in subjects 
with advanced cancers associated with genetic abnormalities, including 1) amplifications of BRD, 
MYC, or AR genes; or 2) mutations in Gnaq/11, KRAS, or SWI/SNF; or 3) translocations of MYC, 
BCL2/6, or NUT.
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2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice, as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the US Code of Federal Regulations, Title 
21, Part 50 (21CFR50).
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 BMS immediately. A serious breach is a breach 
of the conditions and principles of GCP in connection with the study or the protocol, which is 
likely to affect, to a significant degree, the safety or physical or mental integrity of the subjects of 
the study or the scientific value of the study.
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 IB or product labeling information to be 
provided to subjects and any updates. 
The investigator or BMS 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.
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. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form(s) (ICF) which will include all elements required by ICH, GCP and applicable 
regulatory requirements. The sample ICF will adhere to the ethical principles that have their origin 
in the Declaration of Helsinki.
Investigators must:
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•
Provide a copy of the consent form(s) 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 ICF (s) 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 Health Insurance Portability and Accountability Act Authorization.
The consent form(s) must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
Minors who are judged to be of an age of reason as determined by local requirements should also 
give their assent. The assent should be documented based on local regulations. 
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is a Phase 1/2a, open label study to characterize the safety and tolerability of BMS-986158 
monotherapy and/or in combination with nivolumab in subjects with advanced solid tumors and 
hematologic malignancies. The study has two segments: Part 1 (Phase 1 study - dose escalation, 
with Schedules A, B and C enrolling at different dosing schedules) and Part 2 (Initial Expansion 
including subjects with a limited set of tumor types followed by Subsequent Expansion including
subjects with an expanded set of tumor types) (see Figure 3.1-1). In Part 1, BMS-986158 will be 
studied as monotherapy, and in Part 2, BMS-986158 will be studied as monotherapy and may be 
administered in combination with nivolumab depending on
 
available data from the monotherapy-treated subjects. 
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The planned sample size consists of up to approximately 90 subjects for Part 1 and up to 
approximately 327 subjects for Part 2 for a total of up to approximately 417 subjects in the entire 
study.
In Part 1, the continuous dosing Schedule A enrolled first. Each subject in Schedules A, B and C 
of Part 1 is administered a single dose of BMS-986158 on Cycle 1 Day 1 and no additional doses 
are administered until Cycle 2 Day 1. For subjects in Schedule A on Cycle 2 Day 1, which must 
be within approximately 7 days of the Cycle 1 Day 1 dose administration, and on each subsequent 
cycle, subjects receive QD dosing for 5 consecutive days of each week, followed by a 2-day rest 
period, on a 28-day cycle. For subjects in Schedule B on Cycle 2 Day 1, which must be within 
approximately 7 days of the Cycle 1 Day 1 dose administration, and on each subsequent cycle, 
subjects receive QD dosing for 14 consecutive days, followed by a 7-day rest period, on a 21-day 
cycle. For subjects in Schedule C on Cycle 2 Day 1, which must be within approximately 7 days 
of the Cycle 1 Day 1 dose administration, and on each subsequent cycle, subjects receive QD
dosing for 7 consecutive days, followed by a 14-day rest period, on a 21-day cycle. Subjects may 
continue to receive treatment until disease progression, unacceptable AEs or withdrawal of 
consent.
In Part 2, Schedule A for BMS-986158 administration has been selected for expansion of the 
4.5 mg dose, which will be administered for 2 weeks (10 doses) followed by 3.75 mg for the 
remainder of the treatment period. Adult and adolescent subjects weighing ≥40 kg will be 
administered a flat dose of BMS-986158 (see Section 1.1.13). Using Schedule A with a loading 
period of 2 weeks at 4.5 mg followed by 3.75 mg for the remainder of the treatment period, BMS-
986158 will be tested as monotherapy, initially in a limited set of tumor types (NMC, CRPC, DHL, 
Non-DC-DLBCL, and TNBC; Initial Expansion), with Subsequent Expansion into additional 
tumor types upon observing signals of antitumor activity or favorable PD effects in the initial set 
of tumor types. If combination therapy is pursued, nivolumab will be administered as a flat dose 
of 480 mg Q4W in adults and BMS-986158 will be administered using Schedule A.
Further dose modification at the subject level is permitted below the dose level of 3.75 mg 
depending on the observed toxicity and tolerability (see guidelines for dose modification in Section
4.5.2).
Subjects will complete up to 5 study periods (See Figure 3.1-2): Screening (up to 28 days for Part 
1 and up to 40 days for Part 2), Treatment (up to 2 years, until disease progression or other protocol-
specified criteria), Clinical Follow-up (30 days for BMS-986158 monotherapy and 30 days, 
60 days, and 100 days for combination therapy, if pursued), and Survival Follow-up
 
 
. 
 
Only subjects who 
have progressive disease after receiving BMS-986158 in combination with nivolumab may have 
the option to continue treatment with the combination if combination therapy is pursued. Subjects 
who have progressive disease after receiving BMS-986158 monotherapy will not have the option 
to continue treatment with BMS-986158 monotherapy or to receive BMS-986158 in combination 
with nivolumab.
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Safety, PK,
 and efficacy measurements will occur as indicated in Table 5.1-1, 
Table 5.1-2 Table 5.1-3, Table 5.1-4, Table 5.1-5, and Table 5.1-6. Pre- and on-treatment biopsies 
will be required for all adult subjects enrolled in Part 2 to allow the assessment of BMS-986158-
induced changes in tumor immune infiltration 
 
 
 
The overall duration of the study is expected to be approximately 4 years from the time of the first 
visit of the first subject to the required survival follow-up of the last subject enrolled. Subjects may 
discontinue treatment due to disease progression, unacceptable AEs, or withdrawal of consent. The 
Clinical Follow-up visits will occur approximately 30 days (for subjects who receive 
monotherapy), and 60 days and 100 days (for subjects who may receive combination therapy) after 
the subject discontinues study treatment. For subjects in PR or CR who discontinue treatment for 
AEs, tumor assessments will be performed every 12 weeks for the first year then every 6 months 
for the second year. If a subject discontinues treatment due to an AE, the subject should be seen in 
Clinical Follow-up every 30 days until the AEs either resolved to baseline or Grade 1, stabilized, 
or been deemed irreversible. After completing the Clinical Follow-up Period, subjects will 
continue on to a Survival Follow-up Period. 
 
 
 
 
 The end of the 
study will occur after the last treated subject completes their Clinical Follow-up, unless a subject 
discontinues prematurely.
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Figure 3.1-1:
Study Overview
Abbreviations: BL = Burkitt’s lymphoma; CRPC = castrate-resistant prostate cancer; DHL = double-hit lymphoma; ES = Ewing sarcoma; NEPC = neuroendocrine 
prostate cancer; NMC = NUT-midline carcinoma; Non-GC-DLBCL = Non-germinal center diffuse large B-cell lymphoma; NSCLC = non-small cell lung cancer; 
OC = ovarian cancer; RCC = renal cell carcinoma; Res = response; SOC = standard of care; TNBC = triple negative breast cancer; UCS = uterine carcinosarcoma; 
UM = uveal melanoma.
*Up to 45 subjects will be enrolled in the Initial Expansion. Subsequent enrollment of subjects with an expanded set of tumor types within and across biomarker
groups (eg, fusion proteins, BRD amplifications, MYC amplifications, AR amplifications or mutations) as part of the Subsequent Expansion will depend on the 
totality of data obtained from subjects in the Initial Expansion. If combination therapy with nivolumab is pursued, subjects with any listed tumor type will be 
eligible.
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Figure 3.1-2:
Expansion Cohorts
3.1.1
Monotherapy Dose Escalation (Part 1)
In Part 1 (dose escalation), BMS-986158 is administered as monotherapy (Schedules A, B and C). 
The study design schematics are presented in Figure 3.1-1 and Figure 3.1-2.
To minimize risks to subjects from unanticipated acute toxicities, a waiting period of at least 5 
days will occur between administrations of the first dose for the first, second, and third subjects to 
create an observation period prior to subsequent subject exposures. This waiting period is 
mandatory only in the first Cohort of Schedule A of Part 1.
Part 1: Selection of Doses
In Schedule A of Part 1, the first cohort of subjects received a starting dose of 0.75 mg. In this 
schedule, each subject was administered a single dose of BMS-986158 on Cycle 1 Day 1 (4-to 7-
day cycle) and no additional doses were administered until Cycle 2 Day 1. On Cycle 2 Day 1, 
which must be within 7 days of the Cycle 1 Day 1 dose administration, and on each subsequent 
cycle, subjects received QD dosing for 5 consecutive days of each week, followed by a 2-day rest 
period, on a 28-day cycle. The second cohort of subjects on this schedule received a dose of 
1.25 mg. This dose level (a 67% increase) was chosen instead of 1.5 mg dose level (a 100% 
increase) because of the longer than expected half-life that was calculated based on human 
exposure data from the first cohort of (n=5) subjects evaluated at the 0.75 mg dose level.
For Schedule B, each subject is administered a single dose of BMS-986158 on Cycle 1 Day 1 
(7-day cycle) and no additional doses are administered until Cycle 2 Day 1. On Cycle 2 Day 1, 
and on each subsequent cycle, subjects receive QD dosing for 14 consecutive days, followed by a 
7-day rest period, on a 21-day cycle. For Schedule C, subjects are administered a single dose of 
BMS-986158 on Cycle 1 Day 1 (7-day cycle) and no additional doses are administered until Cycle 
2 Day 1. A schedule of 7 days on, 14 days off may be implemented beginning with Cycle 2 Day 1 
and on each subsequent cycle, if agreed upon by the Sponsor/Medical Monitor and investigators.
Refer to Figure 3.1-2 and Section 4. Subjects enrolled previously in Part 1 who are still receiving 
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therapy will continue to be dosed on their original schedule. Subjects may continue to receive 
treatment until disease progression, unacceptable AEs or withdrawal of consent, or as defined in 
Section 3.5. 
Dose escalation for each subsequent cohort of subjects in each of the schedules will be guided by 
the incidence of AEs for which no clear alternative cause is identified as graded by National Cancer 
Institute Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03) in 
the first 32-35 days of dosing for Schedule A of Part 1. Dose escalation will be in increments of 
100% above the previous dose level until the first occurrence of any of the following toxicities that 
have no alternate cause: any DLT (as described in Section 4.5.1), any ≥Grade 2 toxicities with the 
following exceptions: Grade 2 fatigue, Grade 2 alopecia.
Once one or more of the above identified DLTs occurs, a modified Fibonacci dose escalation 
schema will be employed for any subsequent dose escalations at that schedule, with increments of 
67%, 50%, 40%, and 33%. Any further dose escalations will be 33%. In addition, dose 
modification could also include changes in the dosing interval (e.g. twice weekly) based on 
available safety and PK data.
Intermediate doses may be evaluated if agreed upon by the Sponsor/Medical Monitor and 
investigators. The next dose level will not exceed 100% or the dose increment per the modified 
Fibonacci dose escalation schema.
Part 1: Monotherapy Dose Escalation Decision Guide
Figure 3.1.1-1:
Dose Escalation Decision Scheme
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Enrollment in dose escalation and selection of the MTD will adhere to a mTPI design. The design 
provides a simple algorithm for decisions on escalation, expanding at the same dose, and 
de-escalation, depending on the number of observed toxicities after each dose cohort (see Figure 
3.1.1-1). The mTPI method utilizes a target toxicity (DLT) rate and equivalence interval to guide
decisions on escalation after each cohort and to estimate the MTD. For this study, the target DLT 
rate is 27% and the EI is 25%-29%.
Dose escalation decisions will be guided by the cumulative number of subjects who are DLT 
evaluable and who experience a DLT in the DLT Evaluation Period for all arms (Figure 3.1.1-1
and Appendix 1). If no DLTs are observed in the first dose cohort of Part 1, 3-4 subjects will be 
enrolled at the next higher dose level. If 1 DLT is observed in 3 or 4 evaluable subjects, this dose 
level will be expanded by enrolling another cohort of 3-4 at the same dose level. If 2 of 3 or 3 of 
4 subjects are observed with DLTs, the next cohort will be enrolled at the next lower dose level. 
Additional decisions are shown in Figure 3.1.1-1 and Appendix 1. If a decision to treat more 
subjects at a given dose level is suggested by the mTPI algorithm when there are already at least 
13 DLT evaluable subjects treated at the same dose level, a need for further enrollment in the dose 
escalation phase will be determined by the Sponsor. These same rules will be applied to 
Schedules B and C. A total of approximately 30 DLT evaluable subjects is expected to be treated 
per schedule with a total of 90 planned across schedules for the dose escalation phase. 
Decisions to escalate, add more subjects to the current dose, de-escalate (with options to 
re-escalate), or de-escalate and declare the current dose as unacceptable (exceeding the MTD), will 
be based on the rate of DLTs in evaluable subjects within the 32-35-day DLT evaluation period of
Schedule A for Part 1, and within the 35-day DLT evaluation period of Schedules B and C for 
Part 1 (Appendix 1). At least 3 DLT-evaluated subjects treated at each dose level are required to 
enable a decision. To account for subjects who may not be able to complete the DLT evaluation 
period, for reasons other than a DLT, or may not be evaluable for DLT, a fourth subject may be 
enrolled at this dose level, following agreement between the investigator and Sponsor/Medical 
Monitor. 
DLT-evaluable subjects are defined as subjects who received at least 16 of 21 doses of 
BMS-986158 in Schedule A of Part 1; at least 17 of 22 doses of BMS-986158 in Schedule B of 
Part 1; and at least 12 of 15 doses in Schedule C of Part 1 during the DLT evaluation period and 
will be considered for dose escalation decisions. Subjects who developed a DLT during the DLT 
period are considered evaluable regardless of the number of received doses. Subjects with 
insufficient data to establish safety during the DLT evaluation period at the dose level tested may 
be replaced upon agreement of the Sponsor/Medical Monitor and investigators.
There will be no intrasubject dose escalation of BMS-986158.
Figure 3.1.1-1 shows examples of scenarios guiding decisions that may be encountered during 
dose escalation with respect to the number of DLT evaluable subjects and the number of subjects 
with a DLT. All potential combinations of the number of subjects with DLTs and number of treated 
subjects evaluable for DLT are shown in Protocol Appendix 1. In addition to escalation or 
expansion decisions, dose re-escalation is permitted as per Figure 3.1.1-1 and Appendix 1 after a 
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decision to de-escalate is made, except when a dose level has been identified as exceeding the 
MTD. Therefore, a dose level could be revisited multiple times under the mTPI design.
In addition to the guide for escalation decisions, to better assess if a dose level is safe given the 
number of DLTs observed, posterior probabilities of the DLT rate are provided in Section 8.1 to 
inform decisions regarding dose safety. 
Part 1: MTD Determination
At the end of dose escalation, the MTD for each evaluated dosing schedule (Schedules A, B, and C) 
will be selected as the dose with the smaller difference between estimated toxicity and the target 
DLT rate (27%), among the dose levels used, with an isotonic regression model of the accumulated 
DLT data based on the mTPI design (Appendix 1).
3.1.2
Dose Expansion (Part 2)
Treatment in Part 2 can be initiated before Part 1 is completed and when the MTD or maximum 
administered dose (MAD), if no MTD is reached for Part 1, has been determined. Schedule A (QD 
dosing for 5 consecutive days of each week, followed by a 2-day rest period, on a 28-day cycle) 
has been chosen for expansion. This regimen was selected after considering safety, PK 
 
 data generated during Part 1 (see Section 1.1.5). The initial dose level 
of BMS-986158 selected for Part 2 is 4.5 mg with a loading period of 2 weeks (10 doses or half a 
cycle) with subsequent dose level of 3.75 mg for the duration of study treatment for each subject. 
Adult and adolescent subjects weighing ≥40 kg will be administered a flat dose of BMS-986158. 
Further dose modification at the subject level is permitted below the dose level of 3.75 mg 
depending on the observed toxicity and tolerability (see guidelines for dose modification in Section 
4.5.2).
BMS-986158 will be first evaluated as monotherapy. The Initial Expansion will enroll a maximum 
of 45 subjects with tumors harboring specific genetic alterations including fusion proteins (NMC, 
DHL), BRD amplifications (TNBC), MYC amplifications (Non-GC DLBCL) and AR 
amplification (CRPC). 
 
 
 
 
Depending on the 
safety, preliminary efficacy, tolerability, 
 
 a Subsequent Expansion will enroll up to 126 subjects with  tumor types already evaluated 
in the Initial Expansion as well additional tumor types within and across groups of specific genetic 
alterations. Categories of genetic alterations and tumors under consideration for the Subsequent 
Expansion include fusion proteins (NMC, DHL, ES and BL), BRD amplifications (TNBC, OC 
and NEPC), MYC amplifications (Non-GC DLBCL, UCS, OC), AR amplification (CRPC) and 
mutations (RCC, NSCLC and UM). See Figure 3.1-1. 
The decision to assign new cohorts of subjects to BMS-986158 plus nivolumab combination 
therapy will be made upon agreement between the Sponsor/Medical Monitor and investigators 
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after review of 
 available data obtained from both initial and 
subsequently enrolled monotherapy expansion subjects. If combination therapy of BMS-986158 
and nivolumab is pursued, subjects may be enrolled with any of the tumors types listed in Figure 
3.1-1. The tumor types enrolled will depend on the activity of BMS-986158 monotherapy within 
and across biomarker groups. Based on the results of Part 2, including PK 
 
, discussion between Sponsor/Medical Monitor and the investigators, and additional 
considerations, enrollment may be initiated for other indications not listed in Figure 3.1-1 as long 
as subjects meet the specified inclusion criteria (see Section 3.3.1). Up to approximately 
327 subjects will be treated in the dose-expansion phase (Part 2) of this study
3.1.2.1
Safety Evaluation Phase of BMS-986158 Monotherapy Expansion
Clinical safety monitoring of subjects treated with BMS-986158 monotherapy enrolled in Part 2 
of the study will be the same as conducted during the dose escalation portion. During Part 2, if in 
a given tumor cohort the combined incidence of study drug-related AEs that require dose 
modification exceeds 29% (of treated subjects), then further enrollment to that arm may be 
interrupted and the findings will be discussed between the Sponsor/Medical Monitor and 
investigators. An agreement will be reached as to whether a lower dose level or an alternate dose 
schedule of BMS-986158 should be examined, or whether any additional treatment guidelines 
should be implemented prior to enrollment of additional subjects on study in alignment with dose 
modification criteria (Section 4.5.2), discontinuation criteria, and other safety evaluation criteria.
3.1.2.2
Safety Evaluation Phase of BMS-986158 Combination with Nivolumab
If combination therapy with nivolumab is pursued, the safety of the selected BMS-986158 dose 
when given in combination with nivolumab within the dose expansion phase will be evaluated by 
monitoring DLTs in the first 6 to 12 subjects treated across the different tumor cohorts receiving 
combination therapy. Once the selected dose of BMS-986158 in combination with nivolumab is 
deemed safe based on the DLT evaluation, the dose expansion will continue as planned in all 
cohorts. 
The guidance for assessing the DLT-related safety and overall safety will be similar to that used 
in the monotherapy cohorts. The DLT safety monitoring during the dose evaluation phase 
including potential decision to de-escalate to a lower dose will be based on the mTPI-2 design49
with target toxicity (DLT) rate of 29% (-2%, +4%), as presented in Table 3.1.2.2-1. The 
performance of the design is reported in Appendix 8.
Initially, the first 3 to 4 subjects treated in combination will be evaluated for DLT. If 0 or 1 DLT 
is observed during the DLT period established for BMS-986158, an additional 3 subjects will be 
treated at the same BMS-986158 dose level. A decision to stay at the same dose level by treating 
additional 3 to 4 subjects, to expand (continue enrollment) of all subjects treated with combination 
therapy across all tumor cohorts (declaring this dose to be safe), or to consider de-escalation will 
be guided by the number of subjects with DLTs observed during the dose evaluation phase and the 
posterior probability of DLT. (Table 3.1.2.2-1 and Table 3.1.2.2-2). Subjects who do not complete 
the DLT observation period for reasons other than DLTs will not contribute to this safety 
evaluation and can be replaced. De-escalation may be considered if the safety and tolerability 
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profile for the selected BMS-986158 dose is evaluated as not acceptable, after discussion between 
the investigator(s) and the Sponsor/Medical Monitor. 
Table 3.1.2.2-1:
Combination Safety Monitoring Guidance for DLT during Safety
Evaluation Phase by mTPI-2
Number of DLT Evaluable Participants Treated
Number of participants with a DLT
3
4
5
6
7
8
9
10
11
12
0
E
E
E
E
E
E
E
E
E
E
1
E
E
E
E
E
E
E
E
E
E
2
D
D
D
S
E
E
E
E
E
E
3
DU
D
D
D
D
D
S
S
E
E
4
-
DU
DU
D
D
D
D
D
D
S*
5
-
-
DU
DU
DU
DU
D
D
D
D
6
-
-
-
DU
DU
DU
DU
DU
D
D
7
-
-
-
-
DU
DU
DU
DU
DU
DU
Source: Target Toxicity (DLT) Rate used is 29% (-2%, +4%). 
D = de-escalate to lower dose; DLT = dose limiting toxicity; E = expand at this dose in each tumor type; 
DU = de-escalate to lower dose and the current dose will never be used again in the trial; mTPI = modified Toxicity 
Probability Interval; S = stay at the same dose.
*Additional considerations including information from Table 3.1.2.2-2 below will be used. 
In the case where 4 DLTs are observed out of 12 evaluable subjects as shown in Table 3.1.2.2-1, 
the design recommends the decision to stay at the same dose level (S), indicating that more subjects 
need to be evaluated to determine whether the dose level is safe. After considering additional 
information such as provided in Table 3.1.2.2-2, a lower dose may be considered for evaluation 
based on discussion between Sponsor/Medical Monitor and investigators. 
In addition to the above guidance, the following posterior probabilities may be utilized to make a 
more informed decision on the safety based on DLT findings prior to the decision to expand. 
Assuming a 33% acceptable DLT rate in a combination therapy setting, which corresponds to a 
Beta(1,2) distribution, Table 3.1.2.2-2 shows the risk of selecting a BMS-986158 dose level as 
safe based on the observed DLTs and expressed as a posterior probability of toxicity given the 
number of DLTs observed during the combination safety evaluation phase.
Table 3.1.2.2-2:
Posterior Probability of a DLT in Combination Therapy Assuming 
Observed Data
Number of Subjects at a 
Dose Level
Number of Subjects 
with an Observed DLT
Probability of DLT Rate 
>33%
Probability of DLT Rate 
>40%
6
0
4%
2%
6
1
20%
11%
6
2
47%
32%
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Table 3.1.2.2-2:
Posterior Probability of a DLT in Combination Therapy Assuming 
Observed Data
Number of Subjects at a 
Dose Level
Number of Subjects 
with an Observed DLT
Probability of DLT Rate 
>33%
Probability of DLT Rate 
>40%
9
1
8%
3%
9
2
24%
12%
9
3
48%
30%
12
2
11%
4%
12
3
27%
12%
12
4
48%
28%
Posterior probabilities are calculated using a Beta(1,2) prior corresponding to 33% DLT rate (ie, 1 of 3 evaluable 
subjects has a DLT). 
DLT = dose limiting toxicity.
Based on the above, if 0 out of 6, 1 out of 9, or 2 out of 12 subjects experience a DLT, the dose 
level may be considered sufficiently safe to open enrollment to the additional subjects in the 
expansion phase of the study. 
3.1.2.3
Safety Evaluation in Adolescents
Adolescent subjects will be treated with a dose and schedule selected from Part 1 (dose escalation)
in adult subjects. The safety of this selected BMS-986158 dose will be evaluated in adolescents 
(≥12 to <18 years of age) as part of the dose expansion phase (Part 2) in subjects with NMC, BL,
ES, or other tumors with genetic abnormalities in BRD proteins (Section 1.1.7 and Section 1.1.13). 
Initially, 3 to 4 adolescent subjects across different tumor types may be enrolled in the Initial 
Expansion and monitored for DLT. Further enrollment of adolescent subjects into the Subsequent 
Expansion will depend on the totality of data, including safety, PK and PD data obtained from all 
subjects in the initial expansion. Based on safety and other available data, the Sponsor may 
consider decreasing the dose level of BMS-986158 for adolescent subjects. The selected dose may 
be further evaluated in adolescent subjects in combination with nivolumab, if combination therapy 
is pursued, depending on the review of pharmacodynamics results and other data from BMS-
986158 monotherapy. If pursued, 3 to 4 subjects ≥12 to <18 years of age across any eligible tumor 
types (eg, NMC, BL, and ES), will be treated with BMS-986158 in combination with nivolumab 
to establish safety of the combination treatment in this adolescent population. Subjects will be 
observed for DLT, and if safety is considered acceptable, additional adolescent subjects will be 
treated with combination therapy. 
3.1.2.4
BMS-986158 Monotherapy and in Combination with Nivolumab Dose 
Expansion--Number of Subjects
Once the safety and tolerability profile is established at the selected dose of BMS-986158 alone or 
in combination with nivolumab during the dose evaluation phase, the tested dose level will be 
enrollment in the expansion phase will initiate at this dose level to to assess a preliminary efficacy 
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signal, and to obtain additional data, such as 
 safety information across 
the selected tumors. 
Enrollment in the Part 2 expansion will start in the initial BMS-986158 monotherapy cohorts. 
Although a 2-stage (Fleming) design will be used to guide assessment of preliminary anti-tumor 
activity in each of the monotherapy cohorts (and in combination therapy with nivolumab, if 
pursued), up to 9 subjects may be enrolled in each of the initial cohorts to better characterize the 
PK, safety, 
 and inform enrollment in both the subsequent 
monotherapy and potential combination expansion cohorts. The decision to open subsequent 
cohorts (monotherapy or in combination) will take into acount the totality of the available data and 
upon agreement of the Sponsor/Medical Monitor, in consultation with the investigators. The 
decision to continue or discontinue enrollment in one or more cohorts or discontinue treatment in 
existing cohorts will be made by the Sponsor/Medical Monitor based on a comprehensive 
assessment of the accruing on-treatment evidence (see Section 3.1.2.1 and Section 3.5).
Clinical safety monitoring of subjects during dose expansion phase will continue throughout the 
study. If at a selected BMS-986158 dose level, the combined incidence exceeds 33% for study 
drug related toxicity requiring treatment discontinuation, further enrollment to that dose level may 
be interrupted and a decision to continue dosing will be based on discussions of the observed 
aggregate (acute and chronic) toxicities between the investigator(s) and the Sponsor, if needed.
Table 3.1.2.4-1 shows the planned number of subjects per tumor type and setting (monotherapy or 
combination therapy and Initial or Subsequent) in the expansion phase. 
Table 3.1.2.4-1:
Dose Expansion Planned Sample Size
Tumor Cohort and 
Group
Initial 
Monotherapy
Subsequent 
Monotherapy
Combination
Therapy
Total
FUSION PROTEINS
DHL
5 to 9
5 to 9
5 to 9
15 to 27
NMC
5 to 9
5 to 9
5 to 9
15 to 27
ES
5 to 9
5 to 9
10 to 18
BL
5 to 9
5 to 9
10 to 18
BRD AMPLIFICATIONS
TNBC
5 to 9
5 to 9
5 to 9
15 to 27
OC w BRD 
amplifications
5 to 9
5 to 9
10 to 18
NEPC
5 to 9
5 to 9
10 to 18
MYC AMPLIFICATIONS
Non-GC-DLBCL
5 to 9
5 to 9
5 to 9
15 to 27
OC w MYC 
amplifications
5 to 9
5 to 9
10 to 18
UCS
5 to 9
5 to 9
10 to 18
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Table 3.1.2.4-1:
Dose Expansion Planned Sample Size
Tumor Cohort and 
Group
Initial 
Monotherapy
Subsequent 
Monotherapy
Combination
Therapy
Total
AR AMPLIFICATIONS
CRPC
5 to 9
5 to 9
5 to 9
15 to 27
MUTATIONS
RCC
5 to 9
5 to 9
10 to 18
NSCLC
5 to 9
5 to 9
10 to 18
UM
5 to 9
5 to 9
10 to 18
All Cohorts
25 to 45
70 to 126
70 to 126
165 to 297
The minimum overall planned sample sizes are based on Stage 1 initial enrollment, subsequent enrollment, and 
combination therapy enrollment subject counts per cohort. The maximums are determined similarly. The above 
assumes that the selected dose level administered in combination is deemed safe; alternately an additional 6 to12 
subjects may need to be treated to assess safety at a lower dose level and to continue enrolling all combination 
therapy cohorts. 
An additional 6 to 12 subjects may be enrolled to evaluate a lower dose of BMS-986158 in 
combination therapy as well as another 18 subjects may be enrolled to evaluate target gene 
engagement in tumors, and additional PK and safety characteristics in up to 2 cohorts at a different
dose or schedule. Therefore, the potential total for expansion will be approximately up to 201
subjects if only monotherapy is pursued, and approximately up to 327 subjects if all planned 
expansion cohort subjects in monotherapy and combination therapy groups are pursued. 
Administration of Additional Treatment Cycles:
Subjects may discontinue treatment due to disease progression, unacceptable AEs, or at the 
subject’s request. Treatment decisions related to subject management will be based exclusively on 
RECIST version 1.1 (Appendix 4), the Lugano 2014 criteria (Appendix 9), or PCWG3 criteria 
(including PSA assessments) (Appendix 12). Subjects with an objective response of CR, partial 
response (PR) or stable disease, will continue therapy until they develop progressive disease (PD, 
unless in case of treatment beyond progression as detailed in Section 3.6), experience clinical 
deterioration, develop AEs requiring discontinuation of treatment or withdraw consent. Subjects 
who developed disease progression on BMS-986158 monotherapy in Part 2 will not be allowed to 
switch to combination therapy.
Subjects who develop toxicity requiring discontinuation of treatment will enter the Clinical 
Follow-up Period. The subject should be seen in follow-up at least every 30 days, until the AE has 
resolved to baseline, stabilized, or been deemed irreversible. After completion of the Clinical 
Follow-up Period, subjects will then enter the Survival Follow-up Period. During this period, clinic 
visits or telephone contact every 3-4 months will be performed to assess survival status. 
 
 
 
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The end of the study will occur after the last treated subject 
completes their Clinical Follow-up unless if a subject discontinues prematurely. Subjects in 
Survival Follow-up Period who have progression of disease will be eligible to receive anticancer 
therapy as appropriate.
3.2
Post Study Access to Therapy
At the end of the study, BMS will not continue to provide BMS supplied study drugs to 
subjects/investigators unless BMS chooses to extend the study. The investigator should ensure that 
the subject receives appropriate SOC to treat the condition under study.
3.3
Study Population
Subjects will undergo screening evaluations to determine eligibility within 28 days for Part 1 and
up to 40 days for Part 2 prior to first administration of study medication. For entry into the study, 
the subject MUST fulfill the required eligibility data prior to dosing on Day 1. No exceptions will 
be granted.
3.3.1
Inclusion Criteria
1) Signed Written Informed Consent
a) The subject must sign the informed consent form prior to the performance of any study 
related procedures that are not considered part of standard of care.
i)
Part 2 only: Subjects must consent and will be required to undergo mandatory
pretreatment and on-treatment biopsies. Adolescent subjects with genetic alterations 
detected as SOC (eg, IGH/MYC fusion) are exempt from this requirement. Subjects 
must have a lesion that can be biopsied at acceptable clinical risk as judged by the 
investigator. Subjects whose pre-treatment biopsy yields inadequate tissue quantity or 
quality will be eligible if sufficient archival tissue is available, after discussion with the 
Medical Monitor. For subjects with adequate pretreatment biopsy and available 
archival tissue, both specimens should be submitted. Existing formalin-fixed 
paraffin-embedded (FFPE) tumor tissue, either a block or unstained slides (minimum 
20 slides are required) for performance of correlative studies, should also be collected 
if available. Additional information concerning the number of tissue cores and 
preparation are provided in the Laboratory Manual.
2) Target Population
a) Subjects must have a confirmed histologic or cytologic diagnosis of one of the following 
malignancies for participation in the study and meet the other criteria listed (a specific 
exception for disease diagnosis criteria is noted in inclusion criterion k and requirements 
for the 
test are noted in inclusion criterion m)
i)
Ovarian cancer (OC)
(1) Histological or cytological documented epithelial ovarian cancer, primary 
peritoneal carcinoma, or fallopian tube cancer
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(2) Received at least one prior Platinum Based Therapy (PBT) regimen
(3) Have platinum-resistant/refractory disease (progression or recurrence within 
6 months), be intolerant of platinum-containing compounds, and/or have 
hypersensitivity to platinum-containing compounds.
(4) Must have known BRCA1/2 mutation status, and if BRCA1/2 mutation is present, 
must have received treatment with a PARP inhibitor, if available
(5) For Part 2 Expansion only: All OC subjects must have BRD and/or MYC 
amplification in tumor cells
ii) Triple negative breast cancer (TNBC) 
(1) Males and females with histologically or cytologically confirmed triple negative 
breast carcinoma as defined by ASCO/CAP guidelines.
(2) Had progression or refractory disease during or after at least 1 chemotherapy 
regimen for the treatment of metastatic or locally advanced disease.
(3) Part 2 only: all subjects with TNBC must have BRD amplification in tumor cells 
iii) Part 1 only: Small cell lung cancer (SCLC) 
(1) Histologically or cytologically documented SCLC, limited or extensive stage 
disease.
(2) Received at least 1 prior Platinum Based Therapy (PBT) regimen.
iv) Part 2 only: Non-Small cell lung cancer (NSCLC)
(1) Histologically or cytologically documented NSCLC
(2) Had progression during or after at least 2 lines of therapy in the advanced metastatic 
setting
(3) Subjects must have mutations in SWI/SNF complex in tumor cells or detected 
KRAS mutation with wild type STK11 in tumor cells
(4) Subjects must have received at least 1 prior checkpoint inhibitor immunotherapy
(5) Subjects with known abnormalities of EGFR, ALK, ROS1, BRAF must have 
received appropriate targeted therapies
(6) Subjects should be ineligible for or received a platinum-based chemotherapy for 
NSCLC in the adjuvant, neoadjuvant, or recurrent setting
v)
Part 2 only: Renal cell carcinoma (RCC)
(1) Histologically or cytologically confirmed metastatic RCC
(2) Detected mutations in SWI/SNF complex in tumor cells
(3) Had progression or refractory disease during or after at least 2 lines of therapy
vi) Part 2 only: Uveal melanoma (UM)
(1) Histologically or cytologically confirmed unresectable or metastatic UM
(2) Detected Gnaq/11 mutations in tumor cells
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(3) Untreated or had progression or refractory disease during or after any line of 
therapy
vii) Part 2 only: Uterine carcinosarcoma (UCS)
(1) Women with histologically or cytologically confirmed UCS
(2) Detected MYC amplifications in tumor cells
(3) Had progression or refractory disease during or after at least 1L treatment regimen
viii)
Part 2 only: Neuroendocrine prostate cancer (NEPC)
(1) Men with histologically or cytologically confirmed unresectable or metastatic 
NEPC
(2) Detected BRD amplification in tumor cells
(3) Had progression or refractory disease during or after at least 1L treatment regimen
ix) Part 2 only: Castration-resistant prostate cancer (CRPC)
(1) Men with histologically or cytologically confirmed unresectable or metastatic 
CRPC
(2) Detected AR amplification in tumor cells (with or without MYC amplification)
(3) Had progression or refractory disease during or after at least 1 treatment with a 
taxane and with an androgen pathway antagonist (eg, abiraterone or enzalutamide). 
Abiraterone but not enzalutamide may be continued during the study. 
(4) Detected MYC amplification in tumor cells (with or without AR amplification) 
x)
Part 2 only: NUT-midline carcinoma (NMC)
(1) Adult and adolescent subjects with Fluorescence in situ hybridization (FISH)-
confirmed fusion of NUT with BRD3 or BRD4
(2) Unresectable, or had progression or refractory disease during or after any line of 
therapy
xi) Part 2 only: Ewing sarcoma (ES)
(1) Adult and adolescent subjects with FISH-confirmed fusion of EWS with FLI1
(2) Had progression or refractory disease during or after at least 1L chemotherapy 
regimen
xii) Part 2 only: Burkitt’s lymphoma/leukemia (BL)
(1) Adult and adolescent subjects with FISH-confirmed rearrangement of MYC
(2) Had progression or refractory disease during or after at least 1L chemotherapy 
regimen
(3) Confirmed presence or absence of bone marrow involvement before enrollment. 
xiii)
Part 2 only: Double-hit lymphoma (DHL) or non-germinal center subtype of 
diffuse large B-cell lymphoma (non-GC-DLBCL)
(1) FISH-confirmed rearrangement of MYC and of BCL2 or BCL6 DHL
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(2) Had progression or refractory disease during or after at least 1 chemotherapy 
regimen
(3) Confirmed presence or absence of bone marrow involvement before enrollment
(4) IHC confirmed CD 10-, BCL6- DLBCL, or CD10-, BCL6+ and MUM1+ DLBCL. 
Gene expression profile may also be used to confirm a diagnosis of non-GC-
DLBCL
xiv)
Part 2 only: adolescent subjects with malignancies harboring genetic abnormalities 
likely sensitive to BET inhibition who have progressive disease with no effective 
therapeutic options may be enrolled after discussion and agreement between the 
Sponsor/Medical Monitor and Investigator.
b) Subjects with controlled, treated brain metastasis fulfilling all the following criteria may 
be screened: no radiographic progression for at least 2 weeks following radiation and/or 
surgical treatment, off steroids for at least 2 weeks, without new or progressing
neurological signs or symptoms.
c) All subjects must have at least one measurable lesion at baseline by computed 
tomography (CT) or magnetic resonance imaging (MRI) as per RECIST v1.1 for solid 
tumors or Lugano 2014 criteria for lymphomas.
d) For Part 1, all subjects must have archival tumor tissue identified and available 
 
 (if slides are provided, a minimum of 10 (ten) unstained 
slides with at least 5 micron thick tissue sections are required) unless a fresh biopsy is 
provided. All subjects not providing a fresh biopsy must consent to provide tumor 
blocks or slides to the sponsor and the availability of the tissue must be confirmed prior 
to subjects receiving study medication. If an archived tumor specimen is unavailable or 
unsuitable 
, subjects may consent to a pre-treatment 
fresh tumor biopsy to be eligible for this study if it can be performed at minimal 
acceptable clinical risk as judged by the investigator and if it does not include a target 
lesion or lesion in an area treated with prior radiation therapy.
For Part 2, both a pre-treatment and on-treatment fresh biopsy must be provided.
EOT biopsies must be collected for subjects experiencing PD. For adolescent subjects, 
fresh biopsies pre- and post-treatment are preferred but not mandated. If a fresh biopsy 
is not provided, archival tumor tissue is required. The screening tumor tissue for the 
expansion cohorts enrolled in Part 2 of the study must be shipped as described in the 
laboratory manual for biomarker testing including identification of select pre-defined 
genetic biomarkers prior to treatment, with the exception of samples from subjects with 
NMC, ES, BL, and DHL for which the characterization of fusion proteins is a part of 
SOC. Subjects whose pre-treatment biopsy yields inadequate tissue quantity or quality 
will only be eligible if sufficient archival tissue is available, after discussion with the 
Medical Monitor. If there is only 1 measureable lesion and a core needle biopsy is done 
(instead of excisional), the lesion may be used as a measureable lesion. If there are more 
than 1 measureable lesions, the lesion being biopsied should not be a target lesion. Fine 
needle biopsies are not allowed.
e) Subjects must have a life expectancy of at least 3 months.
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f)
Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance 
Status of 0 to 1 (Appendix 5).
g) Subjects who have undergone any major surgery within 4 weeks of study drug 
administration are excluded. Subjects must have recovered from the effects of major 
surgery at least 14 days before the first dose of the study drug.
h) Prophylactic anticoagulation for venous access devices with low-dose heparin or similar 
(e.g. heparin catheter flush) will be permitted. 
i)
For antiplatelet agents, prophylactic doses are permitted (e.g. aspirin < 300 mg daily, 
clopidogrel < 75 mg daily).
j)
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.
k) Subjects with solid tumor types that are not included in the preferred target population 
may also be enrolled after a minimum of 2 subjects with the preferred tumor types have 
been enrolled at a single dose level during escalation, or during monotherapy expansion
after discussion with the Sponsor/Study Director. These subjects must have progressed 
on or had refractory disease to at least one prior anticancer regimen, not be eligible for 
additional effective standard of care therapy for their disease, and must have the 
possibility of being positively impacted by the treatment offered in this study.
l)
Androgen Receptor Deprivation (ARD) therapy is permitted for subjects with prostate 
cancer at doses defined by the investigator if the therapeutic agent is not a strong inducer 
or inhibitor of CYP3A4 activity.
m) If biomarker result from the 
test is inconclusive, 
 
 will repeat the test. If there is not enough tumor material, the tumor biopsy 
must be repeated. Subjects who have had prior tumor biopsy and analysis by 
 
conducted < 6 months prior to enrollment and have data available do not 
need to provide additional sample for 
testing at screening.
3) Previous Treatment
a) Prior anticancer therapy treatments such as chemotherapy, radiotherapy, biological 
immunotherapy, or investigational agents (therapeutic or diagnostic) are permitted.
i)
For cytotoxic agents, at least 4 weeks must have elapsed from last dose of prior 
cytotoxic anticancer therapy and the initiation of study drug administration.
ii) For non-cytotoxic agents, at least 4 weeks or 5 half-lives (whichever is shorter) must 
have elapsed from the last dose of prior non-cytotoxic anticancer therapy and the 
initiation of study drug administration. If 5 half-lives is shorter than 4 weeks, agreement 
with Sponsor/Medical Monitor is mandatory.
b) Not applicable; removed per Revised Protocol 03. If subject had stem cell transplantation, 
the procedure must have occurred at least 3 months prior to treatment initiation (for
autologous SCT) or 4 months (for allogeneic SCT) and without evidence of active graft-
versus-host disease (GVHD).
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c) All acute toxicities, from any prior therapy (radiotherapy, chemotherapy, or surgical 
procedures) must have resolved to Grade ≤1, NCI CTCAE, version 4.03 or to baseline if 
irreversible. 
d) Concomitant therapy with bisphosphonates is acceptable as per American Society of 
Clinical Oncology (ASCO) guidelines. Doses of bisphosphonates must be stable for at least 
30 days prior to treatment initiation, as per ASCO guidelines.
4) Age and Reproductive Status
a) Males and Females, 12 years of age or greater at the time of informed consent. 
i)
For subjects < 18 years of age, age-adjusted normal ranges for all assessments shall be 
used, as appropriate, for inclusion, exclusion, and dose modification criteria. In 
addition, an alternate pediatric assessment (eg, left ventricular shortening fraction
rather than left ventricular ejection fraction [LVEF]) with an institutionally defined 
normal range may be used as appropriate. 
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) during screening 
and within 24 hours prior to the start of study drug.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment plus 5 half-lives of study treatments plus 30 days (duration of ovulatory cycle) 
for a total of 5 months post-treatment completion (see Appendix 11). In addition, female 
participants must be willing to refrain from donation of oocytes during this time.
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception (Appendix 11) for the duration of treatment with study 
treatments plus 5 half-lives of study treatments plus 90 days (duration of sperm turnover) 
for a total of 7 months post-treatment completion. In addition, male participants must be 
willing to refrain from sperm donation during this time (see Appendix 11). 
f)
WOCBP who are continuously not heterosexually active are exempt from contraceptive 
requirements, and still undergo pregnancy testing as described in this section.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy 
investigators shall advise on the use of highly effective methods of contraception. Highly effective 
methods of contraception have a failure rate of < 1% when used consistently and correctly.
One of the highly effective methods of contraception listed in Appendix 11 is required during 
study duration and until the end of relevant systemic exposure, which is defined as 5 months for 
females and 7 months for males.
Local laws and regulations may require use of alternative and/or additional contraception methods.
3.3.2
Exclusion Criteria
1) Medical History and Concurrent Diseases
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a) Evidence of uncontrolled, active infection, requiring parenteral anti-bacterial, anti-viral or 
anti-fungal therapy < 7 days prior to administration of study medication 
b) Current or recent (within 3 months of study drug administration) gastrointestinal disease 
such as chronic or intermittent diarrhea, or uncontrolled disorders that increase the risk of 
diarrhea, such as inflammatory bowel disease. Non-chronic conditions (eg, infectious 
diarrhea) that are completely resolved for at least 2 weeks prior to starting study treatment 
are not exclusionary 
c) Subjects with concomitant second malignancies (except adequately treated non-
melanomatous skin cancers or in situ bladder, breast or cervical cancers) are excluded 
unless a complete remission was achieved at least 3 years prior to study entry and no 
additional therapy is required or anticipated to be required during the study period
d) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days 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. 
e) History of medically significant thromboembolic events or bleeding diathesis within the 
past 6 months, such as cerebrovascular accident (including transient ischemic attacks), 
pulmonary embolism, pulmonary hemorrhage > 2 teaspoonfuls/24hrs or repeated 
pulmonary hemorrhage, gastrointestinal hemorrhage requiring transfusion or procedural 
intervention
f)
Uncontrolled or significant cardiovascular disease including:
i)
Congestive heart failure New York Heart Association [NYHA] Class 3 or greater 
within 3 months (Appendix 6)
ii) History of congenital long QT syndrome or clinically significant ventricular 
arrhythmias (such as ventricular tachycardia, ventricular fibrillation or Torsade de 
Pointes). Controlled atrial fibrillation is not an exclusion criterion
iii) Active coronary artery disease, unstable or newly diagnosed angina or myocardial 
infarction in the past 6 months
g) Inability to tolerate oral medication.
h) HIV-related disease or known positivity for human immunodeficiency virus (HIV).
i)
History of and chronic hepatitis evidenced by:
i)
Positive Test for hepatitis B surface antigen
ii) Positive test for qualitative hepatitis C viral load (by polymerase chain reaction (PCR) 
Note: Participants with positive hepatitis C antibody and negative quantitative hepatitis 
C by PCR are eligible. History of resolved hepatitis A virus infection is not an exclusion 
criterion.
j)
Not applicable; removed per Revised Protocol 02. NCI CTCAE v4.03 Grade 2 or higher 
peripheral neuropathy (sensory or motor).
k) Any other sound medical, psychiatric and/or social reason as determined by the 
investigator.
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l)
Use of strong inhibitors of CYP3A4 or P-gp within 1 week or 5 half-lives (whichever is 
longer) or strong inducers of CYP3A4 or P-gp within 2 weeks or 5 half-lives (whichever 
is longer). See Appendix 3
m) Current uncontrolled autoimmune pneumonitis
n) Use of non-oncology vaccines containing live virus for prevention of infectious diseases 
within 12 weeks prior to study treatment. The use of inactivated seasonal influenza 
vaccines, eg, Fluzone®, will be permitted on study without restriction.
o) Uncontrolled endocrine disorder including thyroid disease
p) Prior organ allograft or allogenic hematopoietic stem cell transplantation (HSCT)
i)
Participants with active, known or suspected autoimmune disease. Note the following 
exceptions: Participants with: vitiligo, type I diabetes mellitus, residual 
hypothyroidism due to autoimmune condition only requiring hormone replacement, 
euthyroid participants with a history of Grave’s disease (participants with suspected 
autoimmune thyroid disorders must be negative for thyroglobulin and thyroid 
peroxidase antibodies and thyroid-stimulating immunoglobulin prior to first dose of 
study treatment), psoriasis not requiring systemic treatment, or conditions expected not
to recur in the absence of an external trigger are permitted to enroll.
2) Physical and Laboratory Test Findings
a) Inadequate bone marrow function defined as:
i)
Absolute neutrophil count (ANC) < 1,500 cells/mm3 for solid tumors and 
<1,000 cells/mm3 for hematologic malignancies
ii) Platelet count < 100,000 cells/mm3 for solid tumors and <75,000 cells/mm3 for 
hematologic malignancies
iii) Hemoglobin < 8 g/dL 
b) Abnormal blood coagulation parameters: 
i)
PT such that international normalized ratio (INR) is > 1.5x ULN (or > 2.5 x baseline, 
if a subject is on a stable dose of therapeutic warfarin) or a PTT > 1.2x upper limit of 
normal (ULN).
c) Inadequate hepatic function defined as:
i)
Aspartate aminotransferase (AST) > 3x ULN 
ii) Alanine aminotransferase (ALT) > 3x ULN 
iii) Total bilirubin > 1.5 x ULN (except known Gilbert’s syndrome, direct bilirubin > 1.5x 
ULN);
d) Inadequate renal function defined as: 
i)
Creatinine clearance (CrCl) ≤ 50 mL/minute (either measured or calculated using a 
standard formula such as Cockcroft and Gault) within 14 days prior to randomization
e) Any of the following on 12-lead electrocardiogram (ECG) prior to study drug 
administration, confirmed by repeat.
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i)
QRS ≥ 120 msec, except right bundle branch block
ii) QTcF > 450 msec, except right bundle branch block
f)
Inadequate thyroid function
Note: Subclinical hypothyroidism (thyroid-stimulating hormone < 10 mIU/mL) or 
controlled hypothyroidism on appropriate thyroid supplementation are acceptable if 
negative for thyroglobulin, thyroid peroxidase antibodies, and thyroid stimulating 
immunoglobulin. 
g) Weight of < 40 kg.
3) Not applicable; removed per Revised Protocol 03. Allergies and Adverse Drug Reaction -
history of significant allergy or severe drug toxicity to one of the mandatory chemotherapeutic 
agents or their diluents (e.g. Cremaphor) excludes a subject from that particular arm, except a 
Grade ≤2 infusion reaction to paclitaxel, with successful subsequent retreatment with 
premedication.
4) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
c) Inability to comply with restrictions and prohibited activities/treatments as listed in 
Section 3.4
d) Women who are pregnant
e) Adolescents who provide active dissent
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.
3.3.3
Women of Childbearing Potential
Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 in the absence of other biological or physiological causes. In addition, 
females under the age of 55 years must have a documented serum follicle stimulating hormone, 
(FSH) level > 40mIU/mL to confirm menopause.
Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. If the serum FSH level is >40 mlU/ml at any time during 
the washout period, the woman can be considered postmenopausal. 
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•
1 week minimum for vaginal hormonal products, (rings, creams, gels)
•
4 week minimum for transdermal products
•
8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months.
3.4
Concomitant Treatments
Glucocorticoids may be administered for treatment of infusion reactions and as premedication to 
prevent infusion reactions.
Palliative radiation therapy to a limited field (eg, painful bone metastasis, painful lumps), if it is 
not the sole site of measurable and/or assessable disease, is allowed any time during study
participation with prior approval of the Sponsor/Medical Monitor.
Subjects with prostate cancer (CRPC and NEPC) are allowed to continue ARD therapy during this 
trial if the therapeutic agent(s) is (are) not prohibited due to CYP3A4 interactions (eg, 
enzalutamide is prohibited). Other agents without strong CYP3A4 interactions, such as androgen 
synthesis inhibitors, gonadotropin realizing hormone analogs, or AR antagonists may be continued 
if the subject is already on a stable dose.
Subjects are permitted to use 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 contrast allergen) is permitted.
Any concomitant therapies within 4 weeks prior to study drug administration and until the final 
follow-up visit must be recorded on the CRF.
3.4.1
Prohibited and/or Restricted Treatments
Prohibited and/or restricted medications taken prior to study drug administration in the study are 
described in Section 3.3.2. Medications taken within 4 weeks prior to study drug administration 
and until the end of the Clinical Follow-up Period must be recorded on the case report form (CRF).
The following medications are prohibited during the study (unless utilized to treat a drug-related 
AE):
•
Concurrent anti-neoplastic therapy (ie, chemotherapy, immunotherapy regimens, or radiation 
therapy, standard or investigational). However, the maintenance of the castrate state by ARD 
therapy is allowed in subjects with CRPC.
•
Prior exposure to BET inhibitors
•
Exposure to any investigational drug within 4 weeks of or concurrent with study drug 
administration
•
Concomitant use of strong inhibitors of CYP3A4 or strong inducers of CYP3A4.
•
Prophylactic use of myeloid growth factors to support neutrophil counts may NOT be used 
before completion of DLT evaluation period. After the completion of the DLT period, the use 
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of hematopoietic growth factors is at the discretion of the treating physician, as per institutional 
guidelines. Subjects with neutropenic fever or infection should be treated promptly and may 
receive therapeutic colony-stimulating factors if appropriate.
•
Immunosuppressive agents
•
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 3.3.2)
•
Live virus vaccine during the study and for a period of three months after the last dose of study 
treatment.
3.4.2
Other Restrictions and Precautions
Subjects may take the study drug with or without food, however it must be documented whether 
the drug was taken with or without (no food approximately1 hour prior and 2 hours after dose)
food. 
•
Grapefruit and Seville oranges and their juices can inhibit CYP3A4 and should not be 
consumed while on study.
•
Because of the potential for reproductive adverse effects, options for sperm and egg banking 
should be discussed with the subject, if appropriate.
•
Subjects should be provided loperamide or lomotil at the first dosing visit, instructed on its use 
and counseled to contact their clinician at the first occurrence of diarrhea or loose stools.
Anti-Emetic and Anti-Diarrheal Medications
Supportive care may include premedication with anti-emetics to limit treatment-related nausea and 
vomiting. Subjects should receive medications for treatment-induced diarrhea, as outlined in 
Section 4.5.3.
Other Concomitant Medications
Anti-inflammatory or narcotic analgesics may be offered as needed. Packed RBC and platelet 
transfusions should be administered as clinically indicated.
3.5
Discontinuation of Subjects following any Treatment with Study Drug
Subjects MUST discontinue BMS-986158 if receiving monotherapy and both BMS-986158 and 
nivolumab if receiving combination therapy (and non-IP at the discretion of the investigator) for 
any of the following reasons:
•
Subject’s request to stop study treatment and/or participation in the study
•
Any clinical 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 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
•
Inability to comply with protocol
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•
Discretion of the investigator
•
AEs requiring discontinuation as outlined in the Dose Modification section (See Section 4.5.2)
•
Pregnancy
•
Documented and confirmed PD as defined by RECIST v1.1 (for solid tumors, see Appendix 
04), or Lugano 2014 (for hematoligic tumors see Appendix 09), or PCWG3 (for CRPC and 
NEPC see Appendix 12) unless participant meets criteria for treatment beyond progression 
(Section 3.6)
All subjects who discontinue investigational product (IP) should comply with protocol specified 
follow-up procedures as outlined in Section 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 drug 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 CRF page.
3.6
Treatment Beyond Progression
Evidence supporting the continuation of BMS-986158 monotherapy in subjects with solid or 
hematologic malignancies beyond progression of their disease is lacking and therefore 
monotherapy treatment beyond progression will not be allowed. If combination therapy is pursued, 
subjects receiving BMS-986158 in combination with nivolumab will be permitted to continue on 
combination therapy beyond initial RECIST v1.1, Lugano 2014 (Appendix 9), or PCWG 
(Appendix 12) defined PD, as long as they meet the following criteria:
•
Investigator-assessed clinical benefit and not having rapid disease progression
•
Continue to meet all other study protocol eligibility criteria
•
Tolerance of study drug
•
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 any BMS-986158 plus nivolumab
treatment using an ICF describing any reasonably foreseeable risks, discomforts, or other 
alternative treatment options
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. All decisions to 
continue treatment beyond initial progression must be discussed with the BMS Medical Monitor 
and an assessment of the benefit/risk of continuing with study drug must be documented in the 
study records. Subjects will be re-consented to explain the rationale for this ongoing treatment.
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3.7
Post Study Drug Follow-up
In this study, safety is a key endpoint of the study. Post study follow-up is of critical importance 
and is essential to preserving subject safety and the integrity of the study. Subjects who discontinue 
study drug must continue to be followed for collection of outcome and/or survival follow-up data 
as required and in line with Section 5 until death or the conclusion of the study.
3.7.1
Withdrawal of Consent
Subjects who request to discontinue study drug 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, whenever 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 drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In the 
event that 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.
3.7.2
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.
4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
•
All products, active or placebo, being tested or used as a comparator in a clinical trial. 
•
Study required premedication, and 
•
Other drugs administered as part of the study that are critical to claims of efficacy 
(eg, background therapy, rescue medications)
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BMS-986158 will be administered orally. The appropriate number of capsules, based on the 
assigned dose level, will be administered. 
Doses should be taken at approximately the same time each day. Dose can be taken with or without 
food (defined as no food approximately 1 hour prior and 2 hours after dose) and this information 
should be recorded in the study diary and the CRF. If a dose is missed on a dosing day, the dose 
should be skipped and dosing should be resumed at the next scheduled dose. Subjects may be 
dosed on the regularly scheduled day in the following week. Doses of BMS-986158 should not be 
repeated if the subject vomits more than 2 hours after taking the dose. Missed dosing information
should be recorded in the study diary, the CRF, and medical record along with a description of the 
reason for the missed dose. The next dosing day should be kept on schedule. If the subject misses
a dose, BMS must be notified. Subjects should bring all drug containers to each study visit for 
drug reconciliation. Empty drug containers should be collected at each visit (or reconciled at least 
once a month, whichever is prior). Table 4-1 indicates the dose and dosage form to be administered 
in this study.
Table 4-1:
Treatment Administration
Product 
Description 
Class and 
Dosage Form
Potency
Primary 
Packaging
(Volume)/ 
Label Type
Secondary
Packaging /
Label Type
Appearance
Storage 
Conditions
(per label)
BMS-986158-01
0.25 mg
Bottle/Open 
Label
N/A
Capsule
Refer to label 
on the 
container
BMS-986158-01
2.0 mg
Bottle/Open 
Label
N/A
Capsule
Refer to label 
on the 
container
Nivolumab
(BMS-936558) 
solution for 
injection
100 mg/vial 
(10 mg/mL)
Vial/Open 
Label
Box
Vial
Refer to label 
on the 
container
The time of dose administration will be called “0” hour.
Product description and storage information is described in Table 4-1.
For study drugs not provided by BMS and obtained commercially by the site, storage should in 
accordance with the product label.
The product storage manager should ensure that the study treatments are 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 treatments arise, the study treatments
should not be dispensed and BMS should be contacted immediately.
IP documentation must be maintained that includes all processes required to ensure drug is 
accurately administered. This includes documentation of drug storage, administration and, as 
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applicable, storage temperatures, reconstitution, and use of required processes (eg, required 
diluents, administration sets).
Infusion-related supplies (eg, IV bags, in-line filters, 0.9% NaCl solution) will not be supplied by 
the Sponsor and should be purchased locally if permitted by local regulations.
Please refer to the current version of the IB and/or pharmacy reference sheets for complete storage, 
handling, dispensing, and infusion information for nivolumab.
4.1
Investigational Product
An IP, also known as investigational medicinal product in some regions, is defined as 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 IP should be stored in a secure area according to local regulations. It is the responsibility of 
the investigator to ensure that IP is only dispensed to study subjects. The IP must be dispensed 
only from official study sites by authorized personnel according to local regulations. 
In this protocol the IP are BMS-986158 and nivolumab. BMS-986158 in combination with 
nivolumab will only be pursued on review of safety information and the totality of data obtained 
from BMS-986158 monotherapy in Parts 1 and 2.
Nivolumab (Part 2)
Nivolumab infusions should start approximately 30 minutes following BMS-986158
administration. Nivolumab should be infused over 30 minutes in adults and adolescents. Further 
details regarding preparation and administration will be provided separately in site pharmacy 
training materials. 
Guidelines for Nivolumab-related Infusion Reactions
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 administrations.
For Grade 2 symptoms: (Moderate reaction requires 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 nivolumab 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 
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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 ensure after 30 minutes, the rate may be increased to 100% of the original 
infusion rate. Monitor subject closely. If symptoms recur then no further nivolumab will be 
administered at that visit.
•
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 to 
1,000 mg should be administered at least 30 minutes before nivolumab infusions. If necessary, 
corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used.
For Grade 3 or Grade 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 ventilator support 
indicated):
•
Immediately discontinue infusion of nivolumab. 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. Nivolumab will be permanently discontinued.
Investigators should follow their institutional guidelines for the treatment of anaphylaxis. 
Remain at bedside and monitor subject until recovery from symptoms.
In the 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).
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the SOC for a given diagnosis, may be considered as non-IPs.
4.3
Storage and Dispensing
The product storage manager should ensure that the study drugs are 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 drugs arise, the study drugs should not be 
dispensed and BMS should be contacted immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
IP 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, 
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administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents, administration sets).
4.4
Method of Assigning Subject Identification
This is an open-label study. Enrolled subjects, including those not dosed, will be assigned 
sequential subject numbers starting with 00001, eg, 00001, 00002, 00003.... 00010. Those enrolled 
subjects meeting eligibility criteria will be eligible to be dosed. Sequential numbering may restart 
at 00001 for each participating site as the distinct subject identification number (PID) will 
ultimately be comprised of the site number and subject number, eg, 0002 00001. 
During Part 1, once informed consent has been obtained, the investigator (or designee) will register 
the subject by transmitting a copy of the completed enrollment worksheet (registration form) to 
the Sponsor.
The following information is required for registration:
•
Subject’s date of birth (month and year only are acceptable if required by local regulation)
•
Gender
•
Diagnosis
•
Statement that subject is eligible
•
Date of informed consent
•
Planned date of first dose
Treatment groups and/or dose levels will be provided to the site study team after the subject has 
registered and eligibility for the study confirmed. Site personnel/investigator will receive a receipt 
confirming treatment assignment. A copy of this documentation should remain in the subject’s 
chart.
In the dose escalation phase, if a subject discontinues treatment with BMS-986158 during the DLT 
Evaluation period for reasons other than DLT, the subject may be replaced if necessary for safety 
assessments. Replacement subjects will receive the same treatment but will be assigned a new 
subject number. 
Subjects may be permitted to rescreen for the study following agreement between the 
Sponsor/Medical Monitor and investigators. 
In Part 2, during the screening visit, the investigative site will call into the enrollment option of 
the interactive response technology (IRT) designated by BMS. Enrolled participants, including 
those not dosed, will be assigned sequential participant numbers for their site starting with 00001, 
(eg, 00001, 00002, 00003.... 00010). The patient identification number (PID) will ultimately be 
comprised of the site number and participant number. Once it is determined that the participant 
meets the eligibility criteria following the screening visit, the investigative site will call the IRT to 
centrally assign the participant into the appropriate monotherapy or combination therapy cohort. 
If both monotherapy and combination cohorts are open for a tumor type, the assignment of subjects 
will alternate between the 2 regimens.
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4.5
Selection and Timing of Dose for Each Subject
In each dose escalation part (Part 1) of the study, subjects will be assigned to a specific dose level 
(see Section 3.1.1). Subjects in the expansion cohorts (Part 2) will be enrolled at or below the MTD 
or alternative dose as agreed upon by the Sponsor/Medical Monitor and investigators 
(Section 3.1.2).
4.5.1
Dose Limiting Toxicities
For the purpose of guiding dose escalation, DLTs will be defined based on incidence, intensity, 
and duration of AEs for which no clear alternative cause is identified. The DLT evaluation period 
for dose escalation in Part 1 Schedule A is 32 to 35 days (depending on the exact day of the start 
of Cycle 2); for Schedules B and C it is 35 days. For Part 1 Schedule A, subjects must receive at 
least 16 of 21 doses of BMS-986158; for Schedule B at least 17 of the 22 doses; and for Schedule C 
at least 12 of 15 doses to be considered DLT evaluable for dose escalation decisions. The DLT 
period for safety assessment of BMS-986158 and, if pursued, nivolumab combination therapy in 
Part 2 will be 28 days for all schedules which excludes a 7-day period for a single dose as in Cycle 
1 in Part 1, to allow similar drug exposure and appropriate comparison of the safety profile between 
Part 1 and Part 2. For Part 2 safety assessment of the combination therapy (if pursued), subjects 
must receive at least 15 of 20 doses on Schedule A. If alternate schedules are explored, subjects 
must receive 16 of 21 doses on Schedule B, and 11 of 14 doses on Schedule C. AEs will be graded 
according to the NCI CTCAE v4.03. For the purpose of subject management, any AE that meets 
DLT criteria, regardless of the cycle in which it occurs, will lead to dose interruption. Subjects 
who withdraw from the study during the DLT evaluation interval for reasons other than a DLT 
may be replaced at the same dose level. The incidence of DLT(s) during the first cycles of 
treatment (the DLT evaluation period) will be used in dose escalation decisions and to define the 
MTD. AEs occurring after the DLT period will be considered for the purposes of defining the 
recommended Phase 2 dose, upon agreement between the Sponsor/ Medical Monitor and 
investigators, if the AEs are determined to have no clear alternative cause and are not related to 
disease progression. 
DLT(s) will be defined as any of the following events unless a clear alternative cause is identified:
Non-Hematologic DLT:
Any of the following events will be considered a Non-Hematologic DLT:
•
≥Grade 3 Non-Hematologic toxicity, with the following exceptions.
♦≥Grade 3 electrolyte abnormalities that are not complicated by associated clinical AEs, 
are not clinically significant, last < 72 hours and either resolve spontaneously or respond 
to conventional medical intervention
♦≥Grade 3 elevations in serum transaminases (AST, ALT), total bilirubin, alkaline 
phosphatase that last < 5 days and are not associated with clinical symptoms.
♦Isolated Grade 3 elevation of amylase or lipase not associated with clinical or radiographic 
evidence of pancreatitis
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♦Grade 3 nausea, vomiting or diarrhea that lasts < 48 hours and either resolves 
spontaneously or responds to conventional medical intervention
♦Isolated Grade 3 fever not associated with hemodynamic compromise (ie hypotension, 
clinical or laboratory evidence of impaired end-organ perfusion)
♦Grade 3 endocrinopathy that is well controlled by hormone replacement
♦Grade 3 fatigue 
Alopecia of any grade is not considered a DLT
Hematologic DLT:
•
Grade 4 neutropenia ≥5 days in duration
•
Grade 3 febrile neutropenia that lasts > 48 hours
•
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with clinically significant 
bleeding
4.5.2
Guidelines for Dose Modifications
Subjects will be monitored continuously for AEs while on study therapy. Subjects will be 
instructed to notify their physician immediately for any and all AEs. The criteria presented in this 
section and Table 4.5.2-1 for dose modifications and delays for BMS-986158 are meant as general 
guidelines.
•
Subjects will continue to receive therapy as long as they have not had disease progression or 
an AE requiring dose modification, as described below.
•
Dose modifications, interruptions, or delays may occur in the setting of lower grade AEs and/or 
be more conservative than indicated in Table 4.5.2-1 based on the clinical judgment of the 
investigator, and in consultation with the Sponsor/Medical Monitor.
•
For BMS-986158, dose reductions should be to the previous lower dose level, or to a dose 
level in between the previous dose level and the current dose level, after discussion between 
Sponsor/Medical Monitor. A decision to remain at the current dose level requires a discussion 
and an agreement between the investigator and the Sponsor/Medical Monitor. 
•
If several AEs of varying grade or severity occur simultaneously, the dose modification applied 
should be the greatest reduction applicable based on the worse grade (or severity) observed 
among the AEs reported.
•
Assessment of causality (chronology, confounding factors such as disease, concomitant 
medications, diagnostic tests and previous experience with the agent) must be determined and 
documented by the investigator, prior to dose modification.
•
If the same Grade 3 non-hematologic AE recurs despite a dose reduction, a second dose 
reduction versus discontinuation of the subject from further protocol therapy will be discussed 
and agreed upon by the Sponsor/Medical Monitor and investigators.
•
Subjects who experience a Grade 4 non-hematologic AE will not receive additional protocol-
related therapy and will be removed from study unless discussed and agreed upon by the 
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Sponsor/Medical Monitor and investigators that it is in the best interest of the subject to receive 
additional therapy with BMS-986158 (for example, if the subject has demonstrated a response 
to therapy).
•
No more than 2 dose level reductions of BMS-986158 will be allowed per subject. If a third 
dose reduction is required, the subject must discontinue BMS-986158 (and nivolumab, if 
receiving combination therapy based on response to therapy). Dose re-escalation after a dose 
reduction may occur in limited circumstances (such as a change in attribution of an AE, or if 
re-escalation is in the best interest of the subject) after discussion and agreement of the 
Sponsor/Medical Monitor and investigators. The number of dose modifications needed for a 
subject should be discussed and agreed between the investigator and the Sponsor/Medical 
Monitor.
•
Skipped doses will not be administered within the same cycle.
•
For an AE requiring dose modification, BMS-986158 (and nivolumab for subjects receiving 
combination therapy) should be interrupted to allow recovery from the AE. Re-initiation of 
study drug cannot occur until AE decreases to ≤Grade 1 or baseline assessment. In case of 
delayed recovery to ≤Grade 1 or baseline (except for alopecia) from treatment-related AEs 
that results in a delay of treatment for > 30 days, the subject will not receive additional 
protocol-related therapy and will be removed from study unless discussed and agreed upon by 
the Sponsor/Medical Monitor and investigators that it is in the best interest of the subject to 
receive additional therapy with BMS-986158 (for example, if the subject has demonstrated a 
response to therapy).
•
For patients receiving combination therapy, if 1 study drug must be discontinued, the other 
study drug may be continued as single agent therapy based on discussion with Sponsor/Medical 
Monitor and the investigator.
•
For subjects in Part 2 monotherapy expansion or (if pursued) combination expansion who 
report an AE requiring dose modification, the dose of BMS-986158 should be reduced from 
3.75 mg to 3 mg. See Table 4.5.2-1.
For data collection and analysis purposes, all subjects will continue to be classified by the original 
treatment arm.
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Table 4.5.2-1:
Dose Modification Criteria for BMS-986158 Drug-Related Adverse 
Events 
Adverse Event
Initial Action
Dose Modification
Grade 4 febrile neutropenia
Discontinue BMS-986158
Discontinue BMS-986158
Grade 3 febrile neutropenia
Hold BMS-986158 until return to 
baseline or Grade 1
1st event: Consider reduction by 
1 dose level.
2nd event: Reduce by 1 dose level
≥Grade 4 hematologic toxicity
(neutropenia or
thrombocytopenia)
Hold BMS-986158 until returns to 
baseline or Grade 1.
1st event: Consider reduction by 
1 dose level.
2nd event: Reduce by 1 dose level.
Grade 3 thrombocytopenia with 
clinically significant bleeding
Hold BMS-986158 until return to 
baseline or Grade 1
1st event: Consider reduction by 
1 dose level.
2nd event: Reduce by 1 dose level
≥Grade 3 non-hematologic AE
in subjects receiving maximum 
medical management.
Hold BMS-986158 until resolves to 
baseline or Grade 1.
1st event: Consider reduction by 1 
dose level.
2nd event: Reduce by 1 dose level.
QTcF > 500 msec confirmed by 
at least one repeat ECG
Discontinue BMS-986158
Discontinue BMS-986158
≥Grade 3 diarrhea not 
adequately controlled with 
medication at maximum doses
Hold BMS-986158 until resolves to 
baseline or Grade 1. 
1st event: Consider reduction by 1 
dose level.
2nd event: Reduce by 1 dose level.
If needed, based on the occurrence of DLTs or other AEs, an individual subject enrolled on any 
arm may have the BMS-986158 schedule revised to match the alternate schedule on an another 
arm, at the agreement of the investigator and Sponsor/Medical Monitor, in order to better manage 
the overall tolerability of study treatment. This schedule change may be in lieu of dose 
modification shown in Table 4.5.2-1. At the agreement of the investigator and Sponsor/Medical 
Monitor, subjects who have already had dose reduction may be restarted at the original dose under 
the revised schedule. For data collection and analysis purposes, all subjects will continue to be 
classified by the original treatment arm.
Reasons for dose modifications or delays, the supportive measures taken and the outcome must be 
documented in the subject’s chart and recorded in the CRF.
Subjects will be monitored continuously for AEs while on study therapy. Subjects will be 
instructed to notify their physician immediately for any and all toxicity. The criteria presented in 
this section for dose modifications and delays are meant as general guidelines.
Assessment of causality (chronology, confounding factors such as disease, concomitant 
medications, diagnostic tests and previous experience with the agent) must be determined and 
documented by the investigator, prior to modifying any drugs.
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4.5.3
Management of Diarrhea for BMS-986158
For symptoms of diarrhea that occur at any time during treatment with BMS-986158, dose 
interruption is recommended until diarrhea resolves. After recovery, dose reduction or 
discontinuation should follow the criteria in Section 4.5.2 depending on the severity of the 
diarrhea. The following are guidelines for the management of diarrhea and are not intended to 
replace the clinical judgment of the treating physician(s):
For Grade 3 or higher events of diarrhea that are not controlled (ie, to Grade 1 or baseline) with 
loperamide or lomotil, dosing of BMS-986158 should be interrupted, as continued dosing will 
likely result in increased severity of diarrhea. In addition, evaluation of infectious causes should 
be considered. After recovery, dose reduction or discontinuation should follow the criteria in the 
protocol, depending on the severity of the diarrhea. The following are guidelines for the 
management of diarrhea, and should be used along with the clinical judgment of the treating 
physician(s). 
•
Diet: Recommendations should include eating small, frequent meals, diet modification 
(avoiding milk products, spicy and/or fatty foods, alcohol, and caffeine), and aggressive oral 
hydration.
•
Treatment with Loperamide: Loperamide should be started at the earliest sign of (1) a poorly 
formed or loose stool, (2) the occurrence of 1 to 2 more bowel movements than usual in 1 day, 
or (3) an increase in stool volume or liquidity. Loperamide may be taken in the following 
manner: 4 mg at the first onset of diarrhea, then 2 mg every 2 hours around the clock until 
diarrhea-free for at least 12 hours. Subjects may take loperamide 4 mg every 4 hours during 
the night. This dose regimen is higher than the standard dose of loperamide but is typical for 
the treatment of diarrhea caused by anticancer therapy. Subjects should be provided with 
loperamide and instructed in its use at the initial treatment visit so that they have sufficient 
supply on hand in case antidiarrheal support is required. It is important that loperamide is taken 
as instructed. For subjects who cannot tolerate loperamide or who do not get adequate relief 
with maximum doses, standard doses of Lomotil® (diphenoxylate/atropine) may be added or 
used instead of loperamide. 
•
Additional antidiarrheal measures, such as octreotide, may be used at the discretion of the 
investigator or treating physician.
•
Increase Fluid Intake and, if applicable, consider stopping anti-hypertensive therapy and 
nonsteroidal anti-inflammatory drugs (NSAIDs): Hypotension and/or renal insufficiency can 
occur in the setting of volume depletion from severe diarrhea. At the onset of any diarrhea, 
subjects should be instructed to increase fluid intake to help maintain fluid and electrolyte 
balance during episodes of diarrhea. Parenteral hydration should be started if oral hydration is 
not sufficient. The investigator should consider interrupting anti-hypertensive therapy and 
NSAIDs, if medically appropriate.
4.5.4
Management Algorithms for Immuno-oncology Agents
Immuno-oncology agents are associated with AEs that can differ in severity and duration from 
AEs caused by other therapeutic classes. Nivolumab is considered an immuno-oncology agent in 
this protocol. Early recognition and management of AEs associated with immuno-oncology agents 
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may mitigate severe toxicity. Management algorithms have been developed form extensive 
experience with nivolumab and ipilimumab to assist investigators in assessing and managing the 
following groups of AEs:
•
Gastrointestinal
•
Renal
•
Pulmonary
•
Hepatic
•
Endocrinopathies
•
Skin
•
Neurological
The clinical nature of AEs noted with nivolumab (in combination with BMS-986158) will 
determine the role of the above algorithms for use in toxicities related to its use in this study. The 
algorithms recommended for utilization in this protocol are included in Appendix 10.
In addition, nivolumab therapy can be associated with visual complaints. Inflammation of 
components within the eye is an uncommon, but clinically important, event. An ophthalmologist 
should evaluate visual complaints with examination of the conjunctiva, anterior and posterior 
chambers, and retina. Topical corticosteroids may be used to manage low-grade events. Low-grade
events that do not resolve and high-grade events should be managed with systemic corticosteroids. 
Consultation with a BMS Medical Monitor should be sought for all cases of ocular inflammatory 
events. Complaints of double vision should also prompt medical evaluation.
Cases of rare events, some with fatal outcome, have been reported with nivolumab (see the 
Investigator Brochure for Nivolumab for details). If a participant develops signs and symptoms of 
myositis, myocarditis or rhabdomyolysis or other rare event, the case should be discussed with 
BMS Medical Monitor, close monitoring should be implemented, and the patient referred to a 
specialist for assessment and treatment without delay. Based on the severity of the event, 
nivolumab should be withheld or discontinued, and appropriate treatment instituted. For Grade 3 
myocarditis, nivolumab should be permanently discontinued.
4.6
Blinding/Unblinding
This study is a non-randomized open-label study for Part 1 and Part 2. Interactive Response 
Technology (IRT) will be used in Part 2 for treatment assignment. Data emerging from this 
exploratory study may be necessary to inform timely decisions for adjusting procedures in 
subsequent portions of the study, including early termination of the study. Additionally, 
availability of the open label treatment assignments may facilitate optimization of the bioanalytical 
analysis of samples.
4.7
Treatment Compliance
At scheduled PK sample collections laboratory evaluation days, BMS-986158 will be administered 
to the subject in the clinical facility. At all other times throughout the study, BMS-986158 will be 
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administered on an outpatient basis. The investigator and the study personnel will ensure that each 
subject receives the calculated dose of the study drug. Treatment compliance will be monitored by 
drug accountability, as well as recording BMS-986158 administration in subjects’ medical records 
and CRF. Subjects must keep a diary of study medication doses and any missed doses (see 
Section 4). Subjects should bring all drug containers to each study visit for drug reconciliation. 
Drug supplies will be inventoried and accounted for throughout the study. The Drug 
Accountability Log will be reviewed by the study monitor during site visits and at the completion 
of the study. Any discrepancy should be brought to the attention of the Sponsor.
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as partially 
used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible BMS Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are 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.
If conditions for destruction cannot be met, the responsible BMS Study Monitor will make 
arrangements for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, 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. 
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused and/or 
partially used study drug that was supplied by BMS must be returned to BMS. The return of study 
drug will be arranged by the responsible Study Monitor. 
Arrangements for the return of study drug will be made by the responsible Study Monitor.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Study assessments and procedures are presented in Table 5.1-1, Table 5.1-2, Table 5.1-3, Table 
5.1-4, Table 5.1-5, and Table 5.1-6.
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Table 5.1-1:
Screening Procedural Outline (Study Days -40 to -1) (CA011001)
Procedure
Screening
Visit
Notes
Eligibility Assessments
Informed Consent
X
A subject is considered enrolled only when a protocol specific informed consent is signed. Minors 
judged to be of an age of reason as determined by local requirements should also give their assent.
Inclusion/Exclusion Criteria
X
All eligibility criteria must be met for subjects to participate in the study.
Medical History
X
Include any toxicities or allergy related to previous treatments, smoking history, and alcohol use.
Prior Treatments
X
Including prior cancer treatment regimens and medications administered within 4 weeks of dosing
Safety Assessments
Physical Examination (PE)
X
If the screening PE is performed within 48 hours prior to dosing on Cycle 1 Day 1 then a single exam 
may count as both the screening and predose evaluation. To include breast examination if clinically 
indicated.
Physical Measurements
X
Includes height and weight.
Vital Signs
X
Includes body temperature, respiratory rate, blood pressure and heart rate. Blood pressure and heart 
rate should be measured after the subject has been resting quietly for at least 5 minutes.
ECOG
X
See Appendix 5 for scale.
Electrocardiogram (ECGs)
X
A single 12-lead ECG. QTcF assessments ≥450 msec must be confirmed on repeat ECG. ECGs 
should be recorded after the subject has been supine for at least 5 minutes. 
Laboratory Tests
X
Includes blood samples and urinalysis. See Section 5.3.2
Thyroid Function Tests
X
TSH with reflex testing to free T3 and free T4 if TSH is abnormal. Results should be reviewed by the 
investigator or appropriate designee within 48 hours of dose administration.
Coagulation Panel
X
aPTT, PT and/or INR. See Section 5.3.2
Serology
X
Includes HIV, Hepatitis B and Hepatitis C. See Section 5.3.2
MUGA/ECHO
X
Must include a quantitative assessment of LVEF and utilize the same modality for any subsequent 
assessments 
Pregnancy Test
X
For WOCBP only. WOCBP must have a negative test during screening. Test must be repeated within 
24 hours prior to the start of study drug. Sensitivity of test must be at least 25 IU/L or equivalent 
units of HCG.
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Table 5.1-1:
Screening Procedural Outline (Study Days -40 to -1) (CA011001)
Procedure
Screening
Visit
Notes
FSH
X
If needed to document post-menopausal status as defined in Section 3.3.3.
PSA for CRPC patients only
X
Adverse Event Reporting
Clinical Complaints
X
Clinical complaints related to the disease under study must be collected within 14 days of the first 
dose of study drug.
Monitor for Serious Adverse Events
X
All SAEs must be collected from the date of subject’s written consent until 30 days post 
discontinuation of monotherapy dosing or 100 days post discontinuation of combination dosing or 
subject’s participation in the study if the last scheduled visit occurs at a later time.
Baseline Assessments 
Archived tumor block or unstained 
slides/Biopsy
X
Study personnel must ensure that paraffin tissue block or FFPE unstained slides physically exist prior 
to initiating therapy. However, if archived tumor tissue is unavailable, subject must have fresh pre-
treatment biopsy. Archival tumor samples are mandatory if pretreatment biopsies are not available or 
sufficient for adult subjects enrolled in Part 2. Adolescent subjects must provide archived tumor 
tissue unless a fresh treatment biopsy is provided (preferred). Slides/tissue block are to be sent to 
central lab after performing specified tests locally (see “Laboratory tests” in this table below). See 
Section 3.3.1.
Fresh Tumor Biopsy
X
For Part 2, a pre-treatment biopsy
 
 is mandatory for adult subjects. Pre-treatment biopsies 
should be conducted during the screening period after all other eligibility criteria have been met. See 
Section 5.6 for details on biopsy collection and specimen handling.
Tumor Assessments 
X
Contrast enhanced CT of the chest, CT/MRI of the abdomen, pelvis, and all other known and/or 
suspected sites of disease or fluorodeoxyglucose - positron emission tomography (FDG-PET) for 
hematologic malignancies should occur within 28 days (Part 1) or 40 days (Part 2) prior to date of 
first dose. See Section 5.3.1 for further details. For participants with CRPC and NEPC, whole body 
scans are required. 
MRI Brain
X
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 
drug administration.
Revised Protocol No.: 07
Date: 18-Mar-2019
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Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
Table 5.1-1:
Screening Procedural Outline (Study Days -40 to -1) (CA011001)
Procedure
Screening
Visit
Notes
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. See Section 5.3.1for further 
details.
Bone Scan
X
Required for participants with prostate cancer (NEPC and CRPC). Others as clinically indicated (ie, 
subjects with a history or symptoms of bone metastases), but bone scans will not be considered a 
modality for assessments for measurable disease.
MRI Breast Imaging
X
For participants with TNBC without measurable lesions outside the breast, contrast enhanced MRI of 
the breasts should also be performed.
If performed at screening, should be continued at same frequency as body imaging. Additional 
imaging may be performed as clinically indicated. See Section 5.3.1 for further details.
Testing
X
Required for adult subjects in Part 2. Subjects who have undergone this testing within 6 months of 
screening and have data available do not need to be tested again. Subjects with NMC, ES, BL, and 
DHL are excluded from this testing.
Clinical Drug Supplies
Dose level assignment
X
At the completion of screening procedures and eligibility determined.
IRT participant assignment
X
For Part 2 only, after participants meet all eligibility criteria, sites will use IRT for participant 
assignment. Subsequent visits will be entered into the IRT system for drug supply (see Section 4.4).
Revised Protocol No.: 07
Date: 18-Mar-2019
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Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
Table 5.1-2:
On Treatment Outline (CA011001)- Part 1 Escalation - Schedule A - 5 days on / 2 days off dosing 
schedule
Procedure
Cycle 1(7 
Days)
Cycle 2 (28 Days)
Cycle 3 (28 Days)
Cycle 4 
and 
beyond 
(28 
days)
EOTa
D 1
D 2
D 3
D 4
D 1
D2
D 5
D 8
D12
D 15
D 19
D 22
D26
D 1
D 8
D 15
D 22
D 1
D 15
Notes
Safety 
Assessments
.
Physical 
Examination (PE)
X
X
X
X
See Screening notes. 
Include breast exam if 
clinically indicated.
Targeted Physical 
Exam
X
X
X
X
X
X
X
X
Targeted physical exam 
involves a visual and 
physical assessment of 
the body area causing 
feeling of discomfort to 
the subject (eg, local 
pain, rash, or swelling)
Physical 
Measurements 
X
X
X
X
X
X
X
X
X
X
X
X
Weight only
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
See Section 5.3 for 
details
ECOG
X
X
X
X
See Appendix 5 for 
details
Revised Protocol No.: 07
Date: 18-Mar-2019
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Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
Table 5.1-2:
On Treatment Outline (CA011001)- Part 1 Escalation - Schedule A - 5 days on / 2 days off dosing 
schedule
Procedure
Cycle 1(7 
Days)
Cycle 2 (28 Days)
Cycle 3 (28 Days)
Cycle 4 
and 
beyond 
(28 
days)
EOTa
D 1
D 2
D 3
D 4
D 1
D2
D 5
D 8
D12
D 15
D 19
D 22
D26
D 1
D 8
D 15
D 22
D 1
D 15
Notes
Electrocardiogram 
(ECGs)b
X
X
X
X
X
X
X
X
X
Triplicate 12-lead ECGs 
will be collected prior to 
the first BMS-986158 
dose during Cycle 1, Day 
1(0 hour), 2 and 4 hours 
post BMS dose. A single 
12 lead ECG will be 
collected thereafter. Refer 
to Table 5.5.1-1 for 
details.
Laboratory Tests
X
c
X
X
X
X
X
X
X
X
X
X
X
Includes blood and 
urinalysis samples. 
Fasting Glucose taken 
predose C1D1, C3D1 and 
on additional days, if 
clinically indicated. IgG 
levels are taken on Day 1 
of every other cycle only, 
starting with Cycle 1. 
Creatinine Clearance 
taken on Day 1 of each 
cycle. See Section 5.3.2
for details.
Revised Protocol No.: 07
Date: 18-Mar-2019
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Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
Table 5.1-2:
On Treatment Outline (CA011001)- Part 1 Escalation - Schedule A - 5 days on / 2 days off dosing 
schedule
Procedure
Cycle 1(7 
Days)
Cycle 2 (28 Days)
Cycle 3 (28 Days)
Cycle 4 
and 
beyond 
(28 
days)
EOTa
D 1
D 2
D 3
D 4
D 1
D2
D 5
D 8
D12
D 15
D 19
D 22
D26
D 1
D 8
D 15
D 22
D 1
D 15
Notes
Coagulation Panel
X
X
X
X
X
X*
X*
aPTT, PT and INR. 
*Cycle 3 and beyond to 
be done if clinically 
indicated (e.g. signs of 
bleeding, especially GI 
bleeding). See 5.3.2 for 
details
MUGA/ECHO
X
Only if clinically 
indicated with the same 
assessment used at 
screening. See notes in 
screening.
Pregnancy Test
X
X
X
X
X
For WOCBP only. 
Sensitivity of test must be 
at least 25 IU/L or 
equivalent units of HCG. 
Pregnancy test must be 
done within 24 hours 
prior to starting study 
drug
Revised Protocol No.: 07
Date: 18-Mar-2019
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Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
Table 5.1-2:
On Treatment Outline (CA011001)- Part 1 Escalation - Schedule A - 5 days on / 2 days off dosing 
schedule
Procedure
Cycle 1(7 
Days)
Cycle 2 (28 Days)
Cycle 3 (28 Days)
Cycle 4 
and 
beyond 
(28 
days)
EOTa
D 1
D 2
D 3
D 4
D 1
D2
D 5
D 8
D12
D 15
D 19
D 22
D26
D 1
D 8
D 15
D 22
D 1
D 15
Notes
Adverse Event 
Reporting
.
Monitor for Non-
Serious Adverse 
Events
X
See Section 6.2. Non-
serious AE will be 
collected from first dose 
of study drug until 30 
days post discontinuation 
of dosing. AEs reported 
during this time period 
should be followed until 
resolved to baseline, 
stabilized or deemed 
irreversible
Monitor for 
Serious Adverse 
Events
X
All SAEs must be 
collected from the date of 
subject’s written consent 
until 30 days post 
discontinuation of dosing 
or subject’s participation 
in the study if the last 
scheduled visit occurs at 
a later time.
Revised Protocol No.: 07
Date: 18-Mar-2019
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Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
Table 5.1-2:
On Treatment Outline (CA011001)- Part 1 Escalation - Schedule A - 5 days on / 2 days off dosing 
schedule
Procedure
Cycle 1(7 
Days)
Cycle 2 (28 Days)
Cycle 3 (28 Days)
Cycle 4 
and 
beyond 
(28 
days)
EOTa
D 1
D 2
D 3
D 4
D 1
D2
D 5
D 8
D12
D 15
D 19
D 22
D26
D 1
D 8
D 15
D 22
D 1
D 15
Notes
Sample 
Collection
Pharmacokinetic 
(PK) Sampling
X
See Section 5.5.
Efficacy 
Assessments
Tumor 
Assessmentse
X
X*
Tumor Assessments 
should occur every 8 
weeks (± 7 days) from 
date of first dose until PD
or treatment 
discontinuation, 
whichever occurs later.
For subjects who have 
been on study for ≥1 
year, tumor assessments 
should occur every 12 
weeks (± 7 days) until PD 
or treatment 
discontinuation.
Revised Protocol No.: 07
Date: 18-Mar-2019
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Approved
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v


Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
Table 5.1-2:
On Treatment Outline (CA011001)- Part 1 Escalation - Schedule A - 5 days on / 2 days off dosing 
schedule
Procedure
Cycle 1(7 
Days)
Cycle 2 (28 Days)
Cycle 3 (28 Days)
Cycle 4 
and 
beyond 
(28 
days)
EOTa
D 1
D 2
D 3
D 4
D 1
D2
D 5
D 8
D12
D 15
D 19
D 22
D26
D 1
D 8
D 15
D 22
D 1
D 15
Notes
*EOT if not assessed 
within the last 9 weeks
Clinical Drug 
Supplies
BMS 986158 
Administration
Dosing regimen is 5 days on, 2 days off. Refer to Section 4
Those supplied by BMS 
or sourced by the 
investigator.
Abbreviations: D = Day; EOT = End of treatment; FDG-PET = fluorodeoxyglucose - positron emission tomography
a Refer to Table 5.1-6 for Clinical Follow-up and Survival Follow-up Periods
b QTcF assessments ≥450 msec must be confirmed on repeat ECG. ECGs should be recorded after the subject has been supine for at least 5 minutes. Serial time 
matched ECGs will also occur on specific days and time points.
Revised Protocol No.: 07
Date: 18-Mar-2019
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Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
c For cycle 1only, assessments may be performed up to 72 hours prior to dosing.
e Contrast enhanced CT of the chest, CT/MRI of the abdomen, pelvis, and all other known and/or suspected sites of disease (see Section 5.3.1 for further details).
Table 5.1-3:
On Treatment Outline (CA011001) - Part 1 Escalation - Schedule B - 14 days on / 7 days off dosing 
schedule
Procedure
Cycle 
1 
(7 
Days)
Cycle 2 
(21 Days)
Cycle 3 
(21 Days)
Cycle 4 and 
beyond 
(21 days)
EOTa
D 1
D 7
D 1
D2
D 4
D 8
D14
D15
D16
D 1
D 4
D8
D14
D18
D 1
D8
D 15
Notes
Safety 
Assessments
Physical 
Examination (PE)
X
X
X
X
See Screening notes. 
Include breast exam 
if clinically indicated.
Targeted Physical 
Exam
X
X
X
X
X
X*
X
*Beginning with 
cycle 4, Day 8 
assessments may be 
done between day 8-
11. This assessment 
may be omitted on 
Day 8 for subjects 
who have been on 
study for ≥1 year.
Revised Protocol No.: 07
Date: 18-Mar-2019
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Approved
1.0
v


Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
Table 5.1-3:
On Treatment Outline (CA011001) - Part 1 Escalation - Schedule B - 14 days on / 7 days off dosing 
schedule
Procedure
Cycle 
1 
(7 
Days)
Cycle 2 
(21 Days)
Cycle 3 
(21 Days)
Cycle 4 and 
beyond 
(21 days)
EOTa
D 1
D 7
D 1
D2
D 4
D 8
D14
D15
D16
D 1
D 4
D8
D14
D18
D 1
D8
D 15
Notes
Physical 
Measurements 
X
X
X
X
X
X
X
X
X*
X
X
Weight only. 
*Beginning with 
cycle 4, Day 8 
assessments may be 
done between day 8-
11. This assessment 
may be omitted on 
Day 8 for subjects 
who have been on 
study for ≥1 year.
Vital Signs
X
X
X
X
X
X
X
X
X*
X
X
*Beginning with 
cycle 4, Day 8 
assessments may be 
done between day 8-
11. See Section 5.3
for details. This 
assessment may be 
omitted on Day 8 for 
subjects who have 
been on study for ≥1 
year.
ECOG
X
X
X
X
See Appendix 5 for 
details
Revised Protocol No.: 07
Date: 18-Mar-2019
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v


Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
Table 5.1-3:
On Treatment Outline (CA011001) - Part 1 Escalation - Schedule B - 14 days on / 7 days off dosing 
schedule
Procedure
Cycle 
1 
(7 
Days)
Cycle 2 
(21 Days)
Cycle 3 
(21 Days)
Cycle 4 and 
beyond 
(21 days)
EOTa
D 1
D 7
D 1
D2
D 4
D 8
D14
D15
D16
D 1
D 4
D8
D14
D18
D 1
D8
D 15
Notes
Electrocardiogram 
(ECGs)b
X
X
X
Xc
X
Triplicate 12-lead 
ECGs will be 
collected prior to the 
first BMS-986158 
dose during Cycle 1, 
Day 1(0 hour), 2 and 
4 hours post BMS 
dose. A single 12 
lead ECG will be 
collected thereafter. 
Refer to Section 5.5.1
for details.
Laboratory Tests
X
d
X
X
*
X
X
X*
X
X
X*
X
X
Includes blood and 
urinalysis samples. 
Fasting Glucose 
taken predose C1D1, 
C3D1 and on 
additional days, if 
clinically indicated. 
IgG levels are taken 
on Day 1 of every 
other cycle only, 
starting with Cycle 1. 
Revised Protocol No.: 07
Date: 18-Mar-2019
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Approved
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Approved
1.0
v


Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
Table 5.1-3:
On Treatment Outline (CA011001) - Part 1 Escalation - Schedule B - 14 days on / 7 days off dosing 
schedule
Procedure
Cycle 
1 
(7 
Days)
Cycle 2 
(21 Days)
Cycle 3 
(21 Days)
Cycle 4 and 
beyond 
(21 days)
EOTa
D 1
D 7
D 1
D2
D 4
D 8
D14
D15
D16
D 1
D 4
D8
D14
D18
D 1
D8
D 15
Notes
Creatinine Clearance 
taken on Day 1 of 
each cycle. See 
Section 5.3.2 for 
details. Beginning 
with cycle 3, the day 
14 assessment has a 
±2 day window
*CBC only. For 
subjects on study ≥1 
year, D8 assessments 
may be done at local 
labs.
Coagulation Panel
X
X
X
X*
X*
aPTT, PT and INR. 
*Cycle 3 and beyond 
to be done if 
clinically indicated 
(e.g. signs of 
bleeding, especially 
GI bleeding). See 
Section 5.3.2 for 
details
MUGA/ECHO
X
Only if clinically 
indicated with the 
same assessment 
used at screening. 
Revised Protocol No.: 07
Date: 18-Mar-2019
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1.0
v


Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
Table 5.1-3:
On Treatment Outline (CA011001) - Part 1 Escalation - Schedule B - 14 days on / 7 days off dosing 
schedule
Procedure
Cycle 
1 
(7 
Days)
Cycle 2 
(21 Days)
Cycle 3 
(21 Days)
Cycle 4 and 
beyond 
(21 days)
EOTa
D 1
D 7
D 1
D2
D 4
D 8
D14
D15
D16
D 1
D 4
D8
D14
D18
D 1
D8
D 15
Notes
See notes in 
screening.
Pregnancy Test
X
X
X
X
X
For WOCBP only. 
Sensitivity of test 
must be at least 25 
IU/L or equivalent 
units of HCG. 
Pregnancy test must 
be done within 24 
hours prior to starting 
study drug
Revised Protocol No.: 07
Date: 18-Mar-2019
109
Approved
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v
Approved
1.0
v


Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
Table 5.1-3:
On Treatment Outline (CA011001) - Part 1 Escalation - Schedule B - 14 days on / 7 days off dosing 
schedule
Procedure
Cycle 
1 
(7 
Days)
Cycle 2 
(21 Days)
Cycle 3 
(21 Days)
Cycle 4 and 
beyond 
(21 days)
EOTa
D 1
D 7
D 1
D2
D 4
D 8
D14
D15
D16
D 1
D 4
D8
D14
D18
D 1
D8
D 15
Notes
Adverse Event 
Reporting
Monitor for Non-
Serious Adverse 
Events
X
See Section 6.2. Non-
serious AE will be 
collected from first 
dose of study drug 
until 30 days post 
discontinuation of 
dosing. AEs reported 
during this time 
period should be 
followed until 
resolved to baseline, 
stabilized or deemed 
irreversible
Revised Protocol No.: 07
Date: 18-Mar-2019
110
Approved
10.0
v
Approved
1.0
v


Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
Table 5.1-3:
On Treatment Outline (CA011001) - Part 1 Escalation - Schedule B - 14 days on / 7 days off dosing 
schedule
Procedure
Cycle 
1 
(7 
Days)
Cycle 2 
(21 Days)
Cycle 3 
(21 Days)
Cycle 4 and 
beyond 
(21 days)
EOTa
D 1
D 7
D 1
D2
D 4
D 8
D14
D15
D16
D 1
D 4
D8
D14
D18
D 1
D8
D 15
Notes
Monitor for 
Serious Adverse 
Events
X
All SAEs must be 
collected from the 
date of subject’s 
written consent until 
30 days post 
discontinuation of 
dosing or subject’s 
participation in the 
study if the last 
scheduled visit 
occurs at a later time.
Sample Collection
Pharmacokinetic 
(PK) Sampling
X
X
See Section 5.5. 
There will be no PK 
collection after cycle 
8.
Revised Protocol No.: 07
Date: 18-Mar-2019
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Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
Table 5.1-3:
On Treatment Outline (CA011001) - Part 1 Escalation - Schedule B - 14 days on / 7 days off dosing 
schedule
Procedure
Cycle 
1 
(7 
Days)
Cycle 2 
(21 Days)
Cycle 3 
(21 Days)
Cycle 4 and 
beyond 
(21 days)
EOTa
D 1
D 7
D 1
D2
D 4
D 8
D14
D15
D16
D 1
D 4
D8
D14
D18
D 1
D8
D 15
Notes
Efficacy 
Assessments
Tumor 
Assessmentsf
X
X*
Tumor Assessments 
should occur every 9 
weeks (+/- 7 days) 
from date of first 
dose until PD or 
treatment 
discontinuation, 
whichever occurs 
later. For subjects 
who have been on 
study for ≥1 year, 
tumor assessments 
should occur every 
12 weeks (± 7 days) 
until PD or treatment 
discontinuation.
*EOT if not assessed 
within the last 9 
weeks
Revised Protocol No.: 07
Date: 18-Mar-2019
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v


Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
Table 5.1-3:
On Treatment Outline (CA011001) - Part 1 Escalation - Schedule B - 14 days on / 7 days off dosing 
schedule
Procedure
Cycle 
1 
(7 
Days)
Cycle 2 
(21 Days)
Cycle 3 
(21 Days)
Cycle 4 and 
beyond 
(21 days)
EOTa
D 1
D 7
D 1
D2
D 4
D 8
D14
D15
D16
D 1
D 4
D8
D14
D18
D 1
D8
D 15
Notes
Clinical Drug 
Supplies
BMS 986158 
Administration
Dosing regimen is 14 days on, 7 days off. Refer to Section 4
Those supplied by 
BMS or sourced by 
the investigator.
Abbreviations: D = Day; EOT = End of treatment;
a Refer to Table 5.1-6 for Clinical Follow-up and Survival Follow-up Periods
b QTcF assessments ≥450 msec must be confirmed on repeat ECG. ECGs should be recorded after the subject has been supine for at least 5 minutes. Serial time 
matched ECGs will also occur on specific days and time points.
c ECGs will be collected on C4D8, C6D8 and C8D8. ECGs will not be collected after cycle 8.
d For cycle 1only, assessments may be performed up to 72 hours prior to dosing.
f Contrast enhanced CT of the chest, CT/MRI of the abdomen, pelvis, and all other known and/or suspected sites of disease. See Section 5.3.1 for further details.
Revised Protocol No.: 07
Date: 18-Mar-2019
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v


Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
Revised Protocol No.: 07
Date: 18-Mar-2019
114
Approved
10.0
v
Approved
1.0
v


Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
Table 5.1-4:
On Treatment Outline (CA011001)- Part 1 Escalation - Schedule C - 7 days on/14 days off dosing 
schedule
Procedure
Cycle 
1(7 
Days)
Cycle 2 (21 Days)
Cycle 3 (21 Days)
Cycle 4 and 
beyond (21 
days)
EOTa
D 1
D 1
D2
D 4
D 7
D10
D 1
D4
D 8
D15
D 1
D8
D15
Notes
Safety 
Assessments
Physical 
Examination 
(PE)
X
X
X
X
See Screening notes. Include breast exam if clinically 
indicated.
Targeted 
Physical Exam
X
X
X
X
C2D14 has a ±1 day window.
Physical 
Measurements 
X
X
X
X
X
X
X
X
Weight only
Vital Signs
X
X
X
X
X
X
X
See Section 5.3 for details
ECOG
X
X
X
X
See Appendix 5 for details
Revised Protocol No.: 07
Date: 18-Mar-2019
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v


Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
Table 5.1-4:
On Treatment Outline (CA011001)- Part 1 Escalation - Schedule C - 7 days on/14 days off dosing 
schedule
Procedure
Cycle 
1(7 
Days)
Cycle 2 (21 Days)
Cycle 3 (21 Days)
Cycle 4 and 
beyond (21 
days)
EOTa
D 1
D 1
D2
D 4
D 7
D10
D 1
D4
D 8
D15
D 1
D8
D15
Notes
Electrocardiog
ram (ECGs)b
X
X
X
Xc
X
Triplicate 12-lead ECGs will be collected prior to the 
first BMS-986158 dose during Cycle 1, Day 1(0 hour), 
2 and 4 hours post BMS dose. A single 12 lead ECG 
will be collected thereafter. Refer to Section 5.5.1for 
details.
Laboratory 
Tests
Xd
X
X
X*
X
X
X*
X
X
X*
X
Includes blood and urinalysis samples. Fasting Glucose 
taken predose C1D1, C3D1 and on additional days, if 
clinically indicated. IgG levels are taken on Day 1 of 
every other cycle only, starting with Cycle 1. 
Creatinine Clearance taken on Day 1 of each cycle. See 
Section 5.3.2 for details. C3D15 and C3D18 has a ±2 
day window. For subjects on study ≥1 year, D8 
assessments may be done at local labs.
* CBC only (±24hours)
Coagulation 
Panel
X
X
X
X*
X*
aPTT, PT and INR. *Cycle 2 and beyond to be done if 
clinically indicated (e.g. signs of bleeding, especially 
GI bleeding). See Section 5.3.2 for details
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CA011001
BMS-986158
BET Inhibitor
Table 5.1-4:
On Treatment Outline (CA011001)- Part 1 Escalation - Schedule C - 7 days on/14 days off dosing 
schedule
Procedure
Cycle 
1(7 
Days)
Cycle 2 (21 Days)
Cycle 3 (21 Days)
Cycle 4 and 
beyond (21 
days)
EOTa
D 1
D 1
D2
D 4
D 7
D10
D 1
D4
D 8
D15
D 1
D8
D15
Notes
MUGA/ECHO
X
Only if clinically indicated with the same assessment 
used at screening. See notes in screening.
Pregnancy 
Test
X
X
X
X
X
For WOCBP only. Sensitivity of test must be at least 
25 IU/L or equivalent units of HCG. Pregnancy test 
must be done within 24 hours prior to starting study 
drug
Adverse 
Event 
Reporting
Monitor for 
Non-Serious 
Adverse 
Events
X
See Section 6.2. Non-serious AE will be collected from 
first dose of study drug until 30 days post 
discontinuation of dosing. AEs reported during this 
time period should be followed until resolved to 
baseline, stabilized or deemed irreversible
Monitor for 
Serious 
Adverse 
Events
X
All SAEs must be collected from the date of subject’s 
written consent until 30 days post discontinuation of 
dosing or subject’s participation in the study if the last 
scheduled visit occurs at a later time.
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CA011001
BMS-986158
BET Inhibitor
Table 5.1-4:
On Treatment Outline (CA011001)- Part 1 Escalation - Schedule C - 7 days on/14 days off dosing 
schedule
Procedure
Cycle 
1(7 
Days)
Cycle 2 (21 Days)
Cycle 3 (21 Days)
Cycle 4 and 
beyond (21 
days)
EOTa
D 1
D 1
D2
D 4
D 7
D10
D 1
D4
D 8
D15
D 1
D8
D15
Notes
Sample 
Collection
Pharmaco-
kinetic (PK) 
Sampling
X
X
See Section 5.5. There will be no PK collection after 
cycle 8.
Efficacy 
Assessments
Tumor 
Assessmentsf
X
X*
Tumor Assessments should occur every 9 weeks (± 7 
days) from date of first dose until PD or treatment 
discontinuation, whichever occurs later. For subjects 
who have been on study for ≥1 year, tumor 
assessments should occur every 12 weeks (± 7 days) 
until PD or treatment discontinuation.
*EOT if not assessed within the last 9 weeks
Optional 
Tumor 
Biopsye
Xg
See Section 5.6 for details on biopsy collection and 
specimen handling.
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CA011001
BMS-986158
BET Inhibitor
Table 5.1-4:
On Treatment Outline (CA011001)- Part 1 Escalation - Schedule C - 7 days on/14 days off dosing 
schedule
Procedure
Cycle 
1(7 
Days)
Cycle 2 (21 Days)
Cycle 3 (21 Days)
Cycle 4 and 
beyond (21 
days)
EOTa
D 1
D 1
D2
D 4
D 7
D10
D 1
D4
D 8
D15
D 1
D8
D15
Notes
Clinical Drug 
Supplies
BMS 986158 
Administration
Dosing regimen is 7 days on, 14 days off. Refer to Section 4
Those supplied by BMS or sourced by the investigator.
Abbreviations: D = Day; EOT = End of treatment
a Refer to Table 5.1-6 for Clinical Follow-up and Survival Follow-up Periods
b QTcF assessments ≥450 msec must be confirmed on repeat ECG. ECGs should be recorded after the subject has been supine for at least 5 minutes. Serial time 
matched ECGs will also occur on specific days and time points.
c ECGs will be collected on C4D8, C6D8 and C8D8. ECGs will not be collected after cycle 8.
d For cycle 1only, assessments may be performed up to 72 hours prior to dosing.
f Contrast enhanced CT of the chest, CT/MRI of the abdomen, pelvis, and all other known and/or suspected sites of disease. See Section 5.3.1 for further details.
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CA011001
BMS-986158
BET Inhibitor
Table 5.1-5:
On Treatment & Follow-Up Outline (CA011001)- Part 2 BMS-986158 Monotherapy and/or in
Combination with Nivolumab Expansion - Schedule A - 5 days on/2 days off dosing schedule
Procedure
Cycle 1 (28 Days)
Cycle 2 (28 Days)
Cycle 3 
and 
beyond (28 
Days)
EOTa
± 3 days (for all visits 
except C1D1 and 
mandatory tumor 
biopsy)
D 1
D 8
D 15
D 22
D 1
D 8
D 15
D 22
D 1
D 15
Notes
Safety Assessments
Physical Examination 
(PE)
X
X
X
X
See Screening notes. Include breast exam if 
clinically indicated.
Target Physical Exam
X
X
X
X
X
X
X
X
Targeted to signs and symptoms
Physical 
Measurements 
X
X
X
X
X
X
X
X
X
X
X
Weight only
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
See Section 5.3 for details
ECOG
X
X
X
X
X
See Appendix 5 for details
Electrocardiogram 
(ECGs)b,c
X
X
X
X
X
12-lead ECG should be recorded after the 
participant has been supine for at least 5 minutes. A 
single ECG must be collected at predose on Day 1 
of each cycle and at EOT. For the ECG/QTc 
assessment in participants treated with 
BMS-986158 monotherapy only, refer to Section 
5.5.1 for details.
Laboratory Testsd
X
X*
X
X*
X
X*
X
X*
X
X
X
Includes blood and urinalysis samples. Fasting 
Glucose taken predose C1D1, C3D1 and on 
additional days, if clinically indicated. . IgG levels 
are taken on Day 1 of every other cycle only, 
starting with Cycle 1. Creatinine Clearance taken 
on Day 1 of each cycle. See Section 5.3.2 for 
details.
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CA011001
BMS-986158
BET Inhibitor
Table 5.1-5:
On Treatment & Follow-Up Outline (CA011001)- Part 2 BMS-986158 Monotherapy and/or in
Combination with Nivolumab Expansion - Schedule A - 5 days on/2 days off dosing schedule
Procedure
Cycle 1 (28 Days)
Cycle 2 (28 Days)
Cycle 3 
and 
beyond (28 
Days)
EOTa
± 3 days (for all visits 
except C1D1 and 
mandatory tumor 
biopsy)
D 1
D 8
D 15
D 22
D 1
D 8
D 15
D 22
D 1
D 15
Notes
* CBC only (±24hours)
Thyroid Function 
Tests e
X
X
X
X
Collect on Day 1 every cycle, predose, beginning 
with Cycle 1 Day 1 and at EOT.
To include TSH with reflex testing (free T3 and 
free T4) if TSH is abnormal. Results should be 
examined by the investigator or appropriate 
designee within 48 hours of dose administration
PSA for CRPC 
subjects only
X
X
X
X
Collect on Day 1 every cycle, predose, beginning 
with Cycle 1 Day 1 and at EOT. 
Coagulation Panel
X
X
X
X
X*
X*
aPTT, PT and INR. * Cycle 2 and beyond to be 
done if clinically indicated (e.g. signs of bleeding, 
especially GI bleeding). See Section 5.3.2 for 
details
MUGA/ECHO
X
Only if clinically indicated with the same 
assessment used at screening. See notes in 
screening.
Pregnancy Test
X
X
X
X
For WOCBP only. Sensitivity of test must be at 
least 25 IU/L or equivalent units of HCG. 
Pregnancy test must be done within 24 hours prior 
to starting study drug
Adverse Event 
Reporting
.
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CA011001
BMS-986158
BET Inhibitor
Table 5.1-5:
On Treatment & Follow-Up Outline (CA011001)- Part 2 BMS-986158 Monotherapy and/or in
Combination with Nivolumab Expansion - Schedule A - 5 days on/2 days off dosing schedule
Procedure
Cycle 1 (28 Days)
Cycle 2 (28 Days)
Cycle 3 
and 
beyond (28 
Days)
EOTa
± 3 days (for all visits 
except C1D1 and 
mandatory tumor 
biopsy)
D 1
D 8
D 15
D 22
D 1
D 8
D 15
D 22
D 1
D 15
Notes
Monitor for Non-
Serious Adverse 
Events
X
See Section 6.2. Non-serious AE will be collected 
from first dose of study drug until 30 days post 
discontinuation of dosing. AEs reported during this 
time period should be followed until resolved to 
baseline, stabilized or deemed irreversible
Monitor for Serious 
Adverse Events
X
All SAEs must be collected from the date of 
subject’s written consent until 30 days post 
discontinuation of dosing or subject’s participation 
in the study if the last scheduled visit occurs at a 
later time.
Sample Collection
Pharmacokinetic (PK) 
Sampling
X
See Section 5.5. Patients who crossover from 
monotherapy to combination therapy will not be 
required to provide samples for PK.
Efficacy Assessments
Tumor Assessmentsg
X
X*
Tumor Assessments should occur every 8 weeks 
(± 7 days) from date of first dose until PD or 
treatment discontinuation, whichever occurs later. 
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CA011001
BMS-986158
BET Inhibitor
Table 5.1-5:
On Treatment & Follow-Up Outline (CA011001)- Part 2 BMS-986158 Monotherapy and/or in
Combination with Nivolumab Expansion - Schedule A - 5 days on/2 days off dosing schedule
Procedure
Cycle 1 (28 Days)
Cycle 2 (28 Days)
Cycle 3 
and 
beyond (28 
Days)
EOTa
± 3 days (for all visits 
except C1D1 and 
mandatory tumor 
biopsy)
D 1
D 8
D 15
D 22
D 1
D 8
D 15
D 22
D 1
D 15
Notes
For participants with CRPC and NEPC, whole 
body bone scans should also be performed.
For participants with TNBC without measurable 
lesions outside the breast, contrast enhanced MRI 
of the breasts should also be performed.
*EOT if not assessed within the last 9 weeks.
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CA011001
BMS-986158
BET Inhibitor
Table 5.1-5:
On Treatment & Follow-Up Outline (CA011001)- Part 2 BMS-986158 Monotherapy and/or in
Combination with Nivolumab Expansion - Schedule A - 5 days on/2 days off dosing schedule
Procedure
Cycle 1 (28 Days)
Cycle 2 (28 Days)
Cycle 3 
and 
beyond (28 
Days)
EOTa
± 3 days (for all visits 
except C1D1 and 
mandatory tumor 
biopsy)
D 1
D 8
D 15
D 22
D 1
D 8
D 15
D 22
D 1
D 15
Notes
Clinical Drug 
Supplies
BMS 986158 
Administration
Dosing regimen is 5 days on, 2 days off. Refer to Section 4
Those supplied by BMS or sourced by the 
investigator. Refer to Section 4
Nivolumab 
Administration
Nivolumab will be administered on a 480 mg Q4W schedule 
beginning on Cycle 1 Day 1. Adolescent doses will be administered 
at 6 mg/kg Q4W up to a maximum of 480 mg. Refer to Section 4
For subjects assigned to combination therapy only. 
Abbreviations: CRPC = castrate resistant prostate cancer; D = Day; EOT = End of treatment; FDG-PET = fluorodeoxyglucose - positron emission tomography; 
PSA = prostate specific antigen; Q2W = every 2 weeks
a Refer to Table 5.1-6 for Clinical Follow-up and Survival Follow up Periods
b QTcF assessments ≥450 msec must be confirmed on repeat ECG. ECGs should be recorded after the subject has been supine for at least 5 minutes. Serial time 
matched ECGs will also occur on specific days and time points.
c ECG collection instructions: For monotherapy treatment ECGs are to be collected at all timepoints indicated in Table 5.1-5 and Table 5.5.1-4. For combination 
therapy treatment ECGs are to be collected at timepoints indicated in Table 5.1-5 only
d For cycle 1only, assessments may be performed up to 72 hours prior to dosing
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BET Inhibitor
e Thyroid function testing only required for Part 2 Combination treatment with Nivolumab
g Contrast enhanced CT of the chest, CT/MRI of the abdomen, pelvis, and all other known and/or suspected sites of disease. FDG-PET for hematologic 
malignancies. See Section 5.3.1 for further details. Bone scan for prostate cancer.
Note: Patients who crossover from monotherapy to combination therapy will begin at Cycle 1.
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CA011001
BMS-986158
BET Inhibitor
Table 5.1-6:
Clinical Follow-up and Survival Follow-up Phase Procedural Outline (CA011001)
Procedure
Clinical 
Follow-up
Clinical 
Follow-up
Clinical 
Follow-up
Survival 
Follow-up
30 days
(+/- 5 days)
60 daysa
(+/- 5 days)
100 daysa
(+/- 5 days)
every 12 weeks
(+/- 2 weeks)
Notes
Safety Assessments
Physical 
Examination (PE)
X
X
X
See Screening notes. Include breast exam if clinically 
indicated.
Vital Signs
X
X
X
Includes body temperature, blood pressure and heart rate
Performance Status 
(ECOG)
X
X
X
ECOG score (se Appendix 5)
Laboratory Tests
X
X
X
See Section 5.3.2 on “Hematology” and “Serum Chemistry” 
for specific tests to be included.
Thyroid Function 
Testsb
X
X
X
To include TSH with reflex testing (free T3 and free T4) if 
TSH is abnormal b
PSA for CRCP 
subjects only
X
X
X
X
Tumor Assessment
X
For the first year of survival follow-up for subjects who do 
not already have PD.
For participants with CRPC and NEPC, whole body bone 
scans should also be performed.
For participants with TNBC without measurable lesions 
outside the breast, contrast enhanced MRI of the breasts 
should also be performed.
Adverse Event Reporting
Monitor for non-
Serious Adverse 
Events
X
X
X
Non-serious AEs will be collected starting with the first dose 
of study medication and through 30 days after discontinuation 
of dosing for subjects receiving BMS-986158 monotherapy, 
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CA011001
BMS-986158
BET Inhibitor
Table 5.1-6:
Clinical Follow-up and Survival Follow-up Phase Procedural Outline (CA011001)
Procedure
Clinical 
Follow-up
Clinical 
Follow-up
Clinical 
Follow-up
Survival 
Follow-up
30 days
(+/- 5 days)
60 daysa
(+/- 5 days)
100 daysa
(+/- 5 days)
every 12 weeks
(+/- 2 weeks)
Notes
and through 100 days for subjects receiving combination 
therapy. 
Monitor for Serious 
Adverse Events
X
X
X
All SAEs must be collected starting at the time a subject signs 
informed consent and through 30 days after discontinuation of 
dosing for subjects receiving BMS-986158 monotherapy, and 
through 100 days for subjects receiving combination therapy.
Sample Collection
Pharmacokinetic 
(PK) Sampling
X
X
See Section 5.5.1; For subjects receiving combination therapy 
only
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CA011001
BMS-986158
BET Inhibitor
Table 5.1-6:
Clinical Follow-up and Survival Follow-up Phase Procedural Outline (CA011001)
Procedure
Clinical 
Follow-up
Clinical 
Follow-up
Clinical 
Follow-up
Survival 
Follow-up
30 days
(+/- 5 days)
60 daysa
(+/- 5 days)
100 daysa
(+/- 5 days)
every 12 weeks
(+/- 2 weeks)
Notes
a Clinical follow-up for patients who receive BMS-986158 in combination with nivolumab will be 60 days and 100 days following the last dose of study drugs
b Thyroid function testing only required for Part 2 participants Combination treatment with Nivolumab
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BMS-986158
BET Inhibitor
5.1.1
Retesting During Screening
Retesting of laboratory parameters and/or other assessments during the Screening or Lead-in 
period will be permitted (in addition to any parameters that require a confirmatory result).
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.
5.2
Study Materials
The site will provide all required materials for the tests performed locally (ie, relevant clinical 
laboratory tests and urine drug screens). The site will have available a well-calibrated scale for 
recording body weight, a 12-lead ECG machine, and a calibrated sphygmomanometer and 
thermometer for vital signs assessments. A current and fully-stocked [advanced cardiac life 
support (ACLS) or basic cardiac life support (BCLS) cart will be immediately available on the 
premises. The site will have urine collection containers, a refrigerated centrifuge, a monitored and 
alarmed refrigerator, and freezer (-20°C or below), as well as containers and dry ice for shipment 
and storage of blood and urine samples. The site will provide all materials required for accurate 
source documentation of study activities and for housing the subjects during the study. 
BMS will provide a BMS-approved protocol and any amendments or administrative letters (if 
required), and IB. CRFs (electronic or hard copy) will be provided by BMS. The Central 
Laboratory will provide labels and tubes for the collection of blood samples for PK 
 
. Enrollment registration worksheets will be provided to the study sites. Sites will 
fax/e-mail enrollment worksheets to BMS at the time of informed consent. NCI CTCAE criteria 
will be provided to study sites prior to site initiation. BMS will also provide subject diaries to 
collect oral dosing, missed dosing information including a description of the reason for the missed 
dose, PID number, date and time of dosing, number of stools, doses of loperamide, etc will also 
be captured in the diary. The subject must record any incidence of vomiting 2 hours post ingestion 
of BMS-986158 dose. Sites may use their own IRB approved subject diaries as long as it captures 
all the information required by the protocol. Subject diaries should be kept on-site and should only 
be provided to BMS upon request. The subjects must bring their diaries to every office visit (or at 
least once a month) so that it can be reviewed by the site staff. Additional instructions will be 
provided along with the subject diary.
5.3
Safety Assessments
All subjects who receive at least one dose of BMS-986158 will be evaluated for safety parameters. 
Additionally, any occurrence of an SAE from the time of consent until 30 days post discontinuation 
of BMS-986158 monotherapy and 100 days post discontinuation of combination therapy will be 
documented. Any occurrence of non-serious AEs will be collected from first dose of study drug 
until 30 days post discontinuation of BMS-986158 monotherapy and 100 days post discontinuation 
of combination therapy. AEs will be coded using the most current version of MedDRA. Safety 
will be evaluated for all treated subjects using the NCI CTCAE v4.03. Safety assessments will be 
based on medical review of AE reports and the results of vital sign measurements (body 
temperature, respiratory rate, heart rate, and blood pressure (heart rate and blood pressure should 
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CA011001
BMS-986158
BET Inhibitor
be measured after subject has been resting quietly for at least 5 minutes), physical examinations 
and clinical laboratory tests. Subjects should be followed until all AEs for which no clear 
alternative cause is identified other than to BMS-986158 have recovered to baseline or are deemed 
irreversible by the investigator. The incidence of AEs will be tabulated and reviewed for potential 
significance and clinical importance. 
The schedule of required visits, tests, procedures and assessments are described Table 5.1-1, Table 
5.1-2 Table 5.1-3, Table 5.1-4, Table 5.1-5, and Table 5.1-6.
In limited instances, scheduled events (including events other than safety assessments) can occur 
outside of the indicated timeframes but the Sponsor should first be notified.
If a subject has a delay in study drug administration for any reason, then assessments and 
laboratory tests (with the exception of any tests needed to ensure subject safety) should be 
correspondingly delayed with the exception of tumor assessments (continue scans every 8-9 weeks 
± 7 days regardless of dosing delays). At baseline, a medical history will be obtained to capture 
relevant underlying conditions. Baseline signs and symptoms are those that are assessed within 
2 weeks prior to subject enrollment. The baseline physical examination should include weight, 
height, heart rate, blood pressure, respiratory rate, temperature, and ECOG status and should be 
performed within 28 days of treatment arm assignment (see Table 5.1-1, Table 5.1-2. Table 5.1-3, 
Table 5.1-4, Table 5.1-5, and Table 5.1-6). If any vital sign is abnormal, the subject must be 
observed further for a period of time, as clinically indicated. Any new or worsening clinically 
significant changes must be reported on the appropriate non-serious or serious AE page.
Additional measures including non-study required laboratory tests should be performed as 
clinically indicated.
Only data for the procedures and assessments specified in this protocol (see Table 5.1-1, Table 
5.1-2. Table 5.1-3, Table 5.1-4, Table 5.1-5, and Table 5.1-6) should be submitted to BMS. 
Additional procedures and assessments may be performed as part of SOC; however, data for these 
assessments should remain in the subject’s medical record and should not be provided to BMS 
unless specifically requested by BMS.
Clinical laboratories will be assessed (see Table 5.1-1, Table 5.1-2. Table 5.1-3, Table 5.1-4, Table 
5.1-5, and Table 5.1-6.). Sites should collect samples between -28 to -1 days from enrollment in 
Part 1 and -40 to -1 days in Part 2 to insure that results required for eligibility purposes are verified 
prior to registration. Pregnancy testing must be performed within 24 hours prior to the initial 
administration of IP at baseline and then prior to administration of either study medication during 
study therapy and at the clinical follow-up visit. CBC plus differential and serum chemistry panel 
should be drawn within 24 hours prior to each subsequent scheduled cycle. Fasting (no food or 
drink for at least 8 hours) glucose samples are to be taken predose on C1D1 and C3D1 for 
Schedules A, B and C of Part 1 and Part 2. On-study laboratory tests will be performed on 
site/locally. Laboratory tests may be obtained more frequently if indicated. Additional laboratory 
tests should be performed as per SOC. 
Laboratory toxicities (eg, suspected drug induced liver enzyme elevations) will be monitored 
during the Clinical Follow-up period via on site/local labs until all study drug toxicities for which 
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CA011001
BMS-986158
BET Inhibitor
no clear alternative cause is identified other than to BMS-986158 resolve, return to baseline, or 
are deemed irreversible.
In case of dose interruption for any reason, assessments and laboratory tests (with the exception of 
any tests needed to ensure subject safety) should be correspondingly delayed with the exception 
of tumor assessments (ie, continue scans every 8-9 weeks ± 7 days regardless of dosing delays).
5.3.1
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 blinded independent 
central review (BICR) at any time during the study. Prior to scanning first participant, sites should 
be qualified and understand the image acquisition guidelines and submission process as outlined 
in the CA011-001 Imaging Manual provided by the central imaging vendor.
Every attempt should be made to image each subject using an identical acquisition protocol on the 
same scanner for all imaging time points.
CT/MRI
Contrast-enhanced CT scans acquired on dedicated CT equipment is preferred for this study. CT 
with contrast of the chest, abdomen, pelvis, and all other known and/or suspected sites of disease 
or FDG-PET (for hematologic malignancies) are to be performed for tumor assessments as 
indicated in Table 5.1-1, through Table 5.1-6. CT scans should be acquired with ≤5mm slices with 
no intervening gap (contiguous). 
If a participant has a contraindication for both MR and CT intravenous contrasts, then a 
non-contrast CT of the chest and a non-contrast MRI of the abdomen, pelvis, and other 
known/suspected sites of disease should be obtained. 
If a participant has a contraindication for MRI (eg, incompatible pacemaker) in addition to 
contraindication to CT intravenous contrast, then a non-contrast CT of the chest, abdomen, pelvis, 
and other known/suspected sites of disease is acceptable.
If a participant has a contraindication for CT IV contrast, a non-contrast CT of the chest and a 
contrast enhanced MRI of the abdomen, pelvis, and other known and/or suspected sites of disease 
may be obtained. MRI’s should be acquired with slice thickness of ≤5 mm with no gap 
(contiguous).
If a patient has only 1 measurable lesion, which will be subjected to a core needle biopsy, the CT 
scan should be conducted after the biopsy to establish a baseline.
Use of CT component of a PET-CT scanner: Combined modality scanning such as with PET 
CT is increasingly used in clinical care, and is a modality/technology that is in rapid evolution; 
therefore, the recommendations outlined here may change rather quickly with time. At present, 
low dose or attenuation correction CT portions of a combined PET-CT are of limited use in 
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BET Inhibitor
anatomically-based efficacy assessments and it is therefore suggested that they should not be 
substituted for dedicated diagnostic contrast enhanced CT scans for anatomically-based lesion 
measurements. However, if a site can document that the CT performed as part of a PET-CT is of 
identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of 
the PET-CT can be used for target lesion measurements. Note, however, that the PET portion of 
the CT introduces additional data which may bias an investigator if it is not routinely or serially 
performed.
Participants with prostate cancer (CRPC or NEPC) should have bone lesions assessed using 
technetium-99m radionuclide bone scans at each imaging assessment. Anterior and posterior 
whole body planar images should be acquired. Additional (including spot views and SPECT) 
images should be submitted if acquired. For other participants, bone scans may be obtained if 
clinically indicated.
For participants with TNBC who do not have measurable lesions outside the breasts, contrast 
enhanced MRI of the breasts should also be performed as outlined in Section 5.1 (Flow Chart/Time 
and Events Schedule).
5.3.2
Laboratory Test Assessments
A local laboratory will perform the safety analyses and will provide reference ranges for these 
tests. A central laboratory will also be utilized for protocol requirements.
Results of clinical laboratory tests performed on Day -1 must be available prior to dosing. Unless 
otherwise specified, analysis may be performed within the 72 hours prior to dosing for cycle 1 
only.
The following clinical laboratory tests will be performed:
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Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Absolute neutrophil count (ANC)/absolute lymphocyte count (ALC) determination
Serum Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
GGT
Amylase
Lipase
Total bilirubin
Direct bilirubin
Alkaline phosphatase
Lactate dehydrogenase (LDH)
Creatinine
Blood Urea Nitrogen (BUN) or UREA
Uric acid
Glucose (Fasting on predose on C1D1 and 
C3D1 for Schedules A, B and C of Part 1 and 
for Part 2)
Prostate-specific antigen (PSA) in CRPC 
patients only
Total Protein
Albumin
Sodium
Potassium
Chloride
Calcium
Phosphorus
Magnesium
Bicarbonate
Thyroid Stimulating Hormone
Thyroid Stimulating Hormone
Thyroid-stimulating hormone (TSH) with reflex testing to free T3 and free T4 if TSH is 
abnormal.
Urinalysis
Protein
Glucose
Blood
Leukocyte esterase
Specific gravity
pH
Microscopic examination of the sediment if blood, protein or leukocytes esterase are positive 
on the dipstick
Serology
Total immunoglobulin (IgG) levels - Day 1 of every other cycle only
Hepatitis C antibody (HCV Ab), Hepatitis C RNA (when HCV Ab is not available), hepatitis 
B surface antigen, HIV-1, -2 antibody (screening only)
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Other Analyses
Pregnancy test (WOCBP only: screening, predose, discharge).
FSH
aPTT, PT and INR (Coagulation Panel)
Creatinine Clearance (CLcr) for Cockcroft and Gault calculation
Results of all laboratory tests required by this protocol must be provided to BMS, either recorded 
on the laboratory pages of the CRF or by another mechanism (eg, provided electronically). If the 
units of a test result differ from those printed on the CRF, the recorded laboratory values must 
specify the correct units. Any abnormal laboratory test result considered clinically significant by 
the investigator must be recorded on the appropriate AE page of the CRF (see Section 6.3
Laboratory Test Result Abnormalities).
5.4
Efficacy Assessments
5.4.1
Primary Efficacy Assessment
Disease assessment with CT and/or MRI (solid tumors and lymphomas), or FDG-PET 
(hematologic malignancies, when SOC), or as appropriate, will be performed at baseline. Disease 
assessment will occur every 8-9 weeks ±7 days from the date of first dose. Disease assessment at 
other time points may be performed if the investigator is concerned about tumor progression. 
Tumor assessments will continue until there is disease progression (unless treatment beyond 
progression in which case imaging should continue as per schedule), or until subjects withdraw 
from the study. Responses will be based on RECIST v1.1 (Appendix 4) for solid tumors. For 
hematologic malignancies, responses will be based on the Lugano 2014 Classification for Initial 
Evaluation, Staging, and Response for Hodgkin Lymphoma (Appendix 9). For prostate cancer 
(NEPC and CRPC), responses will be based on PCWG3 (including PSA assessments; Appendix
12). At the sponsor’s discretion, scans and measurements may be reviewed by independent 
radiologists using RECIST v1.1, Lugano 2014, or PCWG3 criteria at a later date, or at any time 
during the study.
5.4.2
Secondary Efficacy Assessments
Not applicable.
5.5
Pharmacokinetic Assessments
The pharmacokinetics of BMS-986158 monotherapy in Part 1 will be characterized by non-
compartmental data analysis methods and population PK modeling approaches with plasma drug 
and metabolite concentrations collected at predetermined times. In Part 2, sparse PK samples will 
be collected with BMS-986158 monotherapy and in combination with nivolumab will be 
characterized with population PK modeling approaches. 
 
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 Validated assays
will be used to measure BMS-986158 and metabolite(s) in plasma
. 
The PK parameters to be assessed for BMS-986158 following single dose administration include 
but are not limited to:
Cmax
Maximum observed plasma concentration
Tmax
Time of maximum observed plasma concentration
AUC(0-T)
Area under the plasma concentration-time curve from time zero to time of 
last quantifiable concentration
AUC(TAU)
Area under the concentration-time curve in one dosing interval
If data permits, the following single dose PK parameters may also be assessed:
T-HALF
Apparent terminal phase half-life
AUC(INF)
Area under the plasma concentration-time curve from time zero 
extrapolated to infinite time
CLT/F
Apparent total body clearance, reported only for parent, not for metabolite 
Vz/F
Apparent volume of distribution of terminal phase, reported only for 
parent, not for metabolite
The PK parameters to be assessed for BMS-986158 following multiple dose administration in Part 
1 include but are not limited to:
Cmax
Maximum observed plasma concentration
Tmax
Time of maximum observed plasma concentration
AUC(0-T)
Area under the plasma concentration-time curve from time zero to time of 
last quantifiable concentration
AUC(TAU)
Area under the concentration-time curve in one dosing interval
Cmin
The minimum observed concentration within a dosing interval (ie, 
occurring no matter when over the dosing interval)
Ctau
Concentration at the end of a dosing interval.
Ctrough
Trough observed plasma concentration (this includes predose 
concentrations (C0) and concentrations at the end of dosing interval 
(Ctau)).
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AI
Accumulation Index; ratio of an exposure measure at steady-state to that 
after the first dose (exposure measure includes AUC(TAU), Cmax and 
Ctau).
T-HALFeff
Effective elimination half-life that explains the degree of accumulation 
observed for a specific exposure measure (exposure measure includes 
AUC(TAU), Cmax and Ctau).
In addition, the following PK parameters may also be assessed after single and multiple dose 
administrations in Part 1, if data permit:
MR_Cmax
Ratio of metabolite Cmax to parent Cmax, corrected for molecular weight
MR_AUC(0-T)
Ratio of metabolite AUC(0-T) to parent AUC(0-T), corrected for 
molecular weight
MR_AUC(INF)
Ratio of metabolite AUC(INF) to parent AUC(INF), corrected for 
molecular weight (following single dose only)
MR_AUC(TAU)
Ratio of metabolite AUC(TAU) to parent AUC(TAU), corrected for 
molecular weight
 
5.5.1
Pharmacokinetics
Collection 
and Processing 
Table 5.5.1-1, Table 5.5.1-2, and Table 5.5.1-3 list the sampling schedules to be followed for the 
assessment of pharmacokinetics in Part 1. Table 5.5.1-4 lists the sampling schedules to be followed 
for the assessment of PK for BMS-986158 monotherapy in Part 2 and Table 5.5.1-5 lists the 
sampling schedules for BMS-986158 and nivolumab combination therapy in Part 2. Further details 
of blood collection and processing will be provided to the site in the procedure manual.
Table 5.5.1-1:
Pharmacokinetic Specimen Collection & ECG Schedule for BMS-
986158 Monotherapy for Schedule A (5 days on / 2 days off) of 
Part 1
Study Cycle of 
Sample Collection
(Cycle 1= 7 days,
Subsequent cycles 
are 28 days each)
Study Day 
of Sample 
Collection
Event
Time 
(post BMS-986158
Dose)
Hour: Min
BMS-986158
Blood Sample for 
Plasma Analysis
ECG
QTca
1
1
predose
00:00
Xb
X
1
1
00:30
X
1
1
01:00
X
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Table 5.5.1-1:
Pharmacokinetic Specimen Collection & ECG Schedule for BMS-
986158 Monotherapy for Schedule A (5 days on / 2 days off) of 
Part 1
Study Cycle of 
Sample Collection
(Cycle 1= 7 days,
Subsequent cycles 
are 28 days each)
Study Day 
of Sample 
Collection
Event
Time 
(post BMS-986158
Dose)
Hour: Min
BMS-986158
Blood Sample for 
Plasma Analysis
ECG
QTca
1
1
02:00
X
X
1
1
04:00
X
X
1
1
08:00(±2hr)
X
X
1
2
24:00c
X
X
1
3
48:00c
X
1
4
72:00c
X
2
1
00:00
X
X
2
1
00:30
X
2
1
01:00
X
2
1
02:00
X
2
1
04:00
X
2
1
08:00(±2hr)
X
2
2
24:00d
X
X
2
5
predose
00:00
X
X
2
5
00:30
X
2
5
01:00
X
2
5
02:00
X
X
2
5
04:00
X
X
2
5
08:00(±2hr)
X
X
2
6
24:00e
X
X
2
8
predose
00:00
X
X
2
8
04:00
X
4
8 (+3 days)f
24:00
X
a Triplicate 12-lead ECGs will be collected prior to the first BMS-986158 dose during Cycle 1, Day 1(0 hour), 2 and 
4 hours post BMS dose. A single 12 lead ECG will be collected thereafter. The single 12-lead ECG. QTcF 
assessments ≥450 msec must be confirmed on repeat ECG 
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c Time represents hours after Cycle 1 Day 1 dose of BMS-986158
d Time represents approximate hours after the Cycle 2 Day 1 dose of BMS-986158
e Time represents approximate hours after the Cycle 2 Day 5 dose of BMS-986158
f Sample may be collected at any time from Cycle 4 Day 8 through Cycle 4 Day 11
Table 5.5.1-2:
Pharmacokinetic Specimen Collection & ECG Schedule for BMS-
986158 - Monotherapy for Schedule B (14 days on/7 days off) of 
Part 1
Study Cycle of 
Sample Collection
(Cycle 1= 7 days,
Subsequent cycles are 
21 days each)
Study Day of 
Sample 
Collection
Event
Time (post 
BMS-986158 
Dose) 
Hour:Min
BMS-986158 
Blood Sample 
for Plasma 
Analysis
ECG
QTc,a
1
1
predose
00:00
X
X
1
1
00:30
X
1
1
01:00
X
1
1
02:00
X
X
1
1
04:00
X
X
1
1
08:00 (±2hr)
X
X
1
2
24:00c
X
X
1
3
48:00c
X
1
4
72:00c
X
1
5
96:00c
X
2
1
predose
00:00
X
2
14
predose
00:00
X
X
2
14
00:30
X
2
14
01:00
X
2
14
02:00
X
X
2
14
04:00
X
X
2
14
08:00 (±2hr)
X
X
2
15
24:00d
X
X
2
16
48:00d
X
2
17
72:00d
X
2
18
96:00d
X
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Table 5.5.1-2:
Pharmacokinetic Specimen Collection & ECG Schedule for BMS-
986158 - Monotherapy for Schedule B (14 days on/7 days off) of 
Part 1
Study Cycle of 
Sample Collection
(Cycle 1= 7 days,
Subsequent cycles are 
21 days each)
Study Day of 
Sample 
Collection
Event
Time (post 
BMS-986158 
Dose) 
Hour:Min
BMS-986158 
Blood Sample 
for Plasma 
Analysis
ECG
QTc,a
4
8 (+3 days)e
predose
00:00
X
X
6
8 (+3 days)e
predose
00:00
X
X
8
8 (+3 days)e
predose
00:00
X
X
a Triplicate 12-lead ECGs will be collected prior to the first BMS-986158 dose during Cycle 1, Day 1(0 hour), 2 and 
4 hours post BMS dose. A single 12 lead ECG will be collected thereafter. QTcF assessments ≥450 msec must be 
confirmed on repeat ECG.
c Time represents approximate hours after Cycle 1 Day 1 dose of BMS-986158
d Time represents approximate hours after the Cycle 2 Day 14 dose of BMS-986158
e Sample may be collected at any time from Cycle Day 8 through Cycle Day 11
Table 5.5.1-3:
Pharmacokinetic Specimen Collection & ECG Schedule for BMS-
986158 Monotherapy for Schedule C (7 days on / 14 days off ) of 
Part 1
Study Cycle of 
Sample 
Collection
(Cycle 1= 7 days,
Subsequent cycles 
are 21 days each)
Study Day of Sample 
Collection
Event
Time 
(post BMS-986158 
Dose)
Hour: Min
BMS-986158
Blood Sample 
for Plasma 
Analysis 
ECG
QTca
1
1
predose
00:00
X
X
1
1
00:30
X
1
1
01:00
X
1
1
02:00
X
X
1
1
04:00
X
X
1
1
08:00(±2hr)
X
X
1
2
24:00c
X
X
1
3
48:00c
X
1
4
72:00c
X
2
1
predose
00:00
X
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Table 5.5.1-3:
Pharmacokinetic Specimen Collection & ECG Schedule for BMS-
986158 Monotherapy for Schedule C (7 days on / 14 days off ) of 
Part 1
Study Cycle of 
Sample 
Collection
(Cycle 1= 7 days,
Subsequent cycles 
are 21 days each)
Study Day of Sample 
Collection
Event
Time 
(post BMS-986158 
Dose)
Hour: Min
BMS-986158
Blood Sample 
for Plasma 
Analysis 
ECG
QTca
2
7
predose
00:00
X
X
2
7
00:30
X
2
7
01:00
X
2
7
02:00
X
X
2
7
04:00
X
X
2
7
08:00
X
X
2
8
24:00d
X
X
2
9
48:00d
X
X
2
10
72:00d
X
X
2
11
96:00d
X
X
4
8 (+3 days)e
24:00
X
X
6
8 (+3 days)e
24:00
X
X
8
8 (+3 days)e
24:00
X
X
a Triplicate 12-lead ECGs will be collected prior to the first BMS-986158 dose during Cycle 1, Day 1(0 hour), 2 and 
4 hours post BMS dose. A single 12 lead ECG will be collected thereafter. QTcF assessments ≥450 msec must be 
confirmed on repeat ECG.
c Time represents approximate hours after Cycle 1 Day 1 dose of BMS-986158
d Time represents approximate hours after the Cycle 2 Day 7 dose of BMS-986158
e Sample may be collected at any time from Cycle Day 8 through Cycle Day 11
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Table 5.5.1-4:
Pharmacokinetic Specimen Collection Schedule for BMS-986158 
Monotherapy for Schedule A in Part 2 (5 days on / 2 days off) 
Expansion Cohorts
Study Cycle of 
Sample 
Collection
(1 Cycle = 28 days)
Study Day of 
Sample Collection
Event
Time 
(post BMS-986158
Dose)
Hour: Min
BMS-986158
Blood Sample for 
Plasma Analysis
1
1
predose
00:00
X
1
1
00:30a
X
1
1
01:00a
X
1
1
02:00
X
1
1
04:00
X
1
1
06:00a
X
1
2
predose
00:00
X
1
5
predose
00:00
X
1
5
00:30a
X
1
5
01:00a
X
1
5
02:00
X
1
5
04:00
X
1
5
06:00a
X
1
12
predose
00:00
X
1
12b
04:00 – 12:00
X
2
1
predose
00:00
X
2
1
00:30a
X
2
1
01:00a
X
2
1
02:00
X
2
1
04:00
X
2
1
06:00a
X
2
2
predose
00:00
X
2
5
predose
00:00
X
Every 3 cycles 
from cycle 3
1
predose
00:00
X
Progression 
(EOT)
X
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a Sample collection only applies for adolescent subjects
b Sample is preferably taken the same day of biopsy. If biopsy is rescheduled to another time, PK sample day should 
be moved accordingly
Note: Blood sample collection for adolescent subjects will occur at the same frequency but 50% of the volume as that 
for adult subjects.
Table 5.5.1-5:
Pharmacokinetic Specimen Collection Schedule for BMS-986158 in 
Combination with Nivolumab 480 mg Q4W for Schedule A (5 days 
on / 2 days off) of Part 2 Expansion Cohorts
Study Cycle of 
Sample
Collection
(1 Cycle = 28 days)
Study Day of 
Sample 
Collection
Event
Time 
Post Dosea
Hour: Min
BMS-986158
Blood 
Sample for 
Plasma 
Analysis
1
1
predose
00:00
X
1
1
00:30c
X
1
1
01:00
X
1
1
02:00c
X
1
1
04:00
X
1
1
06:00c
X
1
2
predose
00:00
X
1
5
predose
00:00
X
1
5
00:30c
X
1
5
01:00
X
1
5
02:00c
X
1
5
04:00
X
1
5
06:00c
X
1
12
predose
00:00
X
1
12d
04:00 – 12:00
X
2
1
predose
00:00
X
2
1
00:30c
X
2
1
01:00
X
2
1
02:00c
X
2
1
04:00
X
2
1
06:00c
X
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Table 5.5.1-5:
Pharmacokinetic Specimen Collection Schedule for BMS-986158 in 
Combination with Nivolumab 480 mg Q4W for Schedule A (5 days 
on / 2 days off) of Part 2 Expansion Cohorts
Study Cycle of 
Sample
Collection
(1 Cycle = 28 days)
Study Day of 
Sample 
Collection
Event
Time 
Post Dosea
Hour: Min
BMS-986158
Blood 
Sample for 
Plasma 
Analysis
2
5
predose
00:00
X
Every 3 cycles 
from cycle 3
1
predose
00:00
X
Progression 
(EOT)
X
FU1 (30 days)
FU2 (100 days)
Note: Blood sample collection for adolescent subjects will occur at the same frequency but 50% of the volume as that 
for adult subjects. 
a All BMS-986158 sample collection times are with reference to the time of BMS-986158 oral dose administration.
 
c Sample collection only applies to adolescent patients.
d Sample is preferably taken the same day of biopsy. If biopsy is rescheduled to another time, PK sample day should 
be moved accordingly
5.5.2
Pharmacokinetic Sample Analyses
The plasma samples will be analyzed for BMS-986158 and metabolite, BMT-161485 by a 
validated LC-MS/MS assay.
 
Pharmacokinetic analyses will be performed on the tumor tissue.
 
In addition, plasma samples will be archived for potential metabolite analysis, if the need arises 
and to the extent possible.
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5.5.4
Labeling and Shipping of Biological Samples
Detailed instructions for the pharmacokinetic blood collection, labeling, processing, storage, and 
shipping will be provided to the site in the procedure manual.
5.6
Biomarker Assessments
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Tumor Biopsy Collection Details
A minimum of 1 FFPE tumor tissue block (preferred) OR a minimum of 3-4 core biopsies are 
required for biomarker evaluations in adult subjects. Specimens should contain a minimum of 100 
evaluable tumor cells. 
Complete instructions on tissue collection, processing, handling, and shipment of all biopsy 
samples will be provided in a separate procedure manual. Collection procedures at baseline and 
during treatment should be completed on a single, appropriately-assessable lesion when possible. 
Immediate confirmation for presence of viable tumor cells from collected tissue samples is 
strongly recommended. If core needle biopsies are collected, 3 cores plus one additional core is 
required at screening in cases where prospective testing is required by 
 
(16 gauge is preferred if feasible), and 3 cores should be collected during treatment and at the EOT 
in subjects with PD. All cores will be formalin fixed for FFPE block preparation, 1 will be for 
 testing (at screening only, and subjects with NMC, ES, BL, and DHL 
are exempted
 
 
If adequate tissue is not 
obtained following initial passages of the needle, repeat passages may be completed. 
The investigator, in consultation with the radiology staff, must determine the degree of risk 
associated with the biopsy procedure and find it acceptable. Biopsies may be done with local 
anesthesia or conscious sedation. Institutional guidelines for the safe performance of biopsies 
should be followed. Excisional biopsies may be performed to obtain tumor biopsy samples. 
Invasive procedures that require general anesthesia should not be performed to obtain a biopsy 
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specimen. 
 
 
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BET Inhibitor
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5.7
Outcomes Research Assessments
Not applicable.
5.9
Results of Central Assessments
Not applicable
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6
ADVERSE EVENTS
An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical 
condition in a clinical investigation subject administered study drug 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 drug, whether or not considered related to the study drug.
The causal relationship to study drug 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 drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
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. Care should be taken not to introduce bias when collecting 
AE and/or SAEs. Inquiry about specific AEs should be guided by clinical judgement in the context 
of known adverse events, when appropriate for the program or protocol.
BMS will be reporting AEs to regulatory authorities and ethics committees according to the local 
applicable laws including European Directive 2001/20/EC and FDA Code of Federal Regulations 
21 CFR Parts 312 and 320.
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
•
results in death
•
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)
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•
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 drug 
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 (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (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 
(applies to oncology protocols)
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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 drug, 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 
30 days of discontinuation of dosing for subjects receiving BMS-986158 monotherapy and within 
100 days of discontinuation for subjects receiving BMS-986158 in combination with nivolumab.
The investigator should 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 should be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, 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 should be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS (or 
designee) within 24 hours. SAEs must be recorded on the SAE Report Form; pregnancies on a 
Pregnancy Surveillance Form (electronic or paper forms). The preferred 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. 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. The paper forms should be used and submitted immediately, only 
in the event the electronic system is unavailable for transmission. 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.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
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 should begin at initiation of study drug until the time 
points specified in the Schedule of Activities (Section 5). Nonserious AE information should also 
be collected from the start of the screening 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 drug 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.
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 (paper or electronic) as appropriate:
•
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 drug discontinued 
or interrupted
•
Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.
It is expected that wherever appropriate, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, thrombocytopenia versus decreased platelet count, anemia versus 
low hemoglobin value, etc.).
6.4
Pregnancy
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of study exposure, including during at 
least 5 half-lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form 
to BMS Designee within 24 hours and in accordance with SAE reporting procedures described in 
Section 6.1.1.
In all cases, the study drug will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for subject safety). Please call the BMS Medical Monitor within 24 hours of 
awareness of the pregnancy.
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
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Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. 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. 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: 
AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND 
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND 
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
Not applicable
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8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
Dose Escalation (Part 1): 
In the dose escalation part of the study for monotherapy Part 1, the sample size per dose level 
cannot be precisely determined but depends on the observed DLT and the decision rule of mTPI. 
Between 3 and up to 13 DLT evaluable subjects may be enrolled to a given dose level, based on 
the decision guide by the mTPI design. Treating additional subjects beyond the 13 at a dose level 
would be unlikely to alter the decision specified by the mTPI algorithm. A total of approximately 
30 subjects is expected to be treated per schedule, with a total of 90 planned across schedules for 
the dose escalation phase. More subjects may be added at a specific schedule if additional dose 
levels need to be evaluated. Similarly, fewer than 30 subjects may be needed for a different 
schedule if a smaller number of dose levels are evaluated. 
Assuming a 27% acceptable DLT rate, which corresponds to a Beta(1,2.7) distribution, the 
following table shows the risk associated with selecting a dose level as safe given the number of 
DLTs observed at that dose level based on the posterior probability associated with an observed 
DLT. 
Table 8.1-1:
Posterior Probability of DLT in Monotherapy Assuming Observed 
DLTs
Number of Subjects DLT 
Evaluable at a Dose Level
Number of Subjects 
with Observed DLT
Probability DLT Rate 
>33%
Probability DLT Rate 
>40%
6
1
2
16%
41%
8%
25%
9
2
3
20%
43%
9%
25%
12
2
3
9%
23%
3%
10%
13
3
4
19%
37%
7%
18%
Assuming a 27% target DLT (± 2%) rate for the mTPI DLT target, a prior Beta distribution used is Beta(1,2. 7) 
Cohort Expansion (Part 2):
Initial Monotherapy Expansion:
During this part of the study, the efficacy signal assessment will start with initial monotherapy 
cohorts. This assessment will be guided by a Fleming 2-stage design, to provide the option for 
early evaluation and planning based on an initial efficacy signal. The sample sizes for each cohort 
are calculated based on assumptions of true (target) and historic ORR for each tumor type. A 
2-stage design provides criteria for the option to stop early for futility, and an understanding of an 
early signal of preliminary, strong antitumor activity. Approximately 5 to 9 subjects will be treated 
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in each of the cohorts, based on the Fleming (optimal) design criteria. Enrollment may continue 
after the initial 5 subjects to ensure that sufficient subjects are evaluable (eg, with tumor scans) or 
in case of early drop outs. In addition to futility, an efficacy boundary is shown (Table 8.1-2); 
however there will be no stopping due to an efficacy signal. 
In summary, approximately up to 45 subjects are expected to be treated across the Initial 
monotherapy cohorts, with approximately 5 to 9 subjects per cohort (Table 8.1-2). 
Table 8.1-2:
Characteristics for Initial Monotherapy Expansion Cohorts Signal 
assessment when guided by a Two-Stage Design
Tumor Cohort and 
Group
Target
ORR
%
SOC 
ORR
%
Stage 1 / 
Total N
Stage 1 Res 
Futility/ Efficacy 
Boundary
Stage 2 Res 
Futility/ Efficacy 
Boundary
FPR/FNR 
(%)
FUSION PROTEINS
NMC
50
10
5/9
0/2
2/3
10/10
DHL
50
10
5/9
0/2
2/3
10/10
BRD AMPLIFICATIONS
TNBC
50
10
5/9
0/2
2/3
10/10
MYC AMPLIFICATIONS
Non-GC-DLBCL 
35
10
5/9
0/2
1/2
20/20
AR AMPLIFICATIONS
CRPC
35
10
5/9
0/2
1/2
20/20
Abbreviations: CRPC = castrate-resistant prostate cancer; DHL = double-hit lymphoma; FNR = false negative rate; 
FPR = false positive rate; N = number of subjects; NMC = NUT-midline carcinoma; ORR = objective response rate; 
RCC = renal cell carcinoma; Res = response; SOC = standard of care; TNBC = triple negative breast cancer; Non-
GC-DLBCL = Non-germinal center diffuse large B-cell lymphoma; 
Note: Tumor ORR assumptions will also be used when assessing a signal across tumors within a group,
Subsequent Monotherapy Expansion
Based on totality of data obtained from the Initial Expansion, up to 126 subjects may be enrolled 
in the Subsequent Expansion cohorts with an expanded set of tumor types within and across groups 
(Table 8.1-3).
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Table 8.1-3:
Characteristics for Subsequent Monotherapy Expansion Cohorts 
signal assessment when guided by a 2-stage design
Tumor Cohort and 
Group
Target
ORR
%
SOC 
ORR
%
Stage 1 / 
Total N
Stage 1 Res 
Futility/ Efficacy 
Boundary
Stage 2 Res 
Futility/ Efficacy 
Boundary
FPR/FNR 
(%)
FUSION PROTEINS
DHL 
50
10
5/9
0/2
2/3
10/10
NMC 
50
10
5/9
0/2
2/3
10/10
ES 
35
10
5/9
0/2
1/2
20/20
BL 
50
10
5/9
0/2
2/3
10/10
BRD AMPLIFICATIONS
TNBC 
50
10
5/9
0/2
2/3
10/10
OC w BRD 
amplifications
50
10
5/9
0/2
2/3
10/10
NEPC
50
10
5/9
0/2
2/3
10/10
MYC AMPLIFICATIONS
Non-GC-DLBCL 
35
10
5/9
0/2
1/2
20/20
OC w MYC 
amplifications
35
10
5/9
0/2
1/2
20/20
UCS 
35
10
5/9
0/2
1/2
20/20
AR AMPLIFICATIONS
CRPC 
35
10
5/9
0/2
1/2
20/20
MUTATIONS
RCC 
35
10
5/9
0/2
1/2
20/20
NSCLC 
35
10
5/9
0/2
1/2
20/20
UM 
35
10
5/9
0/2
1/2
20/20
Abbreviations: BL = Burkitt’s lymphoma; CRPC = castrate-resistant prostate cancer; DHL = double-hit lymphoma; 
ES = Ewing sarcoma; FNR = false negative rate; FPR = false positive rate; N = number of subjects; 
NEPC = neuroendocrine prostate cancer; NMC = NUT-midline carcinoma; NSCLC = non-small cell lung cancer; 
OC = ovarian cancer; ORR = objective response rate; RCC = renal cell carcinoma; Res = response; SOC = standard 
of care; TNBC = triple negative breast cancer; UCS = uterine carcinosarcoma; UM = uveal melanoma; Non-GC-
DLBCL = Non-germinal center diffuse large B-cell lymphoma; 
Note: Tumor ORR assumptions will also be used when assessing a signal across tumors within a group.
Combination Therapy:
If the combination of BMS-986158 with nivolumab is pursued, the safety of combination treatment 
will be evaluated across the tumor types in the first 6 to 12 evaluable subjects who receive 
combination therapy based on the DLT observed. The mTPI-2 design with DLT target of 29% (-
2%, +4%) will be used to guide decisions in this setting, including potential de-escalation to a 
lower dose of BMS-986158 in combination with nivolumab, if warranted by the observed results
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(see Table 3.1.2.2-1). In addition, calculations related to the risk of selecting a BMS-986158 dose 
level as safe based on the observed DLTs are shown expressed as a posterior probability of toxicity 
in Section 3.1.2 (Table 3.1.2.2-2). 
The sample sizes are based on the assumption that the selected dose level is deemed safe in 
combination therapy. If a lower dose level must be evaluated in combination therapy, an additional 
6 to 12 subjects may be enrolled to assess safety of BMS-986158 prior to fully expanding in 
combination therapy.
Table 8.1-4:
Two-Stage Design Characteristics for Combination Therapy for 
Dose Expansion Cohorts
Tumor Cohort and 
Group
Target
ORR
%
SOC 
ORR
%
Stage 1 / 
Total N
Stage 1 Res 
Futility/ Efficacy 
Boundary
Stage 2 Res 
Futility/ Efficacy 
Boundary
FPR/FNR 
(%)
FUSION PROTEINS
DHL 
50
10
5/9
0/2
2/3
10/10
NMC 
50
10
5/9
0/2
2/3
10/10
ES
35
10
5/9
0/2
1/2
20/20
BL 
50
10
5/9
0/2
2/3
10/10
BRD AMPLIFICATIONS
TNBC 
50
10
5/9
0/2
2/3
10/10
OC w BRD 
amplifications 
50
10
5/9
0/2
2/3
10/10
NEPC 
50
10
5/9
0/2
2/3
10/10
MYC AMPLIFICATIONS
Non-GC-DLBCL 
35
10
5/9
0/2
1/2
20/20
OC w MYC 
amplifications
35
10
5/9
0/2
1/2
20/20
UCS
35
10
5/9
0/2
1/2
20/20
AR AMPLIFICATIONS
CRPC 
35
10
5/9
0/2
1/2
20/20
MUTATIONS
RCC 
35
10
5/9
0/2
1/2
20/20
NSCLC 
35
10
5/9
0/2
1/2
20/20
UM 
35
10
5/9
0/2
1/2
20/20
Abbreviations: BL = Burkitt’s lymphoma; CRPC = castrate-resistant prostate cancer; DHL = double-hit lymphoma; 
ES = Ewing sarcoma; FNR = false negative rate; FPR = false positive rate; N = number of subjects; 
NEPC = neuroendocrine prostate cancer; NMC = NUT-midline carcinoma; NSCLC = non-small cell lung cancer; 
OC = ovarian cancer; ORR = objective response rate; RCC = renal cell carcinoma; Res = response; SOC = standard 
of care; TNBC = triple negative breast cancer; UCS = uterine carcinosarcoma; UM = uveal melanoma; Non-GC-
DLBCL = Non-germinal center diffuse large B-cell lymphoma; 
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Note: Tumor ORR assumptions will also be used when assessing a signal across tumors within a group,
Additionally, another 18 subjects may be enrolled in the expansion, in order to evaluate target gene 
engagement in tumors, and additional PK and safety characteristics in 1-2 cohorts at a second dose 
and schedule.
The potential total for expansion will be approximately up to 201 subjects if only monotherapy is 
pursued, and approximately up to 327 subjects if all planned expansion cohort subjects in 
monotherapy and combination therapy groups are pursued.
8.2
Populations for Analyses
•
All Enrolled Subjects: All subjects who provide an ICF.
•
All Treated Subjects: All subjects who receive at least one dose of study medication
•
Pharmacokinetic Subjects: All subjects who receive at least one dose of BMS-986158 as 
monotherapy or in combination with nivolumab if the combination is pursued and who have 
available serum and plasma concentration data for the corresponding analyte
•
Response Evaluable Population: All treated subjects who have baseline tumor measurement 
and at least one other tumor measurement after treatment, clinical progression, or death prior 
to the first on-treatment tumor assessment.
All subjects who receive study medication will be included in the safety data set. 
8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary objective (to assess the safety and tolerability and to define the DLTs and MTD of 
BMS-986158) will be measured by the primary endpoints of: Incidence of AEs at their worst grade, 
SAEs at their worst grade, AEs leading to discontinuations, deaths, and frequency of laboratory 
test toxicity grade shifting from baseline. Safety will be evaluated from the time that the subject 
signs the informed consent, and for up to 30 days and 100 days after the last dose of BMS-986158 
monotherapy or BMS-986158 in combination with nivolumab, respectively, or until resolution of 
any AE for which alternative causes could not be identified resolve to ≤Grade 1 or baseline or 
until the event has stabilized, whichever is longer.
8.3.2
Secondary Endpoint(s)
The endpoint(s) used to measure efficacy, PK, and ECG objectives are described below: 
8.3.2.1
Efficacy
The first secondary objective (efficacy) will be based on RECIST v1.1 for solid tumors 
(Appendix 4), Lugano 2014 criteria for hematologic malignancies (Appendix 9), or PCWG3 
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criteria for prostate cancer (CRPC or NEPC) (Appendix 12) using the following secondary 
endpoints:
•
Best overall response (BOR): defined as the best response designation, recorded between the 
dates of first dose and the date of first objectively documented progression (per RECIST v1.1 
for solid tumors, Lugano 2014 criteria for hematologic malignancies or PCWG3 for prostate
cancer) or the date of subsequent therapy, whichever occurs first. CR or PR determinations 
included in the BOR for solid tumor assessments must be confirmed by a second scan 
performed no less than 4 weeks, and for hematologic malignancies, no less than 2 weeks after 
the criteria for response are first met. For subjects without documented progression or 
subsequent therapy, all available response designations will contribute to the BOR assessment. 
For subjects who continue treatment beyond progression or begin subsequent therapy, the BOR 
should be determined based on response designations recorded up to the time of the initial 
evaluation (RECIST v1.1 for solid tumors, Lugano 2014 criteria for hematologic malignancies
or PCWG3 criteria for prostate cancer [CRPC or NEPC]) defined progression or subsequent 
therapy, whichever occurs first. For those subjects who have surgical resection, only pre-
surgical tumor assessments will be considered in the determination of BOR. A BOR of SD 
requires a minimum of 49 days on study from date of first dose to the date of the first imaging 
assessment.
•
ORR: defined as the total number of subjects whose BOR is either a CR or PR divided by the 
total number of subjects in the population of interest 
•
Duration of Response (DOR): defined for a subject with confirmed response as the time 
between the date of first response and the date of the first objectively documented disease 
progression (as determined by RECIST v1.1 for solid tumors, Lugano 2014 criteria for 
hematologic malignancies, or PCWG3 (including PSA assessments) for prostate cancer 
[CRPC or NEPC]), or death due to any cause, whichever occurs first. For those subjects who 
remain alive and have not progressed, duration of response will be censored on the date of last 
tumor assessment. Subjects who started subsequent therapy without a prior reported 
progression will be censored at the last tumor assessment prior to initiation of the subsequent 
anticancer therapy. Response duration will only be evaluated in subjects with a BOR of CR or 
PR.
•
PFS: defined as the time from the first dose of study medication to the date of the first objective 
documentation of tumor progression or death due to any cause. Clinical deterioration in the
absence of radiographic evidence is not considered progression for the purpose of determining 
PFS. Subjects who neither progressed nor died will be censored on the date of their last tumor 
assessment. Subjects who did not have any on-study tumor assessments will be censored on 
the date of the first dose of study medication. Subjects who started subsequent therapy without 
a prior reported progression will be censored at the last tumor assessment prior to initiation of 
the subsequent anticancer therapy.
•
Progression Free Survival Rate (PFSR) at week ͂t̓: defined as the proportion of subjects 
who remain progression free and surviving at ͂t̓ weeks (t=12, 24). The proportion will be 
calculated by the product-limit method (Kaplan-Meier estimate) which takes into account 
censored data. 
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8.3.2.2
Pharmacokinetics
PK of BMS-986158 monotherapy and in combination with nivolumab (parent and metabolite, as 
data permits) will be derived from plasma concentration versus time.
The PK parameters to be assessed following single dose administration include:
Cmax
Maximum observed plasma concentration
Tmax
Time of maximum observed plasma concentration
AUC(0-T)
Area under the plasma concentration-time curve from time zero to time of 
last quantifiable concentration
AUC(TAU)
Area under the concentration-time curve in one dosing interval
If data permits, the following single dose PK parameters may also be assessed:
T-HALF
Apparent terminal phase half-life
AUC(INF)
Area under the plasma concentration-time curve from time zero 
extrapolated to infinite time
CLT/F
Apparent total body clearance, reported only for parent, not for metabolite
Vz/F
Apparent volume of distribution of terminal phase, reported only for 
parent, not for metabolite
The PK parameters to be assessed following multiple dose administration include:
Cmax
Maximum observed plasma concentration
Tmax
Time of maximum observed plasma concentration
AUC(0-T)
Area under the plasma concentration-time curve from time zero to time of 
last quantifiable concentration
AUC(TAU)
Area under the concentration-time curve in one dosing interval
Cmin
The minimum observed concentration within a dosing interval 
Ctau
Concentration at the end of a dosing interval 
Ctrough
Trough observed plasma concentration (this includes predose 
concentrations (C0) and concentrations at the end of dosing interval 
(Ctau)); 
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AI
Accumulation Index; ratio of an exposure measure at steady-state to that 
after the first dose (exposure measure includes AUC(TAU), Cmax and 
Ctau).
T-HALFeff
Effective elimination half-life that explains the degree of accumulation 
observed for a specific exposure measure 
In addition, the following PK parameters may also be assessed after single and multiple dose 
administrations, if data permit:
MR_Cmax
Ratio of metabolite Cmax to parent Cmax, corrected for molecular 
weight
MR_AUC(0-T)
Ratio of metabolite AUC(0-T) to parent AUC(0-T), corrected for 
molecular weight
MR_AUC(INF)
Ratio of metabolite AUC(INF) to parent AUC(INF), corrected for 
molecular weight (following single dose only)
MR_AUC(TAU)
Ratio of metabolite AUC(TAU) to parent AUC(TAU), corrected for 
molecular weight
 
Individual subject pharmacokinetic parameter values will be derived by non-compartmental 
methods by a validated pharmacokinetic program. Actual times will be used for the analyses.
8.3.2.4
ECG/QTc
Changes in QTcF, (ǼQTcF) from baseline, at selected times following monotherapy treatment 
with BMS-986158, and association measures of QTc changes with BMS-986158 PK exposure.
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8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
A description of the participant population will be included in the statistical output reported, 
including subgroups of age, gender, and race. Prior cancer therapy (types and number) and other 
baseline characteristics will be tabulated for each tumor type. 
8.4.2
Efficacy Analyses
Efficacy results will be presented by tumor type, dose level, dosing schedule and/or regimen. 
Individual BOR, duration of response and PFS using RECIST v1.1 criteria (Appendix 4) for solid 
tumors, Lugano 2014 criteria for hematologic malignancies (Appendix 9), or PCWG3 (including 
PSA assessments) for prostate cancer (CRPC or NEPC Appendix 12) will be listed. BOR outcomes
and ORR will be tabulated by dose / dose regimen and across doses for each tumor. For ORR, 95% 
confidence intervals (CIs) will be calculated based on the Clopper-Pearson method. The median 
DOR (mDOR) (for responders) and median PFS will be estimated by Kaplan-Meier (K-M) 
methodology. PFS rates (e.g. at 24 weeks) will be similarly estimated, based on K-M methodology, 
with confidence intervals based on the Greenwood formula and tabulated for each tumor. 
Individual changes in the tumor burden versus time will be presented graphically by dose 
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level/study arm/dose regimen within a tumor type. Depending on the purpose of the analysis 
efficacy may be reported for all treated subjects, or for response-evaluable subjects. Additional 
details will be presented in the Statistical Analysis Plan (SAP), as necessary.
 
8.4.3
Safety Analyses
All recorded AEs will be listed and tabulated by system organ class, preferred term and treatment. 
Vital signs and clinical laboratory test results will be listed and summarized by treatment. Any 
significant PE findings, and clinical laboratory results will be listed. ECG readings will be 
evaluated by the investigator and abnormalities, if present, will be listed. Safety data may also be 
presented in adolescent participants based on data availability.
8.4.4
Pharmacokinetic Analyses
PK parameters for BMS-986158 will be calculated using noncompartmental analysis. Summary 
statistics will be tabulated for the PK parameters by dose level, dose regimen, and study cycle/day, 
for each schedule. To describe the dependency on dose, scatter plots of Cmax and AUC(0-T), 
AUC(TAU) versus dose will be provided on indicated study cycle for each dose regimen. 
 
 Geometric means and coefficients of 
variation will be reported for Cmax, AUC, Cmin, Ctau, Ctrough, CLT/F, Vz/F, AI, T-HALFeff 
and MR; Medians and ranges will be reported for Tmax; means and SD will be reported for T-
HALF. PK data may also be summarized separately for adolescent participants depending on data 
availability.
 
In addition, PK data obtained from this study may be used to perform population PK analysis and 
exposure response analysis for selected endpoints, as appropriate and as the data permits. These 
analyses will be described in a separate report.
8.4.5
ECG Analyses
For subjects with serial ECG measurements and time-matched PK following monotherapy 
treatment with BMS-986158, changes in the QTcF (ǼQTcF), ECG intervals QRS, and PR, and in 
heart rate (ǼHR) will be tabulated by treatment and study day. Frequency distributions of max 
QTcF values, max ǼQTcF, and of max HR in pre-specified categories will be tabulated by 
treatment. Scatter plots of heart rate, ǼHR, QTc, and ǼQTcF, vs time-matched BMS-986158 
concentrations will be provided. A concentration-response effect of BMS-986158 on QTcF may 
be assessed by a linear mixed effects regression model for ǼQTcF on plasma and serum 
concentrations, stratified by study day, as well as pooled across days. 
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8.4.7
Outcomes Research Analyses
Not applicable.
8.5
Interim Analyses
Because the exploratory nature of the early phase study, data emerging from each dose level,
treatment arm, or each part of the study will be examined prior to the final lock of the study 
database for timely decisions such as dose level or dose schedule selection, early termination of 
the study or publications. Analyses will consist of listings, summaries, and graphs of the available 
data. In addition, modeling of PK (eg, exploration of exposure-response and simulations) or key 
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safety data may be utilized to inform dose or dose schedule selection, for subsequent parts of the 
study as data permits. No formal inferences requiring any adjustment to statistical significance 
level will be performed, or adjustment for multiplicity.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, 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 IRB/IEC approval/favorable opinion, as soon as possible the deviation or change will be 
submitted to:
•
IRB/IEC for review and approval/favorable opinion
•
BMS
•
Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) 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
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 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. 
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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), 
AE 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. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and procedure, 
electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator 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, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator 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, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include IP and non-investigational 
product(s). Records or logs must comply with applicable regulations 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
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•
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.
BMS 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 BMS 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 
paper or electronic SAE form and Pregnancy Surveillance form, respectively. If electronic SAE 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 BMS. 
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, including any paper or electronic 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. 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 BMS training requirements and 
must only access the BMS electronic data capture tool using the unique user account provided by 
BMS. User accounts are not to be shared or reassigned to other individuals.
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9.3
Clinical Study Report and Publications
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:
•
Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications or 
abstracts arising from this study require approval by BMS prior to publication or presentation and 
must adhere to BMS’s publication requirements as set forth in the approved clinical trial agreement 
(CTA). All draft publications, including abstracts or detailed summaries of any proposed 
presentations, must be submitted to BMS at the earliest practicable time for review, but at any 
event not less than 30 days before submission or presentation unless otherwise set forth in the 
CTA. BMS shall have the right to delete any confidential or proprietary information contained in 
any proposed presentation or abstract and may delay publication for up to 60 days for purposes of 
filing a patent application.
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GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
Complete abstinence as defined as complete avoidance of 
heterosexual intercourse is an acceptable form of 
contraception for all study drugs. This also means that 
abstinence is the preferred and usual lifestyle of the subject. 
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 must be 
discussed in the event that the subject chooses to forego 
complete abstinence.
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11
LIST OF ABBREVIATIONS
Term
Definition
1L
first line
2L
second line 
ACLS
advanced cardiac life support
AE
adverse event
AI
accumulation index
ALT
alanine aminotransferase
AML
acute myeloid leukemia
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AR
androgen receptor
ARD
androgen receptor deprivation 
ASCO
American Society for Clinical Oncology
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve
AUC(0-T)
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration
AUC(INF)
area under the concentration-time curve from time zero extrapolated to 
infinite time
AUC(TAU)
area under the concentration-time curve in one dosing interval
BCRp
breast cancer resistant protein
BET
bromodomain and extra terminal
BID
twice a day
BL
Burkitt’s lymphoma
BMS
Bristol-Myers Squibb
BOR
best overall response
BP
blood pressure
BRD
bromodomain
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Term
Definition
BRD4
bromodomain containing protein 4
B-to-A
basolateral to apical
CAP
College of American Pathologists
CBC
complete blood count
CFR
Code of Federal Regulations 
CI
confidence interval
CLT
total body clearance of drug from plasma
Cmax, CMAX
maximum observed concentration
CNS
central nervous system
CR
complete response
CRF
case report form
CrCl
creatinine clearance
CRPC
castration-resistant prostate cancer
CSR
Clinical Study Report
CT
computed tomography
CTA
clinical trial agreement
CTC
circulating tumor cells
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough, 
CTROUGH
trough observed concentration
CV
coefficient of variation
CYP
cytochrome p-450
DDI
drug-drug interaction
DHL
double-hit lymphoma
DILI
drug induced liver injury
DLBCL
diffuse large B-cell lymphoma
DLT
dose limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response
EC
Ethics Committee
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Term
Definition
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOT
end of treatment
ES
Ewing sarcoma
ET
extra terminal
FDG-PET
fluorodeoxyglucose - positron emission tomography
FFPE
formalin fixed paraffin embedded
FISH
fluorescence in situ hybridization
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal
GLP
Good Laboratory Practice
HCG
human chorionic gonadotropin
HCV
hepatitis C virus
HED
human equivalent dose
HIV
human immunodeficiency virus
HNSTD
highest non-severely toxic dose
HR
heart rate
HRT
hormone replacement therapy
HSCT
hematopioetic stem cell transplant
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation 
IEC
Independent Ethics Committee
IFNγ
interferon gamma
IgG
immunoglobulin G
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Term
Definition
IHC
immunohistochemistry
IL
interleukin
INR
international normalized ratio
IP
investigational product
IRB
Institutional Review Board
IUD
intrauterine device
IV
intravenous
IVRS
interactive voice response system
K
slope of the terminal phase of the log concentration-time curve
LVEF
left ventricular ejection fraction
MLL
mixed lineage leukemia
MM
multiple myeloma
MOA
mechanism of action
MRI
magnetic resonance imaging
mRNA
messenger RNA
MRSD
maximum recommended starting dose
MSI-H
microsatellite instability-high
MTD
maximum tolerated dose
mTPI
modified toxicity probability interval.
MUGA
multiple gated acquisition scan
N/A
not applicable
NCCN
National Comprehensive Cancer Network
NEPC
neuroendocrine prostate cancer
NMC
NUT-midline carcinoma
NOAEL
no-observed adverse effect level
Non-GC-DLBCL
non-germinal center diffuse large B-cell lymphoma
NSAIDs
non-steroidal anti-inflammatory drugs
NSCLC
non-small cell lung cancer
NUT
nuclear protein in testis
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Term
Definition
OC
ovarian cancer
ORR
objective response rate
OS
overall survival
PARP
poly ADP ribose polymerase
PBT
platinum based therapy
P-gp
P-glycoprotein
Pc
permeability coefficient
PC
prostate cancer
PCWG3
Prostate Cancer Working Group 3
PD
progressive disease
PD-1
programmed cell death protein 1
PD-L1
programmed cell death-ligand 1
PD-L2
programmed cell death-ligand 2
p-DILI
potential drug induced liver injury
PDX
patient-derived xenografts
PE
physical examination
PFS
progression free survival
PFSR
progression free survival rate
PID
patient identification number
PK
pharmacokinetic(s)
PPK
population pharmacokinetics
PR
partial response
PSA
prostate specific antigen
PTT
partial thromboplastin time
Q2W
every 2 weeks
Q3W
every 3 weeks
Q4W
every 4 weeks
QD
once daily
RBC
red blood cell
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Term
Definition
RCC
renal cell carcinoma
RD
refractory disease
RECIST
response evaluation criteria in solid tumors
RNA
ribonucleic acid
RP
radical prostatectomy
RP2D
recommended Phase 2 dose
RR
response rate
r/r
relapsed or refractory
SAE
serious adverse event
SAP
statistical analysis plan
SCLC
small cell lung cancer
SD
standard deviation
SNP
single nucleotide polymorphism
SOC
standard of care
TB
total bilirubin
TCGA
The Cancer Genome Atlas
T-HALF
apparent elimination half-life
Tmax, TMAX
time of maximum observed concentration
TNBC
triple negative breast cancer
UCS
uterine carcinosarcoma
UGT
uridine diphosphate glucuronosyltransferase
ULN
upper limit of normal
UM
uveal melanoma
US
United States
WOCBP
women of childbearing potential
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12
REFERENCES
1
www.seer.cancer.gov
2
Haynes SR, et al. The bromodomain: a conserved sequence found in human, Drosophila and 
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Dey A, Nishiyama A, Karpova T, et al. Brd4 marks select genes on mitotic chromatin and 
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Dawson MA, et al. Inhibition of BET recruitment to chromatin as an effective treatment for 
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17 Lovén J, Hoke HA, Lin CY, et al. Selective inhibition of tumor oncogenes by disruption of 
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Liang Y, Ryan J, Doherty E, Mohammed H, Guo H, Stover DG, Ekram MB, Brown J, D'Santos 
C, Krop IE, Dillon D, McKeown M, Ott C, et al. Response and resistance to BET bromodomain 
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Alshalalfa M, Davicioni E, Erho N, Lloyd P, Karnes RJ, Ross AE, Schaeffer EM, Vander 
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Sauter G, Schlomm T, Nykter M, Visakorpi T, Mills IG. Androgen Receptor Deregulation 
Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer. Cell Rep. 2017 Jun 
6;19(10):2045-2059.
23 Wu Q, Lian JB, Stein JL, Stein GS, Nickerson JA, Imbalzano AN. The BRG1 ATPase of 
human SWI/SNF chromatin remodeling enzymes as a driver of cancer. Epigenomics. 2017 
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24 Ambrosini G, Sawle AD, Musi E, Schwartz GK. BRD4-targeted therapy induces Myc-
independent cytotoxicity in Gnaq/11-mutatant uveal melanoma cells. Oncotarget. 2015 Oct 
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171 Shimamura T, Chen Z, Soucheray M, et al. Efficacy of BET bromodomain inhibition in Kras-
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179 Motzer RJ, Hutson TE, Ren M, et al. Independent assessment of lenvatinib plus everolimus in 
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183 Denis GV, McComb ME, Faller DV, et al. Identification of transcription complexes that 
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184 NCCN Clinical Practice Guidelines in Oncology, Melanoma version 1.2017.
185 Lane AM, Egan KM, Harmon D, et al. Adjuvant interferon therapy for patients with uveal 
melanoma at high risk of metastasis. Ophthalmology. 2009;116:2206-2212.
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186 O’Neill PA, Butt M, Eswar CV, et al. A prospective single arm phase II study of dacarbazine 
and treosulfan as first-line therapy in metastatic uveal melanoma. Melanoma Res. 
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residue of bacille Calmette-Guerin as postsurgical adjuvant therapy of uveal melanoma. Am J 
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188 Leyvraz S, Piperno-Neumann S, Suciu S, et al. Hepatic intra-arterial versus intravenous 
fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a 
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189 Carvajal RD, Sosman JA, Quevedo JF, et al. Effect of selumetinib vs chemotherapy on 
progression-free survival in uveal melanoma: a randomized clinical trial. JAMA. 
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190 Triozzi PL, Singh AD. Adjuvant Therapy of Uveal Melanoma: Current Status. Ocul Oncol 
Pathol. 2015;1:54-62.
191 Krantz BA, Dave N, Komatsubara KM, et al. Uveal melanoma: epidemiology, etiology, and 
treatment of primary disease. Clin Ophthalmol. 2017 Jan 31;11:279-289.2017.
192 Kaliki S, Shields CL, Uveal melanoma: relatively rare but deadly cancer. Eye (Lond). 2017 
Feb;31(2):241-257.
193 Tarlan B, Kiratli H. Uveal melanoma: Current trends in diagnosis and management. Turk J 
Ophthalmol. 2016 Jun;46(3):123-137.
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202 Chuk MK, Mulugeta Y, Roth-Cline M, et al. Enrolling adolescents in disease/target 
appropriate adult oncology clinical trials of investigational agents. Clin Cancer Res. 2017; 23: 
9-12.
203 French CA, Kutok JL, Faquin WC, et al. Midline Carcinoma of Children and Young Adults 
with NUT Rearrangement. 2004, J Clin Oncol 22:4135-4139.
204 Bernstein L, Linet M, Smith MA, et al. Renal tumors. In: Ries LAG, Smith MA, Gurney JG, 
eds. Cancer Incidence and Survival Among Children and Adolescents: United States SEER 
Program 1975-1995, SEER Program. Bethesda, MD: National Cancer Institute; 1999:79-90.
205 Maki RG. Pediatric sarcomas occurring in adults. J Surg Oncol 2008 Mar 15;97(4):360-8.
206 Baldini EH, Demetri GD, Fletcher CD, et al. Ann Surg, 1999 Jul;230(1):79-86.
207 Uyeturk U, Helvaci K, Demirci A, et al. Clincal outcomes and prognostic factors of adult’s 
Ewing sarcoma family of tumors: single center experience. Contemp Oncol (Pozn) 2016; 20 
(2):141–146.
208 Cesari M, Righi A, Cevolani L, et al. Ewing sarcoma ni patients over 40 years of age: a 
prospective analysis of 31 patients treated at a single institution. Tumori. 2016 Oct 
13;102(5):481-487.
209 ESMO/European Sarcoma Network Working Group. Bone sarcomas: ESMO Clinical Practice 
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210 Shields CL, Kaliki S, Arepalli S, et al. Uveal melanoma in children and teenagers. Saudi 
Journal of Ophthal 2013 Jul;27(3):197-201.
211 Indolfi P, Terenziani M, Casale F, et al. Renal cell carcinoma in children: a clinicopathological 
study. J Clin Oncol. 2003;21:530-535.
212 Kayton ML, He M, Zakowski MF, et al. Primary lung adenocarcinomas in children and 
adolescents treated for pediatric malignancies. J Thorac Oncol. 2010 Nov;5(11):1764-71.
213 Gualco G, Weiss LM, Harrington WJ Jr, et al. Nodal diffuse large B-cell lymphomas in 
children and adolescents: immunohistochemical expression patterns and c-MYC translocation 
in relation to clinical outcome. Am J Surg Pathol. 2009 Dec; 33(12):1815–1822.
214 Kelly JL, Toothaker SR, Ciminello L, et al. Outcomes of patients with Burkitt lymphoma older 
than age 40 treated with intensive chemotherapeutic regimens. Clin Lymphoma Myeloma. 
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215 Lange J, Lenz G, Burkhardt B. Mature aggressive B-cell lymphoma across age groups -
molecular advances and therapeutic implications. Expert Rev Hematol. 2017 Feb;10(2):123-
135.
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216 Mukhtar F, Bofetta P, Risch HA, et al. Survival predictors of Burkitt’s lymphoma in children, 
adults and elderly in the United States during 2000-2013. Int J Cancer. 2017 Apr 
1;140(7):1494-1502.
217 Cairo MS, Gerrard M, Sposto R, et al. Results of a randomized international study of high-risk 
central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in 
children and adolescents. Blood 2007 Apr 1; 109(7):2736–2743.
218 Cairo MS, Shpsto R, Gerrard M, et al. Advanced stage, increased lactate dehydrogenase, and 
primary site, but not adolescent age (>/=15 years), are associated with an increased risk of 
treatment failure in children and adolescents with mature B-cell non-Hodgkin’s lymphoma: 
results of the FAB LMB 96 study. J Clin Oncol. 2012 Feb 1;30(4):387-93
219 Miles RR, Arnold S, Cairo MS. Risk factors and treatment of childhood and adolescent Burkitt 
lymphoma/leukaemia. Br J Haematol. 2012 Mar;156(6):730-43
220 Short NJ, Kantarjian HM, Ko H, et al. Outcomes of adults with relapsed or refractory Burkitt 
and high-grade B-cell leukemia/lymphoma. Am J Hematol. 2017 Jun;92(6):E114-E117. 
221 Shi R, Derendorf H. Pediatric dosing and body size in biotherapeutics. Pharmaceutics. 2010 
Dec 16;2(4):389-418. 
222 Fernandez D, Perez R, Hernandez A, et al. Factors and mechanisms for pharmacokinetic 
differences between pediatric population and adults. Pharmaceutics. 2011 Feb;7;3(1):53-72.
223 Strolin Benedetti M, Baltes EL. Drug metabolism and disposition in children. Fundam Clin 
Pharmacol. 2003;17(3):281-99.
224 BMS-986158: One-month intermittent-dose oral toxicity study in rats with a three-week post-
dose recovery (Study DM14045). Bristol-Myers Squibb Company; 2015. Document Control 
No. 930086051
225 BMS-986158: One-month intermittent-dose oral toxicity study in dogs with a three-week post-
dose recovery (Study DM14046). Bristol-Myers Squibb Company; 2015. Document Control 
No. 930087870.
226 Bolden JE, Tasdemir N, Dow LE, et al. Inducible in vivo silencing of Brd4 identifies potential 
toxicities of sustained BET protein inhibition. Cell Rep 2014;8(6):1919-29.
227 Shang E, Nickerson HD, Wen D, et al. The first bromodomain of Brdt, a testis-specific member 
of the BET sub-family of double-bromodomain-containing proteins, is essential for male germ 
cell differentiation. Development 2007;134(19):3507-15.
228 BMS-986158: Single-dose oral investigative cardiovascular study in telemeterized male rats 
(Study DT14024). Bristol-Myers Squibb Company; 2015. Document Control No. 930087183
229 BMS-986158: Eleven-Day Oral Expanded Range-Finding Study in Pregnant Rat (DN17205). 
Bristol-Myers Squibb Company (2017). Report preparation in progress
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230 BMS-986158: One-month intermittent-dose oral toxicity study in rats with a three-week post-
dose recovery (Study DM14045). Bristol-Myers Squibb Company; 2015. Document Control 
No. 930086051.
231 Gyuris A., Donovan D., Seymour K.et al., The chromatin-targeting protein Brd2 is required 
for neural tube closure and embryogenesis. Biochimica et Biophysica Acta 1789: 413-421, 
2009.
232 Houzelstein D., Bullock S., Lynch D. et al., Growth and early postimplantation defects in mice 
deficient for the bromodomain-containing protein 4. Molecular and Cellular Biology 22 (11): 
3794-3802, 2002.
233 BMT-152957: Exploratory Ames bacterial reverse-mutation study in Salmonella typhimurium 
(Study DN14038). Bristol-Myers Squibb Company; 2014. Document Control No. 930078706.
234 BMT-152957: Exploratory in vitro micronucleus study in Chinese hamster ovary cells (Study 
DN14037). Bristol-Myers Squibb Company; 2014. Document Control No. 930079933.
235 BMS-986158: Single-dose phototoxicity study to determine the effects of oral administration 
on eyes and skin in rats (Study DM15009). Bristol-Myers Squibb Company; 2015. Document 
Control No. 930092112.
236 BMS-986158: In vitro receptor, ion channel, transporter binding and enzyme interaction 
assessment (Study DT15022). Bristol-Myers Squibb Company; 2015. Document Control No. 
930087855.
237 BMT-152957 (BMS-986158): Effects on cardiac ion channels (Study DT15012). Bristol-
Myers Squibb Company; 2015. Document Control No. 930088251.
 
 
 
 
 
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APPENDIX 1
DOSE ESCALATION ALGORITHM BASED ON MODIFIED 
TOXICITY PROBABILITY INTERVAL (MTPI) DESIGN
Table 1:a
mTPI Designb Decision Rule with up to 15 Subjects at a Dose
Number of subjecs treated at current dose
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Number of subjects with DLT
0
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
1
D
S
S
S
S
S
E
E
E
E
E
E
E
E
E
2
DU
D
D
S
S
S
S
S
S
S
S
E
E
E
3
DU
DU
DU
D
S
S
S
S
S
S
S
S
S
4
DU
DU
DU
DU
D
S
S
S
S
S
S
S
5
DU
DU
DU
DU
DU
DU
D
S
S
S
S
6
DU
DU
DU
DU
DU
DU
DU
D
S
S
7
DU
DU
DU
DU
DU
DU
DU
DU
DU
8
DU
DU
DU
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
DU
DU
DU
10
DU
DU
DU
DU
DU
DU
11
DU
DU
DU
DU
DU
12
DU
DU
DU
DU
13
DU
DU
DU
14
DU
DU
15
DU
b Target DLT at MTD = 27% (+/-2%), flexible cohort size
a E = Escalate to next higher dose, S = Stay at the current dose, D = De-escalate to the next lower dose, U = The 
current dose is unacceptably toxic
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APPENDIX 2
SIMULATION OF MTPI VS 3 + 3 DOSE ESCALATION DESIGNS
WITH 6 DOSE LEVELS
Simulations of mTPI and 3+3 designs, shown below, demonstrate that the mTPI design has a 
greater chance of selecting the correct MTD than the 3+3 design, and treating fewer subjects at 
sub-optimal doses.
The mTPI uses a set of decision rules guided by simple Bayesian models and requires a clinically 
relevant pre-determined target DLT rate and an equivalence interval (EI), within which any dose 
is considered close to the true maximum tolerated dose (MTD). For this study, the selected target 
toxicity (DLT) rate is 27% and EI [25%, 29%]. 
The mTPI design makes decisions using the same two observed numbers as the traditional 3+3 
design, the number of DLT evaluable subjects and the number of subjects with DLT. Based on 
these two numbers, unit probability mass is calculated within each of three regions as stated 
above, and decision is based on which region has the largest unit probability mass:
•
E: escalating to the higher dose if interval (0, 25%) has the largest unit probability mass,
•
S: staying at the same dose if interval [25, 29%] has the largest unit probability mass,
•
D: de-escalating to the lower dose if interval (29, 100%) has the largest unit probability mass.
At the end of the trial, MTD will be picked, by isotonic regression estimation method, to be the 
dose whose estimated toxicity rate is closest to the target toxicity rate among all the tried doses.
Simulations were performed to examine the operating characteristics of mTPI and 3 + 3 designs
for this study. Escalation decisions based on the mTPI are shown in the protocol. Decisions 
based on the 3+3 design are shown below:
•
E: no subject with DLT out of 3 DLT evaluable subjects initially, or at most 1 subject with 
DLT out of 6 DLT evaluable subjects after adding 3 more subjects.
•
S: 1 subject with DLT out of 3 DLT evaluable subjects initially.
•
D: at least 2 subjects with DLT out of 3 DLT evaluable subjects initially, or at least 2 
subjects with DLT out of 6 DLT evaluable subjects after adding 3 more subjects at this dose
Settings for simulation:
•
6 dose-toxicity scenarios, each of which with a number of 6 (expected) dose levels
•
1000 trials per scenario
•
Target toxicity (Pt) for mTPI design: 27% with Equivalence Interval (EI) = [25, 29%]
•
mTPI: Cohort sizes of 3-4 at all dose levels, requiring a min of 3 per cohort for escalation 
decisions. Therefore 4 subjects per cohort and 25% dropout rate were used in simulations.
•
Stopping rule for mTPI: When there are already 13 DLT evaluable subjects treated at a dose 
level, and mTPI suggested decision is to treat more subjects at this dose level, dose escalation 
can be stopped.
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•
Maximum number of DLT evaluable subjects for the study is 30.
•
A nominal dose level of -1 is added in the tables to account for the case when de-escalation 
decision is made from dose level 1. However, the dose level -1 is not used in the simulations.
Dose-Toxicity Curve Scenarios
Six (6) scenarios of dose-toxicity (DLT) curves are selected to cover various possibilities and 
presented in the following figure with scenario ID shown at the end of line. The target toxicity 
rate of 0.27 is also superposed in the figure as a horizontal dashed line. The exact numeric values 
of DLT probability are available in each of the simulation results.
Figure -1:
Dose-Toxicity Probability Scenarios
Simulation Results
Simulation results are summarized from all the simulated trials per scenario, and include the 
following statistics:
•
MTD Selected: Frequency of each dose level being selected as MTD.
•
Subjects Allocated: Number of subjected being allocated to each dose level.
•
DLT rate: The average number of subjects who have DLT across all dose levels.
•
Average Sample Size: The average number of subjects across all dose levels.
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•
Early Stop Prob: mTPI only. The frequency of triggering the mTPI stopping rule during the 
trial.
Scenario 1
Dose Level
DLT
Rate
Average 
Sample 
Size
Early 
Stop 
Prob.
-1
1
2
3
4
5
6
True DLT rate
0.05
0.09
0.14
0.18
0.22
0.27
MTD 
Selected 
(%)
3+3
3
7
16 
18
19
16
21
15.3
mTPI
1
2
12 
23
26
22
15
12.3
16
Subjects 
Allocated
(n)
3+3
3.6
4.0
4.0
3.5
2.8
1.7
19.7
mTPI
5.0
5.8
5.5
3.5
1.6
0.4
21.8
Note: The true MTD is dose level 6, the highest dose level, and all dose levels can be 
considered to be tolerated. In this case, mTPI has a somewhat lower chance of picking the 
highest dose level (15% vs. 21% for 3+3) but greater chance of picking doses closer to the top 
dose, compared to the 3+3 and lower chance (15% vs. 26% for 3+3) of picking the 2 lowest 
doses or dose level -1. 
Scenario 2
Dose Level
DLT 
Rate
Average 
Sample 
Size
Early 
Stop 
Prob.
-1
1
2
3
4
5
6
True DLT rate
0.05
0.10
0.15
0.20
0.27
0.40
MTD 
Selected 
(%)
3+3
3
9
17
23
22
18
9
17.1
mTPI
1
2
13
27
27
19
12
13.6
18
Subjects 
Allocated
(n)
3+3
3.6
4.0
4.0
3.5
2.8
1.7
19.1
mTPI
4.8
6.1
5.7
3.6
1.3
0.3
21.8
Note: The true MTD is dose level 5, the second highest dose level, and there is one over-toxic 
dose. In this scenario. mTPI picks the correct MTD about as often as the 3+3 , and it picks the 
2 lowest doses or dose level -1 less often (29% vs. 16% for the 3+3). The top dose level is 
selected 3% more frequently by mTPI compared to 3+3.
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Scenario 3
Dose Level
DLT 
Rate
Average 
Sample 
Size
Early 
Stop 
Prob.
-1
1
2
3
4
5
6
True DLT rate
0.05
0.10
0.15
0.27
0.40
0.50
MTD 
Selected 
(%)
3+3
2
9
15
35
27
9
2
18.4
mTPI
2
1
11
34
35
14
4
15.2
16
Subjects 
Allocated
(n)
3+3
3.6
4.0
4.3
3.8
2.0
0.6
18.4
mTPI
4.7
6.1
6.3
3.8
0.8
0
21.7
Note: The true MTD is dose level 4, and as such, there are three sub-optimal dose levels and 
two over toxic dose levels. mTPI chooses the correct MTD with 35% rate, vs. 27% for 3+3. 
Selection of over-toxic dose levels is more frequent by mTPI, (18% chance vs. 11% for 3+3), 
while selection of the 2 lowest doses or dose level -1 is less likely for mTPI (14% vs. 26% for 
3+3).
Scenario 4
Dose Level
DLT 
Rate
Average 
Sample 
Size
Early 
Stop 
Prob.
-1
1
2
3
4
5
6
True DLT rate
0.10
0.15
0.27
0.40
0.50
0.55
MTD 
Selected 
(%)
3+3
10
20
32
28
9
1
0
23.5
mTPI
4
7
31
40
14
4
0
20.3
31
Subjects 
Allocated
(n)
3+3
4.2
4.4
3.7
2.1
0.6
0.1
15.1
mTPI
5.9
7.1
5.6
1.6
0.2
0
20.3
Note: The true MTD is dose level 3. Under this scenario, there are two sub-optimal doses and 
three over-toxic dose levels. mTPI picks the correct MTD 12% more often than 3+3 does, and 
picks doses higher than the MTD 8% more often. Selection of sub-optimal dose levels (lower 
than MTD or level -1) by mTPI is 20% less frequent (42% vs. 62% for 3+3).
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Scenario 5
Dose Level
DLT 
Rate
Average 
Sample 
Size
Early 
Stop 
Prob.
-1
1
2
3
4
5
6
True DLT rate
0.15
0.27
0.40
0.50
0.55
0.60
MTD 
Selected 
(%)
3+3
23
37
29
10
2
0
0
29.0
mTPI
9
26
47
15
3
1
0
26.8
52
Subjects 
Allocated
(n)
3+3
4.9
4.1
2.2
0.6
0.1
0
12.0
mTPI
7.9
7.7
2.5
0.3
0
0
18.4
Note: The true MTD is dose level 2, the second lowest dose level. In this case of one sub-
optimal dose level and four over-toxic dose levels mTPI picks the correct MTD almost 20% 
more often (47% vs. 29% for 3+3). Selection of sub-optimal doses by the mTPI is much less 
frequent (35% vs. 60% by the 3+3) while over-toxic dose selection is 7% more likely for mTPI 
than by 3+3. 
Scenario 6
Dose Level
DLT 
Rate
Average 
Sample 
Size
Early 
Stop 
Prob.
-1
1
2
3
4
5
6
True DLT rate
0.27
0.40
0.50
0.55
0.60
0.65
MTD 
Selected 
(%)
3+3
51
36
11
1
0
0
0
40
mTPI
30
48
19
2
1
0
0
38.7
54
Subjects 
Allocated
(n)
3+3
5.2
2.7
0.7
0.1
0
0
8.7
mTPI
9.3
4.0
0.5
0
0
0
13.8
Note: The true MTD is dose level 1, the lowest dose, which represents an unlikely case when
only the lowest dose level is considered to be tolerated. mTPI selects the correct MTD more 
often (48% vs. 36% for the 3+3). mTPI picks no dose (dose level -1) at a much lower rate
(30% vs. 51% for 3+3), but also chooses high dose levels more frequently (22% vs. 12% for
3+3). 
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APPENDIX 3
CYP3A4 GUIDANCE
The lists below are not meant to be all inclusive. Please consult individual drug labels for further 
information. Additional information is also available at:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ ucm080499.htm.
Table 1:
Classification of In Vivo Inhibitors of CYP Enzymes
CYP Enzymes
Strong Inhibitorsa
≥ 5-fold Increase in AUC
or > 80% Decrease in CL
Moderate Inhibitorsb
≥ 2 but < 5-fold Increase in 
AUC or 50-80% Decrease 
in CL
Weak Inhibitorsc
≥ 1.25 but < 2-fold 
Increase in AUC or
20-50% Decrease in CL
CYP3A
Boceprevir, clarithromycin, 
conivaptan, grapefruit 
juice,d indinavir, 
itraconazole, ketoconazole,
lopinavir/ritonavir,
mibefradil,e nefazodone, 
nelfinavir, posaconazole, 
ritonavir, saquinavir,
telaprevir, telithromycin,
voriconazole
Amprenavir, aprepitant,
atazanavir, ciprofloxacin,
darunavir/ritonavir, 
diltiazem, erythromycin, 
fluconazole, fosamprenavir, 
grapefruit juice,d imatinib, 
verapamil
Alprazolam, amiodarone, 
amlodipine, atorvastatin, 
bicalutamide, cilostazol, 
cimetidine, cyclosporine, 
fluoxetine, fluvoxamine, 
ginkgo,f goldenseal,f
isoniazid, nilotinib, oral 
contraceptives, ranitidine, 
ranolazine,
tipranavir/ritonavir, zileuton
Please note that this is not an exhaustive list.
a A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a substrate for that CYP 
by equal or more than 5-fold.
b A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate 
for that CYP by less than 5-fold but equal to or more than 2-fold.
c A weak inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate for 
that CYP by less than 2-fold but equal to or more than 5-fold.
d The effect of grapefruit juice varies widely among brands and is concentration, dose, and preparation dependent. 
Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used 
(eg, high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (eg, low 
dose, single strength).
e Withdrawn from the United States market because of safety reasons.
f Herbal product.
Abbreviations: AUC = area under the concentration-time curve; CYP = cytochrome P450.
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Table 2:
Classification of In Vivo Inducers of CYP Enzymes
CYP Enzymes
Strong Inducers
≥ 80% Decrease in AUC
Moderate Inducers
50-80% Decrease in AUC
Weak Inducers
20-50% Decrease in AUC
CYP3A
Avasimibe,a carbamazepine,
enalutamide, phenytoin, 
rifampin, St. John’s wortb
Bosentan, efavirenz, 
etravirine, modafinil, 
nafcillin
Amprenavir, aprepitant, 
armodafinil, echinacea,c
pioglitazone, prednisone, 
rufinamide
Please note that this is not an exhaustive list.
a Not a marketed drug.
b The effect of St. John’s wort varies widely and is preparation dependent.
c Herbal product.
Abbreviations: AUC = area under the concentration-time curve; CYP = cytochrome P450.
Table 3:
Examples of Sensitive In Vivo CYP Substrates and CYP Substrates 
with Narrow Therapeutic Range
CYP Enzymes
Sensitive Substratesa
Substrates with Narrow 
Therapeutic Rangeb
CYP3A(6)
Alfentanil, aprepitant, budesonide, buspirone, 
conivaptan, darifenacin, darunavir, dasatinib, 
dronedarone, eletriptan, eplerenone, everolimus, 
felodipine, indinavir, fluticasone, lopinavir, 
lovastatin, lurasidone, maraviroc, midazolam, 
nisoldipine, quetiapine, saquinavir, sildenafil, 
simvastatin, sirolimus, tolvaptan, tipranavir, 
triazolam, vardenafil
Alfentanil, astemizole,c cisapride,c
cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus,
terfenadinec
Please note that this is not an exhaustive list.
a Sensitive CYP substrates refers to drugs whose plasma AUC values have been shown to increase 5-fold or higher 
when co-administered with a known CYP inhibitor.
b CYP substrates with narrow therapeutic range refers to drugs whose exposure-response relationship indicates that 
small increases in their exposure levels by the concomitant use of CYP inhibitors may lead to serious safety 
concerns (eg, Torsades de Pointes).
c Withdrawn from the United States market because of safety reasons.
Abbreviations: AUC = area under the concentration-time curve; CYP = cytochrome P450.
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APPENDIX 4
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) 
1
EVALUATION OF LESIONS
Solid tumors will be evaluated using Response Evaluation Criteria In Solid Tumors version 1.1 
(RECIST 1.1) guideline 
.1
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows:
1.1
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
10 mm by CT/MRI scan (scan slice thickness no greater than 5 mm), or ൒2x slice thickness if 
greater than 5mm.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT/MRI scan (scan slice thickness 
recommended to be no greater than 5 mm).
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT/MRI scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be 
recorded as the node measurement. All other pathological nodes (those with short axis ≥10 mm 
but < 15 mm) should be considered non-target lesions. Nodes that have a short axis < 10 mm are 
considered non-pathological and should not be recorded or followed.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.2
Non-Measurable
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with ≥10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
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1.3
Special considerations regarding lesion measurability
1.3.1
Bone lesions
•
Bone scan, PET scan and plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
•
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above.
•
Blastic bone lesions are non-measurable.
1.4
Baseline Documentation Of ‘Target’ And ‘Non-Target’ Lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means 
in instances where patients have only one or two organ sites involved a maximum of two and 
four lesions respectively will be recorded).
Note: A maximum of two lesions can be selected per organ system. For example, a maximum of 
two lung lesions can be selected (selected from one lung or one lesion from each). A maximum 
of two lymph nodes can be selected at baseline, as the lymphatic system is considered one organ.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’).
2
RESPONSE CRITERIA
2.1
Evaluation of Target Lesions
•
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm.
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•
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.
•
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is 
also considered progression).
•
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
•
Not Evaluable (NE): If one or more target lesions cannot be measured or adequately 
assessed as either fully resolved or too small to measure (due to missing or poor quality 
images), and the sum of diameters of the remaining measured target lesions (if any) has not 
increased sufficiently to meet Progressive Disease as defined above. 
2.1.1
Special Notes on the Assessment of Target Lesions
2.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target 
lesions, the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a 
normal lymph node is defined as having a short axis of < 10 mm. Case report forms or other data 
collection methods may therefore be designed to have target nodal lesions recorded in a separate 
section where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, 
SD and PD, the actual short axis measurement of the nodes is to be included in the sum of target 
lesions.
2.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the 
lesion has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is 
believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned as the reference diameter. (Note: It is less likely that this rule will be used for 
lymph nodes since they usually have a definable size when normal and are frequently surrounded 
by fat such as in the retroperitoneum; however, if a lymph node is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well). This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness). The measurement of these lesions is 
potentially non-reproducible, therefore providing this default value will prevent false responses 
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or progressions based upon measurement error. To reiterate, however, if the radiologist is able to
provide an actual measure, that should be recorded, even if it is below 5 mm.
2.1.1.3
Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
2.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol.
•
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (< 10mm short axis). 
•
Non-CR/Non-PD: Persistence of one or more non-target lesion(s)
•
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.
2.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
2.2.1.1
When the patient also has measurable disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in 
presence of SD or PR in target disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy A modest ‘increase’ in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status. Pleural effusions, 
pericardial effusions and ascites will not be followed as target or non-target lesions and will not 
contribute to response or progression. The designation of overall progression solely on the basis 
of change in non-target disease in the face of SD or PR of target disease will therefore be 
extremely rare.
2.2.1.2
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have 
measurable disease. The same general concepts apply here as noted above, however, in this 
instance there is no measurable disease assessment to factor into the interpretation of an increase 
in non-measurable disease burden. Because worsening in non-target disease cannot be easily 
quantified (by definition: if all lesions are truly non-measurable) a useful test that can be applied 
when assessing patients for unequivocal progression is to consider if the increase in overall 
disease burden based on the change in non-measurable disease is comparable in magnitude to the 
increase that would be required to declare PD for measurable disease: ie, an increase in tumor 
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burden representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% 
increase diameter in a measurable lesion). Examples include, an increase in lymphangitic disease 
from localized to widespread, or may be described as ‘sufficient to require a change in therapy’. 
If ‘unequivocal progression’ is seen, the patient should be considered to have had overall PD at 
that point. While it would be ideal to have objective criteria to apply to non-measurable disease, 
the very nature of that disease makes it impossible to do so; therefore the increase must be 
substantial.
2.2.2
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions). This is particularly 
important when the patient’s baseline lesions show partial or complete response. For example, 
necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is 
not.
NOTE: Fluid collections (pleural effusions, pericardial effusions, and ascites) will not be 
considered new lesions and will not contribute to response or progression. In the event a new 
fluid collection is seen on a post-baseline imaging exam, a comment may be made, but the 
appearance of a new fluid collection alone should not result in an assessment of Progressive 
Disease (PD). A lesion identified on a follow-up study in an anatomical location that was not 
scanned at baseline is considered a new lesion and will indicate disease progression. An example 
of this is the patient who has visceral disease at baseline and while on study has a CT or MRI 
brain ordered which reveals metastases. The patient’s brain metastases are considered to be 
evidence of PD even if he/she did not have brain imaging at baseline. A lesion identified on 
Chest X-Ray that was not present in prior CT can be considered a new lesion and will result in 
Progressive Disease (PD).
If a new lesion is equivocal, for example because of its small size, continued follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely 
a new lesion, then progression should be declared using the date of the initial scan. While FDG-
PET response assessments need additional study, it is sometimes reasonable to incorporate the 
use of FDG-PET scanning to complement CT scanning in assessment of progression 
(particularly possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be 
identified according to the following algorithm:
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
2. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
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date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
2.3
Response Assessment
2.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
disease progression or the last response recorded, taking into account any requirement for 
confirmation and censoring rules regarding subsequent therapy. The patient’s best overall 
response assignment will depend on the findings of both target and non-target disease and will 
also take into consideration the appearance of new lesions. Furthermore, depending on the nature 
of the study and the protocol requirements, it may also require confirmatory measurement.
2.3.2
Time Point Response
At each protocol specified time point, a response assessment occurs. Table 2.3.2-1 provides a 
summary of the overall response status calculation at each time point for patients who have 
measurable disease at baseline. When patients have non-measurable (therefore non-target) 
disease only, Table 2.3.2-2 is to be used. 
Table 2.3.2-1:
Time Point Response: Patients With Target (± Non-Target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable
Table 2.3.2-2:
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
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Table 2.3.2-2:
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease and NE = inevaluable
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
2.3.3
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point 
of ≥4 weeks (28 days) later. In this circumstance, the best overall response can be interpreted as 
in Table 2.3.3-1. When SD is believed to be best response, it must meet the protocol specified 
minimum time from the date of first treatment or randomization date.
For example, if the first scheduled follow-up imaging visit is Week 6 (± 7 days) for a particular 
protocol, a Best Response of SD can only be made after the subject is on-study for a minimum of 
6 weeks (42 days) minus 7 days, for an absolute minimum time on-study of 35 days from the 
reference start date (reference date is considered Day 1 on study).  If the subject is not on-study 
for at least this amount of time, any tumor assessment indicating stable disease before this time 
period will have a Best Response of NE unless PD is identified.
Special note on response assessment: When nodal disease is included in the sum of target 
lesions and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement 
reported on scans. This measurement should be recorded even though the nodes are normal in 
order not to overstate progression should it be based on increase in size of the nodes. As noted 
earlier, this means that patients with CR may not have a total sum of ‘zero’ on the case report 
form (CRF).
Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
CR
CR
CR
CR
PR
SD, PD OR PRa
CR
SD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
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Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
PR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). 
Best response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not 
CR at the first time point. Under these circumstances, the original CR should be changed to PR and the best 
response is PR.
2.3.4
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive or subsequent repeat assessments that should be performed no 
less than 28 days after the criteria for response are first met. Subsequent documentation of a CR 
may provide confirmation of a previously identified CR even with an intervening NE or PR (eg, 
CR NE CR or CR PR CR). Subsequent documentation of a PR may provide confirmation of a 
previously identified PR even with an intervening NE or SD (eg, PR NE PR or PR SD PR). 
However, only one (1) intervening time point will be allowed between PR/CRs for confirmation.
Verification of Progression: Progression of disease should be verified in cases where 
progression is equivocal. If repeat scans confirm PD, then progression should be declared using 
the date of the initial scan. If repeat scans do not confirm PD, then the subject is considered to 
not have progressive disease.
REFERENCES
                                                       
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors:
revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47.
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APPENDIX 5
ECOG PERFORMANCE STATUS
ECOG PERFORMANCE STATUS1
Grade
ECOG
0
Fully active, able to carry on all predisease 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 self-care 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
                                                       
1 Oken MM, Creech RH, Tormey 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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APPENDIX 6
NYHA CLASSIFICATION
NYHA Classification
Class I
Subjects with no limitation of physical activity; ordinary physical 
activity does not cause undue fatigue, palpitation, or dyspnea (shortness 
of breath).
Class II
Subjects with slight limitation of physical activity; they are comfortable 
at rest, but ordinary physical activity results in fatigue, palpitation, or 
dyspnea.
Class III
Subjects with marked limitation of physical activity; they are 
comfortable at rest, but less than ordinary activity causes fatigue, 
palpitation, or dyspnea. 
Class IV
Subjects who are unable to carry out any physical activity without 
discomfort; they have symptoms of cardiac insufficiency at rest; if any 
physical activity is undertaken, discomfort is increased.
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APPENDIX 8
SIMULATION OF MTPI-2 VS 3+3 DOSE ESCALATION DESIGNS 
WITH 2 DOSE LEVELS
Simulations of mTPI-2 and 3+3 designs, shown below, demonstrate that the mTPI-2 design has a 
greater chance of selecting the correct MTD than the 3+3 design, and of treating fewer subjects at 
sub-optimal doses.
The mTPI-2 design, similarly to the mTPI, uses a pre-determined relevant target toxicity (DLT)
rate (Pt) and an equivalence interval (EI) defined as [Pt-e1, Pt+e2], within which any dose level is 
considered close to the true maximum tolerated dose (MTD). It recommends decisions to either 
Stay (S) at the current dose, Escalate (E), or de-escalate (D), guided by simple Bayesian probability 
models. These decisions are related to the unit probability mass (UMP) under the posterior 
probability distribution of a DLT rate in the intervals [0,Pt-e1), [Pt-e1, Pt+e2], and (Pt+e2,1] of 
the [0,1] sample space corresponding to decisions of E, S, and D (or DU), respectively. 
As an escalation decision is not of interest in the combination dose safety evaluation of this study, 
a design recommendation to escalate will be used as an indication to Expand more broadly at this 
dose level, (as this dose level is deemed safe to escalate). Therefore the symbol E will be used to 
indicate a decision to Expand in this setting. In contrast the decision S (Stay) indicates that this 
dose level needs to be evaluated further for safety before treating at this dose level in all expansion 
cohorts. For the BMS-986158 combination with nivolumab treatment, the target DLT rate was set 
to 29%, and the EI is: [27%, 33%], based on known toxicity of nivolumab and adverse events rate 
of BMS-986158 to date. 
The mTPI-2 design, similarly to the 3+3 design, provides a decision guide using the number of 
DLT-evaluable subjects and the number of subjects with a DLT observed at each dose level. 
The mTPI-2 design framework mitigates some suboptimal decisions and makes more efficient 
dose finding as compared to the original mTPI. This is achieved by subdividing each of the three
decision intervals into equal length subintervals of length e1+e2 and calculating UMP for each of 
the subintervals within each interval. The decision will be based on the interval in which any of 
these subintervals has the largest UMP, under the posterior probability density, given the observed 
DLT data, as follows: 
•
E: Expanding at this dose (Escalate if relevant) if any sub-interval within (0, 27%) has the 
largest unit probability mass
•
S: staying at the same dose if any subinterval within [27%, 33%] has the largest unit probability 
mass,
•
D: de-escalating to the lower dose if any subinterval within (33%, 100%) has the largest unit 
probability mass.
At the end of the trial, MTD will be picked by isotonic regression estimation method to be the dose 
level whose estimated toxicity rate is closest to the target toxicity rate among all the evaluated dose
levels.
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Simulations were performed to examine the operating characteristics of mTPI-2 and 3+3 designs
for this study. Escalation decisions based on the mTPI2 are shown in the protocol. Decisions based 
on the 3+3 design are shown below:
•
E: no subject with DLT out of 3 DLT evaluable subjects initially, or at most 1 subject with 
DLT out of 6 DLT evaluable subjects after adding 3 more subjects.
•
S: 1 subject with DLT out of 3 DLT evaluable subjects initially.
•
D: at least 2 subjects with DLT out of 3 DLT evaluable subjects initially, or at least 2 subjects 
with DLT out of 6 DLT evaluable subjects after adding 3 more subjects at this dose
Settings for simulation:
•
6 dose-toxicity scenarios, each of which with a number of 2 (expected) dose levels
•
1000 trials per scenario
•
Target toxicity (Pt) for mTPI-2 design: 29% with Equivalence Interval (EI) = [27, 33%]
•
The mTPI-2: initial cohort size of 3 (or 4) followed by cohort size of 3 (or 4) for the remaining 
cohorts at the same (or lower if needed) dose level, requiring a minimum of 3 for a dose 
decision; Therefore cohorts of size 4 and a 25% dropout rate were used in the simulations.
•
Stopping rule for mTPI-2: When there are already 12 DLT evaluable subjects treated at a dose 
level, and mTPI-2 suggested decision is to treat more subjects at this dose level, dose escalation 
can be stopped.
•
Maximum number of DLT evaluable subjects for the study is 12.
•
A nominal dose level of -1 is added in the tables to account for the case when de-escalation 
decision is made from dose level 1. However, the dose level -1 is not used in the simulations. 
•
A Beta(1,2) prior probability distribution is used which corresponds to a 33% expected DLT 
rate assumed for the combination of nivolumab with BMS-986158.
Dose-Toxicity Curve Scenarios
Six (6) scenarios of dose-toxicity (DLT) curves are selected to cover various possibilities and 
presented in the following figure with scenario ID shown at the end of line. 
Scenario
DLT Rate at 
Dose Level 1
DLT Rate at 
Dose Level 2*
1
0.15
0.25
2
0.20
0.27
3
0.15
0.30
4
0.25
0.35
5
0.30
0.35
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6
0.35
0.45
*Starting dose level
Simulation Results
Simulation results are summarized from all the simulated trials per scenario, and include the 
following statistics:
•
MTD Selected: Frequency of each dose level being selected as MTD.
•
Subjects Allocated: Number of subjected being allocated to each dose level.
•
DLT rate: The average number of subjects who have DLT across all dose levels.
•
Average Sample Size: The average number of subjects across all dose levels.
•
Early Stop Prob: mTPI-2 only. The frequency that mTPI-2 stopping rule was triggered during 
the trial.
Scenario 1
Dose Level
DLT 
Rate
Average 
Sample 
Size
Early Stop 
Prob.
True DLT Rate
-1
1 / 15%
2 / 25%
MTD 
Selected (%)
3+3
20%
31%
49%
mTPI-2
9.5%
36%
54%
Subjects 
Allocated (n)
3+3
4.7
3.5
8.2
mTPI-2
4.1
4.4
8.5
Note: The mTPI-2 selects the MTD more frequently than does the 3+3, and the 3+3 selects no 
dose 10.5% more frequently than does the mTPI-2.
Scenario 2
Dose Level
DLT 
Rate
Average 
Sample 
Size
Early Stop 
Prob.
True DLT Rate
-1
1 / 20%
2 / 27%
MTD 
Selected (%)
3+3
32%
28%
41%
mTPI-2
17%
43%
40%
Subjects 
Allocated (n)
3+3
4.8
3.0
7.8
mTPI-2
4.2
3.9
8.1
Note: The correct MTD is selected about as often by both designs but the 3+3 selects no dose 
as the MTD 15% more frequently than does the mTPI-2. 
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Scenario 3
Dose Level
DLT 
Rate
Average 
Sample 
Size
Early Stop 
Prob.
True DLT Rate
-1
1 / 15%
2 / 30%
MTD Selected 
(%)
3+3
22%
36%
42%
mTPI-2
11%
46%
43%
Subjects 
Allocated (n)
3+3
4.9
3.5
8.3
mTPI-2
4.2
4.3
8.5
Note: The correct MTD is selected as often by both designs, but the 3+3 selects no dose (-1) 
twice as frequently (22% vs. 11%) than does the mTPI-2.
Scenario 4
Dose Level
DLT 
Rate
Average 
Sample 
Size
Early Stop
Prob.
True DLT Rate
-1
1 / 25%
2 / 35%
MTD Selected 
(%)
3+3
42%
33%
25%
mTPI-2
24%
51%
25%
Subjects 
Allocated (n)
3+3
5.0
2.7
7.7
mTPI-2
4.4
3.5
7.9
Notes: The higher dose is selected 25% of the times by both designs, the mTPI-2 selects the 
correct MTD 18% more often than does the 3+3. The 3+3 selects no dose more frequently (18% 
more) than does the mTPI-2.
Scenario 5
Dose Level
DLT 
Rate
Average 
Sample 
Size
Early Stop 
Prob.
True DLT Rate
-1
1 / 30%
2 / 35%
MTD Selected 
(%)
3+3
54%
25%
21%
mTPI-2
30%
49%
22%
Subjects 
Allocated (n)
3+3
5.0
2.2
7.2
mTPI-2
4.3
3.4
7.7
Notes: The mTPI-2 design selects the correct dose as the MTD almost twice as often as the 3+3 
(24% more frequently) and the 3+3 selects no dose 24% more frequently than does the mTPI-2.
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Scenario 6
Dose Level
DLT 
Rate
Average 
Sample 
Size
Early Stop 
Prob.
True DLT Rate
-1
1 / 35%
2 / 45%
MTD Selected 
(%)
3+3
69%
22%
8.2%
mTPI-2
44%
46%
11%
Subjects 
Allocated (n)
3+3
4.9
1.6
6.5
mTPI-2
4.4
2.6
7.0
Notes: The mTPI-2 design selects the dose with 35% toxicity more than twice as often as the 
3+3 (24% more frequently) and selects the top toxic dose 3% more often than the 3+3. The 3+3 
selects no dose 25% more frequently than does the mTPI-2.
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APPENDIX 9
LUGANO 2014 CLASSIFICATION FOR INITIAL EVALUATION, 
STAGING, AND RESPONSE FOR HODGKIN LYMPHOMA
Table 1:
Revised Criteria for Response Assessment
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APPENDIX 10
MANAGEMENT ALGORITHMS FOR IMMUNO-ONCOLOGY 
AGENTS
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 intravenous (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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Refer to http://livertox.nih.gov/ for a compendium of agents that may cause liver injury
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APPENDIX 11
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.
Note: Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. 
•
1 week minimum for vaginal hormonal products (rings, creams, gels)
•
4 week minimum for transdermal products
•
8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal.
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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.
Local laws and regulations may require use of alternative and/or additional contraception methods.
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 
Highly Effective Methods That Are User Independent
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb
•
Intrauterine device (IUD)c
•
Intrauterine hormone-releasing system (IUS)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, defined as complete absence of heterosexual intercourse, is considered a 
highly effective method only if defined as refraining from heterosexual intercourse during 
the entire period of risk associated with the study treatment. 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. 
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•
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 treatment, 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
Listed below are the Less Than Highly Effective and Unacceptable Contraceptive Methods that 
are NOT acceptable methods of contraception or protection for participants in this study.
Less Than Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of >1% per year when used consistently and correctly.
•
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
Unacceptable Methods of Contraception
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal(coitus interruptus).
•
Spermicide only
•
Lactation amenorrhea method (LAM)
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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.
•
All male participants will be required to always use a latex or other synthetic condom during 
any sexual contact with WOCBP; even if the participants have undergone a successful 
vasectomy or if their partner is already pregnant or breastfeeding. Males should continue to 
use a condom while on study and until the 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 treatment.
•
Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of treatment.
•
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 6.1.1.
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APPENDIX 12
PROSTATE CANCER WORKING GROUP 3 (PCWG3)
GUIDELINES (WITH MODIFIED RESPONSE EVALUATION 
CRITERIA IN SOLID TUMORS (RECIST) CRITERIA FOR SOFT 
TISSUE LESION ASSESSMENT)
1
EVALUATION OF LESIONS
Bone lesions should be evaluated with Technecium-99m based radionuclide bone scan as per 
PCWG31.
At baseline, soft tissue lesions/lymph nodes will be categorized as measurable or non-measurable 
as follows. 
1.1
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
10 mm by CT/MRI scan (scan slice thickness no greater than 5 mm), or ≥2x slice thickness if 
greater than 5mm.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT/MRI scan (scan slice thickness recommended 
to be no greater than 5 mm).
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of
≥15 mm by CT/MRI scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis ≥10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.2
Non-Measurable
All other soft tissue lesions are considered non-measurable, including small lesions (longest 
diameter < 10mm or pathological lymph nodes with ≥10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
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Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.3
Special considerations regarding bone lesions
Bone lesions will be assessed with Technecium-99m based radionuclide bone scans as per 
PCWG3.
1.4
Baseline Documentation Of ‘Target’ And ‘Non-Target’ Lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of 
20 lesions total (and a maximum of 5 lesions per organ system) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline.
Note: A maximum of 5 lesions can be selected per organ system. For example, a maximum of 
5 lung lesions can be selected. A maximum of 5 lymph nodes can be selected at baseline, as the 
lymphatic system is considered one organ.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Pelvic lymph nodes and extrapelvic 
lymph nodes (retroperitoneal, mediastinal, thoracic and other) may be reported separately, per 
PCWG3. Measurements are not required and these lesions should be followed as ‘present’, 
‘absent’, or in rare cases ‘unequivocal progression’ (more details to follow). In addition, it is 
possible to record multiple non-target lesions involving the same organ as a single item on the case 
record form (e.g., ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’).
2
RESPONSE CRITERIA
2.1
Evaluation of Target Lesions
•
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.
•
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.
•
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression).
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•
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
•
Not Evaluable (NE): If one or more target lesions cannot be measured or adequately assessed
as either fully resolved or too small to measure (due to missing or poor quality images), and 
the sum of diameters of the remaining measured target lesions (if any) has not increased 
sufficiently to meet Progressive Disease as defined above.
2.1.1
Special Notes on the Assessment of Target Lesions
2.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
2.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (e.g., 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned
as the reference diameter. (Note: It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
default value is derived from the 5 mm CT slice thickness (but should not be changed with varying 
CT slice thickness). The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon measurement 
error. To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm.
2.1.1.3
Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
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vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
2.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol.
•
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (< 10mm short axis). 
•
Non-CR/Non-PD: Persistence of one or more non-target lesion(s)
•
Progressive Disease (PD): Unequivocal progression (see below) of existing non-target 
lesions.
2.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
2.2.1.1
When the patient also has measurable disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in presence 
of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy (see examples in Appendix 2 and further details below). A modest 
‘increase’ in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. Pleural effusions, pericardial effusions and ascites will not be 
followed as target or non-target lesions and will not contribute to response or progression. The 
designation of overall progression solely on the basis of change in non-target disease in the face
of SD or PR of target disease will therefore be extremely rare.
2.2.1.2
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in non-measurable 
disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: i.e., an increase in tumor burden representing an additional 
73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
Examples include, an increase in lymphangitic disease from localized to widespread, or may be 
described as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the 
patient should be considered to have had overall PD at that point. While it would be ideal to have 
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objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore the increase must be substantial.
2.2.2
New Lesions
New bone lesions
New bone lesions should be evaluated as per PCWG3 criteria. Bone lesions will be assessed by 
radionuclide bone scan only. Radiographic progression on bone scan is defined by the following 
criteria:
•
At least 2 new lesions on the first post-treatment bone scan, confirmed on the next scan 
(performed at least 6 weeks later) AND with at least two additional lesions  as compared to the 
first post-treatment bone scan. Date of progression is then the date of first post-treatment scan,
•
For scans after the first post-treatment scan, at least 2 new lesions relative to the first post-
treatment scan AND confirmed on a subsequent scan (performed at least 6 weeks later). Date 
of progression is the date of the scan that first documents at least 2 new lesions relative to the 
first post-treatment scan.
New soft tissue lesions
The appearance of new malignant soft tissue lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging modality 
or findings thought to represent something other than tumor. This is particularly important when 
the patient’s baseline lesions show partial or complete response. For example, necrosis of a liver 
lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is not.
NOTE: Fluid collections (pleural effusions, pericardial effusions, and ascites) will not be 
considered new lesions and will not contribute to response or progression. In the event a new fluid 
collection is seen on a post-baseline imaging exam, a comment may be made, but the appearance 
of a new fluid collection alone should not result in an assessment of Progressive Disease (PD). A 
lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline. A lesion identified on Chest X-Ray that was not 
present in prior CT can be considered a new lesion and will result in Progressive Disease (PD).
If a new lesion is equivocal, for example because of its small size, continued follow-up evaluation 
will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan.
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2.3
Response Assessment
2.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
disease progression per PCWG3 criteria, or the last response recorded, taking into account any 
requirement for confirmation and censoring rules regarding subsequent therapy. The patient’s best 
overall response assignment will depend on the findings of both target and non-target disease and 
will also take into consideration the appearance of new lesions. Furthermore, depending on the 
nature of the study and the protocol requirements, it may also require confirmatory measurement.
2.3.2
Time Point Response
At each protocol specified time point, a response assessment occurs. Table 2.3.2-1 provides a 
summary of the overall response status calculation at each time point for patients who have 
measurable disease at baseline. When patients have non-measurable (therefore non-target) disease 
only, Table 2.3.2-2 is to be used. 
Table 2.3.2-1:
Time Point Response: Patients With Target (± Non-Target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable
Table 2.3.2-2:
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease and NE = inevaluable
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a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
2.3.3
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
≥4 weeks (28 days) later. In this circumstance, the best overall response can be interpreted as in 
Table 2.3.3-1. When SD is believed to be best response, it must meet the protocol specified 
minimum time from the date of first treatment or randomization date.
For example, if the first scheduled follow-up imaging visit is Week 6 (± 7 days) for a particular 
protocol, a Best Response of SD can only be made after the subject is on-study for a minimum of 
6 weeks (42 days) minus 7 days, for an absolute minimum time on-study of 35 days from the 
reference start date (reference date is considered Day 1 on study).  If the subject is not on-study 
for at least this amount of time, any tumor assessment indicating stable disease before this time 
period will have a Best Response of NE unless PD is identified.
Special note on response assessment: When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
on scans. This measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted earlier, this 
means that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF).
Table 2.3.3-1:
Best Overall Response (Confirmation of CR&PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
BEST Overall Response
CR
CR
CR
CR
PR
SD, PD OR PRa
CR
SD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
PR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
NE
NE
NE
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Table 2.3.3-1:
Best Overall Response (Confirmation of CR&PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
BEST Overall Response
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
2.3.4
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive or subsequent repeat assessments that should be performed no 
less than 28 days after the criteria for response are first met. Subsequent documentation of a CR 
may provide confirmation of a previously identified CR even with an intervening NE or PR
(eg, CR NE CR or CR PR CR). Subsequent documentation of a PR may provide confirmation of 
a previously identified PR even with an intervening NE or SD (eg, PR NE PR or PR SD PR). 
However, only one (1) intervening time point will be allowed between PR/CRs for confirmation.
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of the 
initial scan. If repeat scans do not confirm PD, then the subject is considered to not have 
progressive disease.
REFERENCES
1
Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated 
Recommendations From the Prostate Cancer Clinical Trials Working Group 3. Scher et al. J 
Clin Oncol 2016, 34(12):1402-1418
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APPENDIX 13
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for Revised Protocol 06, 17-Jul-2018
The purpose of this revised protocol is 1) to update schedules for mandatory on-treatment biopsies 
during Part 2 (Cohort Expansion);
 
3) to update imaging 
requirements for tumor assessments; 4) to update Inclusion criteria for subjects with NSCLC, 5) 
to correct DLT period for Part 2, 6) to update schedules for PK sample collections, 7) to include 
language to allow for release of IRT codes and allow for data review while the study is ongoing,
and 8) to include the PROSTATE CANCER WORKING GROUP 3 (PCWG3) appendix. Study 
design elements including time and events schedules, sample collections, laboratory analyses and 
additional safety measures have been added to align with these changes. Additionally, where 
applicable, sections in the synopsis have been updated, to align with the protocol section changes 
listed below.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 06
Section Number and Title
Description of Change
Brief Rationale
Sections 3.1 Study Design and 
Duration, 3.1.2.1 Sequential or 
Parallel Evaluation of Monotherapy 
and Combination Therapy, 3.1.2.4 
BMS-986158 Monotherapy and in 
Combination with Nivolumab Dose 
Expansion, 8.1 Sample Size 
Determination 
Updated the planned sample size 
To include additional 18 subjects 
which may be enrolled for target 
gene engagement in tumors, and 
additional PK and safety 
characteristics in 1 or 2 cohorts.
Section 3.3.1 Inclusion Criteria, 
Previous Treatment, 3 b)
Clarified that Inclusion Criterion 3 
b) no longer applicable as per 
Revised Protocol 03 
To align with BMS formatting 
guidelines on removed text. 
Section 3.3.2 Exclusion Criteria: 
Medical History and Concurrent 
Diseases
Updated numbering of criteria 
related to history of chronic 
hepatitis (Criterion i). 
Numbering of criteria regarding 
hepatitis was incorrectly formatted.
Clarified that Exclusion Criterion j 
is no longer applicable as per 
Revised Protocol 02.
To align with BMS formatting 
guidelines on removed text. 
Updated exclusion criteria 2 q) to 
include the word “not” in the last 
sentence “...conditions expected not 
to recur”.
Typographical correction
Clarified that Exclusion Criterion 3 
no longer applicable as per Revised 
Protocol 03.
To align with BMS formatting 
guidelines on removed text
Clarified that in regard of prior 
therapies, subjects with NSCLC 
To address a request from health 
Authorities
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 06
Section Number and Title
Description of Change
Brief Rationale
should be “ineligible” instead of 
“offered”.
Sections 3.5 Discontinuation of 
Subjects following any Treatment 
with Study Drug, 3.6 Treatment 
Beyond Progression, 8.3.2.1  
Efficacy, 8.4.2  Efficacy Analysis
Added PCWG3 Criteria for tumor 
assessment in subjects with prostate 
cancers 
To update imaging guidelines for 
subjects with prostate cancers.
Section 4.6 Blinding/Unblinding
Added text to provide IRT 
treatment codes to be released 
during Part 2.
In order to allow access to data for 
review while the study is ongoing.
Section 4.5.1 Dose Limiting 
Toxicities
Changed the DLT period from 35 to 
28 days in Part 2 and added the 
number of doses required for the 
safety assessment in Part 2.
To allow similar drug exposure and 
appropriate comparison of the 
safety profile between Part 1 and 
Part 2.
Section 5.1, Table 5.1-1 Study 
Assessments and Procedures: 
Screening Procedural Outline
Added an “X” to the screening visit 
column for Thyroid Function Test.
Typographical correction.
Section 5.1, Tables 5-1-1  through 
5.1-8
Clarified activities and provided 
more details related to TSH, ECG, 
imaging assessments, and tumor 
biopsies.
To align with updates in safety and 
tumor assessments.
Section 5.3.1, Imaging Assessment 
for the Study
Clarified activities and provided 
more details related to imaging 
assessments.
To implement current BMS 
guidelines on tumor assessment 
using imaging.
Section 5.4.1 Primary Efficacy 
Assessment
Updated activities related to 
imaging assessments
To implement current BMS 
guidelines on tumor assessment 
using imaging.
Section 5.5.1 Pharmacokinetics 
 
 
 Collection and 
Processing, Tables 5.5.1-7, 5.5.1-8 , 
and 5.5.1-9
Clarified nivolumab dose in table 
title
 
To align with updated schedule of 
PK sample collection. 
Revised Protocol No.: 07
Date: 18-Mar-2019
250
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CA011001
BMS-986158
BET Inhibitor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 06
Section Number and Title
Description of Change
Brief Rationale
Section 6.3 Laboratory Test Result 
Abnormalities 
Added “Thrombocytopenia versus 
decreased platelet count”. 
For reporting AEs, an example 
added to illustrate a preferred use of 
a clinical term instead of a 
laboratory parameter.
Section 8.1 Sample Size 
Determination, Cohort Expansion 
(Part 2) 
Added that sample size may be 
adjusted if more than one 
dose/schedule are tested in Part 2
To allow additional biomarker 
evaluation for a selection of optimal 
dose/schedule in Part 2
8.3.2.1 Efficacy
Updated text to include the PCWG3 
criteria for prostate cancers.
Appendix 12 PROSTATE 
CANCER WORKING GROUP 3 
(PCWG3)GUIDELINES(WITH 
MODIFIED RESPONSE 
EVALUATION CRITERIA IN 
SOLID TUMORS 
(RECIST)CRITERIA FOR SOFT 
TISSUE LESION ASSESSMENT)
Added the following appendix:
PROSTATE CANCER WORKING 
GROUP 3 
(PCWG3)GUIDELINES(WITH 
MODIFIED RESPONSE 
EVALUATION CRITERIA IN 
SOLID TUMORS 
(RECIST)CRITERIA FOR SOFT 
TISSUE LESION ASSESSMENT)
To provide additional details for 
tumor assessment in subjects with 
prostate cancers.
Revised Protocol No.: 07
Date: 18-Mar-2019
251
Approved
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Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
Overall Rationale for Revised Protocol 05, 01-Mar-2018:
The purpose of this revised protocol is to 1.) To clarify the acceptable prior lines of therapy for 
participants with Non-Small Cell Lung Cancer (NSCLC) in Part 2; 2) to update Exclusion Criteria 
for subjects participating in Part 2; and 3) To provide updated contraception and protection 
requirements based on recent non-clinical reproductive toxicology study. Study design elements 
including time and events schedules, sample collections, laboratory analyses and additional safety 
measures have been added to align with these changes.
 
 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 05
Section Number and Title
Description of Change
Brief Rationale
Synopsis
Synopsis was updated.
Synopsis was updated to reflect the 
changes made in the protocol.
1.4.2 Toxicity
Added new data from pre-clinical 
rat reproductive toxicology study
To describe recent findings of 
selective developmental toxicity in 
pregnant rats. 
1.5 Overall Risk/Benefit 
Assessment 
Added the toxicity finding of 
embryolethality and teratogenicity 
in pregnant rats.
To interpret recent findings of 
selective developmental toxicity in 
pregnant rats. 
3.1 Study Design and Duration, 
Added that more than one dosing 
schedule  for BMS-986158 
administration may be considered 
in Part 2 
To reflect a potential for evaluating 
multiple dosing schedules in Part 2.
3.1.2 Dose Expansion (Part 2)
Allowing treatment in Part 2 to be 
initiated before Part 1 is completed. 
To allow timely evaluation of the 
selected doses/schedules in Part 2 
3.3.1, Inclusion Criteria, 2) Target 
Population a), iv) 
Added 3 inclusion criteria to Part 2 
NSCLC
•
Subjects must have received at 
least 
1 
prior 
checkpoint 
inhibitor immunotherapy
•
Subjects 
with 
known 
abnormalities of EGFR, ALK, 
ROS1, 
BRAF 
must 
have 
received appropriate targeted 
therapies 
•
Subjects should have been 
offered or received a platinum-
based 
chemotherapy 
for 
NSCLC 
in 
the 
adjuvant, 
neoadjuvant, 
or 
recurrent 
setting
To assure that the selected subjects 
have received appropriate prior 
therapies, inclusion criteria were 
added providing details on the 2 
lines of prior therapy.
Revised Protocol No.: 07
Date: 18-Mar-2019
252
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Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 05
Section Number and Title
Description of Change
Brief Rationale
Inclusion Criteria 4) Age and 
Reproductive Status d)
Added that female participants must 
be willing to refrain from donation 
of oocytes 5 months post-treatment.
To implement recent findings of 
selective developmental toxicity in 
pregnant rats.
Inclusion Criteria 4) Age and 
Reproductive Status f)
Removed the exemption that 
azoospermic males are exempt from 
contraception. 
To implement recent findings of 
selective developmental toxicity in 
pregnant rats.
3.3.2 Exclusion Criteria Medical 
History and Concurrent Diseases 
1), i), ii)
Revised the hepatitis criteria for 
Hepatitis B and Hepatitis C. 
Updates were made on diagnostic 
tests for hepatitis.
3.3.2 Exclusion Criteria Medical 
History and Concurrent Diseases 
1), l), m), n), o) p)
Added additional exclusion criteria: 
current uncontrolled autoimmune 
pneumonitis, use of non-oncology 
vaccines, uncontrolled endocrine 
disorder, prior organ allograft or 
HSCT, and active or known or 
suspected autoimmune disease. 
Updates were made to reduce a 
potential for toxicity in response to 
treatment with Nivolumab.
3.3.2 Exclusion Criteria Physical 
and Laboratory Test Findings 2), f)
Added the following exclusion 
criteria: Inadequate thyroid function
New criterion excludes subjects 
with inadequate thyroid function to 
limit a potential for toxicity in 
response to Nivolumab treatment.
3.4.1 Prohibited and/or Restricted 
Treatments
Added a prohibited/ restricted 
treatment: .Live virus vaccine 
during the study and for a period of 
three months after the last dose of 
study treatment 
New restriction limits subjects with 
a potential for toxicity in response 
to treatment with Nivolumab.  
3.5 Discontinuation of Subjects 
following any Treatment with 
Study Drug
Added to the list of discontinuation 
of study treatment: Documented 
and confirmed PD as defined by 
RECIST v1.1 or Lugano 2014 
unless participant meets criteria for 
treatment beyond progression.
Updated to clarify conditions for 
discontinuation of treatment.
4.5.4 Management Algorithms for 
Immuno-oncology Agents
Added that nivolumab therapy can 
be associated can be associated 
with visual, cardiac and other rare 
events. 
Updated to reflect potential AEs 
related to treatment with 
Nivolumab
Schedule of Events Tables 5.1-1, 
5.1-5 , 5.1-6, 5.1-7, 5.1-8, Section 
5.3.2 Laboratory Test Assessments
Added the requirement for thyroid 
testing at screening and while on 
study.
New criterion excludes subjects 
with inadequate thyroid function to 
limit a potential for toxicity in 
response to Nivolumab treatment.
Schedule of Events Tables 5.1-5, 
5.1-6, 5.1-7 
Added that a  +/- 3 day window is 
allowed  for all visits except C1D1
Updated to reflect a 3 day window 
for visits that can be performed in a 
window of time
Revised Protocol No.: 07
Date: 18-Mar-2019
253
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Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 05
Section Number and Title
Description of Change
Brief Rationale
Appendix 11
Updated the contraception language 
including the requirements for 
acceptable methods of 
contraception and duration of 
contraception.
To implement recent findings of 
selective developmental toxicity in 
pregnant rats 
All
Minor formatting and typographical 
corrections
Minor, therefore have not been 
summarized
Revised Protocol No.: 07
Date: 18-Mar-2019
254
Approved
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Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
Overall Rationale for the Revised Protocol 04, 06-Sep-2017:
The purpose of this amendment is to add treatment in combination with Nivolumab, as well as 
define the biomarker-driven tumor population for Part 2 (dose expansion) of the study. One of the 
treatment arm schedules (updated from “arm” to “schedule”) from Part 1 (monotherapy dose 
escalation) and the corresponding MTD will become the dose and selected dosing schedule for 
Part 2. In Part 2, a small safety cohort of 6 to 12 subjects will be administered BMS-986158 in 
combination with nivolumab to ensure safety and tolerability. Once determined safe and tolerable, 
expansion of combination therapy will occur in parallel to the BMS-986158 monotherapy 
expansion. Subjects with selected tumor types who demonstrate specified genetic profiles (via 
 genetic testing) will be enrolled to the expansion phase to maximize potential 
efficacy of monotherapy and combination therapy: ovarian, TNBC, NSCLC, RCC, UM, UCS, 
NEPC, CRPC, NMC, ES, BL and DHL. All of the study design elements, including the objectives, 
DLT assessments, time and events schedules and sample collections, sample size, dose 
modifications, statistical considerations, and supporting appendices have been added or updated 
to align with these changes. In addition, the expansion phase was updated to include adolescent 
subjects.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number and Title
Description of Change
Brief Rationale
Title Page
Updated the revised date, revised 
protocol number and incorporation 
of amendments, and document 
history. Updated title to align with 
the new study design.
Updates were made to align with 
the new study design and for 
administrative reasons.
Synopsis
Updated to align with the changes 
made in the protocol body
Updates were made to align with 
the new study design
Section 1.1.1 Rationale for 
targeting bromodomains for cancer 
therapy
Rationale for targeting genetic 
abnormalities associated with BET 
inhibition has been added.
Provides rationale for the selected 
BET-associated biomarkers. 
Section 1.1.2 Rationale for 
combining BMS-986158 with 
Nivolumab
New section has been added to 
support rationale for combining 
BMS-986158 and nivolumab 
Provides rationale for BET inhibitor 
plus PD-L1 inhibitor in 
combination therapy.
Section 1.1.3 Rationale for 
targeting PD-1
Language regarding potential 
benefit of targeting PD-1 has been 
added.
Provides rationale for BMS-986158 
to be administered in combination 
with Nivolumab.
Section 1.1.5 Rationale for Dose 
and Schedule 
Updated data in BMS-986158 
subsection. Details regarding 
potential addition of Nivolumab to 
each arm has been added.
Most recent data from the current 
study were added for BMS-986158. 
Nivolumab will be administered at 
a different dose and schedule 
depending on which schedule is 
chosen for Part 2.
Section 1.1.6, Rationale for 
Monotherapy Dose Escalation 
Updated safety monitoring rationale 
for combination therapy
Updates were made to reflect the 
new study design.
Revised Protocol No.: 07
Date: 18-Mar-2019
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Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number and Title
Description of Change
Brief Rationale
Design and Combination Safety 
Monitoring
Section 1.1.7 Rationale for 
Genetically Defined Tumor 
Cohort
 
 
Rationale for targeting tumors 
based on genetic rearrangements 
regulated by BRD proteins was 
added. 
New section provides background 
information on specific tumor types 
and mutations/amplifications for 
expansion enrollment.
Section 1.1.8 Rationale for Specific 
Patient Populations
New section has been added.
New section provides detailed 
rationale for tumor types to be 
enrolled during expansion.
Section 1.1.12 Rationale for 
Inclusion of Adolescent Subjects
New Section has been added.
Provides BET data, dose, and 
rationale for enrollment of 
adolescent subjects for participation 
in the expansion phase of the study 
(Part 2).
Section 1.2 Research Hypothesis 
Added combination therapy.
Updated to reflect the new study 
design.
Section 1.3 Objectives
Primary, Secondary, 
 
 Objectives have been 
updated.
Language regarding combination 
with Nivolumab and biomarker 
driven strategy information has 
been added.
Section 1.4.4 Clinical 
Pharmacology and Safety
Language updated with most recent 
adverse event data and to align with 
the Investigator Brochure.
Most recent safety and 
pharmacology data have been 
provided.
Section 1.4.4.1 Pharmacokinetics of 
BMS-986158
Analysis performed on dose cohorts 
explored thus far is included.
Pharmacokinetic information for 
the BMS-986158 compound 
provided to align with 
pharmacokinetic information of 
Nivolumab.
Section 1.5 Overall Risk/Benefit 
Statement
Section updated with most recent 
clinical data available. Updated 
with language for the new study 
design.
Language provided to align with 
Investigator Brochure. Updated to 
reflect the new study design.
Revised Protocol No.: 07
Date: 18-Mar-2019
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Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number and Title
Description of Change
Brief Rationale
Section 2.3 Informed Consent
Statement added regarding 
adolescent assent.
Adolescents who meet eligibility 
criteria may participate in dose 
expansion.
Section 3.1 Study Design and 
Duration; Section 3.1.1 
Monotherapy Dose Escalation; 
Section 3.1.2 Dose Expansion 
(Part 2)
Section updated with new study 
design, including BMS-986158 
monotherapy and in combination 
with nivolumab dose administration 
information. Study schematics have 
been updated to reflect the new 
study design.
Escalation and expansion details 
regarding tumor population, 
selection of dose, and dose 
administration schedule, have been 
provided for monotherapy and 
combination therapy. 
Section 3.1.2.1 Sequential or 
Parallel Evaluation of Monotherapy 
and Combination Therapy
Section added to provide expansion 
details regarding method for 
assigning monotherapy and/or 
combination therapy.
Dependent on tumor type, specific 
tumor populations will begin in 
monotherapy or combination 
therapy, or be allowed to cross 
over.
Section 3.1.2.2 Safety Evaluation 
Phase of BMS-986158 
Combination with Nivolumab
Language surrounding the dose 
evaluation phase and selection of 
dose of BMS-986158 in 
combination with Nivolumab, has 
been added.
Details regarding the dose 
evaluation phase, which will dose 
up to 12 subjects, and subsequently 
determine the dose/schedule for 
expansion, are provided.
Section 3.1.2.3 Safety Evaluation in 
Adolescents
Language regarding the safety 
cohort of dosing in adolescents 
during expansion has been added.
The number of adolescents and the 
method for selecting the dose of 
BMS-986158 are provided.
Section 3.1.2.4 BMS-986158 
Monotherapy and in Combination 
with Nivolumab Dose Expansion 
Language added regarding number 
of subjects to be enrolled, and the 
design to be utilized to determine 
efficacy. Language added to allow 
for crossover from monotherapy to 
combination therapy for subjects 
enrolled in Part 2.
Language updated to align with 
new Part 2 design and to provide 
patients on BMS-986158 
monotherapy another option for 
therapy after disease progression.
Section 3.3.1 Inclusion Criteria and 
Appendix 11.
Specific information updated 
regarding the following criteria: 
enrollment of adolescent subjects, 
biopsy requirements, Foundation 
One genetic testing, reproductive 
and WOCBP requirements, and the 
following tumor populations: OC, 
TNBC, SCLC, NSCLC, RCC, UM, 
UCS, NEPC, CRPC, NMC, ES, BL 
and DHL.
Specific procedures are now 
required for enrollment; the tumor 
population has been defined for 
Part 2. WOCBP requirements were 
moved into the new standard 
appendix (Appendix 11).
Section 3.3.2 Exclusion Criteria 
Clarifications made to the following 
criterion:
1) Medical History and Concurrent 
Disease
2) Physical and Laboratory Test 
Findings
4) Other Exclusion Criteria
Criteria have been aligned with 
updated tumor population; 
adolescent information has been 
added.
Revised Protocol No.: 07
Date: 18-Mar-2019
257
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Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number and Title
Description of Change
Brief Rationale
Section 3.4 Concomitant 
Treatments; Section 3.4.1 
Prohibited and/or Restricted 
Treatments; Section 3.4.2 Other 
Restrictions and Precautions
Concomitant treatment regarding 
specific therapies has been updated.
Administration of specific 
treatments updated to align with 
expansion tumor population and the 
requirements for nivolumab.
Section 3.5 Discontinuation of 
Subjects following any Treatment 
with Study Drug
Language added to include 
monotherapy and combination 
therapy.
Section clarifies reasons for 
discontinuation from the study 
whether subjects receive BMS-
986158 monotherapy or in 
combination with nivolumab.
Section 3.6 Treatment Beyond 
Progression
Section added clarifying that 
specific subjects, meeting specified 
criteria, may continue therapy 
beyond progression.
Due to some subjects deriving 
clinical benefit despite initial 
evidence of progressive disease, 
criteria has been added for those 
that may be treated after 
progression.
Section 4 Study Drug; Section 4.1 
Investigational Product
Nivolumab language has been 
added, and product information for 
BMS-986158 has been updated.
Product information for BMS-
986158 and nivolumab and 
guidelines regarding infusion 
reactions for nivolumab have been 
added.
Section 4.4 Method of Assigning 
Subject Identification
Language for PID assignment 
utilizing IRT for Part 2 has been 
added.
An IRT will be utilized during 
expansion to aid with cohort 
assignment of specific tumor types.
Section 4.5 Selection and Timing of 
Dose For Each Subject
Preliminary safety data summary 
language has been removed.
As additional data are now 
available, preliminary BMS-986158 
and competitor data have been 
removed.
Section 4.5.1 Dose Limiting 
Toxicities
The DLT period for combination 
therapy in Part 2 has been added. 
Updates were made to hematologic 
DLTs.
The DLT period for combination 
therapy for subjects in Part 2 will 
match the length of the DLT period 
in Part 1.  Neutropenia and 
thrombocytopenia DLTs were 
further defined based on clinical 
data observed thus far.
Section 4.5.2 Guidelines for Dose 
Modifications
Clarifications have been added to 
the third and eighth bullet points; 
Grade 4 neutropenia and 
thrombocytopenia AEs have been 
clarified in Table 4.5.2-1
Dose reduction and escalation for 
BMS-986158, in certain cases, can 
be discussed with the Sponsor. 
Dose modifications suggestions for 
hematologic toxicities were updated 
based on current clinical data.
Section 4.5.3 Management of 
Diarrhea
Language has been clarified that 
suggested methods for management 
of diarrhea is management of BMS-
986158. Algorithms for managing 
adverse events associated with 
nivolumab have been added
Diarrhea management for BMS-
986158 is provided in the protocol; 
language and an Appendix have 
been added for the management of 
nivolumab adverse events.
Revised Protocol No.: 07
Date: 18-Mar-2019
258
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Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number and Title
Description of Change
Brief Rationale
Section 5.1 Flow Chart/Time and 
Events Schedule
Table 5.1-1: Length of screening 
window for Part 2, consent, biopsy, 
 and IRT 
procedures updated. Table 5.1-5: 
Title updated to include nivolumab, 
physical exam, 
 and 
treatment administration procedures 
updated.  Table 5.1-6 and Table 
5.1-7: Title updated to include 
nivolumab, 
 and 
treatment administration procedures 
updated.  Table 5.1-8: 60-day and 
100-day clinical follow-up visits 
added; procedures further clarified.
Screening procedures and Part 2 
Tables (for monotherapy and 
combination therapies in 
expansion) have been further 
clarified.  Clinical Follow-up visits 
clarified to extend time needed to 
monitor those subjects who were 
administered combination therapy.
Section 5.3 Safety Assessments
Clinical follow-up language of 60 
and 100 days for those on 
combination therapy has been 
added. Length of screening period 
was extended to 40 days for 
subjects in Part 2.
Assessments updated to align with 
Part 2 participation requirements.
Section 5.3.1 Imaging Assessment 
for the Study
Statement added that if subject has 
only 1 measureable lesion, a CT 
scan should be performed after 
biopsy to establish a baseline.
Core needle biopsies will be 
allowed in this instance to ensure 
that baseline values are available.
Section 5.4 Efficacy Assessments; 
Section 5.4.1 Primary Efficacy 
Assessment
Language added regarding 
acceptable modalities for assessing 
solid tumors and lymphomas and 
methods for assessing tumor 
response/progression.
Assessment language was updated 
to align with enrollment of specific 
tumor types and inclusion of 
subjects with lymphoma.
Section 5.5 Pharmacokinetic 
Assessments; 5.5.1, 
Pharmacokinetics
 
 
Collection and Processing, Section 
8.3.2.2 Pharmacokinetics
 
 
Sample collection for adolescents 
was added to Tables 5.5.1-4, 5.5.1-
5, and 5.5.1-6, and Tables 5.5.1-7 
through 5.5.1-9 were for subjects 
receiving combination therapy.
Language and tables updated to 
clarify general time points for PK 
sample collection, including 
collection for adolescents and for 
those that receive BMS-986158 in 
combination with nivolumab.
Revised Protocol No.: 07
Date: 18-Mar-2019
259
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Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number and Title
Description of Change
Brief Rationale
Section 8.1 Sample Size 
Determination; Section 8.2 
Populations for Analyses
Population, and sample size for 
Parts 1 and 2 of the study, and 
incidence rate of DLTs have been 
updated.
Information has been updated to 
include nivolumab combination, 
tumor population and biomarker-
driven strategy for Part 2.
Section 8.3.1, Primary Endpoint(s)
Follow-up for safety evaluation has 
been updated to include 
combination therapy cohorts.
Updated to reflect the addition of 
BMS-986158 and nivolumab 
combination therapy.
Section 8.3.2.1 Efficacy; Section 
8.4.2 Efficacy Results
BOR, DoR, and PFS endpoints 
clarified due to biomarker driven 
population of Part 2.
Criteria for efficacy determination 
were updated to include Lugano 
2014 for hematologic malignancies, 
and efficacy measurements for 
endpoints were clarified. 
Synopsis, Section 8.3.2.2 
Pharmacokinetics and Section
8.3.2.4, ECG/QTc
Updated to include the combination 
cohorts for PK and to clarify the 
ECG/QTc assessment is for BMS-
986158 monotherapy treatment 
only.
Updated to reflect addition of 
BMS-986158 and nivolumab 
combination therapy for PK 
assessments and to clarify 
ECG/QTc assessments.
Revised Protocol No.: 07
Date: 18-Mar-2019
260
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Clinical Protocol
CA011001
BMS-986158
BET Inhibitor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number and Title
Description of Change
Brief Rationale
Section 8.4.3 Safety Analyses; 
Section 8.4.4 Pharmacokinetic 
Analyses
Language added confirming 
methods for analysis in adolescent 
subjects.
Adolescent subjects may be 
enrolled to Part 2.
Section 8.4.5 ECG Analyses
Language added to clarify that 
time-matched ECGs (with PK) will 
be performed for monotherapy
only.
No time-matched ECG will be 
performed for subjects receiving 
combination therapy.
Section 12 References
Updated.
Updated to align with new text.
Appendix 3 , CYP3A4 Guidance
Added enalutamide to the strong in 
vivo inducers of CYP enzymes that 
cause ≥ 80% decrease in area under 
the concentration-time curve.
BMS-986158 is a substrate of 
CYP3A4. Enalutamide is 
contraindicated for CYP3A4 
substrates per package insert, thus 
was added to the guidance. 
Appendices 8, 9, and 10
New appendices include:
Appendix 8, Simulation of MTPI-2 
vs 3+3 Dose Escalation Designs 
With 2 Dose Levels
Appendix 9, Lugano 2014 
Classification for Initial Evaluation 
Staging, and Response for Hodgkin 
Lymphoma 
Appendix 10, Management 
Algorithms for Immuno-oncology 
Agents
Added to support the new study 
design.
Appendix 11
Added Appendix 11, Women of 
Childbearing Potential Definitions 
and Methods of Contraception
Details for women of childbearing 
potential and the use of highly 
effective methods of contraception 
were moved from Inclusion Criteria 
4d and 4e to Appendix 11.
All
Minor formatting, clarifications, 
and typographical corrections.
Minor, therefore have not been 
summarized.
Revised Protocol No.: 07
Date: 18-Mar-2019
261
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SAP_001.pdf: 
Official Title of Study: 
A Phase I/IIa Trial With BMS-986158, a Small Molecule Inhibitor of the Bromodomain and 
Extra-Terminal (BET) Proteins, as Monotherapy or in Combination with Nivolumab in Subjects 
with Selected Advanced Solid Tumors or Hematologic Malignancies 
 
 
NCT Number: NCT02419417   
 
Document Date (Date in which document was last revised): 23 Aug 2021 


STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
A PHASE I/IIA TRIAL WITH BMS-986158, A SMALL MOLECULE INHIBITOR OF 
THE BROMODOMAIN AND EXTRA-TERMINAL (BET) PROTEINS, AS 
MONOTHERAPY OR IN COMBINATION WITH NIVOLUMAB IN SUBJECTS WITH 
SELECTED ADVANCED SOLID TUMORS OR HEMATOLOGIC MALIGNANCIES
PROTOCOL(S) CA011001
VERSION # 2.0
Approved
2.0
v
Approved
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v


Statistical Analysis Plan
CA011001
BMS-986158
bet inhibitor
2
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT ...................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................4
LIST OF FIGURES ....................................................................................................................5
1
BACKGROUND AND RATIONALE......................................................................6
2
STUDY DESCRIPTION ........................................................................................11
2.1
Study Design ..........................................................................................................11
2.2
Treatment Assignment............................................................................................16
2.3
Blinding and Unblinding.........................................................................................17
2.4
Protocol Amendments.............................................................................................17
3
OBJECTIVES ........................................................................................................18
3.1
Primary...................................................................................................................18
3.2
Secondary...............................................................................................................18
4
ENDPOINTS..........................................................................................................19
4.1
Safety Endpoint(s)..................................................................................................19
4.2
Secondary Endpoints ..............................................................................................19
4.2.1
Preliminary Antitumor Activity...............................................................................19
4.2.2
Pharmacokinetic Endpoints....................................................................................20
4.2.3
ECG/QTc................................................................................................................22
5
SAMPLE SIZE AND POWER...............................................................................23
5.1
Dose Escalation ......................................................................................................23
5.2
Dose-expansion Cohort...........................................................................................23
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................25
6.1
Study Periods..........................................................................................................25
6.1.1
Baseline Period ......................................................................................................25
6.1.2
Post-Baseline Period ..............................................................................................25
6.2
Treatment Regimens...............................................................................................25
6.3
Populations for Analyses ........................................................................................26
7
STATISTICAL ANALYSES..................................................................................26
7.1
General Methods ....................................................................................................26
7.2
Study Conduct........................................................................................................26
7.2.1
Study Information...................................................................................................26
7.2.2
Accrual...................................................................................................................26
7.2.3
Relevant Protocol Deviations..................................................................................27
7.3
Study Population ....................................................................................................27
7.3.1
Participant Disposition...........................................................................................27
7.3.2
Demographics and Other Baseline Characteristics.................................................28
7.3.3
Prior Anti-Cancer Therapy.....................................................................................28
7.3.4
Baseline Disease Diagnosis....................................................................................28
7.4
Extent of Exposure .................................................................................................29
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7.4.1
Study Therapy.........................................................................................................29
7.4.1.1
Therapy with BMS-986158 .....................................................................................29
7.4.1.2
Modification of BMS-986158 Therapy ....................................................................30
7.4.2
Concomitant Medications.......................................................................................30
7.5
Efficacy..................................................................................................................31
7.6
Safety.....................................................................................................................32
7.6.1
Deaths ....................................................................................................................33
7.6.2
Serious Adverse Events...........................................................................................33
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy.................................33
7.6.4
Adverse Events Leading to Dose Modification or Delay..........................................34
7.6.5
Overall Adverse Events...........................................................................................34
7.6.6
Multiple Events.......................................................................................................34
7.6.7
Clinical Laboratory Evaluations.............................................................................35
7.6.7.1
Abnormal Hepatic Test...........................................................................................35
7.6.8
Vital Signs, and Other Safety Evaluation ................................................................36
7.6.9
DLT information.....................................................................................................36
7.7
Pharmacokinetics....................................................................................................36
7.7.1
Pharmacokinetic Concentrations............................................................................36
7.7.2
Pharmacokinetic Parameters..................................................................................36
7.7.3
Ctrough ..................................................................................................................37
7.7.4
Dose Proportionality ..............................................................................................37
7.9
Electrocardiogram (ECG) .......................................................................................38
8
CONVENTIONS....................................................................................................40
8.1
Date Conventions ...................................................................................................40
8.2
Recurrent Events ....................................................................................................41
8.3
Pharmacokinetic Summaries...................................................................................41
9
CONTENT OF REPORTS .....................................................................................42
10
DOCUMENT HISTORY........................................................................................43
APPENDIX 1
MISSING AND PARTIAL RADIOTHERAPY AND SURGERY 
DATES IMPUTATION ALGORITHMS ...............................................44
11
REFERENCES.......................................................................................................46
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LIST OF TABLES
Table 2.1-1:
Dose Expansion Planned Sample Size ....................................................15
Table 2.4-1:
Protocol Amendments ............................................................................17
Table 4.2.2-1:
Single Dose Pharmacokinetic Endpoints.................................................21
Table 4.2.2-2:
Extended Single and Multi-dose Pharmacokinetic Endpoints..................21
Table 4.2.2-3:
Multi-dose Pharmacokinetic Endpoints...................................................21
Table 4.2.2-4:
Extended Single and Multi-dose Pharmacokinetic Endpoints..................22
Table 5.2-1:
Characteristics for Initial Monotherapy Expansion Cohorts Signal 
assessment when guided by a Two-Stage Design....................................24
Table 10-1:
Document History ..................................................................................43
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LIST OF FIGURES
Figure 2.1-1:
Study Overview......................................................................................13
Figure 2.1-2:
Dose Escalation Decision Scheme ..........................................................14
Figure 7.7.2-1:
Effective Half Life..................................................................................37
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1
BACKGROUND AND RATIONALE
The scope of this SAP is limited to Part 1 and Part 2 Initial expansion, and only relevant objectives 
are included. 
Patients with relapsed or refractory haematologic and solid tumors have a very poor prognosis1. 
Despite advances in multimodal therapy, increases in overall survival in these patient populations 
have been limited. The unmet need resides in the lack of effective treatments to deliver long term 
survival, hence the need to test compounds that have novel mechanisms of action in clinical 
studies.
The bromodomain and extra-terminal (BET) family of adaptor proteins is comprised of 4 members 
(BRD2, BRD3, BRD4, and BRDT), each of which contain two conserved N-terminal 
bromodomains (BD1 and BD2) and an extra terminal (ET) protein interaction motif2,3. 
Bromodomain-mediated interactions with acetylated chromatin result in the localization of BET 
proteins to discrete chromosome regions, where they recruit additional regulatory complexes to 
influence gene transcription4,5,6. BRD4 is dysregulated by chromosomal translocation to form in-
frame fusions with the NUT (nuclear protein in testis) gene in NUT-midline carcinoma (NMC);7
it is also overexpressed in many solid tumors. Early BET inhibitors, JQ1 and I-BET, demonstrated 
therapeutic effects in multiple tumor models of hematologic malignancies8,9 including multiple 
myeloma (MM),10 as well as in solid tumors.11 The therapeutic activity of BET inhibitors in 
hematologic malignancies correlates with transcriptional suppression of key proto-oncogenes, 
including MYC and BCL2.12,13 c-MYC is the most frequently amplified oncogene and is 
deregulated in 40% to 70% of all cancers;14 however, efforts to target MYC inhibition have not 
been successful to date.15,16
BET inhibitors have the potential to provide an effective strategy for targeting the MYC oncogene 
in the treatment of cancer. Examination of BRD4 occupancy at genes whose transcription is highly 
sensitive to JQ1, led to the observation that BRD4 (and potentially other BET family members) 
localizes to the core promoter regions of many oncogenes.17 Additionally, BRD4 is enriched in 
enhancer regions, leading to high expression levels of many growth promoting genes, in addition 
to MYC. Recent studies demonstrated that key lineage-specific survival genes are regulated by 
these super-enhancer regions.18
Because tumor cells are frequently highly reliant on high oncogene expression for survival, 
selective disruption of super-enhancers by a BET inhibitor may represent an effective strategy for 
the treatment of multiple tumor types with an acceptable safety profile.
Cooperative interactions between BET inhibitors and PD-1 inhibitors may involve different 
molecular pathways. Inflammatory cytokines, including IFNγ, are expressed within the tumor 
microenvironment and upregulate PD-L1 levels contributing to immunosuppression.19,20
Induction of PD-L1 expression in tumor cells, as a downstream effect of canonical IFNγ signaling, 
is BRD4-dependent.21  
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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 result in immune responses and cancer cell death. Meanwhile, tumor 
progression may depend upon acquisition of traits that allow cancer cells to evade 
immunosurveillance and escape effective innate and adaptive immune responses.22,23,24 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. T-cell stimulation is a complex process 
involving the integration of numerous positive as well as negative co-stimulatory signals in 
addition to antigen recognition by the T-cell receptor.25 Collectively, these signals govern the 
balance between T-cell activation and tolerance.
In the pivotal 1-month oral toxicity studies, the highest non-severely toxic dose (HNSTD) in dogs 
was 0.15 mg/kg. The dog was considered the most appropriate species for calculation of the 
maximum recommended starting dose (MRSD) because a nontolerated dose was attained in dog 
but not rat and the toxicity profile was similar in both species. The starting dose of 0.75 mg/day 
was selected based upon the human equivalent dose (HED; scaled by body-surface area) of the 
HNSTD in dogs (the more sensitive species between dogs and rats) with a safety factor of 1/6. The 
projected human efficacious dose is estimated to be 2 mg/day. 
To assure safety of human subjects, the initial dose of BMS-986158 tested in this study was 
0.75 mg/day. Part 1 of this study also evaluates different administration schedules: monotherapy 
given 5 consecutive days on with 2 days off each week of a 4-week cycle (Schedule A of Part 1); 
monotherapy given 14 consecutive days on with 7 days off of a 3-week cycle (Schedule B of Part 
1); and monotherapy given 7 days on and 14 days off of a 3-week cycle (Schedule C of Part 1). 
The rationale for the 3 schedules is based on the human half-life of 39 hours. Schedule A 
effectively provides continuous drug exposure, while Schedules B and C provide intermittent 
exposure with a break to allow for platelet recovery as needed at higher doses in human trials of 
other compounds in this class.26,27,28,29
For Part 2, Schedule A, has been selected considering the safety, 
 
and PK obtained during Part 1. In addition to adult subjects, adolescent subjects will be included 
in Part 2. 
The increment in the dose levels used in dose escalation especially in the first schedule tested 
(Schedule A), will be guided by the modified Fibonacci to help mitigate the potential risk inherent 
in the steep dose/toxicity curve and/or the low therapeutic index seen in preclinical studies. Dose 
escalation decisions will utilize a modified toxicity probability interval (mTPI) design. Rationale 
for selection of an mTPI over a 3+3 design includes a more accurate determination of MTD, 
provides flexibility in cohort size, and allows de-escalation and re-escalation to a previously tried 
dose. The design provides a simple dose escalation decision algorithm, and in addition to the higher 
accuracy of MTD selection, it treats fewer subjects at suboptimal doses.
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Drug development strategies in oncology continue to evolve with the advent of histology-agnostic 
biomarkers correlating with the clinical activity of targeted anticancer drugs. Tumors with genetic 
rearrangements that engage molecular pathways regulated by BRD proteins, including gene 
translocations, mutations, or amplifications, have been selected for Part 2 of this study to identify 
early clinical activity in these preselected patient populations. The results of this study may help 
to understand whether the activity of BMS-986158 depends on specific genetic alterations 
observed in selected histologies or may be tumor agnostic.
Translocations
Chromosomal translocations may lead to the formation of fusion proteins with oncogenic 
properties. Examples of these genetic abnormalities include BRD3,4-NUT fusion (in 75% of cases 
of NMC), EWS/FLI1 fusion (in 85% of cases of Ewing sarcoma [ES]), and IGH/L-MYC and IGH-
BCL-2/6 fusions (in Burkitt’s lymphoma [BL] and double-hit lymphoma [DHL]).
Detection of these fusion proteins is required for diagnosis and is a routine clinical practice. 
Initially, only subjects with NMC carrying BRD3,4-NUT fusion will be selected to participate in 
Part 2. 
Mutations
SWI/SNF functions as a tumor suppressing complex and mutations in subunits contribute to 
malignant transformation.30 The KRAS protein is required for signaling in normal cells, and the 
mutation of a KRAS gene contributes to the development of many cancers. Similarly, Gnaq and 
Gnaq/11 mediate the intracellular signal transduction pathway, and mutations in these genes lead 
to oncogenesis.
•
Renal cell carcinoma (RCC): Approximately 40% of patients with RCC harbor mutations 
within the SWI/SNF complex, including ARID1A, ARID1B, SMARCA4, SMARCA2, 
SMARCB1, ARID2, PBRM1 (BAF180) ,31 and BET inhibitors induced RCC cell apoptosis 
and repressed tumor growth in vitro and in vivo.32
•
Non-small cell lung cancer (NSCLC): BMS-986158 suppressed proliferation of NSCLC cell 
lines with SWI/SNF mutations (BMS, data on file). In vitro and in vivo antitumor activity of 
other BET inhibitors has also been reported in NSCLC cells harboring KRAS mutations, 
although this effect was abrogated by concurrent alterations of LKB1, also known as STK11.33
According to TCGA database, 30% of patients with NSCLC harbor SWI/SNF mutations, and 
15% harbor KRAS mutations of which approximately 75% express wild type LKB1. 
•
Uveal melanoma (UM): BET inhibitor demonstrated cytotoxic activity in UM cells carrying 
Gnaq/11 mutations and inhibited tumor growth in xenograft models.
Amplifications
•
BRD: In patients with OC, BRD amplification is associated with worse overall survival. BRD 
gene amplification correlates with overexpression of BRD RNA (TCGA database) and is 
necessary for proliferation and survival of some tumor cell types, including OC and triple 
negative breast cancer (TNBC). Blocking hyperactivity of BRD proteins with a BET inhibitor 
results in growth inhibition of xenografts obtained from patients with OC and from patients 
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with TNBC.,34,35 Approximately 43% of patients with TNBC, 55% of patients with 
neuroendocrine prostate cancer (NEPC), and 17% of patients with OC harbor BRD4 
amplifications (TCGA database). 
•
MYC: Forty-one percent of patients with castration-resistant prostate cancer (CRPC) and 47% 
of patients with OC harbor MYC amplifications (TCGA database). BET inhibition results in 
reduced MYC expression and inhibition of tumor growth in PDX models with high MYC 
expression and inhibition of AR signaling.36 High frequency of MYC amplification 
(approximately 30%) has also been observed in patients with uterine carcinosarcoma (UCS) 
(TCGA database). Also, the non-germinal center subtype of diffuse large B-cell lymphoma 
(non-GC-DLBCL) is often associated with MYC (and BCL2) overexpression.37 A recent 
Phase I study of a BET inhibitor in patients with relapsed and refractory lymphoma reported 
objective clinical responses in the non-GC-DLBCL subtype, in particular in patients with 
activated B cell (ABC)-DLBCL.38
•
AR: Among other genetic abnormalities sensitive to BET regulation is AR amplification. AR 
promotes ligand-independent prostate cancer (PC) progression through c-MYC upregulation.39
BET inhibitors decreased MYC levels and proliferation viability of castration-resistant prostate 
cancer (CRPC) cells, and inhibited growth of PC xenografts. Approximately 67% of CRPC 
patients harbor AR amplification, and 25% to 30% harbor both MYC and AR amplifications 
(TCGA database). 
BRD, MYC, and AR amplifications will be detected in tumor biopsies using Foundation Medicine 
diagnostic platform. Subjects with TNBC, non-GC-DLBCL and CRPC with any of these gene 
amplifications/overexpressions will be eligible to participate in Part 2 as part of the Initial 
Expansion. 
These genetically defined tumor cohorts/patient populations have one or more qualifying 
characteristics:
•
NMC: NUT-midline carcinoma
•
DHL and non-GC-DLBCL: double hit lymphoma and non-germinal center subtype of 
diffuse large B-cell lymphoma
•
TNBC: Triple negative breast cancer
•
CRPC: castrate-resistant prostate cancer
Biomarkers are increasingly playing a key role in the development of cancer therapeutics. By 
interrogating BET-inhibitor-induced PD/gene signature changes in molecular markers measured 
in tissue and body fluids, the activity of this drug may be addressed and may be informative in 
identifying appropriate doses, treatment schedules, as well as potential prediction of responses. 
BET pathway inhibition induces parallel transcriptional changes of multiple genes in tumor cell 
lines, xenografts and in vitro treated mouse and human blood. 
 
 
 
 
 
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In preclinical models, BET pathway inhibition induces parallel transcriptional changes of multiple 
genes in tumor cell lines and patient-derived xenografts.46,47,48,49,50. Some BET-regulated proteins 
are known to play important roles in tumor development and maintenance. and treatment with BET 
inhibitors resulted in downregulation of MYC or BCL2 transcription in many preclinical tumor 
models. 
 
 
 
BMS-986158 treatment also induced differential gene expression in mouse and human blood. 
 
 
Exclusion of adolescent subjects from adult trials may slow the investigation of novel therapies in 
adolescent subjects and delay the delivery of novel efficacious drugs to this patient population. 
Thus, it has been recommended to consider adolescent subjects for tumor type- and molecular 
target-appropriate adult oncology trials.51
Some cancers, including rare diseases such as NMC affect both children and adults. While NMC 
was initially thought to be a childhood cancer, recent studies have shown that it affects people of 
all ages with 30% of new cases reported in pediatric patients. Similar to adult patients, NMC is 
highly lethal in children and adolescent patients with an average of 10 months survival time, 
despite intensive therapies.52 Thus, there is an unmet medical need for new therapeutic approaches 
for patients with NMC across all ages.
During the dose expansion part of this study, BMS-986158 will initially be tested in subjects with 
TNBC, CRPC, DHL, non-GC-DLBCL, and NMC. These cancers are rare in children.53,54,55,56
Some predictors of poor outcome were shared among all age groups, such as multiple primary 
tumor sites and advanced stage disease.57 Because patient numbers are low, there are no 
randomized trials comparing different relapse regimens. These results provide rationale for 
development of alternative treatment approaches focusing on targeted therapy to circumvent 
chemotherapy-resistant disease by providing alternative therapeutic targets across different ages. 
Current experience with BMS-986158 did not identify drug-related adverse events (AEs) that 
warrant exclusion of adolescent subjects from this study. Thus, the balance of benefit to risk may 
be favorable in adolescent subjects with advanced cancers and poor treatment options. Therefore, 
adolescent subjects with NMC will be eligible to participate in this study. Additional indications 
will be allowed at the discretion of the Sponsor if the tumor contains similar genetic abnormalities 
sensitive to regulation by the BET family proteins. 
This SAP supersedes the statistical considerations identified in the protocol; where considerations 
are substantially different, they will be identified as such in this document. In the event that the 
protocol has amendment(s) that do not have an impact on the statistical analysis methodology, this 
SAP will not require an amendment. 
 
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Research Hypothesis 
There is no formal primary research hypothesis for this study to be statistically tested. It is 
anticipated that BMS-986158 as monotherapy will demonstrate adequate safety and tolerability at 
pharmacologically relevant doses, so as to permit further clinical development (at a recommended 
dose range).
Schedule of Analyses:
Data emerging from this study may be needed to for timely decisions about adjustments to 
procedures in subsequent parts of the study. Therefore, data from each part of the study will be 
examined prior to the final lock of the study database. Additional interim analyses may also be 
performed for administrative purposes, early termination of the study or publications. No formal 
inferences requiring any adjustment to statistical significance level will be performed. Efficacy 
analyses based on interim data may use the Response Evaluable Subjects population or the All 
Treated Subjects population depending on the purpose of the analysis.
An interim analysis to summarize safety, PK, and efficacy data may be performed when 
sufficiently treated participants become available. Additional interim analyses on safety and 
efficacy may be performed at various times prior to study completion in order to facilitate program 
decisions and to support scientific publications or presentations.
2
STUDY DESCRIPTION
2.1
Study Design
This is a phase 1/2a, open label study to characterize the safety and tolerability of BMS-986158 
monotherapy in subjects with advanced solid tumors and hematologic malignancies. The study has 
two segments Part 1 (Phase 1 study - dose escalation, with Schedules A, B and C enrolling at 
different dosing schedules) and Part 2 (Initial Expansion including subjects with a limited set of 
tumor types) (see Figure 2.1-1). In Part 1 and Part 2, BMS-986158 will be studied as monotherapy.
In Part 1, the continuous dosing Schedule A enrolled first. Each subject in Schedules A, B and C 
of Part 1 is administered a single dose of BMS-986158 on Cycle 1 Day 1 and no additional doses 
are administered until Cycle 2 Day 1. For subjects in Schedule A on Cycle 2 Day 1, and on each 
subsequent cycle, subjects receive QD dosing for 5 consecutive days of each week, followed by a 
2-day rest period, on a 28-day cycle. For subjects in Schedule B on Cycle 2 Day 1, and on each 
subsequent cycle, subjects receive QD dosing for 14 consecutive days, followed by a 7-day rest 
period, on a 21-day cycle. For subjects in Schedule C on Cycle 2 Day 1, and on each subsequent 
cycle, subjects receive QD dosing for 7 consecutive days, followed by a 14-day rest period, on a 
21-day cycle. 
In Part 2, Schedule A for BMS-986158 administration has been selected for expansion of the 
4.5 mg dose, which will be administered for 2 weeks (10 doses) followed by 3.75 mg for the 
remainder of the treatment period. Adult and adolescent subjects weighing ≥40 kg will be 
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administered a flat dose of BMS-986158. Using Schedule A with a loading period of 2 weeks at 
4.5 mg followed by 3.75 mg for the remainder of the treatment period, BMS-986158 will be tested 
as monotherapy, in a limited set of tumor types (NMC, CRPC, DHL, Non-DC-DLBCL, and 
TNBC; Initial Expansion). 
Enrollment in Part 1 and selection of the monotherapy MTD will adhere to a modified Toxicity 
Probability Interval (mTPI) design. The mTPI method utilizes a target toxicity (DLT) rate and 
equivalence interval (EI) to make decisions on escalation after each cohort and to estimate the 
MTD. For this study the target DLT rate is 27% and the EI is 25%-29%. During Parts 1, the 
monotherapy MTD will be selected as the dose levels with the smaller difference between 
estimated toxicity and the target DLT rate among the dose levels administered based on the mTPI 
design. See Protocol Appendix 1.
Figure 2.1-1 shows a graphical depiction of the study design, which shows only Part 1 and Part 2 
initial expansion as clarified in the scope of this SAP document in the beginning.
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Figure 2.1-1:
Study Overview
Abbreviations: CRPC = castrate-resistant prostate cancer; DHL = double-hit lymphoma; NMC = NUT-midline 
carcinoma; Non-GC-DLBCL = Non-germinal center diffuse large B-cell lymphoma; NSCLC = non-small cell lung 
cancer; Res = response; SOC = standard of care; TNBC = triple negative breast cancer; 
Subjects will complete up to 5 study periods: Screening (up to 28 days for Part 1 and up to 40 days 
for Part 2), Treatment (up to 2 years, until disease progression or other protocol-specified criteria), 
Clinical Follow-up (30 days for BMS-986158 monotherapy), and Survival Follow-up 
 
 
 
. 
Figure 2.1-3 shows the mPTI dose escalation decisions for Part 1 based on scenarios that may be 
encountered during dose escalation with respect to the number of DLT-evaluable subjects and the 
number of subjects with a DLT. Schedule A, B, and C subjects will be evaluated independently 
for establishment of DLTs, MTDs and MAADs in each part.
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Figure 2.1-2:
Dose Escalation Decision Scheme
DLT-evaluable subjects are defined as subjects who received at least 16 of 21 doses of 
BMS-986158 in Schedule A; at least 17 of 22 doses of BMS-986158 in Schedule B ; and at least 
12 of 15 doses in Schedule C of Part 1 during the DLT evaluation period and will be considered 
for dose escalation decisions. Subjects who developed a DLT during the DLT period are 
considered evaluable regardless of the number of received doses.
At the end of dose escalation, the MTD for one evaluated dosing schedule (Schedules A, B, or C) 
will be selected as the dose with the smaller difference between estimated toxicity and the target 
DLT rate (27%), among the dose levels used, with an isotonic regression model of the accumulated 
DLT data based on the mTPI design.
Treatment in Part 2 can be initiated before Part 1 is completed and when the MTD (or maximum 
administered dose if no MTD is determined) for Part 1 has been determined. Schedule A (QD 
dosing for 5 consecutive days of each week, followed by a 2-day rest period, on a 28-day cycle) 
has been chosen for expansion. This regimen was selected after considering safety, PK 
 
data generated during Part 1. The initial dose level of BMS-986158 
selected for Part 2 is 4.5 mg with a loading period of 2 weeks (10 doses or half a cycle) with 
subsequent dose level of 3.75 mg for the duration of study treatment for each subject.
BMS-986158 will be first evaluated as monotherapy. The Initial Expansion will enroll a maximum 
of 45 subjects with tumors harboring specific genetic alterations including fusion proteins (NMC, 
DHL), BRD amplifications (TNBC), MYC amplifications (Non-GC DLBCL) and AR 
amplification (CRPC). 
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Adolescent subjects will be treated with a dose and schedule selected from Part 1 (dose escalation) 
in adult subjects. The safety of this selected BMS-986158 dose will be evaluated in adolescents 
(≥12 to <18 years of age) as part of the dose expansion phase (Part 2) in subjects with NMC. 
Initially, 3 to 4 adolescent subjects across different tumor types may be enrolled in the Initial 
Expansion and monitored for DLT. Based on safety and other available data, the Sponsor may 
consider decreasing the dose level of BMS-986158 for adolescent subjects. 
Once the safety and tolerability profile is established at the selected dose of BMS-986158 alone 
during the dose evaluation phase, enrollment in the expansion phase will initiate at this dose level 
to assess a preliminary efficacy signal, and to obtain additional data, such as 
 
safety information across the selected tumors. 
Enrollment in the Part 2 expansion will start in the initial BMS-986158 monotherapy cohorts. 
Although a 2-stage (Fleming) design will be used to guide assessment of preliminary anti-tumor 
activity in each of the monotherapy cohorts, up to 9 subjects may be enrolled in each of the initial 
cohorts to better characterize the PK, safety
 profiles. The decision to 
continue or discontinue enrollment in one or more cohorts or discontinue treatment in existing 
cohorts will be made by the Sponsor/Medical Monitor based on a comprehensive assessment of 
the accruing on-treatment evidence.
Clinical safety monitoring of subjects during dose expansion phase will continue throughout the 
study. If at a selected BMS-986158 dose level, the combined incidence exceeds 33% for study 
drug related toxicity requiring treatment discontinuation, further enrollment to that dose level may 
be interrupted and a decision to continue dosing will be based on discussions of the observed 
aggregate (acute and chronic) toxicities between the investigator(s) and the Sponsor, if needed.
Table 2.2-1 shows the planned number of subjects per tumor type and setting (Part 2 Initial 
monotherapy) in the expansion phase. 
Table 2.1-1:
Dose Expansion Planned Sample Size
Tumor Cohort and Group
Initial Monotherapy
FUSION PROTEINS
DHL
5 to 9
NMC
5 to 9
BRD AMPLIFICATIONS
TNBC
5 to 9
MYC AMPLIFICATIONS
Non-GC-DLBCL
5 to 9
AR AMPLIFICATIONS
CRPC
5 to 9
All Cohorts
25 to 45
The minimum overall planned sample sizes are based on initial enrollment subject counts per cohort. The maximums 
are determined similarly. 
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Therefore, the potential total for expansion will be approximately up to 45 subjects if only initial 
monotherapy is pursued.
Administration of Additional Treatment Cycles:
Subjects may discontinue treatment due to disease progression, unacceptable AEs, or at the 
subject’s request. Treatment decisions related to subject management will be based exclusively on 
RECIST version 1.1 or the Lugano 2014 criteria, or PCWG3 criteria (including PSA assessments). 
Subjects with an objective response of CR, partial response (PR) or stable disease, will continue 
therapy until they develop progressive disease (PD, unless in case of treatment beyond 
progression), experience clinical deterioration, develop AEs requiring discontinuation of treatment 
or withdraw consent. 
Subjects who develop toxicity requiring discontinuation of treatment will enter the Clinical 
Follow-up Period. The subject should be seen in follow-up at least every 30 days, until the AE has 
resolved to baseline, stabilized, or been deemed irreversible. After completion of the Clinical 
Follow-up Period, subjects will then enter the Survival Follow-up Period.
 
 
 
 
The overall duration of the study is expected to be approximately 6 years from the time of the first 
visit of the first subject to the required survival follow-up of the last subject enrolled. Subjects may 
discontinue treatment due to disease progression, unacceptable AEs, or withdrawal of consent. The 
Clinical Follow-up visits will occur approximately 30 days (for subjects who receive 
monotherapy) after the subject discontinues study treatment. For subjects in PR or CR who 
discontinue treatment for AEs, tumor assessments will be performed every 12 weeks for the first 
year then every 6 months for the second year. If a subject discontinues treatment due to an AE, the 
subject should be seen in Clinical Follow-up every 30 days until the AEs either resolved to baseline 
or Grade 1, stabilized, or been deemed irreversible. After completing the Clinical Follow-up 
Period, subjects will continue on to a Survival Follow-up Period. 
 
 
 
 
 
 The end of the study will occur after the last treated subject completes their Clinical 
Follow-up, unless a subject discontinues prematurely. Subjects in Survival Follow-up Period who 
have progression of disease will be eligible to receive anticancer therapy as appropriate.
2.2
Treatment Assignment
This is an open-label study. Enrolled subjects, including those not dosed, will be assigned 
sequential subject numbers starting with 00001, eg, 00001, 00002, 00003.... 00010. Those enrolled 
subjects meeting eligibility criteria will be eligible to be dosed. Sequential numbering may restart 
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at 00001 for each participating site as the distinct subject identification number (PID) will 
ultimately be comprised of the site number and subject number, eg, 0002 00001.
During Part 1, once informed consent has been obtained, the investigator (or designee) will register 
the subject by transmitting a copy of the completed enrollment worksheet (registration form) to 
the Sponsor. Treatment groups and/or dose levels will be provided to the site study team after the 
subject has registered and eligibility for the study confirmed.
In Part 2, during the screening visit, the investigative site will call into the enrollment option of 
the interactive response technology (IRT) designated by BMS. Enrolled participants, including 
those not dosed, will be assigned sequential participant numbers for their site starting with 00001, 
(eg, 00001, 00002, 00003.... 00010). The patient identification number (PID) will ultimately be 
comprised of the site number and participant number. Once it is determined that the participant 
meets the eligibility criteria following the screening visit, the investigative site will call the IRT to 
centrally assign the participant into the appropriate monotherapy cohort. 
2.3
Blinding and Unblinding
This study is a non-randomized open-label study for Part 1 and Part 2. Interactive Response 
Technology (IRT) will be used in Part 2 for treatment assignment. Data emerging from this 
exploratory study may be necessary to inform timely decisions for adjusting procedures in 
subsequent portions of the study, including early termination of the study. Additionally, 
availability of the open label treatment assignments may facilitate optimization of the bioanalytical 
analysis of samples.
2.4
Protocol Amendments
This SAP incorporates the following protocol amendments (Table 2.4-1).
Table 2.4-1:
Protocol Amendments
Document
Date of Issue
Summary of Major Changes
Amendment 01
10-Aug-2015
Revisions to Inclusion/Exclusion criteria, T&E table, and minor 
typographical edits
Amendment 04
03-Mar-2016
Incorporates new dosing regimens, revisions to the 
inclusion/exclusion criteria, T&E table and minor typographical 
edits
Amendment 05
12-Apr-2016
Removes Parts 1B & 2B and pertaining language from the 
protocol; incorporates revisions to the inclusion/exclusion 
criteria, T&E table, and minor typographical edits.
Revised Protocol 04
06-Sep-2017
Adds nivolumab to Part 2 escalation phase and updates to 
biomarker driven study design with additional tumor types 
added. Includes revisions to rationales, inclusion/exclusion 
criteria, T&E table, sample collection tables and statistics; and 
minor typographical edits. 
Revised Protocol 05
01-Mar-2018
Incorporates Administrative Letter 04 and the following 
changes:1) clarify the acceptable prior lines of therapy for 
participants with Non-Small Cell Lung Cancer (NSCLC) in Part 
2; 2) update Exclusion Criteria for subjects participating in Part 
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Table 2.4-1:
Protocol Amendments
2; and 3) provide updated contraception and protection 
requirements based on recent non-clinical reproductive 
toxicology study. Study design elements including time and 
events schedules, sample collections, laboratory analyses and 
additional safety measures have been added to align with these 
changes.
Revised Protocol 06
17-Jul-2018
Updates schedules for mandatory biopsies during Part 2, updates 
imaging requirements for tumor assessments; updates inclusion 
criteria for subjects with NSCLC, corrects dose-limiting toxicity 
period for Part 2, updates schedules for PK sample collections, 
includes language to allow for release of IRT codes to facilitate 
ongoing data review, and added PROSTATE CANCER 
WORKING GROUP 3 (PCWG3) appendix.
Revised Protocol 07
18-Mar-2019
Identifies the dose and schedule for Part 2 and updates the study 
design for Part 2. Includes revisions to rationales, 
inclusion/exclusion criteria, T&E tables, sample collection tables 
and statistics; minor typographical edits, and an update to 
Appendix 4 RECIST 1.1. 
 
3
OBJECTIVES
3.1
Primary
•
To assess the safety and tolerability and to assess the DLTs, MTD, and recommended Phase 2 
dose (RP2D) of BMS-986158 as monotherapy for subjects with advanced solid tumors and 
hematologic malignancies
3.2
Secondary
•
To assess the preliminary anti-tumor activity of BMS-986158 monotherapy as measured by 
ORR, and response duration based on response evaluation criteria in solid tumors (RECIST)
v1.1, prostate cancers using PCWG3 criteria, or hematologic malignancies using criteria from 
Lugano 2014.
•
To characterize PK of BMS-986158 and metabolite in monotherapy.
•
To assess the dose-response and exposure-response effect of BMS-986158 monotherapy on 
the ECG (QT interval).
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4
ENDPOINTS
4.1
Safety Endpoint(s)
The assessment of safety will be based on the incidence of adverse events (AEs), serious adverse 
events (SAEs), adverse events leading to discontinuation, deaths and frequency of laboratory test 
toxicity grade shifting from baseline. 
Toxicities will be graded using the National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03 in the first 32-35 days of dosing (DLT evaluation period
for Schedule A) and in the first 35 days of dosing (DLT evaluation period for Schedules B and C).
4.2
Secondary Endpoints
Secondary endpoints comprise preliminary antitumor activity, PK, and electrocardiogram (ECG) 
results and are described below.
4.2.1
Preliminary Antitumor Activity
Changes in solid tumor measurements and tumor response will be assessed by the RECIST v1.1 
(Response Evaluation Criteria in Solid Tumors version 1.1)58(Protocol Appendix 4), or PCWG3 
for prostate cancer (Protocol Appendix 12). PCWG3 criteria is intended for Part 2 subjects and not 
Part 1 subjects. Changes in hematologic malignancies will be assessed using Lugano 2014 criteria
(Protocol Appendix 9). In Schedule A (Part 1), tumor assessments will occur 8 weeks (± 1 week) 
after treatment begins and continue every 8 weeks (± 1 week) until investigator-assessed disease 
progression or treatment discontinuation. In Schedules B and C (Part 1), tumor assessments will 
occur 9 weeks (± 1 week) after treatment begins and continue every 9 weeks (± 1 week) until 
investigator-assessed disease progression or treatment discontinuation. In Part 2, Schedule A,
tumor assessments will occur 8 weeks (± 1 week) after treatment begins and continue every 8 (±
1 week) until investigator-assessed disease progression or treatment discontinuation.
The following set of study-level efficacy endpoints will be used.
•
Objective Response Rate (ORR): defined as the total number of subjects whose best overall 
response (BOR) is either a CR or PR divided by the total number of subjects in the population 
of interest. 
−
Best overall response (BOR): defined as the best response designation recorded between 
the dates of first dose and the date of first objectively documented progression per 
Investigator assessed RECIST v1.1 (or Lugano 2014 criteria for hematologic malignancies 
or PCWG3 for prostate cancer) or the date of subsequent therapy, whichever occurs first.
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Investigator reported CR or PR was not always confirmed by a second scan. Therefore, 
ORR summaries will be presented regardless of confirmation. For subjects without 
documented progression or subsequent therapy, all available response designations will 
contribute to the BOR assessment. For subjects who continue treatment beyond 
progression or begin subsequent therapy, the BOR should be determined based on response 
designations recorded up to the time of the initial RECIST v1.1 (or by Lugano 2014 criteria 
for hematologic malignancies, or PCWG3 criteria for prostate cancer [CRPC or NEPC]) 
defined progression or subsequent therapy, whichever occurs first. For those subjects who 
have surgical resection, only pre-surgical tumor assessments will be considered in the 
determination of BOR.
•
Duration of Response (DOR): defined as the time between the date of first response (CR or 
PR) and the date of the first objectively documented disease progression (as determined using 
RECIST v1.1 for solid tumors, Lugano 2014 criteria for hematologic malignancies, or PCWG3
(including PSA assessments) for prostate cancer [CRPC or NEPC]), or death due to any cause, 
whichever occurs first. For those subjects who remain alive and have not progressed , duration 
of response will be censored on the date of last evaluable tumor assessment. Subjects who 
started subsequent therapy without a prior reported progression will be censored at the last 
evaluable tumor assessment prior to initiation of the subsequent anticancer therapy. Response 
duration will only be evaluated in subjects with a BOR of CR or PR. Duration of response will 
be reported if there are more than 5 CR or PR in a tumor type
•
Progression Free Survival (PFS): defined as the time from the first dose of study medication 
to the date of the first objective documentation of tumor progression or death due to any cause. 
Clinical deterioration in the absence of radiographic evidence is not considered progression for 
the purpose of determining PFS. Subjects who neither progressed nor died will be censored on 
the date of their last evaluable tumor assessment. Subjects who did not have any evaluable on-
study tumor assessments will be censored on the date of the first dose of study medication. 
Subjects who started subsequent therapy without a prior reported progression will be censored 
at the last evaluable tumor assessment prior to initiation of the subsequent anticancer therapy. 
•
Progression Free Survival Rate (PFSR) at week ͂t̓: defined as the proportion of subjects 
who remain progression free and surviving at ͂t̓ weeks (t=12, 24). The proportion will be 
calculated by the product-limit method (Kaplan-Meier estimate) which takes into account 
censored data.
4.2.2
Pharmacokinetic Endpoints
Pharmacokinetics of BMS-986158 monotherapy (parent and metabolite, as data permits) will be 
derived from plasma concentrations versus time data.
Throughout the SAP, TAU was replaced by 24 hours or 0-24. This is because it is more meaningful 
to compare PK of first 24 hours following single dose kinetics on cycle 1 day 1, and the dosing 
interval of 24 hours on cycle 2 NCA (Cycle 2 Day 5 for schedule A, Cycle 2 Day 14 for schedule 
B and Cycle 2 Day 7 for schedule C). Therefore, with reference to the protocol, the following PK 
parameters were replaced in the SAP: Ctau was replaced by C24, AUC(TAU) was replaced by 
AUC(0-24), AI_AUC(Tau) was replaced by AI_AUC(0-24), AI_Ctau was replaced by AI_C24 
and MR_AUC(TAU) was replaced by MR_AUC(0-24).
The PK parameters to be assessed following single and multiple dose administration are shown in 
Tables 4.2.2-1 through 4.2.2-4 below.
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Table 4.2.2-1:
Single Dose Pharmacokinetic Endpoints
Parameter
Definition
Cmax
Maximum observed plasma concentration
Tmax
Time of maximum observed plasma concentration
AUC(0-T)
Area under the plasma concentration-time curve from time zero to time of last 
quantifiable concentration
AUC(0-24)
Area under the concentration-time curve from time zero to time 24 hours
Cmax/D
Maximum observed plasma concentration; Dose normalized
AUC(0-24)/D
Area under the concentration-time curve from time zero to time 24 hours; Dose 
normalized
AUC(INF)/D
Area under the plasma concentration-time curve from time zero extrapolated to infinite 
time; Dose normalized
In addition, the following PK parameters may also be assessed after single dose administrations, 
if data permit:
Table 4.2.2-2:
Extended Single and Multi-dose Pharmacokinetic Endpoints
Parameter
Definition
T-HALF
Apparent terminal phase half-life
AUC(INF)
Area under the plasma concentration-time curve from time zero extrapolated to 
infinite time
CLT/F
Apparent total body clearance, reported only for parent, not for metabolite
Vz/F
Apparent volume of distribution of terminal phase, reported only for parent, not 
for metabolite
The PK parameters to be assessed following multiple dose administration include:
Table 4.2.2-3:
Multi-dose Pharmacokinetic Endpoints
Parameter
Definition
Cmax
Maximum observed plasma concentration
Tmax
Time of maximum observed plasma concentration
AUC(0-T)
Area under the plasma concentration-time curve from time zero to time of last 
quantifiable concentration
AUC(0-24)
Area under the concentration-time curve from time zero to time 24 hours
Cmin
The minimum observed concentration within a dosing interval 
C24
Observed concentration at 24 hours
Ctrough
Trough observed plasma concentration (this includes predose concentrations (C0) and 
concentrations at the end of dosing interval (C24)); 
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Table 4.2.2-3:
Multi-dose Pharmacokinetic Endpoints
AI_AUC(0-24)
Accumulation Index; ratio of an exposure measure at steady-state to that after the first 
dose (exposure measure includes AUC(0-24)).
AI_Cmax
Accumulation Index; ratio of Cmax at steady-state to Cmax after the first dose
AI_C24
Accumulation Index; ratio of an C24 at steady-state to C24 after the first dose 
T-HALFeff
Effective elimination half-life that explains the degree of accumulation observed for a 
specific exposure measure
In addition, the following PK parameters may also be assessed after single and multiple dose 
administrations, if data permit:
Table 4.2.2-4:
Extended Single and Multi-dose Pharmacokinetic Endpoints
Parameter
Definition
MR_Cmax
Ratio of metabolite Cmax to parent Cmax, corrected for molecular weight
MR_AUC(0-T)
Ratio of metabolite AUC(0-T) to parent AUC(0-T), corrected for molecular 
weight
MR_AUC(INF)
Ratio of metabolite AUC(INF) to parent AUC(INF), corrected for molecular 
weight (following single dose only)
MR_AUC(0-24)
Ratio of metabolite AUC(0-24) to parent AUC(0-24), corrected for molecular 
weight
Individual subject pharmacokinetic parameter values will be derived by non-compartmental 
methods by a validated pharmacokinetic program. Actual times will be used for the analyses.
4.2.3
ECG/QTc
Changes in QTcF (ΔQTcF) from baseline, at selected times in relation to BMS-986158
monotherapy will be evaluated in the context of dose- or exposure-response as observed. This may 
also be evaluated in relation to Metabolite BMT-161485.
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5
SAMPLE SIZE AND POWER
5.1
Dose Escalation
In the dose escalation part of the study, i.e., Part 1, the sample size per dose level and schedule 
cannot be precisely determined but depends on the observed DLT and the decision rule of mTPI. 
Between 3 and up to 13 DLT evaluable subjects may be enrolled to a given dose level and schedule. 
Treating additional subjects beyond the 13 at a dose level in a dose schedule would be unlikely to 
alter the decision specified by the mTPI algorithm. A total of approximately 30 subjects is expected 
to be treated per schedule, with a total of 90 planned across schedules for the dose escalation phase. 
More subjects may be added at a specific schedule if additional dose levels need to be evaluated. 
Similarly, fewer than 30 subjects may be needed for a different schedule if a smaller number of 
dose levels are evaluated. 
Assuming a 27% acceptable DLT rate, which corresponds to a Beta(1, 2.7) distribution, the risk 
associated with selecting a dose level as safe given the number of DLTs observed at that dose level 
based on the posterior probability associated with an observed DLT is dependent on the number 
of subjects evaluable for DLT at that dose level at the time of the event.
5.2
Dose-expansion Cohort
The purpose of cohort expansion is to gather additional safety, tolerability, preliminary efficacy, 
PK, 
 information regarding BMS-986158 alone. However, the sample size is strictly based 
on efficacy, specifically based on the target ORR relative to historic response rate.
During this part of the study, the efficacy signal assessment in each tumor cohort in monotherapy 
regimens will be guided by a Fleming 2-stage design. The Stage 1 and total (Stages 1 and 2) sample 
size for each cohort is calculated based on assumptions of true (target) and historic ORR for each 
tumor type in the studied population. Using a 2-stage design provides an option to stop early for 
futility, as well as an early signal of preliminary strong antitumor activity. Approximately 5 to 9 
subjects will be treated in each of the 5 parallel cohorts. Enrollment may continue during the initial 
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Stage 1 efficacy evaluation (while the planned number of participants for Stage 1 are followed for 
evaluable tumor assessments) to ensure that sufficient subjects are response evaluable in case of 
early drop outs and to account for design parameters changes (eg, historical rate update). 
The total sample size for each expansion cohort will be calculated to provide a reasonable false-
positive rate (FPR < 10%) and false-negative rate (FNR < 10%) based on assumptions of true 
(target) and historic ORR for each indication. The assumed historic and target response rates may 
change over time and may need to be adjusted by the time of response data from this study are 
available. Enrollment may continue into stage 2 while the planned number of participants for stage 
1 are followed for efficacy evaluable tumor assessments. There will be no stopping of a disease 
cohort for efficacy, although early planning for the next stage of clinical development may be 
initiated. 
If one or more of the 5 subjects in a Stage 1 cohort respond to therapy, the Fleming Stage 1 futility 
boundary will have been exceeded and enrollment will continue in Stage 2. If 2 or fewer of 9 
subjects enrolled through Stage 2 respond to therapy, the cohort will have failed to evidence the 
targeted ORR (Table 5.2-1).
Table 5.2-1:
Characteristics for Initial Monotherapy Expansion Cohorts Signal 
assessment when guided by a Two-Stage Design
Tumor Cohort and 
Group
Target
ORR
%
SOC 
ORR
%
Stage 1 / 
Total N
Stage 1 Res 
Futility/ Efficacy 
Boundary
Stage 2 Res 
Futility/ Efficacy 
Boundary
FPR/FNR 
(%)
FUSION PROTEINS
NMC
50
10
5/9
0/2
2/3
10/10
DHL
50
10
5/9
0/2
2/3
10/10
BRD AMPLIFICATIONS
TNBC
50
10
5/9
0/2
2/3
10/10
MYC AMPLIFICATIONS
Non-GC-DLBCL 
35
10
5/9
0/2
1/2
20/20
AR AMPLIFICATIONS
CRPC
35
10
5/9
0/2
1/2
20/20
Abbreviations: CRPC = castrate-resistant prostate cancer; DHL = double-hit lymphoma; FNR = false negative rate; 
FPR = false positive rate; N = number of subjects; NMC = NUT-midline carcinoma; ORR = objective response rate; 
RCC = renal cell carcinoma; Res = response; SOC = standard of care; TNBC = triple negative breast cancer; Non-
GC-DLBCL = Non-germinal center diffuse large B-cell lymphoma; 
The planned sample size consists of up to approximately 90 subjects for Part 1 and up to 
approximately 45 subjects for Part 2 Initial expansion for a total of up to approximately 135 
subjects in the entire study (up to Part 2 Initial expansion, as clarified in the scope of this SAP 
document in the beginning).
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6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
This study consists of four periods: Screening (up to 28 days for Part 1 and up to 40 days for Part 
2), Treatment, Clinical Follow-up (30 days), and Survival Follow-up.
6.1.1
Baseline Period
•
The screening period is up to 28 days for Part 1 and up to 40 days for Part 2 and is 
immediately prior to the first study drug administration. The screening period begins by 
establishing the participant’s initial eligibility and signing of the informed consent form 
(ICF).
−
Baseline evaluations or events will be defined as evaluations or events that occur before 
the date and time of the first dose of study treatment unless otherwise specified. 
6.1.2
Post-Baseline Period 
•
The On-treatment period starts at the time of the first dose of study medication and ends 
when the decision to discontinue a subject from study therapy is made.
•
The clinical follow-up period begins when the decision to discontinue a subject from study 
therapy is made, and for subjects treated with BMS-986158 in monotherapy extends until 
30 days after a subject discontinues.
•
The survival follow-up period begins 30 days after a subject discontinues from study 
therapy, and ends 2 years after the first dose of study drug unless continuing on study 
treatment for more than 2 years, or 6 months after his/her last treatment date, whichever 
occurs later.
6.2
Treatment Regimens
The treatment group “as assigned” will be retrieved from the IRT system, if applicable. The 
treatment group “as treated” will be the same as the arm as assigned by IRT. However, if a 
participant received an incorrect treatment for the entire period of treatment, the participant’s 
treatment group will be defined as the incorrect treatment the participant actually received.
Statistical analysis and reporting will be performed based on the treatment regimen assigned to 
subjects at the time of study therapy initiation unless otherwise specified. For Part 1 Schedule A
the 5 days on / 2 days off regimen will be considered as the assigned treatment, even though 
subjects are expected to receive a single dose in Cycle 1 (i.e., the first week of therapy), with the 
exception of the PK analysis where the single dose PK will be presented separately for the Cycle 
1 Week 1 schedule. The regimens administered in Part 1 via Schedules B and C will be handled 
equivalently. Part 2 Schedule A (QD dosing for 5 consecutive days of each week, followed by a 
2-day rest period, on a 28-day cycle) has been chosen for expansion. The initial dose level of BMS-
986158 selected for Part 2 is 4.5 mg with a loading period of 2 weeks (10 doses or half a cycle) 
with subsequent dose level of 3.75 mg for the duration of study treatment for each subject. 
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6.3
Populations for Analyses
•
All Enrolled: All participants who provided an informed consent form.
•
All Treated: All participants who received at least one dose of any study medication.
•
Pharmacokinetic: All participants who received at least one dose of BMS-986158 and have 
available serum or plasma concentration data for the corresponding analyte
•
Pharmacokinetic evaluable: Subset of Pharmacokinetic population with adequate PK Profiles
who have at least 1 valid PK parameter. Pharmacokinetic summaries and statistical analyses 
will be based on this dataset.
•
ECG Evaluable: all treated participants who had a baseline ECG and at least one on study 
ECG.
•
Response-evaluable: all treated participants with measurable disease at baseline and at least 
one of the following: 1) at least one post-baseline tumor assessment, 2) clinical progression, 
or 3) death.
All subjects who receive study medication will be included in the safety population.
7
STATISTICAL ANALYSES
All analyses will be performed using the SAS System Version 9.2 or later. Some figures will be 
generated using S-Plus or R.
7.1
General Methods
Continuous variables will be summarized using descriptive statistics including mean, standard 
deviation (SD), standard errors of the mean (SEM), median, minimum, and maximum. PK 
endpoints will also report geometric means, standard deviations, and standard errors of the mean. 
Categorical variables will be summarized using frequencies and percentages. Percentages will be 
rounded to one decimal precision and may sum to more or less than 100.0. Percentages less than 
0.1 will be indicated as ‘< 0.1’. For summaries, tumor types that have less than 5 participants may 
be grouped together with “Other”.
Time-to-event (TTE) endpoints will be evaluated using Kaplan-Meier (K-M) methods. Regimen 
describes BMS-986158 monotherapyStudy Conduct
7.2.1
Study Information
•
Listing:
•
Batch number listing for all treated subjects will be provided. 
7.2.2
Accrual
The following will be presented using the All Enrolled population.
Summary:
•
Number (%) of participants accrued by country and investigational site: include country, site 
number, number of subjects enrolled, and number of participants treated
•
Listing:
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•
Participants accrued by country and investigational site
7.2.3
Relevant Protocol Deviations
Non-programmable relevant eligibility and on-treatment protocol deviations, as well as significant 
(both programmable and non-programmable) deviations will be reported through ClinSIGHT 
listings. The following programmable deviations from inclusion and exclusion criteria will be 
considered as relevant protocol deviations and a listing will be provided, based on data availability. 
At entrance:
•
Participants with baseline ECOG performance status > 1
•
Participants who used strong inhibitors of CYP3A4 or P-gp within 2 weeks or strong inducers 
of CYP3A4 or P-gp within 2 weeks.
•
Participants with inadequate hepatic function:
−
Aspartate aminotransferase (AST) > 3x ULN 
−
Alanine aminotransferase (ALT) > 3x ULN
−
Total bilirubin > 1.5 x ULN (except known Gilbert’s syndrome)
•
Participants with inadequate bone marrow function:
−
Absolute neutrophil count (ANC) < 1,500 cells/mm3;
−
Platelet count < 100,000 cells/mm3;
−
Hemoglobin < 8 g/dL 
•
Participants with abnormal blood coagulation parameters: 
−
PT such that international normalized ratio (INR) is > 1.5 (or > 3, if a subject is on a stable 
dose of therapeutic warfarin) and a PTT > 1.2x upper limit of normal (ULN).
•
Participants with positive blood screen for hepatitis C antibody or hepatitis B surface antigen
On-Study:
•
Participants receiving concurrent anti-cancer therapy (defined as chemotherapy, hormonal 
immunotherapy, non palliative radiation therapy, standard or investigational agents for 
treatment of NSCLC).
•
Participants who received the wrong dose level
7.3
Study Population
7.3.1
Participant Disposition
Status of participants at the end of pre-treatment period will be summarized and listed by including 
all enrolled participants. Status of participants at the end of treatment period will be summarized 
by treatment and overall, based on All Treated population. In addition, status of participants at the 
end of each study period will be summarized as appropriate. A listing will be provided for those 
participants who were treated and reason for discontinuation of treatment or not being followed 
will be described.
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7.3.2
Demographics and Other Baseline Characteristics
Summary:
Descriptive statistics will be summarized the following baseline characteristics for all treated 
subjects by treatment and overall, and may also be presented by tumor type.
•
Age (in years) ; age category (<65, 65 - 84,≥85),
•
Sex at Birth
•
Race
•
Ethnicity (if applicable)
•
Country 
•
Physical characteristics
−
Height
−
Weight
•
ECOG PS
Listing:
•
All relevant data, generally the variables listed above by treatment.
•
General medical history
7.3.3
Prior Anti-Cancer Therapy
Summary:
Summary statistics will be provided by treatment and overall for each tumor type for:
•
Prior systemic cancer therapy
o
Number of prior therapies and lines of therapy
•
Prior surgery
o
Number of subjects with prior surgery
•
Prior radiotherapy therapy
o
Number of subjects with prior radiotherapy
Listing:
•
Prior surgery and radiotherapy
•
Prior systemic cancer therapy
o
Best response to therapy
7.3.4
Baseline Disease Diagnosis
Summary:
Summary statistics will be provided by treatment and overall and also separately by tumor type.
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•
Baseline Disease Diagnosis, and disease characteristics (e.g. stage)
Listing:
•
Baseline Disease Diagnosis
7.4
Extent of Exposure
Subjects’ extent of BMS-986158 exposure will be characterized using the number of subjects 
exposed, and the duration of exposure by the BMS-986158 dose levels assigned. Analyses in this 
section will be performed using the All Treated population.
Three BMS-986158 dosing schedules in Part 1 will be described: monotherapy single weekly
dosing followed by 1) five consecutive daily doses per week, 2) 14 consecutive daily doses 
followed by 7 days of non-dosing per three week period, 3) 7 consecutive daily doses followed by 
14 days of non-dosing per three week period. BMS-986158 schedule A will be administered in 
Part 2 initial expansion as BMS-986158 Monotherapy. 
Extent of exposure to BMS-986158 will be characterized by the number of oral dosings, duration 
of therapy, cumulative exposure, and absolute and relative dose intensity.
7.4.1
Study Therapy
7.4.1.1
Therapy with BMS-986158
Summary 1:
Descriptive statistics will be provided by treatment and overall for the following.
•
Number (%) of treated subjects exposed for specified periods of time such as less than or equal 
to 1 week, more than 1 but less than 4 weeks, etc.
Summary 2:
Descriptive statistics will be provided by treatment and overall for the following.
•
Number of actual BMS-986158 doses
•
BMS-986158 Duration of therapy (weeks)
-
The (last dosing date - the first dosing date + DI) / 7, where DI is the dosing interval
between the end of the scheduled dose(s) and the start of the next dose(s) in days for 
the study part and dosing schedule(s) administered; the denominator (7) scales the 
duration to units of weeks.
-
As Part 1 consists of a single dose delivered in the first 7 days (Cycle 1), without plan 
to be repeated, a dosing interval in this schedule is not defined, and Part 1 Cycle 1 
will not be included in the summary of the exposure.
-
Dosing Interval (DI) number of days between planned set of doses per a schedule is:
o
Part 1 and Part 2, while “on” dose during the “on cycle”, DI=1 day
o
Part 1, Schedule A, Cycle 2 and beyond, and Part 2, Schedule A: (5 single daily 
doses followed by 2 days of no dosing per week), after 4th consecutive dose for 7 
day cycle, DI=2 days
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o
Part 1, Schedule B (Three Week dosing schedule), after 13th consecutive dose for 
14 day cycle, DI=7 days
o
Part 1, Schedule C (Three Week dosing schedule), after 6th consecutive dose for 
7 day cycle, DI=14 days
-
The duration of therapy will be adjusted for subjects who are known to have died 
prior to receiving the next dose by using instead of DI the number of days between 
the death date and the last dose date. For subjects who discontinued or were lost to 
follow-up, DI will be 
o
Parts 1, 2, using Schedule A, DI= 1 day if they received <=3 of the 5 doses, and 
DI= 2 if they received 4 or 5 doses. 
o
Part 1, using Schedule B, DI will still be set to 7 days if discontinued or lost to 
followup.
o
Part 1, using Schedule C, DI will still be set to 14 days if discontinued or lost to 
followup.
-
Duration of therapy for subjects admitted to Study Part 1 will be left censored to 
exclude the single dose administered on Cycle 1 Day 1. The dose administered on 
Cycle 2 Day 1 will be considered to establish the date of first dose for dose intensity 
and relative dose intensity calculation.  
•
BMS-986158 cumulative dose (mg) is the sum of the actual doses administered to a subject
•
BMS-986158 dose intensity (mg/week) per subject is the ratio of the cumulative dose (mg) 
to the duration of therapy (weeks) for the study part to which the subject is enrolled: 
•
BMS-986158 relative dose intensity (%) is the ratio of the dose intensity (mg/week) to the 
planned dose level per week and is scaled to units of percent for presentation.
−
Relative dose intensity will be summarized using categories: <50%; 50 - < 70%; 
70 - < 90%; 90 - < 110%; ≥ 110%
Listing:
•
Drug administration of BMS-986158
•
Duration of therapy (weeks) , cumulative dosing, dosing intensity, and relative dose intensity
7.4.1.2
Modification of BMS-986158 Therapy
Summary:
•
Descriptive statistics will be provided by treatment and overall for:
−
Number (%) of subjects with dose modifications with reasons.
7.4.2
Concomitant Medications
Concomitant medications, defined as medications other than study medications which are taken at 
any time on-treatment (i.e. on or after the first day of study therapy and within 100 days following 
the last dose of study therapy), will be coded using the UMC WHO Drug Global Dictionary.
Concomitant medication by-subject listing will be provided.
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7.5
Efficacy
•
PCWG3 criteria is intended for Part 2 subjects and not Part 1 subjects. Lugano and PCWG3 
criteria will be used if relevant data is available.
•
The primary efficacy analyses will be performed on All Treated Population for the final 
analysis. Efficacy analyses based on the Response-evaluable Population may be performed as 
supportive analyses. If the majority of All Treated Population is included in Response-
evaluable Population, limited efficacy analyses will be performed on Response-evaluable 
Population (e.g., ORR). 
•
For interim analyses when the minimum follow-up period is less than sufficient to warrant 
adequate interpretation of the result, efficacy analyses may be performed on Response-
evaluable Population.
•
Efficacy results will be presented by treatment and overall, for each tumor type. For efficacy 
endpoints, treatment comprises dose schedule.
•
Efficacy will be reported based on investigator BOR. Investigator reported CR or PR was not
always confirmed by a second scan. Therefore, ORR summaries will be presented regardless 
of confirmation.
Time-to-event distributions (e.g. for progression free survival, 
 and duration of 
response) will be estimated using K-M methodology. When appropriate, the median along with 
95% CI will be provided using Brookmeyer and Crowley methodology59 (i.e., using log-log 
transformations for the construction of confidence intervals). 
Rates at fixed time points (e.g. PFSR at 24 weeks or OS at 12 months) will be derived from the K-
M estimates and corresponding confidence intervals will be derived based on the Greenwood 
formula. Confidence intervals for binomial proportions will be derived using the Clopper-Pearson 
method. Additional time points will be considered based on data availability.
Summary:
The following will be summarized by treatment and overall, for each tumor type.
•
ORR with corresponding 2-sided 95% CI based on Clopper-Pearson method along with each 
category of BOR
•
Duration of response (DOR) with median (95% CI using the log-log transformation method) 
and range (min, max) by K-M method. The number of subjects still in response at the time of 
database lock will be indicated. If the number of responders per tumor type is too small (e.g., 
5 or less confirmed CR or PR in a tumor type), DOR will not be presented.
•
PFS with median (95% CI) and range (min, max) by K-M method. The number of subjects still 
progression free at the time of database lock will be indicated.
•
PFSR at specified timepoints (e.g., Week 24, Week 48) by K-M method using the Greenwood 
formula for confidence intervals
Figure:
•
Percent change from baseline in target lesions over time (aka spider plot)
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Best change in baseline target lesions (aka waterfall plot)
•
K-M plot of duration of response for responders only (if sufficient number of responders, i.e. 
more than 5 confirmed CR or PR in a tumor type)
•
Swimmer plot of time to response, duration of response and tumor progression for all 
participants
•
K-M plot of PFS
•
K-M plot of OS
Listing:
The following will be listed by treatment and tumor type as appropriate.
•
Tumor lesion measurements
•
Tumor evaluation at each visit
•
Participant level efficacy for all treated participants- tumor best overall response (BOR), best
change in tumor burden, PFS, death indicator
•
Duration of response for responders - BOR, time to response, time on therapy, response 
duration
•
Subsequent therapy
7.6
Safety
Analyses of safety will be based on All Treated population and will be presented principally by 
treatment (“as treated”) and overall unless otherwise indicated. Deaths will be summarized by 
schedule.
Adverse events (AEs) will be coded according to the most current version of MedDRA and be 
graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Drug-related AEs are those events with relationship to study drug “Related” as recorded on the 
CRF. If the relationship to study drug is missing, the AE will be considered to be drug-related. 
Listing of AEs will include all enrolled subjects as well as SAEs and deaths, which are collected 
pretreatment. Summaries of AEs will include (1) events occurring from the first dose date to 30 
days (inclusive) after the last dose of BMS-986158 monotherapy for subjects who are off study 
treatment and (2) all events occurring from first dose date for subjects who are still on study 
medication. AEs and treatment-related AEs will be tabulated by descending frequency of SOC and 
descending frequency of PT within each SOC, unless specified otherwise.
When reporting adverse events by CTC grade, summary tables will be provided based on events’
worst CTC grade (independently of relationship to study medication). Subjects will only be 
counted (1) once at the preferred term (PT) level, (2) once at the system organ class (SOC) level, 
and (3) once in the ‘Total subject’ row at their worst CTC grade, regardless of SOC or PT.
Unless otherwise specified, the AE summary tables will be restricted to on-treatment events 
regardless of the causality.
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The analysis of laboratory results will be based on the All Treated population in participants with 
data. Laboratory results will be categorized according to NCI CTCAE (version 4.03) grade. 
Baseline is defined as the last non-missing measurement prior to the first dosing date and time. 
Summaries of laboratory results include baseline and (1) post-baseline results up to 30 days 
(inclusive) after the last dose of BMS-986158 monotherapy for subjects who are off study 
treatment and (2) all available post-baseline results for subjects who are still on study medication.
Vital signs and clinical laboratory test results will be listed and summarized by treatment. Any 
significant physical examination findings and clinical laboratory results will be listed. ECG 
readings will be evaluated by the investigator and abnormalities, if present, will be listed.
7.6.1
Deaths
•
Summary:
All deaths during the study and within 30 days after the last dose of BMS-986158 monotherapy 
will be summarized for causes of death by schedule.
•
Listing:
All recorded deaths for All Enrolled subjects will be listed.
7.6.2
Serious Adverse Events
•
Overall summary of SAEs and treatment-related SAEs by worst CTC grade will be presented 
by SOC/PT. By- participant SAE listing will be provided for the All Enrolled population.
•
Summary:
•
Overall summary of SAEs by worst CTC grade (grade 1, 2, 3, 4, 3-4, 5, unknown) presented 
by SOC/PT
•
Overall summary of treatment-related SAEs by worst CTC grade (Grade 1, 2, 3, 4, 3-4, 5) 
presented by SOC/PT
•
Listing:
A by-subject SAE listing will be provided for the All Enrolled population.
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy
Adverse events leading to study drug discontinuation are AEs with action taken classification of
“Drug was discontinued”.
Overall summary of AEs leading to discontinuation and 
treatment-related AEs leading to discontinuation by worst CTC grade will be presented by 
SOC/PT. By-participant AEs leading to discontinuation listing will be provided.
Summary:
•
Overall summary of AEs leading to discontinuation by worst CTC grade (grade 1, 2, 3, 4, 3-4, 
5, unknown) presented by SOC/PT
•
Overall summary of treatment-related AEs leading to discontinuation by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by SOC/PT.
•
Listing:
•
A by-participant AEs leading to discontinuation listing will be provided.
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7.6.4
Adverse Events Leading to Dose Modification or Delay
AEs leading to dose delay/reduction/interruption will be summarized by treatment and overall if 
sufficient data are available.
Summary:
•
Overall summary of AEs leading to dose reduction by worst CTC grade (grade 1, 2, 3, 4, 3-4, 
5, unknown) presented by SOC/PT.
•
Listing:
•
A by-subject listing of AEs leading to dose delay/reduction/interruption will be provided.
7.6.5
Overall Adverse Events
•
AEs and drug-related AEs will be tabulated by descending frequency of SOC and descending 
frequency of PT within each SOC.
Summary:
•
Overall summary of any AEs by worst CTC grade (grade 1, 2, 3, 4, 3-4, 5, unknown) presented 
by SOC/PT
•
Overall summary of treatment-related AEs by worst CTC grade (grade 1, 2, 3, 4, 3-4, 5) 
presented by SOC/PT.
•
Overall summary of AEs occurring in at least 5% of subjects across treatments. This table will 
be restricted to events with an incidence greater or equal to 5% in any treatment group.
•
Overall summary of non-serious AEs presented by SC/PT. This table will be restricted to 
events with an incidence greater or equal to 5% in any treatment group.
•
Listing:
•
All recorded Adverse Events occurring in the screening, on-treatment, and clinical follow-up 
periods will be listed.
7.6.6
Multiple Events
Analyses that take into account the multiple occurrences of a given adverse event will be 
conducted. In order to prepare these analyses, the CRF data will be processed according to standard 
BMS algorithms60 in order to collapse adverse event records into unique records based on the 
preferred term. This data will be presented as the rate per 100 subject-years of exposure. This 
analysis will take into account all on-treatment events (allowing more than 1 event per subject) 
and the total duration of exposure. The subject-years exposure will be computed as the sum over 
the subjects’ exposure expressed in years where the duration of exposure is defined as: 
•
Date of last dose of study treatment - date of first dose of study treatment + 30+1 days, for 
subject who are off study treatment and were followed at least 30 days after last dose of study 
medication. Units for this calculation are subject-days.
•
Last known date alive - date of first dose of study medication +1, for subjects who are still on-
treatment or who are off study treatment and were followed less than 30 days after last dose of 
study medication. Units for this calculation are subject-days.
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•
Subject-years are defined as the sum of subject-days divided by 365.25 and are rounded to a 
single decimal place of precision.
Summary:
The following summary tables will be provided by treatment and overall and may also be provided 
by schedule.
•
Total number and rate (exposure adjusted, i.e., patient-year event rate) of occurrences for all 
AEs 
Listing:
•
Unique instances of all AEs, i.e., after duplicates have been eliminated and overlapping and 
contiguous occurrences of the same event (i.e., having the same PT) have been collapsed into 
the worst severity observed.
7.6.7
Clinical Laboratory Evaluations
Clinical laboratory data will be analyzed using International System of Units (SI). Analyses will 
be repeated using US conventional units.
Summary:
The number (%) of subjects with the following will be summarized by treatment and overall, if
appropriate, using the worst CTC grade on-treatment per subject.
•
Post-baseline grade
•
Grade change from baseline
•
Descriptive statistics of laboratory test result and their changes from baseline 
Listing:
A by-subject listing of these laboratory parameters will be provided. Laboratory abnormality
criteria and laboratory results outside of normal range will be listed.
7.6.7.1
Abnormal Hepatic Test
Summary:
The number of subjects with the following laboratory abnormalities from on-treatment evaluations 
will be summarized by treatment:
•
ALT or AST > 3 x ULN, > 5 x ULN, > 10 x ULN and > 20 x ULN
•
Total bilirubin > 2 x ULN
•
Concurrent (within 1 day) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN
•
Concurrent (within 30 days) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN
Figure:
•
Scatter plot of Total bilirubin peak vs. AST peak
•
Scatter plot of Total bilirubin peak vs. ALT peak
On-treatment peak total bilirubin and on-treatment peak AST/ALT within 30 days of liver testing
will be plotted.
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Listing:
A by-subject listing of these specific abnormalities will be provided.
7.6.8
Vital Signs, and Other Safety Evaluation
Summary:
Vital sign measurements will be summarized by treatment.
•
Vital signs summary and changes from baseline 
Listing:
•
Vital signs
•
Echocardiogram measurements and findings
•
Physical examination findings
7.6.9
DLT information
Available DLT data as per the database will be listed.
7.7
Pharmacokinetics
All available plasma/serum concentration-time data from participants who receive BMS-986158 
will be reported. The Pharmacokinetic (PK) population will be used for all listings. Evaluable PK 
population will be used for summaries and statistical analyses. Only Part 1 participants will be 
summarized unless there are more than 5 participants in Part 2.
7.7.1
Pharmacokinetic Concentrations
Participant concentration-time profiles will be listed and summarized by treatment and nominal 
collection time for BMS-986158 and Metabolite BMT-161485. Plot of individual concentration 
profiles over time will be provided. Plots of mean (+SD) concentration profiles versus time will 
be presented by treatment (ie, dose schedule, dose and visit) on the same plot. The concentration-
time data will be handled by CPAR&O group.
7.7.2
Pharmacokinetic Parameters
PK parameters for plasma concentrations from subjects who receive BMS-986158 will be 
calculated using non-compartmental analysis. All available plasma concentration-time data from 
subjects who receive BMS-986158 will be reported. All available derived PK parameter values 
will be included in the PK dataset and reported, but only subjects with adequate PK profiles will 
be included in summary statistics and statistical analysis.
PK parameters will be provided separately for parent compound BMS-986158 and Metabolite 
BMT-161485. In general, summary statistics will be tabulated for the pharmacokinetics parameters 
by dose schedule, dose and visit for each select analyte. To assess the attainment of steady state, 
geometric mean Ctrough values will be plotted versus study day by dose schedule and dose.
Effective plasma half life, T-HALFeff will be calculated for Accumulation Index (AI) values of 
AUC(0-24). The formula is as shown in Figure 7.7.2-1 below.
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Figure 7.7.2-1:
Effective Half Life
, where τ is the length of one dosing interval in hours, AI>1.
Summary:
•
Summary statistics will be provided for all parameters listed in Section 4.2.2 by treatment, for 
each dosing schedule.
•
Geometric means and coefficients of variation will be presented for all parameters (including 
Cmax, AUC(0-T), AUC(0-24), AUC(INF), C24, CLT/F, AI_AUC, and T-HALFeff except for 
Tmax). Median, minimum, and maximum will be presented for Tmax. 
•
Dose proportionality analysis for Cmax, AUC(INF) (single dose only) and AUC(0-24) will be 
presented by analyte as warranted by completeness of the data.
•
Means and standard deviations will be presented for other PK parameters like T-HALF. 
•
Figure:
•
Plot of geometric mean Ctrough vs. study day will be presented by dose level for each dose 
schedule. 
•
Scatter plot of AUC(INF) vs. dose level in log-log scale by dose schedule and superposed with 
the regression line from the power model
•
Scatter plot of AUC(0-24) vs. dose level in log-log scale by dose schedule and superposed with 
the regression line from the power model
•
Scatter plot of Cmax vs. dose level in log-log scale by dose schedule and superposed with the 
regression line from the power model
•
Listing:
•
All individual PK parameters will be listed including any exclusions and reasons for exclusion 
from summaries.
7.7.3
Ctrough
Ctrough values will be listed and summarized by dose and time point. To evaluate the steady state 
of BMS-986158 concentration in the body, the geometric means of Ctrough vs. cycle will be 
plotted by dose level for each dose schedule. 
7.7.4
Dose Proportionality
To assess the dose proportionality, the power model described by Gough et al.61
PK Parameter = A*Doseβ
will be estimated by the simple linear regression of the natural log of the PK Parameter (Cmax, 
AUC) on the natural log of Dose:
E[log(PK Parameter)| Dose] = α + β*log(Dose).
A slope (β) equal to 1 would indicate perfect dose proportionality. For each PK parameters (Cmax, 
AUC), the point estimates and 90% CI of the slopes will be provided.
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Plots of individual BMS-986158 PK parameter (Cmax, AUC) values versus dose with fitted 
regression line on a log-log scale will be presented.
Note that dose proportionality analysis may not be performed if there are too few different dose 
levels (e.g. <=2) under some dose schedule.
As MAD studies are neither optimally designed nor powered to confirm the presence or absence 
of meaningful departures from dose proportionality, these results should be interpreted with 
caution. The estimated regression line will be overlaid on the individual points in the 
corresponding scatter plot. For MAD studies, these dose proportionality assessments can be done 
for each day of serial PK sampling, but, unless there are differences from one day to another, only 
the assessments on the last such day will be discussed.
7.9
Electrocardiogram (ECG)
All of the available ECG parameter values, single and triplicates, from each participant will be 
included in the ECG data set. Although all recorded ECG parameter values will be included in the 
data listings, only ECG parameters with scheduled visits will be included in the summary statistics, 
graphs, and statistical analysis. Only Part 1 participants will be summarized unless there are more 
than 5 participants in Part 2.
The triplicate measurements will be averaged at each scheduled measurement timepoints. Baseline 
values are defined as the average of last recorded triplicate values prior to the first dosing. If 
triplicate values are not the last recorded values prior to the first dosing, the last recorded value 
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prior to the first dosing will be used as baseline. For ECG parameters such as QTcF, QT, QTcB, 
heart rate (HR), QRS, and PR, summary measures (n, mean, standard deviation, median, minimum, 
and maximum) will be provided.
Summary:
ECG measurements will be summarized by treatment and study day, for each dose schedule
separately and across dose schedule.
•
ECG measurements will be summarized as follows:
−
The frequency distribution of subjects’ maximum recorded post-dose QTcF, PR, QRS, 
ΔQTcF will be summarized and tabulated for the following ranges:
♦For QTcF: QTcF ≤ 450 msec, 450 msec < QTcF ≤ 480 msec, 480 msec < QTcF ≤ 500 
msec, QTcF > 500 msec
♦For PR: PR ≤ 200 msec, PR > 200 msec
♦For QRS: QRS ≤ 120 msec, QRS > 120 msec
♦For ΔQTcF: ΔQTcF ≤ 30 msec, 30 msec < ΔQTcF ≤ 60 msec, ΔQTcF > 60 msec
−
The frequency distribution of subjects’ maximum recorded post-dose HR and ΔHR and of 
minimum recorded post-dose HR and ΔHR will be summarized and tabulated for the 
following ranges:
♦HR and ΔΗR: HR Value >100 bpm with ΔΗR > 30 bpm or 
♦HR value < 55 bpm with ΔΗR < −15 bpm
−
Summary statistics (n, mean, standard deviation, median, minimum, and maximum) will 
be presented for each ECG parameter and the corresponding changes from baseline by 
treatment and time point.
−
Linear mixed effects regression model of ΔQTcF vs. BMS-986158 will be provided across 
dose schedules at Cycle 1 Day 1 (single dose), and may also be provided separately by 
dose schedule at steady state. The same model will be repeated on the active metabolite 
plasma concentrations if the latter is sufficiently measured
♦The plot of ΔQTcF versus drug concentrations will include the estimated linear 
regression taken from the results of fitting a mixed effect model, if available. Mixed 
effect model with random intercept and slope will be used to explore the relationship 
between the ΔQTcF and plasma concentration data. The following SAS® code is 
recommended.
proc mixed data=Data Set Name method=reml;
class usubjid;
model ΔQTcF =concentration/solution cl alpha=0.10 ddfm=kenwardroger;
random intercept concentration/subject=usubjid type=un;
♦Use of option “empirical” will provide more robust estimate; Start with “type=un”, and 
then examine the covariance structure and adjust to reduce the number of parameters 
to be estimated, as needed. If, however, the SAS log file contains the “Note: Estimated 
G matrix is not positive definite.”, then the variances of the random intercepts or slopes 
may be so small that one or both should be replaced by fixed effects, i.e., dropped from 
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the random statement. The point estimate and 90% confidence interval for the slope 
will be reported within the CSR text
Figure:
•
ECG measures 
−
Scatter plot and regression of ΔQTcF on BMS-986158 concentration (with fitted line) on 
each study day. Scatter plots of QTcF, ΗR, ΔHR on BMS-986158 concentration on each 
study day.
Listing:
•
ECG measures
−
Individual QTcF, PR, QRS, HR, ΔHR, and ΔQTcF values will be listed.
•
ECG abnormalities
8
CONVENTIONS
8.1
Date Conventions
The following conventions may be used for imputing missing or partial dates for analyses requiring 
dates:
AE onset date following Adverse Event Domain Requirements Specification62
AE resolution/end date (these conventions may change)
•
If only the day of the month is missing, the last day of the month will be used to replace the 
missing day. If the imputed date is after the death date or the last known alive date, then the 
latest known alive date or death date is considered as the resolution date.
•
If the day and month are missing or a date is completely missing, it will be considered as 
missing
Non-study medication date
following Non-Study Medication Domain Requirements 
Specification63.
•
Missing and partial radiotherapy and surgery dates will be imputed using algorithm described 
in APPENDIX 1.
Death date
•
If only the day of the month is missing, the 1st of the month will be used to replace the missing 
day. The imputed date will be compared to the last known date alive and the maximum will be 
considered as the death date.
•
If month or the year is missing, the death date will be imputed as the last known date alive. 
•
If the date is completely missing but the reason for death is present the death date will be 
imputed as the last known date alive.
Disease progression date
•
If only the day of the month is missing, the 1st of the month will be used to replace the missing 
day
•
If the day and month are missing or a date is completely missing, it will be considered as 
missing
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•
In case of the date of death is present and complete, the imputed progression date will be 
compared to the date of death. The minimum of the imputed progression date and date of death 
will be considered as the date of progression.
For other partial dates, the following conventions apply:
•
If only the day of the month is missing, the 15th of the month will be used to replace the 
missing day
•
If both the day and the month are missing, “July 1” will be used to replace the missing 
information
•
If a date is completely missing, it will be considered as missing
The following conversion factors will be used to convert days to months or years: 1 month = 
30.4375 days and 1 year = 365.25 days.
Duration (e.g. time-to onset, time-to resolution) will be calculated as follows:
Duration = (Last date - first date + 1)
Last known alive date will be defined based on all appropriate dates collected on the CRF.
All statistical analyses will be carried out using SAS (Statistical Analysis System software, SAS 
Institute, North Carolina, USA) unless otherwise noted.
8.2
Recurrent Events
In order to prepare adverse events for recurrent or multiple event analyses (Section 7.6.6), the CRF 
data will be processed according to standard BMS algorithms64 in order to collapse adverse event 
records into unique records based on the preferred term. This data will be presented as the rate per 
100 subject-years of exposure. This analysis will take into account all on-treatment events 
(allowing more than 1 event per subject) and the total duration of exposure. The subject-years 
exposure will be computed as the sum over the subjects’ exposure expressed in years where the 
duration of exposure is defined as: 
•
Date of last dose of study treatment - date of first dose of study treatment + 100 (or 30 for 
monotherapy)+1 days, for subject who are off study treatment and were followed at least 100
(or 30 for monotherapy) days after last dose of study medication. Units for this calculation are 
subject-days.
•
Last known date alive - date of first dose of study medication +1, for subjects who are still on-
treatment or who are off study treatment and were followed less than 100 (or 30 for 
monotherapy) days after last dose of study medication. Units for this calculation are subject-
days.
Subject-years are defined as the sum of subject-days divided by 365.25 and are rounded to a single 
decimal place of precision.
8.3
Pharmacokinetic Summaries
In-text Tables
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For in-text pharmacokinetic tables, coefficient of variation (%CV) will be reported as integers. For 
other statistics except for standard deviations, values of 100 or higher will be presented as integers, 
values of 10 - <100 will be displayed to one decimal place, and values of 1 - < 10 will be displayed 
to two decimal places. Values less than 1 will be displayed to three decimal places. Ratios will 
also be displayed to three decimal places. Standard deviations will be reported to a precision of 1 
decimal place more than the mean.
Handling of Non-Quantifiable Concentrations
For the summaries of concentration-time data, concentrations that are less than the lower limit of 
quantification (LLOQ) should be displayed as “< LLOQ” in the listings and be treated as missing 
in summary tables and plots. For the purpose of calculating PK parameters, other than Ctrough, 
pre-dose concentrations that are less than LLOQ and concentrations prior to the first quantifiable 
concentration that are less than LLOQ will be set to zero, and all other concentrations less than 
LLOQ will be set to missing.
Summary statistics for Ctrough concentrations, analyses of PD-concentrations and ECG-
concentrations relationships will be calculated by imputing values less than LLOQ as ½ * LLOQ. 
This imputation is done for Ctrough concentrations because it is treated like a PK parameter; the 
imputation is not done for Day 1 pre-dose concentrations. Individual Ctrough listings will display 
these concentrations as “< LLOQ.”
All available concentration-time data and derived pharmacokinetic parameter values will be 
included in the PK data set and listed accordingly.
PK Exclusions
PK Analysis, Reporting, and Exclusion criteria should following the BMS PK Harmonization 
document Version 4.0. Specific guideline for exclusionary criteria for half-life and how other PK 
parameters are affected for exclusion is under section 9.2 of the BMS PK Harmonization 
document.
Exclusion of one or more parameters or the entire dataset may be considered due to incomplete 
profile such as AUC(INF) or when T-HALF cannot be reliably calculated, or there is no sample 
around the suspected Cmax. 
9
CONTENT OF REPORTS
One or more interim analysis reports may be prepared. 
 
 No 
formal adjustments for multiplicity will be employed.
The clinical study report will be prepared to address the clinical objectives and endpoints identified 
in the protocol following closure and locking of the clinical database (CDBL).
All analyses describe in this SAP will be included in final Clinical Study Report (per data 
availability). Refer to the Data Presentation Plan for mock-ups of all tables and listings.
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10
DOCUMENT HISTORY
The history of this document is as shown below in Table 10-1 below.
Table 10-1:
Document History
Version 
Number
Author(s)
Description
1.0
   
Initial approved version
2.0
Revisions to align with revprot02-revprot07
Scope of this SAP is limited to Part 1 and Part 2 
Initial expansion
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APPENDIX 1
MISSING AND PARTIAL RADIOTHERAPY AND SURGERY 
DATES IMPUTATION ALGORITHMS
Procedures – Imputation Rules. 
If reported procedure start date is a full valid date then set start date equal to the date part of 
procedure start date. 
In case of partial date use imputation rules described below: 
•
If only day is missing then 
−
If month and year of procedure match month and year of first dose date then impute as date 
of first dose; 
−
If month and year of procedure don't match month and year of first dose date then impute 
as first day of that month and year. 
•
If both day and month are missing, then impute as maximum between 01JAN of the year and 
date of the first dose; 
•
If date is completely missing or invalid then leave missing. 
Note: Imputation is not applicable to data where start date is not collected (for example "PRIOR 
RADIOTHERAPY" CRF). Set start date to missing in this case. 
If reported end date is a full valid date then set end date equal to the date part of the reported end 
date. 
In case of partial date use imputation rules described below: 
•
If reported end date is partial then set end date equal to the last possible reported end date based 
on the partial entered reported end date. 
•
If reported end date is missing, continuing, unknown or invalid then set end date equal to the 
most recent database extraction date. 
If end date was imputed then compare end date to the death date or last known alive date if subject 
is not dead. If posterior then end date should be imputed to death date (or last known alive date if 
subject not dead). 
Note: Imputation of partial dates only applies to data entered on "RADIOTHERAPY” CRF page. 
For other CRF pages in case of partial dates set end date to missing.
Surgeries – Imputation Rules. 
If reported surgery date is a full valid date then set start date equal to the date part of surgery date. 
In case of partial date, use one of the two imputation rules described below: 
A. For data collected on "PRIOR SURGERY RELATED TO CANCER" CRF page: 
•
If only day is missing then impute as the first day of the month; 
•
If both day and month are missing then then impute as 01JAN of the year; 
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•
If date is completely missing or invalid then leave missing. 
B. For data collected on other CRF pages (deemed to be on-treatment/subsequent surgeries): 
•
If only day is missing then
−
If month and year of surgery match month and year of first dose date then impute the 
missing date as the date of first dose; 
−
If month and year of surgery don't match month and year of first dose date then impute as 
first day of that month and year; 
•
If both day and month are missing then impute as maximum between 01JAN of the year and 
date of the first dose; 
•
If date is completely missing or invalid then leave missing. 
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11
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58 Eisenhauer EA, Therasse P, Bogaerts J, et al. New Response Evaluation Criteria in Solid 
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