Clinical trial NCT03695250
Conditions: Metastatic Hepatocellular Carcinoma Stage III Hepatocellular Carcinoma AJCC v8 Stage IIIA Hepatocellular Carcinoma AJCC v8 Stage IIIB Hepatocellular Carcinoma AJCC v8 Stage IV Hepatocellular Carcinoma AJCC v8 Stage IVA Hepatocellular Carcinoma AJCC v8 Stage IVB Hepatocellular Carcinoma AJCC v8 Unresectable Hepatocellular Carcinoma
Sponsor: Edward Kim
Start date: 2018-10-16; Completion date: 2021-03-12
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase I/II trial studies the side effects and best dose of IDO1 inhibitor BMS-986205 (BMS-986205) when given together with nivolumab and how well it works as first or second line therapy in treating patients with liver cancer. BMS-986205 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as nivolumab, may interfere with the ability of tumor cells to grow and spread. Giving BMS-986205 and nivolumab may work better in treating patients with liver cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To obtain the safety and tolerability of BMS-986205 in combination with nivolumab in unresectable / metastatic hepatocellular carcinoma (HCC) in the first or second line setting using Common Terminology Criteria for Adverse Events (CTCAE) version (V)5.0 criteria.

II. To determine efficacy as defined by objective response rate (ORR) of BMS-986205 in combination with nivolumab in unresectable / metastatic HCC in the first or second line setting using Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1).

SECONDARY OBJECTIVES:

I. To determine disease control rate (DCR), duration of response (DOR), progression free survival (PFS), and overall survival (OS) by RECIST 1.1 and ORR using immune RECIST (iRECIST) of BMS-986205 in combination with nivolumab in unresectable HCC. (Phase II) II. To further evaluate safety of BMS-986205 in combination with nivolumab in unresectable HCC. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of IDO1 inhibitor BMS-986205 followed by a phase II study.

Patients receive IDO1 inhibitor BMS-986205 orally (PO) once daily (QD) on days 1-14 and nivolumab intravenously (IV) over 30 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 100 days, and then every 3 months thereafter.

Arms: arm 1: Patients receive IDO1 inhibitor BMS-986205 PO QD on days 1-14 and nivolumab IV over 30 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: IDO1 Inhibitor BMS-986205 intervention 2: Nivolumab
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
BMS-986205 
 
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UC Davis Comprehensive Cancer Center 
 
 
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PHASE I/II TRIAL OF BMS-986205 AND NIVOLUMAB AS FIRST OR SECOND LINE 
THERAPY IN HEPATOCELLULAR CARCINOMA 
 
Protocol Number: 
UCDCC#276 (BMS #: CA017-084) 
Indication: 
Hepatocellular carcinoma 
Phase: 
I/II 
Funding Source: 
Bristol-Myers Squibb 
Agent(s): 
BMS-986205 in combination with Nivolumab 
Principal Investigator: 
Edward J Kim MD, PhD 
Division of Hematology and Oncology 
UC Davis Comprehensive Cancer Center 
4501 X Street, Suite 3016 
Sacramento, CA 95817 
  
  
 
Co-Investigators: 
Arta M. Monjazeb, MD (Radiation Oncology / Correlative Science) 
May Cho, MD (Medical Oncology) 
Sepideh Gholami, MD (Surgical oncology) 
Kit Tam, MD (Medical Oncology) 
Christopher Bowlus, MD (Hepatology) 
Souvik Sarkar, MD (Hepatology) 
Eric Chak, MD (Hepatology) 
John McGahan, MD (Radiology) 
Michael Corwin, MD (Radiology) 
Ghaneh Fananapazir, MD (Radiology) 
Sima Naderi, MD (Radiology) 
Statistician: 
Susan Stewart, PhD 
Division of Biostatistics 
University of California, Davis 
  
 
 
Protocol History: 
Version 1.0 (Original) 5/1/18 
Version 2.0 (6/21/18) 
Version 3.0 (12/05/18) 
Version 4.0 (09/25/19) 
IND # : 
 
IND Sponsor:  
UC Davis Comprehensive Cancer Center 
 
 


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PROTOCOL SIGNATURE PAGE 
 
Protocol Number: UCDCC#276 
Protocol Title: Phase I/II Trial of BMS-986205 and Nivolumab as First or Second Line Therapy 
in Hepatocellular Carcinoma 
I have read this protocol and agree that it contains all necessary details for carrying out this 
study. I will conduct the study as outlined herein and will complete the study within the time 
designated, in accordance with all stipulations of the protocol and in accordance with Good 
Clinical Practices, local regulatory requirements, and the Declaration of Helsinki.  
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that 
they are fully informed regarding the study agent(s) and the conduct of the study. 
 
 
__________________________________ 
Investigator Name (print)                          
 
__________________________________ 
Investigator Signature  
 
__________________ 
Date  
 
 
 


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PROTOCOL SYNOPSIS 
Title: 
Phase I/II Trial of BMS-986205 and Nivolumab as First or Second Line Therapy in 
Hepatocellular Carcinoma 
Protocol No.: 
UCDC#276 (BMS ISR: CA017-084) 
Phase of 
Development: 
I/II 
Investigational 
Product, Dose 
Regimen 
BMS-986205 100mg daily (provided by BMS at no cost to subject) 
Nivolumab 240mg every 2 weeks (provided by BMS at no cost to subject) 
Primary 
Objective: 
1. To determine the safety and tolerability of BMS-986205 in combination with nivolumab in 
unresectable / metastatic HCC in the first or second line setting using CTCAE V5.0 
criteria.  
2. To determine efficacy as defined by objective response rate (ORR) of BMS-986205 in 
combination with nivolumab in unresectable / metastatic HCC in the first or second line 
setting using RECIST (version 1.1). 
Secondary 
Objective(s): 
1. To determine disease control rate (DCR), duration of response (DOR), progression free 
survival (PFS), and overall survival (OS) by RECIST 1.1 and ORR using immune RECIST 
(iRECIST) of BMS-986205 in combination with Nivolumab in unresectable HCC. 
2. To further evaluate safety of BMS-986205 in combination with Nivolumab in unresectable 
HCC. 
Correlative 
Objective(s): 
1. To analyze serial blood samples for serum cytokine and tryptophan / kynurenine levels, 
and to quantify the number, function, and gene expression of peripheral blood 
mononuclear cells (PBMCs). 
2. To evaluate serial tumor tissue biopsies for tumor infiltrating immune cell subsets, 
expression of immune regulatory proteins including IDO1 and PD-L1, gene expression 
signatures, and mutational load. 
3. To evaluate pre-treatment stool samples for microbiome signatures 
4. To explore potential biomarkers. 
Study Schema: 
Phase I/II study with phase 1 being dose escalation of BMS-986205 with nivolumab and 
phase 2 being an open-label expansion in patients with HCC.  
Study 
Population and 
Sample Size: 
• Unresectable / metastatic HCC in the first or second line setting.  
• 3-12 patients in the phase I (50mg or 100 mg daily of BMS-986205 and 240mg every two 
week of nivolumab)  
• 17 patients in the phase II expansion cohort at MTD (either 50mg or 100mg daily of BMS-
986205 and 240mg every two week of nivolumab) with the 6 patients accrued in the phase 
I at MTD counting towards the total. 
Eligibility 
Criteria  
Inclusion Criteria: 
1. Men and women ≥18 years of age at the time of study entry. 
2. Willing and able to provide written informed consent for the trial. 
3. Life expectancy >12 weeks. 
4. Histologically or imaging confirmed hepatocellular carcinoma (mixed 
hepatocellular/cholangiocarcinoma or fibrolamellar subtypes are excluded). 
5. Have disease that is not amenable for curative treatment approach. 


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6. Have measurable disease based on RECIST v1.1.   
7. ≥1 liver lesions accessible for core biopsy that was either not previously treated by liver-
directed therapy or progressed following liver-directed therapy. 
8. Child-Pugh score of A 
9. ECOG performance status of 0 or 1. 
10. Adequate hematology parameters: 
a) Absolute neutrophil count (ANC) ≥ 1000 cell/mm3 
b) Platelet count ≥ 50,000/mm3 
c) Hemoglobin (Hgb) ≥ 8 g/dL 
11. Acceptable blood chemistry levels: 
a) AST/SGOT, ALT/SGPT ≤ 5 x upper limit of normal (ULN) 
b) Total bilirubin ≤ 2 ULN 
c) Creatinine ≤ 2 x ULN 
12. Subjects with active hepatitis B virus (Hep B) are allowed if antiviral therapy for 
hepatitis B has been given for >8 weeks and viral load is <100 IU/ml prior to first dose 
of trial treatment. Subjects with untreated hepatitis C virus (HCV) are allowed.  
13. Willingness to undergo mandatory pre-treatment biopsy (unless there is adequate 
archival tumor specimen available) and mandatory on-treatment biopsy.  
14. Criterion modified per Amendment v4.0. 
a. Women of child-bearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hr 
prior to planned treatment initiation.  
b. Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception (Appendix 9) for the duration of treatment with study 
treatment(s) plus 5 months post-treatment completion (i.e., 30 days [duration of 
ovulatory cycle] plus the time required for nivolumab to undergo approximately 5 half-
lives). 
c. Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study treatment(s) plus 7 
months post-treatment completion (i.e., 90 days [duration of sperm turnover] plus the 
time required for nivolumab to undergo approximately 5 half-lives). In addition, male 
participants must be willing to refrain from sperm donation during this time. 
d. Males who are sexually active with WOCBP must agree to use a latex or synthetic 
condom during sexual activity (see Appendix 4) for the duration of treatment with study 
treatment plus 7 months after the last dose of the study treatment (i.e., 90 days [duration 
of sperm turnover] plus the time required for nivolumab to undergo approximately 5 
half-lives). This criterion applies to azoospermic males as well. 
e. Investigators shall counsel WOCBP, and male participants 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, which have a failure rate of < 1% when used consistently and correctly. 
Hormonal contraceptives are not considered highly effective methods of contraception 
for participants receiving BMS-986205 in this study who are WOCBP. 
15. Ability to adhere to the study visit schedule and other protocol requirements 
16. Participants must be able to swallow pills intact. 
Exclusion Criteria: 
1. Received more than 1 prior systemic HCC-related therapy or currently receiving HCC-
related systemic treatment or participating in a clinical trial and receiving study therapy. 


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2. Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). 
3. Known diagnosis of immunodeficiency or active autoimmune disease or requiring 
systemic steroid equivalent of prednisone ≥ 10 mg/day or any immunosuppressive 
therapies ≤7 days of before the first dose of the study. 
4. Active bacterial, viral (except Hepatitis B and C - see Inclusion Criterion 12), or fungal 
infection(s) requiring systemic therapy, defined as ongoing signs/symptoms related to 
the infection without improvement despite appropriate antibiotics, anti-viral therapy, 
anti-fungal therapy, and/or other treatment. 
5. Active pneumonitis or history of interstitial lung disease (ILD) / pneumonitis requiring 
steroids. 
6. Clinically significant ascites. 
7. Hepatic encephalopathy. 
8. Any significant medical condition including additional malignancies, laboratory 
abnormalities, or psychiatric illness that would prevent the subject from participating and 
adhering to study related procedures. 
9. Live attenuated vaccine ≤30 days before the first dose of study treatment. Examples of 
live vaccines include, but are not limited to, the following: measles, mumps, rubella, 
chicken pox, yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid 
vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and 
are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated 
vaccines and are not allowed. 
10. Use of strong inhibitor / inducer of CYP3A4 or CYP1A2. 
11. Known history of surgery or medical condition that may affect drug absorption, per 
investigator discretion. 
12. Participants with a history of G6PD deficiency or other congenital or autoimmune 
hemolytic disorders. All participants will be screened for G6PD deficiency prior to 
enrollment using quantitative or qualitative G6PD assay results to suggest underlying 
G6PD deficiency. 
13. Participants with a personal or family (i.e., in a first-degree relative) history or presence 
of cytochrome b5 reductase deficiency (previously called methemoglobin reductase 
deficiency) or other diseases that puts them at risk of methemoglobinemia. All 
participants will be screened for methemoglobin levels prior to enrollment using blood 
methemoglobin > ULN, assessed in an arterial or venous blood sample or by co 
oximetry. 
14. Subjects with screening QTc interval > 480 ms.  
15. Liver directed therapy ≤4 weeks before the first dose of study.  
16. History of esophageal or gastric variceal bleeding within 3 months of study enrollment. 
17. Treatment with botanical preparations (e.g., herbal supplements or traditional Chinese 
medicines) intended for general health support or to treat the disease under study within 
2 weeks prior to enrollment. 
18. Prior history of serotonin syndrome. 
19. Prior treatment with BMS-986205 or any other IDO1 inhibitors.  
20. Women who are breastfeeding.  
21. History or presence of hypersensitivity or idiosyncratic reaction to methylene blue. 
22. History of allergy or hypersensitivity to any study treatment components, specifically to 
that of BMS-986205. 


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23. Participants who have had major surgery requiring general anesthesia or significant 
trauma who have not recovered per physician determination for at least 14 days prior to 
enrollment. 
24. Participants who have had major surgery requiring general anesthesia or significant 
trauma who have not recovered per physician determination for at least 14 days prior to 
enrollment. 
25. Participants with uncontrolled adrenal insufficiency. 
Endpoints: 
Phase I: 
• Safety profile of BMS-986205 in combination with nivolumab in unresectable HCC using 
CTCAE V5.0 criteria 
Phase II:  
• Safety profile of BMS-986205 in combination with nivolumab in unresectable HCC using 
CTCAE V5.0 criteria 
• ORR of BMS-986205 in combination with nivolumab in unresectable HCC using RECIST 
1.1 criteria. 
 
Secondary Endpoints 
• DCR which include CR, PR and SD from the first report of SD or better until progression 
by RECIST 1.1 
• DOR defined by the first report of SD or better until progression by RECIST 1.1 
• ORR using immune RECIST (iRECIST) 
• PFS defined by date of enrollment until the first date of documented disease progression or 
death by RECIST 1.1 
• OS defined by date of enrollment until death from any cause by RECIST 1.1. 
• Correlation of PD-1/L1 expression (+/-) and IDO1 expression (+/-) at:  1) baseline, 2) on 
treatment, and 3) progression, with ORR, PFS and OS. 
 
Statistical 
Considerations 
This is a phase I/II study using a Simon optimal two-stage design for efficacy of BMS-
986205 in combination with nivolumab. In the phase I portion, we will treat patients 
following 3+3 standard design with dose escalation in BMS-986205 along with fixed dose of 
nivolumab.  BMS-986205 dose level 1 will be 50mg and dose level 2 will be 100mg.  3 
patients will be treated with BMS-986205 at dose level 1 of 50mg along with fixed dose of 
nivolumab.  If no patient experiences a DLT at dose level 1, we will add 3 patients will be 
treated at a dose of 100 mg of BMS-986205 with fixed dose of nivolumab.  If 1 of 3 patients 
has a DLT at DL1, we will add 3 patients at a dose of 50 mg.  If ≤1 of 6 patients has a DLT 
at 50mg of BMS-986205, 3 patients will be treated at 100mg.  Maximum tolerated dose will 
be defined as ≤1 of 6 patients at DL1 or DL2 experiencing a DLT.  After identifying the 
MTD, the phase II expansion phase will be initiated with 3 additional patients at the MTD.  
A maximum total of 17 patients at MTD will be treated on trial including 6 patients treated 
during phase I portion at MTD.  An interim efficacy analysis will be done after 9 patients 
(including the 6 patients in phase I portion) have been treated.   If at least 1 patient out of the 
9 initial patients treated at MTD achieves a response, we will accrue 8 more patients at the 
MTD. If at least 3 of the 17 patients treated at MTD achieve a response, we will deem the 
treatment worthy of further study, provided the safety profile is acceptable.  
The Simon optimal two stage design described above provides 80% power to detect the 
difference between an acceptable response rate of 25% vs. an unacceptable rate of 5% at the 
0.05 level (1-sided). The estimated time to accrue 20-23 patients is 18 months, at 
approximately 1.1 patients per month. The ORR will be estimated as the proportion of 
participants who experience an objective response, along with its exact 95% confidence 


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interval; the disease control rate will be analyzed similarly.  DOR, PFS, and OS will be 
analyzed using Kaplan-Meier methods; medians and 95% confidence intervals will be 
computed. DLTs, adverse events, serious adverse events, and clinical laboratory values 
outside normal limits will be listed for each patient and summarized by body system and 
dose level in frequency tables. 
Estimated 
Accrual Period: 
Estimated 
Duration of 
Participation: 
Estimated Study 
Duration: 
24 months 
 
30 months to complete study assessments  
 
36 months   
Correlatives: 
Tissue - Multi-plex IHC/IF for PD-L1, IDO, CD3, FOXP3 and other markers of interest. 
Immune related gene expression analysis. Flow cytometry of fresh tumor core to analyze 
TME with focus on T-cell and dendritic cell activation/functional markers.  TCR deep 
sequencing to evaluate T cell clonal diversity and proliferation. 
PBMCs - Flow cytometry to determine peripheral immune phenotype. Ex-vivo analysis of 
PD-1+ T-cells for proliferative and cytokine production activity and metabolic analysis using 
the Seahorse platform. TCR deep sequencing to evaluate T cell clonal diversity and 
proliferation. 
Plasma - Cytokine analysis by Luminex. Tryptophan and Kynurenine levels. 
Stool – Microbiome Analysis 
 
 
 
 


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STUDY SCHEMA 
General Enrollment Criteria 
• 
Advanced HCC with Child Pugh A  
• 
Age ≥18 
• 
At least one candidate lesion to biopsy  
• 
At least one candidate target lesion for response per RECIST 1.1 
• 
Adequate hematologic and end organ function 
• 
No active autoimmune disease 
• 
No more than 1 prior systemic therapy 
 
 
Phase I Dose Finding 
3+3 Design: (3-6 patients per dose level) 
Dose level 1: 
50 mg PO daily of BMS-986205 + 240mg IV of nivolumab 
Dose level 2: 
100 mg PO daily of BMS-986205 + 240mg IV of nivolumab 
 
Phase II Dose Expansion (Simon Two-stage) Design 
17 patients including those from Phase 1 at MTD  
P0=0.05, p1=0.20, r1=1, n1=16, rTot=3, nTot=30, α=0.05, power=0.8 
 
 
 ≤ 28 days                      D1                    D15                   D29                  D43                  D57                  At Progression                           
// 
Baseline 
Imaging 
Tissue Biopsy 
Correlatives 
Stool Sample 
On Treatment 
Imaging 
Correlatives 
At Progression 
Imaging 
Tissue Biopsy 
Correlatives 
On Treatment 
Tissue Biopsy 
BMS-986205 50mg or 100mg daily 
Nivo 
Nivo 
Nivo 
Nivo 
Nivo 


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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation/Term 
Definition 
°C 
degrees Celsius 
µM 
micromolar 
AE 
adverse event 
ALP 
alkaline phosphatase 
ANC 
absolute neutrophil count 
ALT 
alanine transaminase (SGPT) 
AST 
aspartate transaminase (SGOT) 
BCG 
Bacillus Calmette–Guérin 
BN 
BMS-986205 and nivolumab 
CR 
complete response 
CRC 
clinical research coordinator 
CRF 
case report form 
CRP 
C-reactive protein 
CT 
computed tomography 
CTCAE 
(NCI) Common Terminology Criteria for Adverse Events 
DCR 
disease control rate 
Dbil 
direct bilirubin 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
DSMB 
Data and Safety Monitoring Board 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
EBV 
Epstein-Barr Virus 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
γ-glutamyl transpeptidase 
GLP 
Good Laboratory Practice 
HBV 
Hepatitis B virus 
HCC 
hepatocellular carcinoma 
HCV 
Hepatitis C virus 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonization 
IDO 
indoleamine-2,3-dioxygenase 
IEC 
independent ethics committee 
IND 
Investigational New Drug 
INR 
international normalized ratio 
irAE 
immune related AEs 
IRB 
institutional review board 
IV 
intravenous 
LDH 
lactate dehydrogenase 
MAOI 
Monoamine oxidase inhibitor 
m3 
cubic meters 


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Abbreviation/Term 
Definition 
mg 
milligram 
Min 
minute 
mL 
milliliter 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NSCLC 
non-small cell lung cancer 
OCR 
Office of Clinical Research 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed death-1 
PD-L1 
programmed death-ligand 
PFS 
progression-free survival 
PI 
principal investigator 
PR 
partial response 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RP2D 
recommended phase II dose 
SAE 
serious adverse event 
SCCHN 
squamous cell carcinoma of the head and neck 
SGOT 
Serum glutamic oxaloacetic transaminase (AST) 
SGPT 
Serum glutamic pyruvic transaminase 
SRC 
Scientific Review Committee 
SSRI 
serotonin reuptake inhibitors 
Tbil 
total bilirubin 
TSH 
Thyroid-Stimulating Hormone 
UCD 
University of California, Davis (UC Davis) 
UCDCCC 
UC Davis Comprehensive Cancer Center 
ULN 
upper limit of normal 
US 
United States 
 
 
 


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TABLE OF CONTENTS 
PHASE I/II TRIAL OF BMS-986205 AND NIVOLUMAB AS FIRST OR SECOND LINE 
THERAPY IN HEPATOCELLULAR CARCINOMA ................................................................... 1 
PROTOCOL SIGNATURE PAGE .............................................................................................................. 2 
PROTOCOL SYNOPSIS .............................................................................................................................. 3 
STUDY SCHEMA........................................................................................................................................ 8 
LIST OF ABBREVIATIONS AND TERMS ............................................................................................... 9 
TABLE OF CONTENTS ............................................................................................................................ 11 
LIST OF TABLES ...................................................................................................................................... 13 
LIST OF FIGURES .................................................................................................................................... 13 
1.0 
INTRODUCTION ......................................................................................................................... 14 
1.1 
Cancer Immunotherapy ..................................................................................................... 14 
1.2 
Hepatocellular Carcinoma ................................................................................................ 14 
1.3 
BMS-986205 ..................................................................................................................... 14 
1.4 
Nivolumab ........................................................................................................................ 19 
1.5 
Combination of BMS-986205 and Nivolumab ................................................................. 22 
1.6 
Summary of Available Nonclinical and Clinical Data ...................................................... 24 
1.7 
Correlative Studies ............................................................................................................ 24 
2.0 
STUDY OBJECTIVES .................................................................................................................. 25 
2.1 
Primary Objective ............................................................................................................. 25 
2.2 
Secondary Objectives (Phase II) ....................................................................................... 25 
2.3 
Correlative Objectives ...................................................................................................... 25 
3.0 
STUDY DESIGN .......................................................................................................................... 26 
4.0 
SUBJECT SELECTION ................................................................................................................ 27 
4.1 
Inclusion Criteria .............................................................................................................. 27 
4.2 
Exclusion Criteria ............................................................................................................. 29 
4.3 
Inclusion of Women, Minorities, and Other Underrepresented Populations .................... 31 
5.0 
DOSAGE AND ADMINISTRATION .......................................................................................... 31 
5.1 
Study Drug Administration ............................................................................................... 31 
5.2 
Dose Modification and Management of Toxicity ............................................................. 31 
5.3 
Eligibility Criteria ............................................................................................................. 31 
5.4 
Monitoring ........................................................................................................................ 31 
5.5 
Management of Adverse Events from Immunotherapy .................................................... 32 
5.6 
Definition of Dose-Limiting Toxicity ............................................................................... 38 
5.7 
Treatment Compliance ...................................................................................................... 39 
6.0 
TREATMENT DURATION ......................................................................................................... 40 
6.1 
Discontinuation Criteria .................................................................................................... 40 
7.0 
DURATION OF FOLLOW UP ..................................................................................................... 44 
8.0 
TERMINATION OF TREATMENT AND/OR STUDY PARTICIPATION ............................... 44 
9.0 
CONCOMITANT AND EXCLUDED THERAPIES ................................................................... 45 
9.1 
Concomitant Therapy ....................................................................................................... 45 
9.2 
Prohibited Treatments ....................................................................................................... 45 


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9.3 
Restricted Treatments ....................................................................................................... 46 
9.4 
Other Restrictions and Precautions ................................................................................... 47 
9.5 
Permitted Therapy ............................................................................................................. 47 
10.0 
STUDY CALENDAR ................................................................................................................... 48 
11.0 
STUDY EVALUATIONS ............................................................................................................. 50 
11.1 
Screening Phase ................................................................................................................ 50 
11.2 
Treatment Phase ................................................................................................................ 50 
11.3 
End of Treatment Visit ..................................................................................................... 50 
11.4 
Follow-up Phase ............................................................................................................... 50 
11.5 
Efficacy ............................................................................................................................. 50 
11.6 
Safety ................................................................................................................................ 54 
12.0 
CORRELATIVES ......................................................................................................................... 54 
12.1 
Blood ................................................................................................................................. 54 
12.2 
Tissue ................................................................................................................................ 55 
12.3 
Stool .................................................................................................................................. 55 
13.0 
DRUG INFORMATION ............................................................................................................... 56 
13.1 
BMS-986205 ..................................................................................................................... 56 
13.2 
Nivolumab ........................................................................................................................ 57 
14.0 
STATISTICAL CONSIDERATIONS ........................................................................................... 59 
14.1 
Study Design and Overview of Primary and Secondary Endpoints ................................. 59 
14.2 
Sample Size Estimation /Accrual Rate ............................................................................. 59 
14.3 
Evaluation of Efficacy ...................................................................................................... 59 
14.4 
Evaluation of Safety .......................................................................................................... 59 
15.0 
SAFETY REPORTING OF ADVERSE EVENTS ....................................................................... 60 
15.1 
Adverse Events ................................................................................................................. 60 
15.2 
Procedures for Reporting Adverse Events ........................................................................ 65 
16.0 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE PROCEDURES ........................... 68 
16.1 
Ethics and Good Clinical Practice .................................................................................... 68 
16.2 
Institutional Review Board/Independent Ethics Committee ............................................. 68 
16.3 
Study Documentation ....................................................................................................... 69 
16.4 
Informed Consent ............................................................................................................. 69 
16.5 
Discontinuation of Study Support ..................................................................................... 70 
16.6 
Amendments to the Protocol ............................................................................................. 70 
16.7 
Patient Confidentiality ...................................................................................................... 70 
16.8 
Protocol Deviations ........................................................................................................... 70 
16.9 
Study Close-Out ................................................................................................................ 70 
16.10 Quality Assurance ............................................................................................................. 70 
17.0 
OVERSIGHT AND MONITOROING .......................................................................................... 71 
17.1 
Data and Safety Monitoring .............................................................................................. 71 
17.2 
Investigator Monitoring Guidelines .................................................................................. 72 
18.0 
REFERENCES .............................................................................................................................. 73 
19.0 
APPENDICES ............................................................................................................................... 76 
Appendix 1: ECOG Performance Status Scale .............................................................................. 76 
Appendix 2: Study Registration ..................................................................................................... 77 
Appendix 3: Data Submission Schedule ........................................................................................ 78 


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Appendix 4: Molecular Correlative Sample Handling .................................................................. 79 
Appendix 5: Anaphylaxis Precautions ........................................................................................... 84 
Appendix 6: Child-Pugh Score ...................................................................................................... 85 
Appendix 7: Pill Diaries................................................................................................................. 86 
Appendix 8: Instructions on Taking BMS-986205 ........................................................................ 87 
Appendix 9: Women of Childbearing Potential Definitions and Methods of Contraception ........ 88 
Appendix 10: Adverse Event Management Algorithms ................................................................ 92 
Appendix 11: CYP3A4, CYP1A2 and CYP2B6 Guidance ......................................................... 100 
Appendix 12: Immune RECIST Criteria ..................................................................................... 102 
Appendix 13: Medications Associated with QT Prolongation .................................................... 104 
Appendix 14: P-gp and BCRP Guidance ..................................................................................... 105 
Appendix 15: Agents Known to Cause Methemoglobinemia...................................................... 106 
Appendix 16: BMS-986205 Diagnostic Criteria for HLH and DRESS Syndrome ..................... 107 
 
 
LIST OF TABLES 
Table 1.  Signs and Symptoms of Serotonin Syndrome ............................................................... 36 
Table 2. Best Overall Response Evaluation .................................................................................. 52 
 
LIST OF FIGURES 
Figure 1. Concordance of IDO1 and PD-L1 Expression in Human Sarcoma .............................. 23 
 
 
 
 


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1.0 
INTRODUCTION  
1.1 
Cancer Immunotherapy 
The allure of cancer immunotherapy as a magic bullet against cancer has intrigued researchers 
for over a century.  The rationale underlying anti-cancer immunotherapy stems from the concept 
of immune surveillance first attributed to Ehrlich and colleagues over a century ago[1].  It was 
founded in the idea that tissue rejection is actually a manifestation of an immune surveillance 
mechanism that guards against spontaneous arising tumors.  If such a mechanism does exist then 
it stands to reason that it can be re-invigorated and harnessed to battle malignancy in cancer 
patients.  This idea, in its simplest form, is particularly attractive given that the immune system 
should be able to identify and specifically eradicate malignant cells based on the expression of 
abnormal antigens not expressed or present in normal tissues [2].  On a cellular level antigen 
presenting cells (APCs), such as dendritic cells, phagocytize fragments of dying cancer cells and 
present them on their cell surface.  CD8+ T cells can recognize these abnormal antigens and 
become activated to kill cells expressing that antigen.  CD4+ T cells can either help this process 
by expressing ligands and cytokines which help activate and sustain the APCs or they can 
become immunosuppressive regulatory T cells (Tregs) which express FOXP3 (forkhead box P3) 
and inhibit CD8+ T cells.  In reality this is a gross oversimplification and the true complexity of 
the interactions between the host immune system and cancer are not fully understood but many 
cell types and factors are involved. 
1.2 
Hepatocellular Carcinoma 
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide and US 
and incidence of HCC is rising and estimated 782,000 new cases per year worldwide[3]. Surgery 
is the mainstay of therapy for early stage disease but due to medical comorbidities or advanced 
disease many patients are not candidates for surgical resection or liver-directed therapies and 
effective and tolerable systemic treatment options are desperately needed[4]. The only first line 
systemic therapy is sorafenib, a multi-targeted tyrosine kinase inhibitor (TKI) with moderate 
overall survival (OS) of 3 months over supportive care with commonly intolerable side 
effects[5]. Regorafenib, another multi-targeted TKI was recently approved in the second-line 
setting with median OS 10.6 months compared to 7.8 months with placebo[6]. Nivolumab has 
recently been approved in patients with unresectable HCC, refractory to sorafenib, as second line 
therapy with the objective response rate of 20%[7].  
1.3 
BMS-986205 
BMS-986205 (FLX287 or F-1287) potently and selectively inhibits human IDO1 with no activity 
against another tryptophan degradation enzyme, tryptophan 2,3-dioxygenase (TDO). IDO1 
catalyzes the degradation of tryptophan to N-formyl-kynurenine, which is the first and rate 
limiting step leading to the production of kynurenine and downstream metabolites. The activity 
of IDO1 causes immune tolerance by inhibiting T-cell function through local depletion of the 


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essential amino acid tryptophan and through generation of inhibitory kynurenine pathway 
metabolites. In healthy humans, IDO1 is expressed in the placenta, the mucosa of the female 
genital tract, the lungs, and the lymphoid organs. IDO1 expression in the placenta is believed to 
play a role in maternal tolerance to allogeneic fetuses. However, functional roles of IDO1 in the 
lungs and female genital tract are not as clear, but may be involved in combating infections or 
play a role in immune tolerance. In the immune system, IDO1 is expressed in dendritic cells and 
macrophages. IDO1 is strongly induced by pro-inflammatory mediators such as IFN-γ and 
endotoxins during the late phase of inflammatory reactions, in which its immunosuppressive role 
contributes to the physiologic feedback control of the immune response.  
IDO1 is highly expressed in several types of human malignancies. High levels or frequencies of 
IDO1 expression are detected in multiple tumor types. IDO1 expression in tumors is believed to 
induce immune tolerance as evident by a decrease in tumor infiltration of immune cells and an 
increase in the proportion of regulatory T-cells (Treg) in tumor infiltrating lymphocytic 
populations. Increased IDO1 is also correlated with diverse tumor progression parameters and 
shorter patient-survival times in many cancer indications. IDO1 has been shown to be 
significantly up-regulated together with the programmed death receptor ligand 1 (PD-L1). The 
enzyme is also reported to provide a critical resistance mechanism in anti-tumor T-cell 
immunotherapy targeting CTLA-4. Furthermore, tumor IDO1 transcript is increased in patients 
with advanced melanoma and metastatic renal cell carcinoma (RCC) after treatment with the 
anti-PD-1 antibody nivolumab. These findings suggest that IDO1 is an important regulator of the 
immunosuppressive mechanisms responsible for tumor escape from host immune surveillance. 
Inhibition of IDO1 using pharmaceutical agents such as BMS-986205 may alleviate the 
immunosuppressive properties of the tumor microenvironment and achieve more durable 
responses and greater patient survival benefits, particularly when used in combination with other 
cancer immunotherapy agents, such as nivolumab. 
A series of studies have demonstrated the role of IDO in the immune escape of multiple types of 
tumors, specifically correlating with reduced intratumoral T cell infiltration, disease progression, 
and shorter survival[19].  With regards to HCC specifically, increased expression and activation 
of IDO has been associated with both the early and late phases of liver carcinogenesis. 
Moreover, HCC tumors with IDO overexpression have been associated with poor prognosis[20, 
21] . Notably, persistent IDO expression within the liver microenvironment may play a critical 
role in declining HBV and HCV specific T-cell response [22, 23]. 
Of the studies in humans in which BMS-986205 has been administered as of 15-Nov-2017, 
Study CA017-003, Study CA017-048, and Study CA018-001 include efficacy endpoints. No 
preliminary efficacy data are currently available from Study CA017-048 or Study CA018-001. 
Preliminary efficacy data are available from a 13-Oct-2017 data cutoff date from select cohorts 
from Part 2 (Cohort Expansion) of Study CA017-003, in which BMS-986205 was administered 
with nivolumab in subjects with advanced malignancies. Objective responses have been 
observed in subjects with bladder, cervical, SCCHN, pancreatic, DLBCL, melanoma, NSCLC, 


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renal, triplet negative breast, and endometrial cancers. Mature but preliminary aggregate data 
have been presented for bladder and cervical cancers below (please see IB for more details) 
In a cohort of 25 previously treated advanced bladder cancer subjects, 8 partial responses 
(7 confirmed) led to an objective response rate of 32.0%, with a disease control rate of 44.0%. 
The overall response rate (ORR) was 40% for participants with 1 prior therapy and 20% for 
participants with 2 or more prior therapies. The ORR was 46.2% for PD-L1 positive participants 
(tumor PD-L1 expression 1%), and 22.2% for PD-L1 negative participants (tumor PD-L1 
expression < 1%).  
In a cohort of 22 previously treated advanced cervical cancer subjects, 3 partial responses 
(1 confirmed) led to an objective response rate of 13.6%, with a disease control rate of 63.6%. 
The ORR was 18.2% for participants with 1 prior therapy and 29.1% for participants with 2 or 
more prior therapies. The ORR was 25.0% for PD-L1 positive participants (tumor PD-L1 
expression 1%), and 0% for PD-L1 negative participants (tumor PD-L1 expression < 1%). 
1.3.1 
Safety Profile of BMS-986205 
The overall safety experience with BMS-986205 is based on treatment of 477 subjects to date, 
the majority of whom have been treated with BMS-986205 and nivolumab in Study CA017-003.   
As monotherapy and in combination with nivolumab, BMS-986205 overall has been well 
tolerated in both subjects with malignancies and healthy volunteers.  Treatment-related adverse 
events (TRAEs) have generally been of low grade and are manageable.  The safety profile of 
combination therapy with nivolumab and BMS-986205 has been largely comparable to that of 
nivolumab given as monotherapy.  The most commonly reported TRAEs (in > 10% of subjects) 
during combination therapy with nivolumab were fatigue (14.1%) and nausea (11.1%).  Grade 3 
TRAEs have been reported in approximately 11% of subjects receiving the combination and 
treatment-related SAEs in approximately 7%.  There has been 1 treatment-related death due to 
myocarditis prior to the clinical data cut-off date (15-Nov-2017), which occurred during 
combination with nivolumab, and 2 additional treatment related deaths due to Stevens-Johnson 
syndrome and hepatic failure, both of which occurred after the clinical data cutoff date.  Safety 
data on the combination of BMS-986205 with both nivolumab and ipilimumab are limited at this 
time as only 7 subjects have been treated as of the clinical cutoff date.   
With regard to p-chloroaniline, there have been no clinically significant methemoglobin (metHb) 
events at the 100mg dose level, and the highest reported metHb value was 16% in a subject 
receiving 200mg of BMS-986205; no other subjects had reported metHb levels over 10%, none 
have required specific treatment for methemoglobinemia, and there have been no treatment 
discontinuations due to methemoglobinemia.  Anemia and hemolytic anemia have also occurred 
infrequently (2.5% and 0.3% of subjects receiving combination therapy with nivolumab, 
respectively) and responded to dose holding, reductions, and other standard clinical measures. 


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The selection of the RP2D for BMS-986205 in combination with nivolumab is primarily based 
on available data from the ongoing Phase 1/2, first-in-human Study CA017-003. While 200 mg 
QD was the MTD established in dose escalation of BMS-986205 in combination with 
nivolumab, preliminary PK, PD, and safety data support the selection of 100 mg QD. At 100 mg, 
preliminary PK data indicated that average trough plasma levels of BMS-986205 exceeded the in 
vitro human whole blood IC90. Significant and sustained inhibition of serum kynurenine levels 
was observed at all dose levels. PK-pharmacodynamic analysis of BMS-986205 exposure and 
kynurenine inhibition further suggests the effects to plateau at doses starting at 100 mg QD. 
Maximum inhibition of serum kynurenine levels was predicted to be similar at 100 mg QD and 
200 mg QD. Marked but variable inhibition of intratumoral kynurenine levels was also observed 
at both dose levels.  
The preliminary safety data presented herein from Study CA017-003 indicate that BMS-986205 
is safe and tolerable at both 100 mg QD and 200 mg QD. The data suggest a more favorable 
tolerability profile at 100 mg, with fewer participants experiencing treatment-related ≥ Grade 3 
AEs (10.9% at 100 mg QD [n=303] versus 23.5% at 200 mg QD [n=68]) and TRAEs requiring 
dose discontinuation (3.6% versus 5.9%, respectively) in subjects receiving the 100 mg QD dose. 
Furthermore, treatment-related Grade 3 anemia was reported in 0.3% of subjects receiving the 
100 mg dose versus 4.4% of subjects receiving the 200 mg dose, and hepatic events may also 
occur more frequently at 200 mg compared to 100 mg (see Section 7.1.2). Lastly, a single case of 
methemoglobin elevation over 10% occurred in a subject receiving 200 mg, while the peak 
methemoglobin reported in the 100 mg group was 6%. No formal evaluation of efficacy between 
the 100 and 200 mg dose was included in the study or planned for future studies, but responses 
have been seen in subjects treated with both doses when combined with nivolumab. 
In summary, BMS-986205 at 100 mg QD achieves trough plasma concentrations that exceed the 
human whole blood IC90, produces substantial serum kynurenine reductions similar to those 
observed at higher dose levels, demonstrates target engagement in the tumor microenvironment, 
appears (in combination with nivolumab) to have a more favorable tolerability profile compared 
to higher doses and overall similar to that of nivolumab monotherapy, and demonstrates clinical 
activity in combination with nivolumab[24]. Based on this evidence, BMS-986205 100 mg QD 
is the recommended phase 2 Dose (RP2D) in combination with nivolumab. For this study, we 
have chosen 50 mg QD as the starting dose level to be given with nivolumab 240mg to observe 
hepatotoxicity in an HCC population. BMS-986205 will be escalated to 100 mg QD with 
nivolumab when dose 1 level is shown to be tolerated.  
 
 


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1.3.2 
BMS-986205 Dose Justification 
All participants enrolled will receive BMS-986205 50 mg or 100 mg PO QD according to each 
cohort in combination with nivolumab 240mg Q2W. The selection of the dose and schedule for 
BMS 986205 is primarily based on available data from the ongoing Phase 1/2, first-in-human 
Study CA017003. 
While 200 mg QD was the MTD established in dose escalation of BMS-986205 in combination 
with nivolumab, preliminary PK, PD, and safety data support the selection of 100 mg QD. At 
100 mg, preliminary PK data indicated that average trough plasma levels of BMS-986205 
exceeded the in vitro human whole blood IC90. Significant and sustained inhibition of serum 
kynurenine levels was observed at all dose levels. PK-pharmacodynamic analysis of BMS-
986205 exposure and kynurenine inhibition further suggests the effects to plateau at doses 
starting at 100 mg QD. Maximum inhibition of serum kynurenine levels was predicted to be 
similar at 100 mg QD and 200 mg QD. Marked but variable inhibition of intratumoral 
kynurenine levels was also observed at both dose levels. 
The preliminary safety data presented herein from Study CA017-003 indicate that BMS-986205 
is safe and tolerable at both 100 mg QD and 200 mg QD. The data suggest a more favorable 
tolerability profile at 100 mg, with fewer participants experiencing treatment-related ≥ Grade 3 
AEs (10.9% at 100 mg QD [n=303] versus 23.5% at 200 mg QD [n=68]) and TRAEs requiring 
dose discontinuation (3.6% versus 5.9%, respectively) in participants receiving the 100 mg QD 
dose. 
Furthermore, treatment-related Grade 3 anemia was reported in 0.3% of participants receiving 
the 100 mg dose versus 4.4% of participants receiving the 200 mg dose, and hepatic events may 
also occur more frequently at 200 mg compared to 100 mg (see Section 7.1.2 of the Investigator 
Brochure). Lastly, the only methemoglobin elevation over 10% occurred in a participant 
receiving 200 mg, while the peak methemoglobin reported in the 100 mg group was 6%. 
No formal evaluation of efficacy between the 100 and 200 mg dose was included in the study or 
planned for future studies, but responses have been seen in participants treated with both doses 
when combined with nivolumab. 
1.3.3 
Justification for Administration of BMS-986205 with Food 
Effect of food on the PK of BMS-986205 was evaluated in healthy subjects in Study CA017 053. 
Preliminary PK data indicate that following a single 100 mg dose, BMS-986205 geometric mean 
Cmax and AUC(0-168h) are 114% and 52.8% higher, respectively, when dosed after a high fat 
meal compared to under fasting condition. BMS-986205 Cmax and AUC(0-168h) are 96.5% and 
42.6% higher respectively, when dosed after a light meal compared to under fasting condition. 
Tmax ranged from 2 hours to 4 hours when dosing fasted and from 2 hours to 5 hours when 
dosed after a meal. PK variabilities are generally smaller when dosed after a meal. The terminal 
half-life averaged from 52 hours to 62 hours across the treatment groups. In preclinical studies in 


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dogs, approximately 2- to 3-fold higher exposures were observed when BMS-986205 was 
administered with food compared to under fasting condition. In the ongoing Study CA017003, 
BMS-986205 has been administered after a light meal in order to optimize its systemic exposure. 
Effects of food on the PK of BMS-986205 are further evaluated in a clinical pharmacology 
substudy in oncology participants in Study CA017003. Available preliminary PK results suggest 
a moderate effect of food on exposure to BMS-986205 in humans compared to that observed in 
dogs. In 7 participants, the geometric mean (90% CI) Cmax and AUC (0 168h) for BMS-986205 
were 23% (-17%, 80%) and 43% (11%, 84%) higher when administered with a high fat meal 
compared to under fasting conditions. Preliminary data are also available in 4 participants who 
received BMS-986205 with both a high fat meal and a light meal. The geometric mean (90% CI) 
Cmax and AUC(0-24h) for BMS-986205 were 17% (-18%, 66%) and 13% (-15%, 49%) higher, 
respectively, when administered with a high fat meal compared to dosing with a light meal. 
Observed variability in BMS-986205 PK was generally similar among the different dosing 
conditions. Given the modest exposure differences observed between dosing with a high fat meal 
vs a light meal, BMS-986205 will be administered after a meal in the current study without 
further restriction on the types of meal. 
Based on these results, the BMS-986205 is recommended to be taken after a meal in the current 
study. 
1.4 
Nivolumab 
Nivolumab (also referred to as BMS-936558, MDX1106, or ONO-4538) is a human monoclonal 
antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the programmed death-1 
(PD-1) cluster of differentiation 279 (CD279) cell surface membrane receptor. PD-1 is a negative 
regulatory molecule expressed by activated T and B lymphocytes.1 Binding of PD-1 to its 
ligands, programmed death–ligands 1 (PD-L1) and 2 (PD-L2), results in the down-regulation of 
Lymphocyte activation. Inhibition of the interaction between PD-1 and its ligands promotes 
immune responses and antigen-specific T-cell responses to both foreign antigens as well as Self-
antigens. Nivolumab is expressed in Chinese hamster ovary (CHO) cells and is produced using 
standard mammalian cell cultivation and chromatographic purification technologies. The clinical 
study product is a sterile solution for parenteral administration. 
The pharmacokinetics (PK), clinical activity, and safety of nivolumab have been assessed in 
subjects with non-small cell lung cancer (NSCLC), melanoma, clear-cell renal cell carcinoma 
(RCC), classical Hodgkin Lymphoma (cHL), urothelial carcinoma (UC), squamous cell 
carcinoma of the head and neck (SCCHN), in addition to other tumor types [25]. Nivolumab 
monotherapy is approved in multiple regions, including the US and EU, for unresectable or 
metastatic melanoma, previously treated metastatic NSCLC, previously treated advanced RCC, 
previously treated relapsed or refractory cHL, and previously treated advanced or metastatic UC, 
previously treated recurrent or metastatic SCCHN and previously treated HCC in the US. In 
addition, nivolumab has been approved for use in combination with ipilimumab for unresectable 


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melanoma in multiple countries, including the US and EU. Nivolumab is being investigated both 
as monotherapy and in combination with chemotherapy, targeted therapies, and other 
immunotherapies for the treatment of several types of cancer. Single dose nivolumab 
monotherapy is also being investigated for the treatment of sepsis.   
The HCC tumor microenvironment has been shown to have an abundance of immunosuppressive 
factors and the correlation between the presence of tumor infiltrating lymphocytes and outcomes 
present an opportunity for immunotherapeutic approaches in this disease setting[26]. PDL-1 
overexpression is shown to have poor prognosis in HCC. The safety and efficacy of nivolumab 
were evaluated in a phase 1/2 dose escalation and expansion trial in patients with advanced HCC 
among whom a majority of patients had progressed on prior sorafenib [7]. In that study, 48 
patients participated in a dose escalation phase (which allowed Child-Pugh score (CP) of 7 or 
less) and 214 patients were treated in the dose expansion phase limited to patients with CP 6 or 
less. The objective response rate was 15% in dose-escalation phase and 20% in dose expansion 
phase. Interestingly, patients with no prior therapy experienced better objective response of 23% 
and 9 month overall survival of 82%. Transient reduction in HCV RNA was observed in some 
patients and no viral reactivation was reported in the study. 
Any grade and grade 3/4 treatment-related adverse were reported in sixteen (7%) and nine (4%) 
patients respectively. Grade 3/4 adverse events were observed as AST increase in nine (4%), 
ALT increase in five (2%), diarrhea in three (1%) and fatigue in three (1%). 
1.4.1 
Justification for Nivolumab Dose 480 mg Q4W  
The US FDA has recently approved nivolumab 480 mg Q4W for the indications of adjuvant 
melanoma, unresectable and metastatic melanoma, metastatic NSCLC, advanced RCC, cHL, 
head & neck cancer, and urothelial carcinoma and hepatic carcinoma (HCC). The EMA has 
recently approved nivolumab 480 mg Q4W for the indications of advanced melanoma and RCC. 
Data in support of the 480 mg dosing regimen for these indications included extensive clinical 
pharmacology analyses, population pharmacokinetic and safety analyses, using data from studies 
in multiple tumor types with body weight-normalized dosing (mg/kg). A flat dose is expected to 
reduce prescription dosing errors, shorten pharmacy preparation time, and improve ease of 
administration. Extending the dosing interval to 4 weeks provides numerous benefits to patients 
as they would have increased flexibility between clinical visits. The PPK analyses have shown 
that exposure to nivolumab increased dose proportionally over the dose range of 0.1 to 10 mg/kg 
administered Q2W, and no clinically meaningful differences in PK across ethnicities and tumor 
types were observed. Nivolumab clearance and volume of distribution were found to increase as 
body weight increases but less than proportionally with increasing weight, indicating that 
milligram-per-kilogram dosing represents an over-adjustment for the effect of body weight on 
nivolumab PK.  
Using the PPK and exposure-response models, nivolumab exposures and probabilities of efficacy 
responses and risks of AEs were predicted following nivolumab 480 mg Q4W and were 


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comparable to those following nivolumab 3 mg/kg Q2W. The overall distributions of average 
nivolumab steady state exposures (Cavgss) were comparable following administration with 
either nivolumab 3 mg/kg Q2W or nivolumab 480 mg Q4W over a wide range of body weight 
ranges. Nivolumab 480 mg Q4W is predicted to result in approximately 43% greater steady state 
peak concentrations (Cmaxss) compared to nivolumab 3 mg/kg Q2W; however, these exposures 
are predicted to be lower than the exposure ranges observed at doses up to nivolumab 10 mg/kg 
Q2W used in the nivolumab clinical program. Although the Cmaxss of nivolumab is expected to 
be greater following nivolumab 480 mg Q4W compared to nivolumab 3 mg/kg Q2W, the 
predicted Cmaxss following nivolumab 480 mg Q4W is well below the median Cmaxss achieved 
following administration of nivolumab 10 mg/kg Q2W, a safe and tolerable dose level.  
Exposure-safety analysis demonstrated that the exposure margins for safety are maintained 
following nivolumab 480 mg Q4W, and the predicted risks of discontinuations due to AEs or 
death, AE ≥ Grade, and IMAEs Grade 2+, are predicted to be similar following nivolumab 480 
mg Q4W relative to nivolumab 3 mg/kg Q2W across tumor types. Safety analyses using 
available data following nivolumab 3 mg/kg Q2W and 10 mg/kg Q2W administration indicated 
there were no differences in AE profiles across body weight groups. Finally, initial evidence 
demonstrates that, following administration of nivolumab 480 mg Q4W, nivolumab has been 
well tolerated. 
Nivolumab 480 mg Q4W is predicted to have approximately 16% lower steady-state trough 
concentrations (Cminss) compared to nivolumab 3 mg/kg Q2W. While these exposures are 
predicted to be lower, they are on the flat part of the exposure-response curves and are not 
predicted to affect efficacy. Exposure-efficacy analyses of multiple PK measures and efficacy 
endpoints (eg, OS, ORR) indicated that, following administration of nivolumab 480 mg Q4W, 
efficacy is predicted to be similar to that following administration of nivolumab 3 mg/kg Q2W 
across multiple tumor types. Based on these data, nivolumab 480 mg Q4W is expected to have 
similar efficacy and safety profiles to nivolumab to nivolumab 240 mg Q2W or nivolumab 3 
mg/kg Q2W.  
1.4.2 
Justification for Nivolumab 30-Minute Infusion 
Long infusion times place a burden on participants and treatment centers. Using shorter infusion 
times of 30 minutes duration in participants will diminish the burden provided there is no change 
in safety profile. The US FDA has recently approved nivolumab 30-minute infusion with both 
240 mg Q2W and 480 mg Q4W. Previous clinical studies show that nivolumab has been 
administered safely over 60 minutes at doses ranging up to 10 mg/kg over a long treatment 
duration. For example, in CA209010 (a Phase 2, randomized, double-blinded, dose-ranging 
study of nivolumab in participants with advanced/metastatic, clear cell RCC, N = 167), a dose 
association was observed for infusion site reactions and hypersensitivity reactions (5.1% at 0.3 
mg/kg, 3.7% at 2 mg/kg and 18.5% at 10 mg/kg). All the events were Grade 1 - 2 and were 
manageable. The safety of nivolumab 3 mg/kg administered as a 30-minute infusion was 


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assessed in CA209153 in participants with previously treated advanced NSCLC. Overall, there 
were no clinically meaningful differences in the frequency of hypersensitivity/infusion-related 
reactions (of any cause or treatment-related) in participants administered nivolumab over a 30 
minute infusion time compared with that reported for participants with the 60-min infusion time. 
An infusion duration of 30 minutes for nivolumab 480 mg (~ 60% of the dose provided at 10 
mg/kg) is not expected to present any safety concerns compared to the prior experience at 10 
mg/kg nivolumab dose infused over a 60-minute duration. Key safety results from the interim 
safety population of CA209511 (Part 2) demonstrate that the safety profile of nivolumab 480 mg 
IV over 30 minutes Q4W (N=142) is consistent with the established safety profile of nivolumab 
(3 mg/kg Q2W administered IV over 60 minutes) across multiple indications with respect to 
Grade 3 4 AEs, SAEs, AEs leading to discontinuation, and IMAEs including 
hypersensitivity/infusion reactions IMAEs. There were no new safety concerns identified. In 
addition, in Study CA017003, the Phase 1/2a trial of BMS-986205 combined with nivolumab, 
nivolumab was administered at doses of 240 mg Q2W and 480mg Q4W, both over 30 minutes, 
in combination with BMS-986205 given daily. There have been no signals of adverse tolerability 
with nivolumab given over 30 minutes at a dose of 480 mg Q4W in that study. 
1.5 
Combination of BMS-986205 and Nivolumab  
Despite the overall impressive results of immune checkpoint inhibitors as therapeutic anti-cancer 
agents, clinical efficacy of PD-(L)1 pathway inhibition as a monotherapy has been limited to 
subsets of patients, with response rates of 20% or less in most tumor types.  Additionally, many 
responsive patients eventually develop resistance to monotherapy, making combinatorial 
strategies attractive. 
Preclinical and clinical data suggest that IDO may be a pathway contributing to primary and 
acquired resistance of PD-(L)1 inhibitors. Both pathways are up-regulated by interferon 
signaling suggesting that many PD-L1 positive tumors may also up-regulate IDO. Our data from 
clinical sarcoma samples confirms this (Figure 1) and others have demonstrated this in 
NSCLC[27]. Additionally, preclinical data and preliminary clinical reports have shown synergy 
of IDO inhibitors and immune checkpoint blockade[19]. Inhibition of IDO inhibition in 
combination with Ipilimumab in patients with advanced melanoma suggested potential improved 
overall response rates and PFS in immunotherapy-naïve patients compared to monotherapy 
(NCT01604889).  Importantly, early reports also suggest the relative safety of combining IDO 
and checkpoint inhibition. A number of clinical trials are currently underway testing 
combinatorial strategies of IDO inhibitors plus CTLA-4 or PD-(L)1 inhibition in various tumors 
with promising results in preliminary reports.   
Phase I/II study of the ECHO-202/KEYNOTE-037 trial showed that combination of IDO1 
inhibitor (epacadostat) and pembrolizumab produced ORR of 56% and DCR of 71% in untreated 
melanoma patient. The median PFS was 12.4 months for all protocol patients. Response occurred 
in all subgroups including BRAF positive or negative tumor, normal vs elevated LDH, the 


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presence or absence of liver metastases. The most common adverse events were rash (46%), 
fatigue (43%), pruritus (29%), arthralgia (17%), diarrhea (15%), nausea (12%), increased AST 
(12%), increased lipase (11%), ALT increased (11%), and liver enzyme elevation (11-12%). 
However, only 4 patients (6%) discontinued the study due to adverse event[28].  
In particular, the CA017-003 Phase 1/2a study reported that the maximum tolerated dose of 
BMS-986205 was 200 mg when combined with nivolumab, [24]. Anti-tumor activity was found 
during the dose expansion phase of BMS-986205 100mg among a group of heavily pre-treated 
bladder (25 patients) and cervical cancer patients (22 patients). In the bladder group, the 
objective response rate (ORR) was 32 percent (8/ 25 patients) and the disease control rate (DCR) 
was 44 percent (11/25 patients). In the cervical cancer cohort, ORR was 14 percent (3/ 22 
patients) and DCR was 64 percent (14/22 patients). Patients with more than 1% of PD-L1 had 
ORR of 46% and 25% in bladder and cervical cancer respectively. The combination regimen was 
well tolerated with only 4 patients (1.4%) discontinuing from the study due to the drug toxicity. 
The most commonly reported adverse effect of any grade were fatigue (13.6%), nausea (11.5%), 
and decreased appetite (10.5%). 
Given the success of immune checkpoint blockade in HCC, the existing data for synergistic 
effects with IDO inhibition and the known expression of IDO in HCC, we propose a phase I/IIa 
evaluating the safety and demonstrating the efficacy of BMS-986205 + nivolumab in 
unresectable HCC.   
Figure 1. Concordance of IDO1 and PD-L1 Expression in Human Sarcoma 
 
 
Figure 1: Concordance of IDO1 and PD-L1 expression in human sarcoma 


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1.6 
Summary of Available Nonclinical and Clinical Data 
Refer to the investigator’s brochures for nivolumab and BMS-986205 for preclinical and clinical 
study data. 
1.7 
Correlative Studies  
One of the major shortcomings of immunotherapy trials has been the lack of in depth correlative 
studies to help identify the mechanism of action, identify biomarkers of response, and explain the 
mechanisms governing treatment response or failure. To address this we plan to perform in depth 
immunological analysis of patient blood and tumor samples.  This study incorporates serial 
tissues samples pre-treatment, during therapy and at progression (optional). The design of this 
study allows us to compare immune mechanisms pre-, on- to post-therapy.   
Tumor PD-L1 expression has been linked to response rates of PD-1 checkpoint blockade [29].  
Additionally, little is known about how the pattern of expression (i.e., tumor cells vs. infiltrating 
immune cells) affects response.    Data presented at ASCO and SITC meetings indicate that 
durvalumab monotherapy response rates in NSCLC are 27% in PD-L1 positive tumors and 5% in 
PD-L1 negative tumors.  TILs and a T-cell inflamed phenotype have been linked with response 
to CTLA-4 checkpoint blockade in melanoma [30, 31].  Exclusion of T-cells in the tumor 
microenvironment has also been linked with lack of response to checkpoint inhibition [32] with 
down-regulation of CCL4 mediated dendritic cell recruitment as one potential mechanism [32].  
Whether PD-L1 expression or the presence of TILs is important for response to IDO inhibitors is 
unknown. 
Mutational burden and antigenic load are thought to represent a surrogate for tumor antigenicity 
and have been linked with response to checkpoint blockade in NSCLC [34].  Whether mutational 
load is true indicator of tumor antigenicity and how this correlates with response to IDO 
inhibitors is unknown. To address this we plan to perform in depth immunological analysis of 
patient blood and tumor samples. We will evaluate immunologic changes systemically and in the 
tumor and tumor microenvironment within patient’s pre to post therapy and across the cohort of 
patients to identify predictive biomarkers and elucidate the mechanistic immunologic effects of 
therapy.  
 
 


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2.0 
STUDY OBJECTIVES  
2.1 
Primary Objective 
1. To obtain the safety and tolerability of BMS-986205 in combination with nivolumab 
in unresectable / metastatic HCC in the first or second line setting using CTCAE V5.0 
criteria.  
2. To determine efficacy as defined by objective response rate (ORR) of BMS-986205 
in combination with nivolumab in unresectable / metastatic HCC in the first or second 
line setting using RECIST (version 1.1).  
 
2.2 
Secondary Objectives (Phase II) 
1. To determine disease control rate (DCR), duration of response (DOR), progression 
free survival (PFS), and overall survival (OS) by RECIST 1.1 and ORR using 
immune RECIST (iRECIST) of BMS-986205 in combination with Nivolumab in 
unresectable HCC. 
2. To further evaluate safety of BMS-986205 in combination with Nivolumab in 
unresectable HCC. 
 
2.3 
Correlative Objectives 
1. To analyze serial blood samples for serum cytokine and tryptophan / kynurenine 
levels, and to quantify the number, function, and gene expression of peripheral blood 
mononuclear cells (PBMCs). 
2. To evaluate serial tumor tissue biopsies for tumor infiltrating immune cell subsets, 
expression of immune regulatory proteins including IDO1 and PD-L1, gene 
expression signatures, and mutational load. 
3. To evaluate pre-treatment stool samples for microbiome signatures 
4. To explore potential biomarkers 
 
 
 


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3.0 
STUDY DESIGN 
This is a phase I/II study using a Simon optimal two stage design for efficacy of BMS-986205 in 
combination with nivolumab as illustrated in the schema. For the phase I portion the primary 
endpoint is to determine safety profile of BMS-986205 in two dose levels with nivolumab in 
unresectable HCC using CTCAE V5.0 criteria. For the phase II portion the primary endpoints are 
safety and toxicity and the objective response rate using the using RECIST criteria. Exploratory 
endpoints include disease control rate (DCR), duration of response (DOR), ORR using iRECIST, 
progression free survival (PFS), overall survival (OS), and correlative studies.   
For phase I dose escalation, up to two dose levels of BMS-986205 will be evaluated: 50 mg daily 
and 100mg daily. These two dose levels were selected based on the clinical data described 
above.  We have chosen 50 mg daily as the starting dose level given the existing safety data for 
this dose and the safe use of this dose in use with other immunotherapy combinations. The dose 
of BMS-986205 will be escalated to 100 mg daily if 0 of the first 3 patients experience a dose 
limiting toxicity (DLT) at 50 mg BMS-986205. Three additional patients will be added to 
receive 50 mg BMS-986205 if 1 of the first 3 patients experiences a DLT. The dose of 
BMS-986205 will be escalated to 100 mg daily if no more than one of six patients experience a 
DLT at 50 mg BMS-986205.The expansion phase will be conducted after MTD is reached, 
which will be defined as no more than one of six patients develops a DLT at 50 mg or 100 mg of 
BMS-986205 daily with nivolumab. If BMS-986205 50mg daily is not tolerated the study will be 
halted and modified after discussion with the principal investigator (PI) and BMS. The 6 patients 
at the maximum tolerated dose in the phase I portion treated at MTD will count towards the 17 
patients needed in the phase II expansion cohort. The phase II cohort will be run as a Simon two-
stage design to allow for early trial stoppage for futility.  We designate an ORR as defined by 
RECIST criteria of 5% as not worthy of further investigation and of 25% as worthy of further 
investigation. In the first stage 9 patients will be accrued and at least 1 response must be 
observed within 6 months of treatment (or longer at PI discretion) to continue the trial (n1=9, 
r1=0) (see study schema).  BMS-986205 will be administered orally daily and nivolumab will be 
administered intravenously until disease progression.   
Toxicity will be assessed using the NCI CTCAE, version 5.0 unless otherwise specified. A DLT 
is defined (See section 5.6) as any of the following that occur during the 56-day DLT period.   
If subjects cannot receive 75% of intended dose of BMS-986205 for reasons other than toxicity 
and did not experience a DLT, they will be replaced for DLT assessment. Subjects treated at 
MTD will be monitored for chronic toxicity for 3 months to determine a recommended Phase 2 
dose (RP2D).  
 
 


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4.0 
SUBJECT SELECTION 
4.1 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for study entry. 
1. Men and women ≥18 years of age at the time of study entry. 
2. Willing and able to provide written informed consent for the trial. 
3. Life expectancy >12 weeks. 
4. Histologically or imaging confirmed hepatocellular carcinoma (mixed 
hepatocellular/cholangiocarcinoma or fibrolamellar subtypes are excluded). 
5. Have disease that is not amenable for curative treatment approach. 
6. Have measurable disease based on RECIST v1.1.   
7. ≥1 liver lesions accessible for core biopsy that was either not previously treated by liver-
directed therapy or progressed following liver-directed therapy.  
8. Child-Pugh score of A. 
9. ECOG performance status of 0 or 1. 
10.  Adequate hematology parameters: 
a. Absolute neutrophil count (ANC) ≥ 1000 cell/mm3 
b. Platelet count ≥ 50,000/mm3 
c. Hemoglobin (Hgb) ≥ 8 g/dL 
11. Acceptable blood chemistry levels: 
a. AST/SGOT, ALT/SGPT ≤ 5 x upper limit of normal (ULN) 
b. Total bilirubin ≤ 2 ULN 
c. Creatinine ≤ 2 x ULN 
12. Subjects with active hepatitis B virus (Hep B) are allowed if antiviral therapy for hepatitis 
B has been given for >8 weeks and viral load is <100 IU/ml prior to first dose of trial 
treatment. Subjects with untreated hepatitis C virus (HCV) are allowed.  
13. Willingness to undergo mandatory pre-treatment biopsy (unless there is adequate archival 
tumor specimen available) and mandatory on-treatment biopsy.   


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14. Criterion modified per Amendment v4.0. 
a.  Women of child-bearing potential (WOCBP) must have a negative serum or 
urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) 
within 24 hr prior to planned treatment initiation.  
b. Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception (Appendix 9) for the duration of treatment with study 
treatment(s) plus 5 months post-treatment completion (i.e., 30 days [duration of 
ovulatory cycle] plus the time required for nivolumab to undergo approximately 5 
half-lives). 
c. Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study treatment(s) 
plus 7 months post-treatment completion (i.e., 90 days [duration of sperm 
turnover] plus the time required for nivolumab to undergo approximately 5 half-
lives). In addition, male participants must be willing to refrain from sperm 
donation during this time. 
d. Males who are sexually active with WOCBP must agree to use a latex or synthetic 
condom during sexual activity (see Appendix 4) for the duration of treatment with 
study treatment plus 7 months after the last dose of the study treatment (i.e., 90 
days [duration of sperm turnover] plus the time required for nivolumab to undergo 
approximately 5 half-lives). This criterion applies to azoospermic males as well. 
e. Investigators shall counsel WOCBP, and male participants 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, which have a failure rate of < 1% when 
used consistently and correctly. Hormonal contraceptives are not considered 
highly effective methods of contraception for participants receiving BMS-986205 
in this study who are WOCBP. 
 
15. Ability to adhere to the study visit schedule and other protocol requirements. 
16. Participants must be able to swallow pills intact. 
 
 
 


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4.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry.  
1. Received more than 1 prior systemic HCC-related therapy or currently receiving HCC-
related systemic treatment or participating in a clinical trial and receiving study therapy. 
2. Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). 
3. Known diagnosis of immunodeficiency or active autoimmune disease or requiring 
systemic steroid equivalent of prednisone ≥ 10 mg/day or any immunosuppressive 
therapies ≤7 days of before the first dose of the study. 
4. Active bacterial, viral (except Hepatitis B and C - see Inclusion Criterion 12), or fungal 
infection(s) requiring systemic therapy, defined as ongoing signs/symptoms related to the 
infection without improvement despite appropriate antibiotics, anti-viral therapy, anti-
fungal therapy, and/or other treatment. 
5. Active pneumonitis or history of interstitial lung disease (ILD) / pneumonitis requiring 
steroids. 
6. Clinically significant ascites. 
7. Hepatic encephalopathy. 
8. Any significant medical condition including additional malignancies, laboratory 
abnormalities, or psychiatric illness that would prevent the subject from participating and 
adhering to study related procedures. 
9. Live attenuated vaccine ≤30 days before the first dose of study treatment. Examples of 
live vaccines include, but are not limited to, the following: measles, mumps, rubella, 
chicken pox, yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. 
Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated 
vaccines and are not allowed. 
10.  Use of strong inhibitor / inducer of CYP3A4 or CYP1A2. 
11. Known history of surgery or medical condition that may affect drug absorption, per 
investigator discretion. 
12.  Participants with a history of G6PD deficiency or other congenital or autoimmune 
hemolytic disorders. All participants will be screened for G6PD deficiency prior to 


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enrollment using quantitative or qualitative G6PD assay results to suggest underlying 
G6PD deficiency. 
13. Participants with a personal or family (i.e., in a first-degree relative) history or presence 
of cytochrome b5 reductase deficiency (previously called methemoglobin reductase 
deficiency) or other diseases that puts them at risk of methemoglobinemia. All 
participants will be screened for methemoglobin levels prior to enrollment using blood 
methemoglobin > ULN, assessed in an arterial or venous blood sample or by 
co oximetry. 
14. Subjects with screening QTc interval > 480 ms.  
15. Liver directed therapy ≤4 weeks before the first dose of study.  
16.  History of esophageal or gastric variceal bleeding within 3 months of study enrollment. 
17. Treatment with botanical preparations (e.g., herbal supplements or traditional Chinese 
medicines) intended for general health support or to treat the disease under study within 
2 weeks prior to enrollment. 
18. Prior history of serotonin syndrome. 
19. Prior treatment with BMS-986205 or any other IDO1 inhibitors. 
20. Women who are breastfeeding. 
21. History or presence of hypersensitivity or idiosyncratic reaction to methylene blue.  
22. History of allergy or hypersensitivity to any study treatment components, specifically to 
that of BMS-986205. 
23. Participants who have had major surgery requiring general anesthesia or significant 
trauma who have not recovered per physician determination for at least 14 days prior to 
enrollment. 
24. Participants who have had major surgery requiring general anesthesia or significant 
trauma who have not recovered per physician determination for at least 14 days prior to 
enrollment. 
25. Participants with uncontrolled adrenal insufficiency.  
 


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4.3 
Inclusion of Women, Minorities, and Other Underrepresented Populations 
Recruitment is open to all minorities and both genders.  Although distributions may vary by 
disease type, our recruitment procedures have been developed to enroll patients who are 
representative of the respective target population.   
 
5.0 
DOSAGE AND ADMINISTRATION 
5.1 
Study Drug Administration 
BMS-986205 is administered orally once day; dosing will vary 50 mg or 100 mg according to 
each cohort (see schema). BMS-986205 is recommended to be taken within 30 minutes after a 
meal. Nivolumab 240 mg is administered intravenously every 14 days (1 cycle = 14 days). 
At the end of the study period, Bristol-Myers Squibb Company will not continue to supply study 
drug to subjects/investigators unless the Sponsor-Investigator chooses to extend their study. The 
investigator is responsible to ensure that the subject receives appropriate standard of care or other 
appropriate treatment in the independent medical judgement of the Investigator to treat the 
condition under study. 
5.2 
Dose Modification and Management of Toxicity 
Measures will be taken to ensure the safety of patients participating in this trial, including the use 
of stringent inclusion and exclusion criteria (see Sections 4) and close monitoring (as indicated 
below and in the study calendar). Refer to section 5.5. 
5.3 
Eligibility Criteria 
Eligibility criteria were selected to guard the safety of patients in this trial.  Results from the 
nonclinical toxicology studies as well as the nonclinical/clinical data from other studies were 
taken into account. 
5.4 
Monitoring 
Safety will be evaluated in this study through the monitoring of all serious and non-serious AEs, 
defined and graded according to NCI CTCAE V5.0.  Patients will be assessed for safety 
(including laboratory values) according to the Study Calendar.  Patients will be followed for 
protocol-related toxicity for 100 days following the last dose of study treatment or until receipt 
of another anticancer therapy, whichever comes first. General safety assessments will include 
serial interval histories, physical examinations, and specific laboratory studies, including serum 
chemistries and blood counts (see Study Calendar for the list and timing of study assessments).  
All serious adverse events (SAEs) will be reported in an expedited fashion. In addition, the 
investigators will review and evaluate observed AEs on a regular basis. 


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Patients who have an ongoing study treatment−related AE upon study completion or at 
discontinuation from the study will be followed until the event has resolved to baseline grade, the 
event is assessed by the investigator as stable, new anticancer treatment is initiated, the patient is 
lost to follow-up, the patient withdraws consent, or until it has been determined that study 
treatment or participation is not the cause of the AE.  
5.5 
Management of Adverse Events from Immunotherapy 
5.5.1 
Dose Delay BMS-986205 and Nivolumab 
BMS-986205 and nivolumab administration should be delayed for the following: 
• Grade 2 non-skin, drug-related AE, with the exception of fatigue, nausea, vomiting and 
anemia 
• Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities 
• Grade 3 skin, drug-related AE 
• Grade 3 drug-related fatigue, nausea, vomiting, and anemia 
• Grade 3 drug-related laboratory abnormality, with the following exceptions:  
o Grade 3 lymphopenia or asymptomatic amylase or lipase elevations do not require 
dose delay 
o Hepatic events should be managed as detailed in Section 5.5.3 
• Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication 
 
In addition, only BMS-986205 should be delayed for the following: 
• Methemoglobin ≥ 15% 
• Clinically significant elevations in methemoglobin (generally 10% with a normal hemoglobin 
level) with any associated Grade 3 AE (hypoxia, dyspnea, confusion, etc.) attributable to 
sustained elevations of methemoglobin and not attributable to another etiology 
• QTcF > 500 msec confirmed by at least 1 repeat ECG and at least 60 msec above baseline 
• If nivolumab dosing is delayed for reasons other than study drug toxicity (e.g., administrative 
issues, holidays, etc.), BMS-986205 dosing should continue uninterrupted 
 
If nivolumab dosing is delayed for reasons other than study drug toxicity (e.g., administrative 
issues, holidays, etc.), BMS-986205 dosing should continue uninterrupted. Participants may 
continue to receive nivolumab during dose delays of BMS-986205 for elevations of 
methemoglobin and associated events, as well as QTcF prolongations.  


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For participants with methemoglobin elevations with associated Grade 3 AEs, if contribution of 
nivolumab to the associated AE cannot be ruled out (e.g., a participant with dyspnea in whom 
pneumonitis has not yet been ruled out), nivolumab dosing should be delayed as well.  If 
BMS-986205 dosing is delayed, dose reduction may be necessary.  
If dosing is resumed after a delay, BMS-986205 may be resumed as soon as the criteria to 
resume treatment are met. Nivolumab should be resumed as soon as possible after criteria to 
resume treatment are met but may be resumed later than BMS-986205 given the differences in 
each drug’s administration.  
Participants who require delay of any study treatment should be re-evaluated weekly or more 
frequently if clinically indicated and resume dosing when re-treatment criteria are met.  
Tumor assessments for all subjects should continue as per protocol even if study drug dosing is 
delayed. 
5.5.2 
Dosage Modification 
5.5.2.1 
Nivolumab Dose Modifications 
No dose modifications for Nivolumab are permitted 
5.5.2.2 
BMS-986205 Dose Modifications 
A dose reduction of BMS-986205 is defined as a change from a 100 mg QD tablet to a 50 mg 
QD tablet.  
 
Doses of BMS-986205 should be reduced for the following AEs attributable to study therapy that 
do not otherwise meet criteria for discontinuation: 
• Grade 3 fatigue, nausea, vomiting, or anemia related to study treatment 
• Methemoglobin >15% 
• Clinically significant elevations in methemoglobin (generally 10%, with a normal 
hemoglobin level) with any associated Grade 3 AE (hypoxia, dyspnea, confusion, etc.) 
attributable to sustained elevations of methemoglobin and not attributable to another etiology 
• QTcF > 500 msec confirmed by at least 1 repeat ECG and at least 60 msec above baseline  
 
Dose modification and interruption of BMS-986205 may occur in the setting of lower grade AEs 
and/or be more conservative than indicated above based on the clinical judgment of the PI. For 
an AE requiring dose modification, BMS-986205 should be interrupted to allow improvement of 
the AE, even if the AE does not otherwise meet criteria for dose delay. 
 
Re-escalation of BMS-986205 will not be permitted once the dose of BMS-986205 has been 
reduced for a participant. 
 


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Only one dose reduction is permitted. The participant must discontinue study treatments if a 
subsequent dose reduction of BMS-986205 is required. 
 
5.5.3 
Protocol-Specific Recommendation for Management of Hepatic Events  
Subjects with advanced HCC generally have underlying cirrhosis with decreased hepatic 
function. They may also have a concomitant chronic viral infection. For this study, the upper 
limits for inclusion were therefore adjusted to account for baseline liver dysfunction. Subjects 
with AST or ALT elevations within the CTCAE Grade 2 range are allowed to enroll in the study. 
This requires a protocol-specific approach for the management of hepatic events outlined as 
follows: 
• Both BMS-986205 and nivolumab should be delayed for 
o Grade ≥2 toxicity in subjects with baseline AST or ALT within normal limit,  
o Grade ≥3 toxicity in subjects with baseline AST or ALT within grade 1 toxicity range 
o Drug related increase in AST or ALT at 2x baseline value or when AST or ALT is 8x 
ULN (whichever is lower) in subjects with baseline AST or ALT in grade 2 toxicity 
range. 
• If AST or ALT levels do not improve with a dose delay of 3 - 5 days or if the levels worsen, 
initiate steroid therapy at 0.5 - 2 mg/kg/day methylprednisolone or oral equivalent. 
• For ALT or AST levels > 8x ULN, initiate steroid therapy promptly at 1 - 2 mg/kg/day 
methylprednisolone or oral equivalent 
• For all subjects initiating steroids, consult the PI within 24 hours after initiation of steroids. 
Gastroenterology consult is recommended. 
• If AST or ALT levels do not improve within 3- 5 days or the levels worsen after the start of 
steroid therapy, discuss with the PI the possibility of adding mycophenolate mofetil at 1 g 
BID. 
• Tapering of steroids can start once AST or ALT levels have declined by one CTCAE grade. 
Taper steroids slowly over no less than 1 month. 
 
As outlined in above, nivolumab and BMS-986205 therapy may resume when AST or ALT have 
returned to patient’s baseline unless the criteria for permanent discontinuation are reached. 
Subjects who require delay of therapy should be re-evaluated weekly or more frequently if 
clinically indicated. It is recommended to monitor elevations in AST or ALT approximately 
every 3-5 days until levels peak or begin to decline. Both therapies can be resumed when re-
treatment criteria are met. The PI must be consulted prior to resuming nivolumab for all subjects 
who required steroid intervention. Tumor assessments for all subjects should continue as per 
protocol even if study drug dosing is delayed.  


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• For participants with baseline up to Grade 2 AST, ALT and/or Total Bilirubin abnormalities, 
dosing may resume when laboratory values return to baseline and management with 
corticosteroids, if needed, is complete. 
• Any drug-related liver function test (LFT) abnormality that meets the following criteria 
require discontinuation: 
o AST or ALT >10 x ULN for >2 weeks 
o AST or ALT >15 x ULN irrespective of duration 
o T. Bilirubin >8 x ULN irrespective of duration for subjects with elevated bilirubin at 
study entry or >5 x ULN for those with normal T bilirubin at entry 
• Subjects with AST, ALT, or bilirubin values meeting discontinuation parameters should have 
treatment permanently discontinued. 
 
5.5.4 
Management of Subjects Exhibiting Serotonin Syndrome (SS) 
The development of serotonin syndrome has been associated with exposure to another 
investigational agent that inhibits the IDO1 enzyme.  No case of serotonin syndrome has been 
observed with administration of BMS-986205.  Given the possibility of a class effect, there is a 
theoretical risk that BMS-986205 could cause an increase in serotonin levels in the brain that 
might trigger serotonin syndrome when administered in combination with serotonergic agents or 
tryptophan supplements. Use caution and monitor for symptoms of serotonin syndrome in 
participants receiving concurrent serotonergic psychiatric medications and/or tryptophan 
supplements. 
This syndrome has been most closely associated with use of MAOIs, Demerol®, or linezolid; all 
of these agents are prohibited during the study.  Selective serotonin reuptake inhibitors (SSRIs) 
and serotonin/norepinephrine reuptake inhibitors (SNRIs) are permitted in the study.  The 
following procedures will be implemented if subjects exhibit the signs/symptoms of SS 
described in Table 1, including tremor; hyperreflexia; and spontaneous, ocular, or inducible 
clonus, together with agitation, fever, diaphoresis, or muscle rigidity: 
• Immediately discontinue BMS-986205 administration.  Administration of other study drugs 
may continue. 
• Immediately interrupt any SSRI or SNRI administration. 
• Provide appropriate medical management of the subject until all signs/symptoms are resolved 
(e.g., IV fluids and/or sympathomimetic amines for hypotension, benzodiazepines for 
agitation, administration of 5-hydroxytryptamine antagonists, such as cyproheptadine). 


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• If subject chooses to withdraw from the study or must restart treatment with SSRI or SNRI, 
the subject should be scheduled for a follow-up visit.  Treatment with SSRI or SNRI may be 
initiated 2 weeks after resolution of signs and symptoms of SS. 
 
Table 1.  Signs and Symptoms of Serotonin Syndrome 
Tremor and hyperreflexia 
Spontaneous clonus 
Muscle rigidity, temperature > 38°C (100.4°F), and either ocular clonus or inducible clonus 
Ocular clonus and either agitation or diaphoresis 
Inducible clonus and either agitation or diaphoresis 
 
5.5.5 
Treatment of Methemoglobinemia Associated with BMS-986205 
5.5.5.1 
Detection  
BMS-986205 may produce a p-chloroaniline metabolite. P-chloroaniline has been associated 
with the production of methemoglobin. Symptoms of methemoglobinemia are related to the lack 
of oxygen delivery to tissues and are proportional to the fraction of methemoglobin, as described 
below for participants with normal hemoglobin levels.  
Symptoms associated with elevations of methemoglobin are as follows: 
0% to 10% 
Usually asymptomatic 
10% to 20% 
Cyanosis without other symptoms 
20% to 50% 
Headache, dyspnea, lightheadedness (possibly syncope), 
weakness, confusion, palpitations, chest pain 
50% to 70% 
Coma, seizures, arrhythmias; acidosis 
> 70% 
Usually death 
 
Note that participants with anemia may experience symptoms at lower methemoglobin 
percentages than listed above, depending on the degree of anemia.  
Increasing levels of methemoglobin may confound the results of standard pulse oximeters, with 
values of around 85% reported consistently as methemoglobin levels increase, regardless of the 
true oxygen saturation. 
When methemoglobinemia is suspected, part of the diagnostic work-up includes evaluation for 
other disorders that can present with a similar clinical picture, including cardiac and pulmonary 
disease. A fresh peripheral blood sample (either venous or arterial) should be sent for evaluation 
of methemoglobin levels; methemoglobin levels may vary with storage of blood. Testing is done 
at Screening, each treatment cycle, or more frequently if clinically indicated based on symptoms. 


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5.5.5.2 
Treatment 
The following management recommendations are intended as guidelines for the investigator and 
may be modified based on institutional practices or local standard of care, as appropriate.  
Initial care includes supportive measures and the administration of supplemental oxygen. In mild 
cases, recovery often occurs simply by interrupting the administration of the offending 
medication. Concomitant medication lists should be reviewed for medications besides study 
treatment which can cause methemoglobinemia  
Further treatment is generally indicated when the methemoglobin level is above 20% or is 
associated with symptoms. 
Intravenous methylene blue is the first-line antidotal agent and works by restoring the oxygen 
carrying capacity of hemoglobin by reduction of methemoglobin from its oxidized state. It is 
given as a 1% solution at a dose of 1 to 2 mg/kg. Most participants require only 1 dose, and 
symptoms should resolve within 1 hour. Methylene blue may confound the interpretation of 
methemoglobin levels detected by co-oximetry; alternative methods should be used after 
treatment with methylene blue if methemoglobin level monitoring is required. Methylene blue 
should be used with caution in participants with concurrent use of serotonergic psychiatric 
medications, as this could increase the risk of serotonin syndrome.  
Exchange transfusion and hyperbaric oxygen treatment are second-line options for participants 
with severe methemoglobinemia whose condition does not respond to methylene blue or who 
cannot be treated with methylene blue. Participant transfer should occur when life-threatening 
methemoglobinemia that is refractory to treatment occurs in a facility that cannot provide the 
appropriate critical care. 
5.5.6 
Criteria to Resume Treatment 
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to 
Grade ≤ 1 or baseline value, with the following exceptions:  
• Subjects may resume treatment in the presence of Grade 2 fatigue. 
• Subjects who have experienced a Grade 3 drug-related skin AE may resume treatment in the 
presence of Grade 2 skin toxicity. 
• Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment 
• Participants with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the Investigator.  
o Adrenal insufficiency requires discontinuation regardless of control with hormone 
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• For participants with Grade 2 AST, ALT and/or Total Bilirubin abnormalities, dosing may 
resume when laboratory values return to baseline and management with corticosteroids, if 
needed, is complete. 
• Participants with combined AST/ALT AND total bilirubin values meeting discontinuation 
parameters should have treatment permanently discontinued. 
 
For participants who have BMS-986205/BMS-986205 held for elevations of methemoglobin, 
dosing may resume when the methemoglobin levels have decreased to below the institutional 
ULN and any associated AEs have resolved to Grade < 1 or baseline value. Dose modification of 
BMS-986205 should be considered when resuming after a delay.  
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab and BMS-986205 are considered as 
immuno-oncology agents in this protocol. Early recognition and management of AEs associated 
with immuno-oncology agents may mitigate severe toxicity. Management algorithms have been 
developed to assist investigators in assessing and managing the following groups of AEs: 
• Gastrointestinal 
• Renal 
• Pulmonary (For participants with dyspnea, CBC and methemoglobin should be measured) 
• Hepatic 
• Endocrinopathy 
• Skin 
• Neurological (For participants with confusion, methemoglobin should be measured) 
 
The above algorithms are found in the Nivolumab IB. 
 
5.6 
Definition of Dose-Limiting Toxicity  
Dose limiting toxicities are defined as any of the items listed below which occur during the first 
6 weeks. 
• Any Grade 2 drug-related uveitis or eye pain that does not respond to topical therapy and 
does not improve to Grade 1 severity within 2 weeks of starting therapy OR requires 
systemic treatment 
• Any Grade 2 drug-related pneumonitis or interstitial lung disease that does not respond to 
dose delay and systemic steroids in 14 days (radiologic changes may take longer to resolve) 
or Grade 2 myocarditis of any duration.  


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• Any Grade 3 or greater nondermatologic, nonhepatic, nonhematologic toxicity will be 
considered a DLT with the following specific EXCEPTIONS: 
o Grade 3 or Grade 4 electrolyte abnormalities that are not complicated by associated 
clinical adverse experiences, last less than 48 hours and either resolve spontaneously 
or respond to conventional medical intervention 
o Grade 3 nausea, vomiting, or diarrhea that lasts less than 48 hours and either resolves 
spontaneously or responds to conventional medical intervention 
o Isolated Grade 3 elevation of amylase or lipase not associated with clinical or 
radiographic evidence of pancreatitis 
o Isolated Grade 3 fever not associated with hemodynamic compromise (e.g., 
hypotension, clinical or laboratory evidence of impaired end-organ perfusion) 
o Grade 3 endocrinopathy that is well-controlled by hormone replacement 
o Grade 3 tumor flare (defined as pain, irritation, or rash that localizes to site of known 
or suspected tumor) 
o Grade 3 fatigue 
o Grade 3 infusion reaction that returns to Grade 1 in less than 6 hours. Any Grade 4 
drug-related adverse event including laboratory abnormalities except Grade 4 
leukopenia or neutropenia lasting < 14 days. 
• Grade 4 methemoglobin levels ≥ 15 % and Grade ≥ 3 hemolysis (i.e., requiring transfusion or 
medical intervention such as steroids) 
• Any of the following drug-related hepatic function laboratory abnormalities: 
o AST or ALT >10x ULN for > 2 weeks 
o AST or ALT > 15 x ULN irrespective of duration 
o T. Bilirubin >5 x ULN irrespective of duration 
If subjects cannot receive 75% of intended dose of BMS-986205 for reasons other than toxicity 
and did not experience a DLT, they will be replaced for DLT assessment. Subjects treated at 
MTD will be monitored for chronic toxicity for 3 months to determine a recommended Phase 2 
dose (RP2D).  
5.7 
Treatment Compliance 
Subjects will be encouraged to comply with all study-related medications by the Investigator, 
pharmacist, and research coordinator. Subjects will be given a pill diary to track medication that 
has been taken. Subjects will bring all bottles of unopened or unused study drug with them to 
each visit. Unused drug tablets will be counted for compliance and recorded. Treatment 
compliance of nivolumab will be documented in the electronic medical record.   
 


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6.0 
TREATMENT DURATION 
Patients will complete therapy unless one of the following criteria applies: 
• Confirmed Disease progression per iRECIST 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse events 
• Patient withdrawal from study (patient choice) 
• Pregnancy 
• Failure of patient to adhere to study requirements 
• Physician Discretion 
• Study termination 
• Patient receives alternative treatment 
 
6.1 
Discontinuation Criteria 
6.1.1 
Discontinuation Due to Disease Progression  
Immunotherapeutic agents such as BMS-986205 and nivolumab may produce antitumor effects 
by potentiating endogenous cancer-specific immune responses.  The response patterns seen with 
such an approach may extend beyond the typical time course of responses seen with cytotoxic 
agents and can manifest as a clinical response after an initial increase in tumor burden or even 
the appearance of new lesions.  
Immune RECIST will be used for assessment of tumor response for the purposes of managing 
subjects on study treatment and decision-making for discontinuation of study therapy due to 
disease progression.  PD should be confirmed no earlier than 4 weeks later according to the 
criteria outlined in Table 2. Subjects who are deemed clinically unstable or who have biopsy 
proven new metastatic lesions are not required to have repeat imaging for confirmation.  This 
decision will be based on the Investigator’s clinical judgment of a subject's overall clinical 
condition, including performance status, clinical symptoms, and laboratory data.  At a minimum, 
subjects must meet the below criteria for continued treatment on study after disease progression 
is identified at a tumor assessment. 
When feasible, subjects should not be discontinued until progression is confirmed; however, the 
decision to continue study treatment after the first evidence of disease progression is at the 
Investigator's discretion based on the clinical status of the subject. 
 
 


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Subjects may receive study treatment while waiting for confirmation of PD if they are clinically 
stable as defined by the following criteria: 
• No decline in ECOG performance status. 
• Absence of new or worsening symptoms. 
• Absence of rapid progression of disease. 
• Absence of progressive tumor at critical anatomical sites (e.g., spinal cord compression) 
requiring urgent alternative medical intervention. 
 
6.1.2 
Discontinuation from Study Treatment 
Participants MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons: 
• Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant 
to provide this information 
• Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the participant 
• Termination of the study by Bristol-Myers Squibb (BMS) 
• Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (e.g., infectious disease) illness. (Note: Under 
specific circumstances, a participant who has been imprisoned may be permitted to continue 
as a participant. Strict conditions apply and BMS approval is required). 
• Additional protocol-specified reasons for discontinuation.  
 
In the case of pregnancy, the investigator must immediately notify the PI of this event. In the 
event a normal healthy female participant becomes pregnant during a clinical trial, the study 
treatment must be discontinued immediately. In most cases, the study treatment will be 
permanently discontinued in an appropriate manner (e.g., dose tapering if necessary for 
participant safety). Please notify the PI within 24 hours of awareness of the pregnancy. If the 
investigator determines a possible favorable benefit/risk ratio that warrants continuation of study 
treatment, a discussion between the investigator and the PI must occur. 
The assessment for discontinuation of nivolumab should be made separately from the assessment 
made for discontinuation of BMS-986205. Although there is overlap among the discontinuation 


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criteria, if discontinuation criteria are met for BMS-986205 but not for nivolumab, treatment 
with nivolumab may continue if BMS-986205 is discontinued. 
If a participant in any of the nivolumab/BMS-986205 combination arms meets criteria for 
discontinuation and investigator is unable to determine whether the event is related to both or 
one study drug, the participant should discontinue both nivolumab and BMS-986205 and be 
taken off the treatment phase of the study. 
6.1.3 
Discontinuation of BMS-986205 
BMS-986205 treatment should be permanently discontinued for the following: 
• Any event requiring discontinuation of nivolumab as in Section 6.1.2 
• Any event requiring more than 1 dose reduction of BMS-986205 (see Section 5.5.2) 
• Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, presents a substantial clinical risk to the participant with continued 
BMS-986205 dosing 
• For participants who delay BMS-986205 but continue nivolumab, any dose delay of 
BMS-986205 lasting > 10 weeks due to toxicity attributable to BMS-986205 and not 
nivolumab (e.g., methemoglobin, hemolysis, or QTc >500 msec) will result in the 
discontinuation of BMS-986205 only, and participants may continue treatment with 
nivolumab after discussion with the PI.  
• Any occurrence of serotonin syndrome 
 
6.1.4 
BMS-986205 and Nivolumab Discontinuation Due to AEs 
BMS-986205 and nivolumab treatment should be permanently discontinued for the following: 
 
• Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within 2 weeks of starting therapy OR 
requires systemic treatment 
• Any event requiring more than 1 dose reduction of BMS-986205 
• Any Grade 3 non-skin, drug-related AE lasting > 7 days or recurs, with the following 
exceptions: 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, neurologic toxicity, 
myocarditis, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation. 
o Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement. 


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o Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except: 
 Hepatic events should be managed as detailed in Section 5.6.4 
 Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding 
requires discontinuation 
 Grade ≥ 3 drug-related AST, ALT or total bilirubin requires discontinuation* 
 Concurrent AST or ALT > 3 × ULN and total bilirubin > 2 × ULN 
 
* In most cases of Grade 3 AST or ALT elevation, study treatment will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that warrants 
continuation of study treatment, a discussion between the investigator and BMS must occur. 
• Any Grade 4 drug-related AE or laboratory abnormality (including but not limited to 
creatinine, AST, ALT, or Total Bilirubin) except for the following events which do not 
require discontinuation: 
o Grade 4 neutropenia ≤ 7 days. 
o Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase. 
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 3 calendar days of their onset. 
o Grade 4 drug-related endocrinopathy AEs, such as, hyper- or hypothyroidism, or 
glucose intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-controlling 
agents, respectively, may not require discontinuation after discussion with and 
approval from the PI.  
• Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, presents a substantial clinical risk to the participant with continued 
BMS-986205 and nivolumab dosing. 
• Any event that leads to delay in dosing lasting > 10 weeks from the previous dose requires 
discontinuation, with the following exceptions: 
o Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs are 
allowed.  
o Dosing delays lasting > 10 weeks from the previous dose that occur for non-drug-
related reasons may be allowed if approved by the PI.  
 
Prior to re-initiating treatment in a participant with a dosing delay lasting > 10 weeks, the PI 
must be consulted. Tumor assessments should continue as per protocol even if dosing is delayed. 


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Periodic study visits to assess safety and laboratory studies should also continue every 4 weeks 
or more frequently if clinically indicated during such dosing delays. 
Participants who are discontinued from nivolumab, must also discontinue BMS-986205. 
7.0 
DURATION OF FOLLOW UP 
All patients will be followed for 100 days after the last dose of treatment with the agent under 
this IND or until all treatment related clinical significant toxicities resolve to baseline or grade ≤ 
1. Adverse events with attribution of possible, probable or definite will be reported following 
guidelines for adverse event reporting and all SAEs will be reported for 100 days after the last 
dose.  Patients will be followed every 3 months per standard of care for PFS and OS until death, 
loss to follow up, consent withdrawal, or study termination.  
8.0 
TERMINATION OF TREATMENT AND/OR STUDY PARTICIPATION 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care. The investigator also has the right to withdraw 
patients from the study for safety, behavioral or administrative reasons.  
The Investigator will make every reasonable effort to keep each patient in the study unless it is in 
the patient’s best interests to discontinue participation.  If a patient is removed from the study or 
declines further participation, all End of Treatment evaluations should be performed if the patient 
is willing and able to be assessed.  A description of the reason(s) for withdrawal from the study 
must be recorded on the case report form (CRF).  The Investigator should also ensure that all 
patients are followed up for survival status after the Final Visit. 
Patients who discontinue following entry will have relevant information completed and recorded 
on the CRF.  All patients who discontinue because of adverse events or clinically significant 
laboratory abnormalities should be followed up until they recover or stabilize, and the 
subsequent outcome will be recorded.  If any patient should die during the trial or within 30 days 
of stopping study treatment, the Investigator will inform the IRB and Sponsor (if applicable)  
The cause of death should be recorded in detail, within 24 hours, on a serious adverse event 
(SAE) form and reported to institutional, federal and any other appropriate committees and/or 
sponsors.  
 


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9.0 
CONCOMITANT AND EXCLUDED THERAPIES 
9.1 
Concomitant Therapy 
The patient must be told to notify the investigational site about any new medications he/she takes 
after the start of the study drug. All medications (other than study drug) and significant non-drug 
therapies (including blood transfusions) administered during the study should be recorded.  
Concomitant therapy includes any prescription medications or over-the-counter preparations 
used by a patient between the 7 days preceding the screening evaluation and the treatment 
discontinuation visit. Medications taken within 14 weeks prior to study treatment administration 
must be recorded on the case report form (CRF). Document vaccine use for 30 days prior to first 
dose of study drug. 
Patients who experience infusion-associated symptoms may be treated symptomatically with 
antipyretics (ibuprofen preferred), diphenhydramine, and/or famotidine or another H2 receptor 
antagonist, as per standard practice. Serious infusion-associated events manifested by dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory 
distress should be managed with supportive therapies as clinically indicated (e.g., supplemental 
oxygen and β2-adrenergic agonists). 
Systemic corticosteroids and TNFα inhibitors may attenuate potential beneficial immunologic 
effects of treatment but may be administered at the discretion of the treating physician.  If 
feasible, alternatives to corticosteroids should be considered.  Premedication may be 
administered for Cycles ≥ 2 at the discretion of the treating physician.  The use of inhaled 
corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic 
hypotension or adrenocortical insufficiency is allowed.  Megastrol administered as appetite 
stimulant is acceptable while the patient is enrolled in the study.  
Patients who use hormone-replacement therapy, prophylactic or therapeutic anticoagulation 
therapy (such as low-molecular-weight heparin or warfarin at a stable dose level), or other 
allowed maintenance therapy should continue their use, unless prohibited.   
9.2 
Prohibited Treatments 
The following medications are prohibited during the study (unless utilized to treat a drug-related 
AE): 
• Concomitant use of strong inhibitors of CYP3A4 and/or CYP1A2 or strong inducers of 
CYP3A4 and/or CYP1A2 (see Appendix 11)  
• Immunosuppressive agents (except used to treat a drug-related AE) 


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• Immunosuppressive doses of systemic corticosteroids (exceptions:  participants are permitted 
the use of topical, ocular, intra-articular, intranasal, and inhalational corticosteroids [with 
minimal systemic absorption]. Adrenal replacement steroid doses > 10 mg daily prednisone 
are permitted. A brief [less than 3 weeks] course of corticosteroids for prophylaxis (eg, 
contrast dye allergy) or for treatment of non-autoimmune conditions [eg, delayed type 
hypersensitivity reaction caused by a contact allergen] is permitted.) 
• Any concurrent anti-neoplastic therapy (i.e., chemotherapy, hormonal therapy, 
immunotherapy, non-palliative radiation therapy, or standard or investigational agents for 
treatment of malignancy) 
• Any botanical preparation (e.g., herbal supplements or traditional Chinese medicines) 
intended to treat the disease under study or provide supportive care.  Please see restrictions 
on use of marijuana in section 9.3.  
• Prophylactic antimicrobial therapy 
• Any live / attenuated vaccine (e.g. varicella, zoster, yellow fever, rotavirus, oral polio and 
measles, mumps, rubella [MMR]) during treatment and until 100 days post last dose. 
 
9.3 
Restricted Treatments 
Restricted therapies are not prohibited but are not recommended; Investigators should consider 
possible benefit/risk implications of enrolling and treating participants in whom the following are 
clearly medically indicated: 
• Grapefruit and Seville oranges and their juices can inhibit CYP3A4 (see Appendix 11) and 
should not be consumed while on treatment. 
• Concurrent use of moderate inhibitors or inducers of CYP3A4 and/or CYP1A2 may affect 
the systemic exposure of BMS-986205. See Appendix 11 for a list of CYP3A4 and CYP1A2 
modulators. 
• Concurrent smoking (tobacco, marijuana, etc.) may induce CYP1A2 and decrease the 
systemic exposure of BMS-986205.  
• Caution is warranted when consuming marijuana by means other than smoking as it may lead 
to increased exposure of BMS-986205 through interaction with metabolic enzymes.  
• Caution is warranted when administering BMS-986205 to participants taking drugs that are 
highly dependent on CYP3A4 or CYP2B6 for metabolism. See Appendix 11 for a list of 
sensitive CYP3A4 and CYP2B6 substrates. 
• Caution is warranted when administering BMS-986205 to participants taking drugs that may 
be associated with QT prolongation. See Appendix 13 for a list of common medications 
associated with QT prolongation. 


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• Caution is warranted when administering BMS-986205 to participants taking drugs that are 
subject to extensive intestinal efflux by P-gp/BCRP. See Appendix 14 for a list of common 
P-gp/BCRP substrates. 
• In vitro solubility data indicate that BMS-986205 has decreased solubility with increasing 
pH. Participants should avoid taking proton pump inhibitors during the treatment period if 
possible. H2 antagonists and short-acting antacid agents may be taken, but it is recommended 
that these not be taken 4 hours before or 4 hours after dosing of BMS-986205. 
• Caution is warranted when using other agents known to cause methemoglobinemia (see 
Appendix 15). Dapsone, topical anesthetics, and antimalarial drugs are the most likely 
agents, and thus these medications should only be used after discussion with the Principal 
Investigator. 
9.4 
Other Restrictions and Precautions 
Use caution and monitor for symptoms of serotonin syndrome in participants receiving 
concurrent serotonergic psychiatric medications and/or tryptophan supplements.  
9.5 
Permitted Therapy 
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, 
delayed type hypersensitivity reaction caused by a contact allergen) is permitted. 
 
 


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10.0 
STUDY CALENDAR 
 
Evaluation 
Pre-Treatment 
Treatment Cycles 
End of Treatment 
Post-Treatment 
Treatment Cycle / Title 
Screening 
Day 1 of Each Cycle12 
End of 
Treatment16 
Safety 
Visit17 
Follow 
Up18 
Day 100 
Visit19 
Scheduling Window 
≤28 days 
prior to 
registration 
≤14 days 
prior to 
registration 
± 3 days 
± 7 days 
± 7 days 
± 7 days ± 7 days 
History 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Clinical/Laboratory/Assessments 
 
 
 
 
 
 
 
Physical Exam1: height2, weight, 
BSA3, performance status4 
 
X 
X 
 
X 
X 
 
Vital signs5 
 
X 
X 
 
X 
X 
 
Adverse Events and Concomitant 
Medications10 
X 
 
Continuously 
 
X 
Hematology: CBC with differential 
 
X 
X 
 
X 
 
 
Biochemistry6 
 
X 
X 
 
X 
 
 
AFP, TSH, hepatitis viral load if 
applicable  
 
X 
X13 
 
 
 
 
G6PD7 
 
X 
 
 
 
 
 
Methemoglobin and Oxygen 
Saturation8 
 
X 
X 
 
 
 
 
HIV, HBV, HCV serology  
 
X 
 
 
 
 
 
Pregnancy test if applicable9 
 
X 
X 
 
 
 
 
ECG 
 
X 
 
X 
 
 
 
Chest/abdomen/pelvis CT scan 
(MRI if appropriate) 
X11 
 
X14 
Correlatives 
 
 
 
 
 
 
 
Correlative Samples: Plasma, 
Serum, Whole Blood  
 
X15 
X15 
Tumor Tissue 
 
X15 
X15 
Stool sample 
 
X 
 
 
 
 
 
Study Treatment Administration 
 
 
 
 
 
 
 
Nivolumab 
 
 
X 
 
 
 
 
BMS-986205 
 
 
daily 
 
 
 
 


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Evaluation 
Pre-Treatment 
Treatment Cycles 
End of Treatment 
Post-Treatment 
1. 
Complete physical examination at screening only; subsequent physical examinations are limited to signs and symptoms of disease 
or toxicity. Clinical tumor measurements (if applicable).  
2. 
Height is required at Baseline only.  
3. 
BSA should be calculated prior to each dose of treatment.  
4. 
ECOG only.  
5. 
Vital signs: temperature, systolic and diastolic blood pressure, respiratory rate, and pulse. 
6. 
Biochemistry: creatinine (serum), sodium, potassium, total bilirubin, alkaline phosphatase, AST, ALT, albumin, INR 
7. 
Quantitative or qualitative G6PD assay must performed within 28 days prior to enrollment to screen for underlying G6PD 
deficiency.  
8. 
Methemoglobin levels must be performed within 14 days prior to enrollment, C1D1, each treatment cycle or more frequently if 
clinically indicated based on symptoms. Methemoglobin levels to be assessed on arterial or venous blood sample or by co-
oximetry. Oxygen saturation levels must be measured within 14 days prior to C1D1 and every cycle while on treatment by pulse 
oximetry at rest. 
9. 
Female subject of child-bearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or 
equivalent units of human chorionic gonadotrophin [hCG]) within 14 days of C1D1, and ≤ 24 hr prior to planned treatment 
initiation, and prior to each cycle while on treatment. Women with childbearing potential and males must be willing to use adequate 
birth control on trial and until 5 months for women or 7 months for men after the last of study therapy. Refer to Appendix 9. 
10. Baseline symptoms will be documented prior to starting study treatment. SAE will be collected starting from time of consent. 
Adverse Events collection will begin from the time of first dosing through 100 day post-treatment. Adverse events will be coded as 
per CTCAE V5.0. 
11. ≤ 28 days prior to registration. 
12. One cycle consists of 2 weeks. 
13. Every other cycle. If TSH >2x ULN, check free T3 and T4. 
14. Radiology to be repeated at the following time points (± 7 days): at the end of 8 and 16 weeks, then every 12 weeks, and at End of 
Treatment. Patients that go off treatment without radiological progression will have scans repeated every 3 months until 
documented disease progression or start of new therapy. 
15. Blood samples for correlative studies will be obtained at the following time points (± 7 days): day 15, day 29, day 57, day 85 and 
end of treatment. Core biopsy of tumor will be obtained at Baseline (unless there is adequate archival tumor specimen available), 
day 29 (± 7 days), and End of Treatment (end of treatment biopsy is optional). 
16. End of Treatment is at the time the decision is made to take the patient off study treatment.  
17. Safety Visit: 28 days after taken off protocol treatment. 
18. Follow up: Every 3 months from End of Treatment for survival follow up. 
19. 100 day visit for safety follow up. 
 
 
 
 
 


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11.0 
STUDY EVALUATIONS 
11.1 
Screening Phase 
The screening phase is defined as the interval between the day the subject signs the inform 
consent (ICF) and the day of registration. The screen phase will allow a total of 28 days. The 
subject can re-screen if he/she fails the first screen due to temporary illness. 
11.2 
Treatment Phase 
One cycle of treatment is 14 days in which the subject will receive the combination therapy and 
the treatment phase is up to a total of 24 months. The subject may stop both therapy at 24 months 
or continue therapy per treating physicians based on standard of care. 
11.3 
End of Treatment Visit 
The end of treatment visit should be performed when the treating physician decides to 
permanently discontinue study drug combinations.  
11.4 
Follow-up Phase 
The safety follow up phase is the interval between the end of treatment visit and scheduled safety 
follow up visit which will occur 28 (±7 days) days after discontinuation of combination therapy. 
If the subject starts on a new anticancer drug before 28 (±7 days) days after discontinuation of 
study drugs, the safety follow up visit should be prior to the start of new therapy. If the subject 
discontinues treatment without disease progression, the subject will be followed every 84 days 
(12 weeks ±7 days) by imaging to monitor disease status. Once the subject starts a new therapy 
or has progression of disease, the subject’s survival status should be followed with telephone or 
email until death or withdrawal of consent. 
11.5 
Efficacy 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [35] as well as iRECIST criteria. Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions is used in the RECIST criteria. Radiologic assessment is to be 
repeated at the following time points (+/- 7 days): at the end of 8 and 16 weeks, then every 12 
weeks, and at End of Treatment. Patients that go off treatment without radiological progression 
will have scans repeated every 3 months until documented disease progression or start of new 
therapy. 
 


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11.5.1 
Disease Parameters 
11.5.1.1 
Measurable Disease 
The presence of at least one measurable lesion. If the measurable disease is restricted to a 
solitary lesion, its neoplastic nature should be confirmed by cytology/histology.  
11.5.1.2 
Measurable Lesions 
Lesions that can be accurately measured in at least one dimension with longest diameter 20mm 
using conventional techniques or 10mm with spiral CT scan.  
11.5.1.3 
Non-Measurable Lesions 
All other lesions, including small lesions (longest diameter <20 mm with conventional 
techniques or <10 mm with spiral CT scan), i.e., bone lesions, ascites, pleural/pericardial 
effusion, cystic lesions, and abdominal masses that are not confirmed and followed by imaging 
techniques. 
All measurements should be taken and recorded in metric notation, using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment, 
preferably within two weeks of treatment initiation, and never more than 4 weeks before the 
beginning of the treatment.  
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow up.  
11.5.2 
Methods of Measurements 
CT and MRI are the best currently available and reproducible methods to measure target lesions 
selected for response assessment. Conventional CT and MRI should be performed with cuts of 
10 mm or less in slice thickness contiguously. Spiral CT should be performed using a 5 mm 
contiguous reconstruction algorithm. This applies to tumors of the chest, abdomen and pelvis. 
Head and neck tumors and those of extremities usually require specific protocols.  
11.5.3 
Response Criteria 
11.5.3.1 
Evaluation of Target Lesions by RECIST 1.1 
• Complete Response (CR): Disappearance of the target lesion  
• Partial Response (PR):  At least a 30% decrease in the sum of the LD of target lesions, 
taking as reference the baseline sum LD  
• Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesion, or 
the appearance of one or more new lesions  
• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the treatment started  
 
 
 


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11.5.3.2 
Evaluation of Best Overall Response  
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria.  
 
Table 2. Best Overall Response Evaluation 
Best Overall Response Evaluation 
Target Lesion 
New Lesion 
Overall Response 
CR 
No 
CR 
PR 
No 
PR 
SD 
No 
SD 
PD 
Yes or No 
PD 
 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration”. Every effort should be made to document the objective progression 
even after discontinuation of treatment.  
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response 
status.  
11.5.3.3 
Confirmation  
The main goal of confirmation of objective response is to avoid overestimating the response rate 
observed. For reporting the study outcomes the response rate and confirmed response rate will be 
made clear. For interval evaluation of response rates during the Simon-two stage study responses 
do not need to be confirmed for the study to progress. To be assigned the status of confirmed 
responses must be confirmed by repeat assessments that should be performed no less than 4 
weeks after the criteria for response are first met. Longer intervals as determined by the study 
protocol may also be appropriate. In the case of SD, follow-up measurements must have met the 
SD criteria at least once after study entry at a minimum interval (in general, not less than 6-8 
weeks) that is defined in the study protocol. For PD all results should be confirmed as described 
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11.5.3.4 
Duration of Overall Response  
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever status is recorded first) until the first date that recurrence or PD is objectively 
documented, taking as reference for PD the smallest measurements recorded since the treatment 
started.  
11.5.3.5 
Duration of Stable Disease  
SD is measured from the start of the treatment until the criteria for disease progression are met, 
taking as reference the smallest measurements recorded since the treatment started. The clinical 
relevance of the duration of SD varies for different tumor types and grades. Therefore, it is 
highly recommended that the protocol specify the minimal time interval required between two 
measurements for determination of SD. This time interval should take into account the expected 
clinical benefit that such a status may bring to the population under study.  
11.5.3.6 
Objective Response Rate 
ORR is defined as the percentage of patients that achieve PR or CR. 
11.5.3.7 
Disease Control Rate (DCR) 
DCR is defined as the percentage of patients that achieve an objective tumor response or have 
stable disease to therapy. 
11.5.3.8 
Progression-Free Survival (PFS) 
PFS is defined as the duration of time from date of enrollment to time of progression or death, 
whichever occurs first. 
11.5.3.9 
Overall Survival (OS) 
OS is defined as the duration of time from date of enrollment to death from any cause. 
11.5.4 
Reporting of Results  
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible. Each patient will be assigned one of 
the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, insufficient data).  
All of the patients who met the eligibility criteria should be included in the main analysis of the 
response rate. Patients in response categories 4-9 should be considered as failing to respond to 
treatment (disease progression). Thus, an incorrect treatment schedule or drug administration, or 
failure to complete all prescribed study therapy, does not result in exclusion from the analysis of 
the response rate. All conclusions should be based on all eligible patients. Sub analyses may then 
be performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early discontinuation of 


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treatment, major protocol violations, etc.). The reasons for excluding patients from the analysis 
should be clearly reported.   
11.6 
Safety 
Safety assessments will consist of monitoring and recording all adverse events, including serious 
adverse events, the monitoring of hematology, blood chemistry, coagulation parameters, 
urinalysis and the regular monitoring of vital signs, and physical condition as shown in 
corresponding tables. For details on AE collection and reporting, refer to the Safety section in the 
protocol. 
12.0 
CORRELATIVES 
One of the major shortcomings of immunotherapy trials has been the lack of in depth correlative 
studies to help identify the mechanism of action of these therapies, identify biomarkers of 
response, and provide a foundation for further improving these approaches.  To address this we 
plan to perform in depth immunological analysis of patient blood and tumor samples.  Pre- and 
post-treatment blood and tumor biopsies (when available) will be obtained as outlined in the 
study calendar. Briefly, blood and tumor samples will be collected as detailed in the study 
calendar. Optional blood and tumor biopsies can be obtained at progression. Participation in the 
correlative studies is mandatory unless waived by the study principal investigator due to safety 
concerns or other reasons. Archival tumor blocks will also be collected when available. We will 
evaluate immunologic changes systemically and in the tumor and tumor microenvironment 
within patient’s pre to post therapy and across the cohort of patients to identify predictive 
biomarkers and elucidate the mechanistic immunologic effects of therapy.  For further details, 
refer to Appendix 4. Correlative studies will include (in order of priority): 
12.1 
Blood 
• FACS for quantification, immunophenotyping, and functional assessment of PBMCs  
•  Evaluation of immune related gene signatures by RNAseq and/or Nanostring 
• Whole exome sequencing (as normal tissue baseline for determining mutational burden and 
neoantigen load of tumors) 
• Ex Vivo evaluation of T cell function by in vitro stimulation studies and metabolic status by 
seahorse analysis  
• Evaluation of systemic plasma tryptophan to kynurenine ratios 
• Luminex evaluation of plasma for systemic cytokine / chemokine signatures 
• T-cell receptor (TCR) deep sequencing to determine clonal expansion and diversity of T-cells 
in the systemic circulation  
• Other studies as deemed feasible and informative by the principal investigator 


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12.2 
Tissue   
• Multi-plexed IHC/IF to determine expression of markers including PD-1, PD-L1, CD8, CD4, 
IDO1, Ki-67, Granzyme b and FOXP3 
• Evaluation of immune related gene signatures by RNAseq and/or Nanostring 
• T-cell receptor (TCR) deep sequencing to determine clonal expansion and diversity of T-cells 
in the tumor microenvironment  
• Evaluating mutational burden and neoantigen load of tumors using RNAseq and WES data 
• Flow cytometry and ex-vivo analysis of T-cells from fresh tumor biopsies  
• Other studies as deemed feasible and informative by the principal investigator 
12.3 
Stool 
• Stool microbiome analysis  
 
A comprehensive analysis of tumor, blood, and stool samples will provide valuable insight into 
potential biomarkers and into the mechanism of action of our combined therapy.  
Blood samples will be separated into PBMCs and plasma and stored at -80°C for batched 
analysis.  PBMCs will be stained for FACS analysis using well characterized antibodies against 
markers such as CD45, CD3, CD4, CD8, FOXP3, Granzyme B, Interferon gamma, tumor 
necrosis factor (TNF) alpha, PD-1, PD-L1 etc.  Results will be analyzed using a BD Fortessa 
multi-color flow cytometer and Flowjo software.  An aliquot of PBMCs will also be set aside for 
RNA isolation and batched analysis of gene expression. An aliquot of PBMCs at baseline blood 
draw will also be set aside for DNA extraction for WES. To determine if certain clones of T cells 
are preferentially expanding after therapy, an aliquot of PBMCs will also be used for TCR deep 
sequencing. Plasma will be evaluated for systemic cytokine and chemokine signatures using 
Luminex technology.  Markers will include IL-2, IL-6, IL-10, IL-12p70, GM-CSF (granulocyte-
macrophage colony-stimulating factor), TNF alpha, IFN (interferon) gamma, CXCL10 (C-X-C 
motif chemokine 10), RANTES (regulated on activation, normal T cell expressed and secreted), 
MIP1 (Macrophage Inflammatory Protein) alpha, MIP1 beta, TGF-beta and others. Systemic 
tryptophan and kynurenine levels will also be evaluated.  
Tissue biopsies will be formalin fixed and paraffin embedded using standard protocols.  Tissue 
will be analyzed by multi-plexed IHC/IF staining for markers including PD-1, PD-L1, CD8, 
CD4, IDO, Ki-67, Granzyme b and FOXP3.  An aliquot of tumor tissue will be stored in RNA 
later for batched analysis of gene expression signatures and TCR deep sequencing. If sufficient 
tissue is available an aliquot will be freshly processed to evaluate T cell function and metabolic 
status. Pre-treatment stool samples will be collected to analyze the gut microbiome 
 


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13.0 
DRUG INFORMATION 
13.1 
BMS-986205 
13.1.1 
Dosing and Administration 
BMS-986205 will be dispensed once every 28 days and administered at 50-100mg orally, daily 
throughout the study period. Subjects will take their dose of BMS-986205 once a day around the 
same time during the day. Subjects should take the tablet with 240 ml/8 ounces of water 
following a meal.  
13.1.2 
Formulation, Packaging, and Handling 
BMS-986205-04 Film-coated Tablet, 100 mg (30 tablets per bottle): BMS-986205-04 tablet is a 
light pink to pink, oval-shaped, plain-faced, film-coated tablet. In addition to BMS-986205-04 
drug substance, the following formulation excipients are used: anhydrous lactose, 
microcrystalline cellulose, crospovidone, silicon dioxide, magnesium stearate, and Opadry® pink 
color dispersion. The tablets are supplied in tightly-closed high-density polyethylene bottles with 
child-resistant closures containing a desiccant. 
BMS-986205-04 Film-coated Tablet, 50 mg (30 tablets per bottle): BMS-986205-04 tablet is a 
beige, oval-shaped, plain-faced, film-coated tablet. In addition to BMS-986205-04 drug 
substance, the following formulation excipients are used: anhydrous lactose, microcrystalline 
cellulose, crospovidone, silicon dioxide, magnesium stearate, and Opadry® beige color 
dispersion. The tablets are supplied in tightly-closed high-density polyethylene bottles with 
child-resistant closures containing a desiccant. 
BMS-986205-04 tablets should be stored at 2°C to 30°C (36°F to 86°F) in a tightly-closed 
container protected from light. 
For complete details on drug preparation, administration, storage conditions, clinical 
pharmacology, pharmacokinetics, and known precautions and adverse reactions please see the 
BMS-986205 IB. 
13.1.3 
Preparation 
No preparation is required for BMS-986205-04 capsules or tablets. 
13.1.4 
Ordering / How Supplied 
BMS-986205 will be supplied by BMS at no cost to study patients.  
13.1.5 
Accountability, Handling and Disposal  
Responsibility for drug accountability is on the investigator and the assigned pharmacist or 
designee. Drug supply will be disposed of according to institutional standard operating 


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procedure. Accurate records of all investigational product received at and dispensed from the 
study site should be recorded on the Drug Log. 
13.2 
Nivolumab 
13.2.1 
Dosing and Administration 
Patients should be administered nivolumab 240 mg as an in intravenous infusion over 30 minutes 
every 2 weeks (± 1 day for cycles 1 to 3 and ± 3 days for subsequent cycles). For the first 
infusion, the patient’s vital signs (heart rate, respiratory rate, blood pressures, and temperature) 
should be determined within 60 minutes before, during (every 15 [±5] minutes), and 30 (±10) 
minutes after the infusion. For subsequent infusions, vital signs will be collected within 60 
minutes before infusion. Patients will be informed about the possibility of delayed post-infusion 
symptoms and instructed to contact their study physician if they develop acute symptoms. 
13.2.2 
Formulation, Packaging, and Handling 
Nivolumab will be supplied by Bristol-Myers Squibb and labeled appropriately as investigational 
material for this study. Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody. 
Nivolumab vials must be stored in the refrigerator at 2-8°C, protected from light and freezing. If 
stored in a glass front refrigerator, vials should be stored in the carton. The product does not 
contain a preservative, and as such after preparation, nivolumab should be used immediately. If 
not used immediately, nivolumab infusions should be stored at room temperature (20-25°C) and 
room light for no more than 4 hours from time of preparation. This includes room temperature 
storage of infusion in IV container and time for administration of infusion. Alternatively, 
nivolumab infusion can be stored under refrigeration at 2 to 8oC (36-46°F) for no more than 24 
hours from the time of infusion preparation and protected from light. The infusion should not be 
frozen. 
Recommended safety measures for preparation and handling of nivolumab include laboratory 
coats and gloves. 
For complete details on drug preparation, administration, storage conditions, clinical 
pharmacology, pharmacokinetics, and known precautions and adverse reactions please see the 
Nivolumab IB. 
13.2.3 
Preparation 
Preparation of nivolumab should be performed by trained personnel in accordance with package 
insert and good practices rules, especially with respect to asepsis. The required volume of 
nivolumab should be withdrawn and transferred into an intravenous container. Nivolumab should 
be then be diluted with either 9 mg/mL (0.9%) sodium chloride solution for injection, USP or 50 
mg/mL (5%) dextrose solution for injection, USP, to prepare an infusion with a final 
concentration ranging from 1 mg/mL to 10 mg/mL. Diluted solution should be mixed by gentle 


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inversion, but should not be shaken. Partially used or empty vials of nivolumab should be 
discarded. 
13.2.4 
Ordering / How Supplied 
Nivolumab will be supplied by BMS at no cost to study patients.  
13.2.5 
Accountability, Handling and Disposal  
Responsibility for drug accountability is on the investigator and the assigned pharmacist or 
designee. Drug supply will be disposed of according to institutional standard operating 
procedures. Accurate records of all investigational product received at and dispensed from the 
study site should be recorded on the Drug Log. 
 
 
 
 


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14.0 
STATISTICAL CONSIDERATIONS  
14.1 
Study Design and Overview of Primary and Secondary Endpoints 
This is a phase I/II study using a Simon optimal two-stage design for efficacy of BMS-986205 in 
combination with nivolumab. In the phase I portion, we will treat patients following 3+3 
standard design with dose escalation in BMS-986205 along with fixed dose of nivolumab.  
BMS-986205 dose level 1 will be 50mg and dose level 2 will be 100mg.  3 patients will be 
treated with BMS-986205 at dose level 1 of 50mg along with fixed dose of nivolumab.  If no 
patient experiences a DLT at dose level 1, we will add 3 patients will be treated at a dose of 100 
mg of BMS-986205 with fixed dose of nivolumab.  If 1 of 3 patients has a DLT at DL1, we will 
add 3 patients at a dose of 50 mg.  If <1 of 6 patients has a DLT at 50mg of BMS-986205, 
3 patients will be treated at 100 mg.  Maximum tolerated dose will be defined as ≤1 of 6 patients 
at DL1 or DL2 experiencing a DLT.  After identifying the MTD, the phase II expansion phase 
will be initiated with 3 additional patients at the MTD.  A maximum total of 17 patients at MTD 
will be treated on trial including 6 patients treated during phase I portion at MTD.  An interim 
efficacy analysis will be done after 9 patients (including the 6 patients in phase I portion) have 
been treated.   If at least 1 patient out of the 9 initial patients treated at MTD achieves a response, 
we will accrue 8 more patients at the MTD. If at least 3 of the 17 patients treated at MTD 
achieve a response, we will deem the treatment worthy of further study, provided the safety 
profile is acceptable.  
14.2 
Sample Size Estimation /Accrual Rate 
The Simon optimal 2 stage design described above provides 80% power to detect the difference 
between an acceptable response rate by RECIST of 25% vs. an unacceptable rate of 5% at the 
0.05 level (1-sided). The estimated time to accrue 23 patients is 24 months, at approximately 1 
patient per month. 
14.3 
Evaluation of Efficacy 
The ORR will be estimated as the proportion of participants who experience an objective 
response, along with its exact 95% confidence interval; the disease control rate will be analyzed 
similarly.  DOR, PFS, and OS will be analyzed using Kaplan-Meier methods; medians and 95% 
confidence intervals will be computed. 
14.4 
Evaluation of Safety 
DLTs, adverse events, serious adverse events, and clinical laboratory values outside normal 
limits will be listed for each patient and summarized by body system and dose level in frequency 
tables. 
 
 
 


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15.0 
SAFETY REPORTING OF ADVERSE EVENTS 
15.1 
Adverse Events 
An adverse event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant 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 investigational product, whether or not considered 
related to the investigational product.  
15.1.1 
Severity of Adverse Events 
The severity of an AE is graded as follows: 
Grade 1 (Mild): 
The event causes discomfort that affects normal daily 
activities. 
Grade 2 (Moderate): 
The event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status. 
Grade 3 (Severe): 
The event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status. 
Grade 4 (Life-threatening): 
The patient was at risk of death at the time of the event. 
Grade 5 (Fatal): 
The event caused death. 
 
15.1.2 
Causality (Attribution) of Adverse Events 
The investigator is to assess the causal relation of all AEs (i.e., whether there is a reasonable 
possibility that the study drug caused the event) using the following definitions: 
Not Related: 
Another cause of the AE is more plausible; a temporal sequence cannot be 
established with the onset of the AE and administration of the 
investigational product; or, a causal relationship is considered biologically 
implausible. 
Unlikely: 
The current knowledge or information about the AE indicates that a 
relationship to the investigational product is unlikely. 


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Possibly Related: There is a clinically plausible time sequence between onset of the AE and 
administration of the investigational product, but the AE could also be 
attributed to concurrent or underlying disease, or the use of other drugs or 
procedures.  Possibly related should be used when the investigational 
product is one of several biologically plausible AE causes. 
Related: 
The AE is clearly related to use of the investigational product. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.) 
Any other AE not listed as an expected event in the Investigator’s Brochure or in this protocol 
will be considered unexpected. 
15.1.3 
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 participant was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused death 
if it were more severe) 
• Requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below) 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect  
• Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [e.g., 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.)  
• Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the 
study drug is an SAE.  
 
Although pregnancy, overdose, potential drug-induced liver injury (DILI), and cancer are not 
always serious by regulatory definition, these events must be handled as SAEs. 


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Any component of a study endpoint that is considered related to study therapy should be reported 
as an SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported). 
All Serious Adverse Events (SAEs) that occur following the subject’s written consent to 
participate in the study through 100 days after discontinuation of dosing must be reported to 
BMS Worldwide Safety, whether related or not related to study drug. If applicable, SAEs must 
be collected that relate to any later protocol-specified procedure (e.g., a follow-up skin biopsy). 
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, are collected, including those thought to be associated with protocol-
specified procedures. The investigator should report any SAE occurring after these 
aforementioned time periods, which is believed to be related to study drug or protocol-specified 
procedure. 
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. 
NOTE: (PI determines if this information regarding hospitalizations are considered SAEs and 
should be included in the protocol. This is supplemental information that is included in BMS 
sponsored trials) 
The following hospitalizations will not be considered SAEs:  
• 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 (e.g., 
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 (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason). 
• Admission for administration of anticancer therapy in the absence of any other SAEs  
 


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15.1.4 
Adverse Events of Special Interest  
15.1.4.1 
What is considered an adverse event of special interest?  
Adverse events of special interest (AESI) requiring expedited reporting by the investigator have 
been defined for this protocol.  These are: 
• Hemophagocytic lymphohistiocytosis (HLH; also known as histiocytosis haematophagic) 
• Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome 
 
15.1.4.2 
Reporting Timeframe 
These AESI, whether related or not related to study drug, must be reported to BMS or designee 
within 24 hours of awareness of the event. These AESI are medically important events and are 
therefore considered SAEs. The reporting system for SAEs should be used (See Section 15.2). 
15.1.4.3 
Diagnostic Scoring Criteria 
HLH and DRESS syndrome may both pose diagnostic challenges due to varying clinical 
manifestations and signs and symptoms that may overlap with other clinical events. To assist 
investigators in identifying constellations of clinical symptoms that may be consistent with one 
of these diagnoses, standardized scoring criteria are provided. Formal evaluation and 
documentation of diagnostic scores based on these systems is not required; investigators should 
use their best clinical judgement as informed by these provided criteria to determine if a 
participant has experienced one of these AESI. 
 
15.1.5 
Non-Serious Adverse Event 
• Non-serious Adverse Events (AE) are to be provided to BMS in aggregate via interim or 
final study reports as specified in the agreement or, if a regulatory requirement [e.g., IND US 
trial] as part of an annual reporting requirement.  
• Non-serious AE information should also be collected from the start of a placebo lead-in 
period or other observational period intended to establish a baseline status for the subjects.  
A non-serious adverse event is an AE not classified as serious.  
15.1.5.1 
Non-Serious Adverse Event Collection and Reporting 
The collection of non-serious AE information should begin at initiation of study drug. All non-
serious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following the last dose 
of study treatment.  
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious. Follow-up is also required for non-serious AEs that cause interruption or 
discontinuation of study drug and for those present at the end of study treatment as appropriate. 


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15.1.6 
Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following institutional 
procedures. Test results that constitute SAEs should be documented and reported to BMS as 
such. 
The following laboratory abnormalities should be documented and reported appropriately: 
• Any laboratory test result that is clinically significant or meets the definition of an SAE 
• Any laboratory abnormality that required the participant to have study drug discontinued or 
interrupted 
• Any laboratory abnormality that required the subject to receive specific corrective therapy.  
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (e.g., anemia versus low hemoglobin value). 
15.1.7 
Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study 
participant is pregnant or may have been pregnant at the time of investigational product 
exposure, including during at least 5 half-lives after product administration, the investigational 
product will be permanently discontinued in an appropriate manner (e.g., dose tapering if 
necessary for participant).  
The investigator must immediately notify Worldwide.Safety@bms.com of this event via 
MedWatch or appropriate Pregnancy Surveillance Form in accordance with SAE reporting 
procedures.  
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the MedWatch or a 
BMS Pregnancy Surveillance Form.  A BMS Pregnancy Surveillance Form may be provided 
upon request. 
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. In 
order for Sponsor or designee to collect any pregnancy surveillance information from the female 
partner, the female partner must sign an informed consent form for disclosure of this 
information. 


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15.1.8 
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 (section 15.2). 
Potential drug induced liver injury is defined as:  
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN), AND 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase), AND 
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or 
the administration of other drug(s) known to be hepatotoxic. 
 
15.1.9 
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. All occurrences of overdose must be 
reported as an SAE. 
15.1.10 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, X-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a non-serious or serious AE, 
as appropriate, and reported accordingly. 
15.2 
Procedures for Reporting Adverse Events 
15.2.1 
Methods and Timing for Assessing and Recording Safety Variables 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study are collected and reported to the FDA, appropriate IRB(s), BMS in accordance 
with CFR 312.32 (IND Safety Reports).  
15.2.2 
Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins at initiation of study 
treatment and ends 100 days following the last administration of study treatment or study 
discontinuation/termination, whichever is earlier. After this period, investigators should only 
report SAEs that are attributed to prior study treatment. 


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15.2.3 
Procedures for SAE Reporting 
15.2.3.1 
Initial and Follow up Reports 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
within 24 hours / 1 Business Day of becoming aware of the event. SAEs must be recorded on 
either MedWatch or approved site SAE form.  
 
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  +1 609-818-3804 
 
Pregnancies must be reported and submitted to BMS on any of the following form(s): 
1. MedWatch or 
2. BMS Pregnancy Surveillance Form or,  
3. Approved site SAE form 
 
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 / 1 Business Day to 
BMS using the same procedure used for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
 
15.2.3.2 
Additional Reporting Requirements for IND Holders 
For Investigator-Sponsored IND Studies, some additional reporting requirements for the FDA 
apply in accordance with the guidance set forth in 21 CFR § 312.32.  
Sponsor-investigators of studies conducted under an IND are required to report all serious, 
unexpected, and related adverse events directly to the FDA on a MedWatch Form FDA 3500A 
within 7 (if fatal or life-threatening) or 15 calendar days of first awareness, as described below.  
Before submitting this report, the sponsor needs to ensure that the event meets all three of the 
definitions contained in the requirement:  
• Suspected adverse reaction  
• Serious  
• Unexpected  
 
 


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The Sponsor-Investigator will notify the FDA according to the following timelines: 
• within 7 calendar days of any unexpected fatal or life-threatening adverse event with 
possible relationship to study drug; 
• Within 15 calendar days of any event that is considered: 1) serious, 2) unexpected, and 3) at 
least possibly related to study participation. 
 
FDA fax number for IND Safety Reports: 
(800) FDA-0178 or (800) 332-0178 
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report to the FDA.  For adverse events that are either serious but don’t 
meet the criteria for expedited reporting or are not serious, the FDA will be notified at the time 
of the IND Annual Report. 
MedWatch Form FDA 3500A Reporting Guidelines 
In addition to completing appropriate demographic and suspect medication information, the 
report should include the following information within the Event Description of the MedWatch 
Form FDA 3500A: 
• Treatment regimen (dosing, frequency, combination therapy) 
• Protocol description (include number if assigned) 
• Description of event, severity, treatment, and outcome, if known 
• Supportive diagnostic and laboratory results 
• Investigator’s assessment of the relationship of the SAE to each investigational product and 
suspect medication 
Follow-up information: 
• Additional information may be added to a previously submitted report by any of the 
following methods: 
• Adding to the original MedWatch Form FDA 3500A and submitting it as follow-up 
• Adding supplementary summary information and submitting it as follow-up with the original 
MedWatch Form FDA 3500A 
• Summarizing new information and faxing it with a cover letter including subject identifiers 
(i.e., DOB, initials, subject number), protocol description and number, suspect drug, brief 
adverse event description, and notation that additional or follow-up information is being 
submitted 
 


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15.2.3.3 
Reporting to the Institutional Review Board 
Both serious and non-serious adverse events will be reported in accordance with UCD IRB 
Administration and UCD Office of Clinical Research (OCR) policies. The UC Davis IRB can be 
reached at (916) 703-9151.  
15.2.4 
Reconciliation 
The Sponsor-Investigator will reconcile the clinical database SAE cases (case level only) 
transmitted to BMS Global Pharmacovigilance (Worldwide.Safety@bms.com). Reconciliation 
will be done at the end of study prior to the database lock or final data summary. BMS GPV&E 
will email, upon request from the Investigator, the GPV&E reconciliation report. Requests for 
reconciliation should be sent to aepbusinessprocess@bms.com. The data elements listed on the 
GPV&E reconciliation report will be used for case identification purposes. If the Investigator 
determines a case was not transmitted to BMS GPV&E, the case should be sent immediately to 
BMS. 
16.0 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE PROCEDURES  
16.1 
Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and Good Clinical Practice, as 
described in:  
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. Directive 91/507/EEC, The Rules Governing Medicinal Products in the European 
Community. 
3. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 
concerning informed consent and IRB regulations). 
4. Declaration of Helsinki, concerning medical research in humans (Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, 
amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996). 
 
The investigator agrees, when signing the protocol, to adhere to the instructions and procedures 
described in it and thereby to adhere to the principles of Good Clinical Practice that it conforms 
to. 
16.2 
Institutional Review Board/Independent Ethics Committee 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by a properly constituted Institutional Review 
Board/Independent Ethics Committee (IRB/IEC/REB). A signed and dated statement that the 
protocol and informed consent have been approved by the IRB/IEC/REB must be given to BMS 


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before study initiation. The name and occupation of the chairman and the members of the 
IRB/IEC/REB must be supplied to BMS. Any amendments to the protocol, other than 
administrative ones, must be approved by this committee. 
16.3 
Study Documentation 
The required documents include, but are not limited to the following: IRB approvals (i.e., 
protocol, consent form, amendments, patient brochures and recruitment material, etc.), IRB 
membership rosters, summary of unanticipated problems or protocol deviations, and 
documentation of expertise of the investigators.  
16.4 
Informed Consent 
The investigator must explain to each subject (or legally authorized representative) the nature of 
the study, its purpose, the procedures involved, the expected duration, the potential risks and 
benefits involved and any discomfort it may entail. Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any time 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in non-
technical language. The subject should read and consider the statement before signing and dating 
it, and should be given a copy of the signed document. If the subject cannot read or sign the 
documents, oral presentation may be made or signature given by the subject’s legally appointed 
representative, if witnessed by a person not involved in the study, mentioning that the patient 
could not read or sign the documents. No patient can enter the study before his/her informed 
consent has been obtained. 
The informed consent form is considered to be part of the protocol, and must be submitted by the 
investigator with it for IRB/IEC/REB approval.  
Fertile men and women of child bearing potential should be informed that taking the study 
medication may involve unknown risks to the fetus if pregnancy were to occur during the study 
and agree that in order to participate in the study they must adhere to the contraception 
requirement for the duration of the study. 
Refer to Appendix 9. 
If there is any question that the patient will not reliably comply, they should not be entered in the 
study. 
In accordance with UCD OCR policy an original signed and dated participant Informed Consent 
document will reside in a secured location at participating institutions. Copies of the signed and 
dated Informed Consent document will be provided to the study participant and a copy will be 
stored in the patient’s electronic medical record at the participating institution.  


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16.5 
Discontinuation of Study Support 
BMS reserves the right to discontinue support for any study under the conditions specified in the 
clinical trial agreement. 
16.6 
Amendments to the Protocol 
Any change or addition to this protocol requires a written protocol amendment that must be 
approved by BMS and the investigator before implementation. Any protocol amendment requires 
approval by the IRB/IEC/REB. A copy of the written approval of the IRB/IEC/REB, must be 
sent to BMS. 
16.7 
Patient Confidentiality 
In order to maintain patient privacy, all study reports and communications will identify the 
patient by initials and the assigned patient number.  Data capture records and drug accountability 
records will be stored in secure cabinets in the UCD OCR or at the participating institutions.  
Medical records of patients will be maintained in strict confidence according to legal 
requirements.  The patient’s confidentiality will be maintained and will not be made publicly 
available to the extent permitted by the applicable laws and regulations. 
16.8 
Protocol Deviations 
All protocol deviations will be reported in accordance with UCD IRB Administration and UCD 
Comprehensive Cancer Center OCR policies. 
16.9 
Study Close-Out 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to BMS. 
This includes all IND annual reports and the Clinical Study Report (final study report). 
Additionally, any literature articles that are a result of the study should be sent to BMS.  
16.10 Quality Assurance 
Quality assurance audits of select patients and source documents may be conducted by the 
Quality Assurance and/or Data Safety Committees at participating institutions or UC Davis 
Comprehensive Cancer Center as outlined in the UC Davis Comprehensive Cancer Center Data 
and Safety Monitoring plan. 
 
 


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17.0 
OVERSIGHT AND MONITOROING 
17.1 
Data and Safety Monitoring 
In addition to the requirements for adverse event reporting as outlined in Section 7.0, this 
protocol is also subject to the UC Davis Comprehensive Cancer Center’s (UCDCCC) Data and 
Safety Monitoring Plan. The UCDCCC is committed to pursuing high-quality patient-oriented 
clinical research and has established mechanisms to ensure both scientific rigor and patient 
safety in the conduct of clinical research studies. The UCDCCC relies on a multi-tiered 
committee system that reviews and monitors all cancer clinical trials and ensures the safety of its 
participants, in compliance with institutional and federal requirements on adverse event (AE) 
reporting, verification of data accuracy, and adherence to protocol eligibility requirements, 
treatment guidelines, and related matters. The Scientific Review Committee (SRC) assumes 
overall oversight of cancer studies, with assistance and input from two independent, but 
interacting, committees: the Quality Assurance Committee and the Data and Safety Monitoring 
Committee. A multi-level review system strengthens the ability of the UCDCCC to fulfill its 
mission in conducting high quality clinical cancer research. 
As per University of California Davis Comprehensive Cancer Center (UCDCCC) Office of 
Clinical Research (OCR) SOP AM 506: Protocol Specific Meetings, the principal investigator 
(PI) and clinical research coordinator meet at least monthly for ongoing study information, to 
discuss patient data and adverse events and to determine if dose escalation is warranted, when 
applicable.   
According to the UCDCCC Data and Safety Monitoring Plan, any new serious adverse events 
related to the drugs being used on this trial are reviewed monthly by the UCDCCC Data and 
Safety Monitoring Committee and any applicable changes to the study are recommended to the 
PI, if necessary. 
The UCDCCC SRC determines if a UCDCCC Data and Safety Monitoring Board (DSMB) is 
required.  If required, the Data and Safety Monitoring Committee will appoint a DSMB. The 
DSMB is responsible for reviewing study accrual logs, adverse event information and dose 
escalation meeting minutes (where applicable) to ensure subject safety and compliance with 
protocol defined guidelines. 
The Research Monitor is responsible to oversee the safety of the research and report 
observations/findings to the IRB or a designated institutional official. The Research Monitor will 
review all unanticipated problems involving risks to subjects or others associated with the 
protocol and provide an independent report of the event to the IRB. The Research Monitor may 
discuss the research protocol with the investigators; shall have authority to stop a research 
protocol in progress, remove individual human subjects from a research protocol, and take 
whatever steps are necessary to protect the safety and well-being of human subjects until the IRB 
can assess the monitor’s report; and shall have the responsibility to promptly report their 
observations and findings to the IRB or other designated official and the HRPO. 


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17.2 
Investigator Monitoring Guidelines 
Investigators will conduct continuous review of patient safety. Patients will be monitored 
bi-weekly during the study.  All patients on active treatment will be discussed at weekly 
conferences that are held at the University of California Davis. Per Cancer Center guidelines, a 
trial cannot proceed to the next dose level until a DLT meeting is conducted to comprehensively 
review all toxicity data and approve the dose de-escalation. The discussion will include for each 
dose level: the number of patients, significant toxicities as described in the protocol, doses 
adjustments, and responses observed. 
 
 
 
 


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18.0 
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19.0 
APPENDICES 
Appendix 1: ECOG Performance Status Scale 
 
ECOG Grade 
ECOG Status* 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, e.g., light house 
work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair 
5 
Dead 
*Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.:  Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
 
 
 


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Appendix 2: Study Registration 
 
Once signed, informed consent has been obtained; patients will be entered on study.  To register 
a patient, the study coordinator must complete the Eligibility Checklist. The study coordinator 
will register the patient onto the study and assign a unique patient number.    
 
 
 


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Appendix 3: Data Submission Schedule 
 
All data will be collected using UC Davis data collection forms. Any and all source 
documentation should be maintained.  
 
 
 


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Appendix 4: Molecular Correlative Sample Handling 
 
Specimen Submission for Correlative Studies:  
Participation in these molecular correlative studies is mandatory. With the patient's consent, 
tissue and blood specimens will be submitted as outlined below. Samples will be de-identified 
and coded with a new patient ID number to protect patient’s identity. 
A specimen submission form should be filled out for each specimen obtained. All specimens 
must be labeled with protocol number, site identification, patient registration number, date of 
specimen collection, and number of cells (for PBMCs) or weight of tissue (for tissue biopsies). 
Correlative studies will be performed at UC Davis or samples will be shipped in a de-identified 
manner to other institutions / companies for analysis. 
For correlative studies the following samples should be collected: 
• Peripheral blood samples obtained per study calendar 
• Fresh tumor biopsy per study calendar. Optional biopsy at progression.  
• Stool sample collected pre-treatment. 
Correlative studies will include (in order of priority):  
 
Blood  
•  FACS for quantification, immunophenotyping, and functional assessment of PBMCs  
•  Evaluation of immune related gene signatures by RNAseq and/or Nanostring 
• Whole exome sequencing (as normal tissue baseline for determining mutational burden and 
neoantigen load of tumors) 
• Ex Vivo evaluation of T cell function by in vitro stimulation studies and metabolic status by 
seahorse analysis  
• Evaluation of systemic plasma tryptophan to kynurenine ratios 
• Luminex evaluation of plasma for systemic cytokine / chemokine signatures 
• T-cell receptor (TCR) deep sequencing to determine clonal expansion and diversity of T-cells 
in the systemic circulation  
• Other studies as deemed feasible and informative by the principal investigator 
 
Tissue  
• Multi-plexed IHC/IF to determine expression of markers including PD-1, PD-L1, CD8, CD4, 
IDO, Ki-67, Granzyme b and FOXP3 


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• Evaluation of immune related gene signatures by RNAseq and/or Nanostring 
• T-cell receptor (TCR) deep sequencing to determine clonal expansion and diversity of T-cells 
in the tumor microenvironment  
• Identification of tumor neo-antigens by RNA deep sequencing in conjunction with peripheral 
blood WES data. 
• Flow cytometry and ex-vivo analysis of T-cells from fresh tumor biopsies  
• Other studies as deemed feasible and informative by the principal investigator 
 
Stool 
• Evaluation of stool microbiome 
 
1.0 Peripheral Blood 
1.1 Blood Collection 
Blood specimens will be collected from each patient as indicated in the study calendar. ~30ml 
should be collected into lavender top EDTA tubes for the first blood draw and ~20ml 
should be collected into lavender top EDTA tubes for subsequent blood draws.  It is 
important that each tube be filled to 5ml to ensure sufficient specimens for the planned analyses. 
It is important that a blood specimen be obtained at the time the patient is removed from protocol 
treatment or if the patient's disease progresses. 
1.2 Blood Specimen Processing and handling – lavender top EDTA tubes 
~30 mls will be collected from each patient at each time point. If possible five tubes should be 
collected for the first pre-treatment draw and 4 tubes thereafter. Each lavender-top (EDTA) tube 
should be inverted several times, placed on wet ice, and delivered to the appropriate lab for 
processing. Every effort should be made to process blood samples within 1 hour of collection. 
Samples should be processed in sterile fashion. 
The tube should be centrifuged as soon as possible at approximately 1,000-1,500 rpm (400 x g) 
for 10 minutes. The Plasma layer should be removed and kept on ice (see 1.2.1).  PBMCs should 
be separated using sterile and endotoxin free Ficoll density gradient solution.  The peripheral 
blood mononuclear cells (PBMCs) should be removed and pooled. The PBMC layer should be 
resuspended in three times the volume of cold sterile PBS. Cells should be counted using a 
hemocytometer and the total cell number should be noted. The expected yield is 1-2 million cells 
per ml of blood.   
For the first pretreatment blood draw, the PBMCs collected from 5 lavender top tubes will 
be divided into three aliquots. Roughly 60% of the cells should be cryopreserved for future 
analysis. The second aliquot consisting of roughly 20% of the cells will be placed in RNAlater 


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and snap frozen with liquid nitrogen and stored at -70 to -80°C for future RNA extraction. The 
third aliquot consisting of the last 20% of cells will be snap frozen in liquid nitrogen and stored 
at -70 to -80°C for future DNA extraction. If there are more than 20 x 106 viable cells the RNA 
and DNA extraction aliquots should be limited to a total of 5 x 106 cells each and the additional 
cells should be cryopreserved thus deviating from the 3:1:1 aliquoting. 
For the subsequent blood draws the PBMCs collected in 20 mls will be divides into two 
aliquots. Roughly 75% of the cells should be cryopreserved and roughly 25% should be placed 
in RNA later. DNA extraction is performed only for the pre-treatment sample and not for 
subsequent samples. If there are more than 15 x 106 viable cells the RNA later aliquot should be 
limited to a total of 5 x 106 cells and the additional cells should be cryopreserved thus deviating 
from the 3:1 aliquoting. 
1.2.1 Blood plasma 
The removed plasma layers should be pooled and centrifuged at 1000 x g for 10 minutes to 
clarify the plasma. The plasma should then be placed in up to eight 0.5 ml aliquots in labeled 
cryotubes. Any additional plasma can be discarded. The plasma will be frozen (snap frozen with 
liquid nitrogen if possible) and stored at -70 to -80°C.  
1.2.2 Cryopreservation 
After counting, PBS washed PBMCs should be divided into aliquots of 5 million cells and spun 
down at approximately 1,000-1,500 rpm (400 x g) for 10 minutes. Each aliquot should be 
resuspended in 1ml of cold sterile CryoStor CS10 freeze media (catalog number 07930, 
STEMCELL technologies) which contains 10% DMSO. Each 1ml aliquot should be placed in a 
cryopreservation tube and the lid should be tightly secured. Tubes should be placed into a “Mr. 
Frosty” or other slow freeze container and placed into a -70 to -80°C freezer for 12-24 hours. 
Tubes should then be transferred to and stored in vapor phase liquid nitrogen (-135°C). In a 
batched manner tubes should be shipped overnight in liquid nitrogen to UC Davis at the 
indicated address.  
1.2.3 RNA later 
After counting, PBS washed PBMCs should be spun down at approximately 1,000-1,500 rpm 
(400 x g) for 10 minutes. The cell pellet should be re-suspended in 1ml of RNAlater solution and 
allowed to sit at room temperature for 30 minutes then snap frozen in liquid nitrogen and stored 
at  -70 to -80°C.  
1.2.3 Snap frozen for DNA extraction 
This specimen will be collected from the pre-treatment blood draw only. After counting, PBS 
washed PBMCs should be spun down at approximately 1,000-1,500 rpm (400 x g) for 10 
minutes. The cell pellet should be immediately snap frozen in liquid nitrogen and stored at  -70 
to -80°C. 


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1.3 Peripheral Blood Analysis 
1.3.1 Plasma  
Plasma samples will be stored at UC Davis for batched analysis. Plasma will be interrogated for 
chemokine and cytokine levels using the luminex platform as well as  
1.3.2 Cryopreserved samples 
Cryopreserved samples will be stored at UC Davis for batched analysis. Samples will be thawed 
and stained with fluorophore-conjugated antibodies against CD4, CD8, CD25, CD62L, 
CD45RA, CD127, ICOS, PD-1, PD-L1, FoxP3, CD3, CD56, CD16, CD83, TIM-3, Ki-67, 
CD19, CD20, CD33, CD15, CD11b, HLA-DR  and others. Stained cells will be interrogated by 
flow cytometry and results analyzed using FlowJo software. PBMCs will also be evaluated ex 
vivo for  T cell function by in vitro stimulation studies and metabolic status by seahorse analysis 
1.3.3 RNAlater samples 
Cells in RNA later will be stored at UC Davis for batched analysis. Samples will be thawed and 
RNA will be extracted. The transcriptome will be analyzed by RNA deep sequencing (RNAseq) 
using the Illumina HiSeq platform or nanostring. Targeted RT-PCR will be used to validate 
genes of interest identified by RNAseq or nanostring. TCR deep sequencing data will also be 
obtained from the RNAseq. 
2.4.5 Snap frozen samples 
Snap frozen cell pellets will be stored at UC Davis for batched analysis. Samples will be thawed 
and genomic DNA will be extracted. Whole exome sequencing will be performed using the 
Illumina HiSeq platform.  
2.0 Fresh tumor biopsy  
2.1 Tumor biopsy collection 
Fresh tumor biopsy is collected pre-treatment and at end of cycle 2. Optional biopsy can be 
obtained at progression.  Tumor biopsies should be collected by core needle biopsy using 18 
gauge needle and number of passes deemed safe with a goal of 4 cores. The same lesions should 
be targeted for all fresh tissue biopsies.  
2.2 Tumor biopsy processing and handling 
On site at the time of the biopsy tumor tissues should be aliquoted into two or three portions. The 
top priority assay is IHC/IF and biopsy samples should be placed in formalin fixative and later 
embedded into FFPE blocks. In general samples should be placed in fixative at a 10:1 ratio and 
fixed for at least 48 hours but thicker tissue samples may require longer fixation.  


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If sufficient tissue is available (which there generally should be if more than one biopsy pass has 
been undertaken) then no less than 10mg and but preferably 20 - 50mg of tumor tissue should be 
placed in 1ml of RNAlater for 30 minutes at room temperature then snap frozen in liquid 
nitrogen and stored at -70 to -80°C.  
If sufficient tissue is available (at least one entire core) it should be placed in RPMI, place on ice, 
and taken immediately to the UC Davis Laboratory of Cancer Immunology for processing and 
flow cytometry.  
2.3 Tumor biopsy analysis 
FFPE tissue biopsy blocks will be collected and stored at UC Davis. Tissues will be sectioned, 
prepared, and mounted for IHC/IF using standard procedures. When possible, IHC/IF should be 
performed within two weeks of slide sectioning. Biopsy samples will be stained by multi-plex 
IHC/IF at UC Davis or collaborating laboratories to immunologically profile the tumor 
microenvironment. Markers examined will include CD3, CD8, CD4, FoxP3, Ki-67, PD-1 and PD-
L1.  
Tissue in RNA later will be stored at UC Davis for batched analysis. Samples will be thawed and 
RNA will be extracted. The transcriptome will be analyzed by RNAseq using the Illumina HiSeq 
platform. Targeted RT-PCR will be used to validate genes of interest identified by RNAseq. 
TCR deep sequencing data will also be obtained from the RNAseq. RNAseq data will also be 
used in conjunction with PBMC WES to identify putative neoantigens. 
Tissue in RPMI will be processed into a single cell suspension and evaluated by flow cytometry 
and ex-vivo analysis of T-cells from fresh tumor biopsies.  
 
3.0 Stool 
A stool sample will be collected from patients pre-treatment. Samples will be collected at home 
using a provided take home stool collection kit. Samples should be returned to UC Davis within 
24 hours of collection and will be snap frozen in liquid nitrogen and stored at  -70 to -80°C. 
 
   
 
 
 


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Appendix 5: Anaphylaxis Precautions 
 
EQUIPMENT NEEDED 
• 
Tourniquet 
• 
Oxygen 
• 
Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
• 
with standard practice 
• 
Antihistamines 
• 
Corticosteroids 
• 
Intravenous infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
a) In the event of a suspected anaphylactic reaction during drug administration, the following 
procedures should be performed: 
b) Stop the study drug administration. 
c) Apply a tourniquet proximal to the injection site to slow systemic absorption of drug. Do not 
obstruct arterial flow in the limb. 
d) Maintain an adequate airway. 
e) Administer antihistamines, epinephrine, or other medications as required by patient status and 
directed by the physician in charge. 
f) Continue to observe the patient and document observations. 
 
 
 
 


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Appendix 6: Child-Pugh Score 
 
Measure 
1 point 
2 points 
3 points 
Total bilirubin, μmol/L (mg/dL) 
<34 (<2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin, g/L (g/dL) 
>35 (>3.5) 
28-35 (2.8-3.5) 
<28 (<2.8) 
PT INR 
<1.7 
1.71-2.30 
>2.30 
Ascites 
None 
Mild 
Moderate to Severe 
Hepatic encephalopathy 
None 
Grade I-II (or suppressed 
with medication) 
Grade III-IV  
(or refractory) 
 
Points 
Class 
5-6 
A 
7-9 
B 
10-15 
C 
 
Source:  
Child CG, Turcotte JG. “Surgery and portal hypertension”. In Child CG. The liver and portal hypertension. 
Philadelphia:Saunders. 1964. pp. 50-64.   
Pugh RN, Murray-Lyon IM, Dawson L, Pietroni MC, Williams R . “Transection of the oesophagus for bleeding 
oesophageal varices”.  The British journal of surgery, 1973;60: 646-9. 
 
 
 
 


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Appendix 7: Pill Diaries 
 
Patient Name: _________________________________ 
Medical Record #: _____________ 
Cycle#: _________ 
Start Date: ____________________ Dose: ___________ 
 
Instructions to Patients: In the table below, please provide time and date of each dose taken. If 
a dose is missed, please leave blank and confirm with study coordinator upon return of pill diary.  
BMS-986205 – Daily 
BMS-986205 is an oral tablet that should be taken daily every day throughout the study period. 
BMS-986205 should be taken with 240 ml (8 ounces) of water following a meal.   
Day 
1 
2 
3 
4 
5 
6 
7 
 
 
 
________ 
Time:  
________ 
Date: 
 
________ 
Time:  
________ 
Date: 
 
________ 
Time:  
________ 
Date: 
 
________ 
Time:  
________ 
Date: 
 
________ 
Time:  
________ 
Date: 
 
________ 
Time:  
________ 
Date: 
 
________ 
Time:  
________ 
Date: 
Day 
8 
9 
10 
11 
12 
13 
14 
 
 
________ 
Time:  
________ 
Date: 
 
________ 
Time:  
________ 
Date: 
 
________ 
Time:  
________ 
Date: 
 
________ 
Time:  
________ 
Date: 
 
________ 
Time:  
________ 
Date: 
 
________ 
Time:  
________ 
Date: 
 
________ 
Time:  
________ 
Date: 
 
 
 
Patient Signature: _____________________________   Date: ___________ 
 
 
 
 
 
 
Date Returned 
# of pills left 
Collector’s Initials 
Returned to Pharmacy 
 
 
 
Yes or N/A 


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Appendix 8: Instructions on Taking BMS-986205 
 
BMS-986205 is a tablet and should be taken orally (by mouth). You will take these at home as 
instructed by the study staff. BMS-986205 tablets should be stored at room temperature.  
You should take the prescribed number of BMS-986205 tablet(s) one time a day (approximately 
24 hours apart), around the same time during the day. BMS-986205 is recommended to be taken 
within 30 minutes after a meal. 
Tablets should be taken with 240 ml (8 ounces) of water following a meal. You should not 
consume grapefruit, grapefruit juice, or Seville oranges while on study. All other types of 
oranges are acceptable to eat.    
If a dose is missed for more than 12 hours, do not take the tablet until the next scheduled dose 
(i.e., next day).  Do not take a double dose of study drug to make up for a missed dose.  Missed 
doses should be recorded on the pill diary. 
If you vomit after taking the dose, you should not repeat the dose. You should contact your study 
doctor and resume dosing at the time of the next scheduled dose (i.e., next day).   
On the day before your next study clinic visit, please provide the date and time of your dose on 
the last page of the pill diary. 
 
 
 


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Appendix 9: Women of Childbearing Potential Definitions and Methods of 
Contraception 
 
Definitions  
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
Women in the following categories are not considered WOCBP 
Premenarchal 
Premenopausal female with 1 of the following: 
− Documented hysterectomy 
− Documented bilateral salpingectomy 
− Documented bilateral oophorectomy 
 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
Postmenopausal female 
− A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females 
under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level > 
40 mIU/mL to confirm menopause. 
 
Contraception Guidance for Female Participants of Child Bearing Potential 
One of the highly effective methods of contraception listed below is required during study 
duration and until the end of relevant systemic exposure, defined as 5 months after the end of 
study treatment.* 
Note: Hormone-based contraceptives are not considered highly effective methods of 
contraception for WOCBP participants in Arms, which include BMS986205 IDO. 
 
 
 


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Highly Effective Contraceptive Methods That Are User Dependent  
Failure rate of <1% per year when used consistently and correctly.a  
Not in Arms which include BMS-986205 IDO: Combined (estrogen- and progestogen-
containing) hormonal contraception associated with inhibition of ovulationb  
− oral  
− intravaginal  
− transdermal  
Not in Arms which include BMS-986205 IDO. Progestogen-only hormonal contraception 
associated with inhibition of ovulationb  
− oral  
− injectable  
Highly Effective Methods That Are User Independent  
Not in Arms which include BMS-986205 IDO. Implantable progestogen-only hormonal 
contraception associated with inhibition of ovulation b 
Not in Arms which include BMS-986205 IDO. Hormonal methods of contraception 
including oral contraceptive pills containing a combination of estrogen and progesterone, 
vaginal ring, injectables, implants and intrauterine hormone-releasing system (IUS)c 
Intrauterine device (IUD)c 
Bilateral tubal occlusion 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used.  
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant. 
It is not necessary to use any other method of contraception when complete abstinence is 
elected.  
WOCBP participants who choose complete abstinence must continue to have pregnancy tests, 
as specified in Section 10. Acceptable alternate methods of highly effective contraception must 
be discussed in the event that the WOCBP participants chooses to forego complete abstinence  


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NOTES:  
a Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
participants participating in clinical studies.  
b Hormonal contraception may be susceptible to interaction with the study drug, which may 
reduce the efficacy of the contraceptive method.  Hormonal contraception is permissible only 
when there is sufficient evidence that the IMP and other study medications will not alter 
hormonal exposures such that contraception would be ineffective or result in increased 
exposures that could be potentially hazardous.  In this case, alternative methods of 
contraception should be utilized.  
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of 
contraception in the absence of definitive drug interaction studies when hormone exposures 
from intrauterine devices do not alter contraception effectiveness. The absence of such 
interactions is not known for BMS-986205 when administered with nivolumab. Therefore, for 
participants of child-bearing potential who receive these 2 medications, intrauterine hormone 
releasing systems are not acceptable methods of contraception. 
 
Unacceptable Methods of Contraception* 
• Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously 
• Diaphragm with spermicide 
• Cervical cap with spermicide 
• Vaginal Sponge with spermicide 
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action 
• Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
• Withdrawal (coitus interruptus). 
• Spermicide only 
• Lactation amenorrhea method (LAM) 
* Local laws and regulations may require use of alternative and/or additional contraception 
methods. 
 
 


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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. 
• Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 7 months after the end of study treatment. 
• Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 7 months after the end 
of treatment in the male participant. 
• Male participants with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile vaginal intercourse or use a male condom during each episode of penile 
penetration during the treatment and until 7 months after the end of study treatment.  
• Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of study treatment. 
 
Collection of Pregnancy Information 
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in the Pregnancy Surveillance Form-Quick Reference Guide.  
 
 
 
 


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Appendix 10: Adverse Event Management Algorithms 
These general guidelines constitute guidance to the investigator and may be supplemented by 
discussion with the Principal Investigator. The guidance applies to all immune-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 immune-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids.  
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedures, is recommended. 
The frequency and severity of the related adverse event covered by these algorithms will depend 
on the immune-oncology agent or regimen being used.  
Refer to nivolumab Investigator’s Brochure for additional information. 
 
 


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GI Adverse Event Management Algorithm 
 
 
 
 
 
 


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Renal Adverse Event Management Algorithm 
 
 
 
 
 


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Pulmonary Adverse Event Management Algorithm 
 
 
 
 
 
 


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Hepatic Adverse Event Management Algorithm 
 
 
 
 
 


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Endocrinopathy Management Algorithm 
 
 
 
 
 
 
 


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Skin Adverse Event Management Algorithm 
 
 
 
 
 
 
 


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Neurological Adverse Event Management Algorithm 
 
 
 
 
 


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Appendix 11: CYP3A4, CYP1A2 and CYP2B6 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/ucm093664.htm 
 
Table A 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 
CYP1A2 
ciprofloxacin, enoxacin, 
fluvoxamineg, zafirlukast 
methoxsalen, mexiletine, 
oral contraceptives 
acyclovir, allopurinol, 
cimetidine, peginterferon 
alpha-2a, piperine, 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 1.25-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. 
g 
Strong inhibitor of CYP1A2 and CYP2C19, and moderate inhibitor of CYP2D6 and CYP3A 
Abbreviations: AUC = area under the concentration-time curve; CYP = cytochrome P450. 
 
 
 


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Table A 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, 
phenytoin, rifampin,  
St. John’s wortb 
Bosentan, efavirenz, 
etravirine, modafinil, 
nafcillin 
Amprenavir, aprepitant, 
armodafinil, echinacea,c 
pioglitazone, prednisone, 
rufinamide 
CYP1A2 
 
Phenytoind, rifampine, 
ritonavirf, smoking, 
teriflunomide 
 
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. 
d 
Strong inducer of CYP3A and moderate inducer of CYP1A2, CYP2C19. 
e 
Strong inducer of CYP2C19, CYP3A, and moderate inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9. 
f 
Strong inducer of CYP2C19 and moderate inducer of CYP1A2, CYP2B6, CYP2C9. 
Abbreviations: AUC = area under the concentration-time curve; CYP = cytochrome P450. 
 
Table A 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 
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 
CYP2B6 
Bupropion, efavirenz 
 
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 12: Immune RECIST Criteria  
 
 
 


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Source: Lancet Oncol. 2017 Mar;18(3):e143-e152. 
 
 
 


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Appendix 13: Medications Associated with QT Prolongation 
 
The list below is not meant to be all inclusive. Please consult individual drug labels for further 
information.  
quinidine, procainamide, disopyramide, 
amiodarone, sotalol, ibutilide, dofetilide, 
erythromycins, clarithromycin, 
chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide, 
cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, 
halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine 
 
 
 
 


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Appendix 14: P-gp and BCRP Guidance 
 
The list below is 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 A 4: Examples of In Vivo Substrates for Selected Transporters 
Transporter 
Gene 
Substrate 
P-gp 
ABCB1 
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, 
digoxin, everolimus, fexofenadine, imatinib, lapatinib, 
maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, 
sirolimus, sitagliptin, talinolol, tolvaptan, topotecan 
BCRP 
ABCG2 
Methotrexate, mitoxantrone, imatinib, irrinotecan, lapatinib, 
rosuvastatin, sulfasalazine, topotecan 
Please note that this is not an exhaustive list. 
Abbreviations: BCRP = breast cancer resistance protein; P-gp = P-glycoprotein. 
 
 
 


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Appendix 15: Agents Known to Cause Methemoglobinemia  
 
Acetanilid 
p-Amino salicylic acid 
Aniline, aniline dyes 
Benzene derivatives 
Clofazimine 
Chlorates 
Chloroquine 
Dapsone 
Local anesthetic agents  
Benzocaine  
Lidocaine  
Prilocaine  
Menadione 
Metoclopramide 
Methylene blue* 
Naphthoquinone 
Naphthalene 
Nitrites  
Amyl nitrite  
Farryl nitrite  
Sodium nitrite  
Nitroglycerin  
Nitric oxide  
Nitrobenzene 
Paraquat 
Phenacetin 
Phenazopyridine 
Primaquine 
Rasburicase 
Resorcinol 
Sulfonamides 
* While methylene blue is a recognized treatment for methemoglobinemia, it is an agent with oxidant potential (and may worsen 
the clinical situation) since in individuals with glucose-6-phosphate dehydrogenase deficiency, it induces acute hemolysis 
that can further decrease oxygen delivery to the tissues. Paradoxically, in high doses, methylene blue can also increase 
methemoglobinemia. 
 
 
 
 


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Appendix 16: BMS-986205 Diagnostic Criteria for HLH and DRESS Syndrome 
  
 
 


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