Combination of Checkpoint Inhibition and IDO1 Inhibition Together With Standard Radiotherapy or Chemoradiotherapy in Newly Diagnosed Glioblastoma. A Phase 1 Clinical and Translational Trial
Phase: PHASE1
Conditions: Glioblastoma
Sponsor: Northwestern University

CONFIDENTIAL
This material is the property of the Robert H. Lurie Comprehensive Cancer Center of Northwestern 
University.
Do not disclose or use except as authorized in writing by the study sponsor (PI).
CONFIDENTIAL
This material is the property of the Robert H. Lurie Comprehensive Cancer Center of Northwestern 
University.
Do not disclose or use except as authorized in writing by the study sponsor (PI).
Combination of checkpoint inhibition and IDO1 inhibition together 
with standard radiotherapy or chemoradiotherapy in newly diagnosed 
glioblastoma. A phase 1 clinical and translational trial.
Principal Investigator:
Rimas V. Lukas, MD
Associate Professor
Associate Director, Neuro-Oncology Division
Department of Neurology
Northwestern University Feinberg School of Medicine 
676 N. St Clair St, Suite 1300
Abbott Hall 1114
Chicago, IL 60611
E-mail: rimas.lukas@nm.org
Phone: 312 695 0990
RHLCC of Northwestern University-Chicago 
Participating Northwestern
Medicine Network Site:
Northwestern Memorial Healthcare (West Region)
Participating Northwestern Memorial Healthcare Location:

Northwestern Medicine Cancer Center Warrenville
4405 Weaver Parkway
Warrenville, IL 60555
Phone: 630-352-5450
Northwestern Memorial Healthcare Principal Investigator:
Vinai Gondi, MD
Director of Research & Education 
Northwestern Medicine Proton Center
Co-Director, Brain & Spine Tumor Center
Northwestern Medicine Cancer Center Warrenville
4405 Weaver Parkway
Warrenville, IL 60555
Phone: (630) 352-5350
Email: vinai.gondi@nm.org
Sub-Investigators:
Roger Stupp. MD
Priya Kumthekar, MD
Karan Dixit, MD
Department of Neurology
Northwestern University Feinberg School of Medicine
Maciej S. Lesniak. MD
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Department of Neurosurgery
Northwestern University Feinberg School of Medicine
Sean Sachdev, MD
Department of Radiation Oncology
Northwestern University Feinberg School of Medicine
Lab Co-Investigators:
Derek A. Wainwright, PhD
Department of Neurosurgery
Loyola University
C. David James, PhD
Department of Neurosurgery
Northwestern University
Csaba Juhasz MD, PhD
Professor, Pediatrics, Neurology, Neurosurgery
Wayne State University
PET Center and Translational Imaging Laboratory
Children's Hospital of Michigan
3901 Beaubien St. 
Detroit, MI, 48201
Phone: 313-966-5136
Fax: 313-966-9228
Email: csaba.juhasz@wayne.edu
Pathology: 
Craig M. Horbinski, MD
Department of Pathology
Northwestern University
Radiology: 
Ben Liu, MD
Northwestern University
Biostatistician:
Hui Zhang, PhD 
Professor, Department of Preventive Medicine 
Division of Biostatistics
Northwestern University Feinberg School of Medicine
Chicago, IL 60611
(312) 503-8185
E-mail: hzhang@northwestern.edu
Study Intervention(s):
BMS-986205, Nivolumab (Opdivo), Temozolomide
IND Number:
143926
IND Holder:
Rimas Lukas, MD
Funding Source: 
Department of Neurosurgery, Northwestern University
Version Date:
October 13, 2022
Coordinating Center:
Clinical Trials Office
Robert H. Lurie Comprehensive Cancer Center 
Northwestern University
676 N. St. Clair, Suite 1200
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Chicago, IL  60611
http://cancer.northwestern.edu/research/clinical-trials-office/index.html
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LIST OF ABBREVIATIONS .............................................................................................................1
STUDY SCHEMA ............................................................................................................................2
STUDY SUMMARY .........................................................................................................................3
1
INTRODUCTION – BACKGROUND & RATIONALE...........................................................5
1.1
Glioblastoma....................................................................................................................5
1.2
Intervention Background & Overview ..............................................................................8
1.3
Rationale for the Current Study.....................................................................................16
2
OBJECTIVES.....................................................................................................................22
2.1
Primary Objective ..........................................................................................................22
2.2
Secondary Objectives....................................................................................................22
2.3
Exploratory Objectives...................................................................................................22
3
PATIENT ELIGIBILITY.......................................................................................................22
3.1
Inclusion Criteria............................................................................................................23
3.2
Exclusion Criteria...........................................................................................................24
4
TREATMENT PLAN...........................................................................................................26
4.1
Overview........................................................................................................................26
Treatment Administration ..............................................................................................27
4.3
BMS-986205 Dose Escalation.......................................................................................31
4.4
Toxicity Management & Dose Delays/Modifications......................................................35
4.5
Concomitant Medications/Treatments ...........................................................................46
4.6
Duration of Therapy.......................................................................................................48
4.7
Duration of Follow Up....................................................................................................48
4.8
Removal of Subjects from Study Treatment and/or Study as a Whole .........................49
4.9
Patient Replacement .....................................................................................................49
5
STUDY PROCEDURES.....................................................................................................50
5.1
Table 5-1: Study Procedures.........................................................................................50
5.2
Table 5-2: Study Procedures During Maintenance Phase ............................................53
6
ENDPOINT ASSESSMENT...............................................................................................55
6.1
Definitions......................................................................................................................55
6.2
Primary Endpoint ...........................................................................................................56
6.3
Secondary Endpoints ....................................................................................................56
6.4
Exploratory Endpoints ...................................................................................................57
7
ADVERSE EVENTS...........................................................................................................57
7.1
Adverse Event Monitoring .............................................................................................57
7.2
Definitions & Descriptions..............................................................................................58
7.3
Adverse Event Reporting...............................................................................................60
8
DRUG INFORMATION ......................................................................................................62
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8.1
BMS-986205..................................................................................................................62
8.2
Nivolumab......................................................................................................................66
8.3
Temozolomide ...............................................................................................................69
8.4
Tumor Treating Fields ...................................................................................................70
9
CORRELATIVES/SPECIAL STUDIES...............................................................................73
9.1
Sample Collection Guidelines........................................................................................73
9.2
Sample Processing, Storage, and Shipment.................................................................74
9.3
Assay Methodology .......................................................................................................74
9.4
Specimen Banking.........................................................................................................75
9.5
Patient Questionnaires ..................................................................................................75
9.6
AMT-PET Study.............................................................................................................76
10
STATISTICAL CONSIDERATIONS...................................................................................79
10.1
Study Design/Study Endpoints......................................................................................79
10.2
Analysis sets..................................................................................................................80
10.3
Sample Size and Accrual ..............................................................................................81
10.4
Data Analyses Plans .....................................................................................................81
11
STUDY MANAGEMENT ....................................................................................................83
11.1
Institutional Review Board (IRB) Approval and Consent...............................................83
11.2
Amendments .................................................................................................................83
11.3
Registration Procedures................................................................................................83
11.4
Data Submission ...........................................................................................................84
11.5
Data Collection and Record Keeping ............................................................................84
11.6
Data Management and Monitoring/Auditing ..................................................................84
11.7
Adherence to the Protocol.............................................................................................85
11.8
Investigator Obligations.................................................................................................85
11.9
Publication Policy ..........................................................................................................86
11.10
Discontinuation of Study................................................................................................86
REFERENCES ..............................................................................................................................87
APPENDICES................................................................................................................................91
Appendix A: Common Terminology Criteria for Adverse Events V5.0 (CTCAE)........................91
Appendix B: Karnofsky Performance Scale (KPS).....................................................................92
Appendix C: Female Participants of Child Bearing Potential Definitions and Methods of  Contraception
93
Appendix D: Management Algorithms........................................................................................97
Appendix E: CYP3A4, CYP2B6 and CYP1A2 Guidance .........................................................106
Appendix F: Medications Associated with QT Prolongation.....................................................108
Appendix G: Agents Known to Cause Methemoglobinemia.....................................................109
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Appendix H: P-GP and BCRP Guidance..................................................................................110
Appendix I: BMS-986205 and Nivolumab Dose Delay Criteria ................................................111
Appendix J: BMS-986205 Diagnostic Criteria for HLH and DRESS Syndrome.......................112
Appendix K: Beck's Depression Inventory Questionnaire ........................................................116
Appendix L: PROMIS Emotional Distress - Anxiety .................................................................120
Appendix M: Summary of Changes..........................................................................................125
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1
LIST OF ABBREVIATIONS
AE
Adverse Event
ALT
Alanine Aminotransferase
ALC
Absolute Lymphocyte Count
AST
Aspartate Aminotransferase
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CMP
Comprehensive Metabolic Panel
CR
Complete Response
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLT
Dose Limiting Toxicity
DSMC
Data and Safety Monitoring Committee
GBM
Glioblastoma
H&PE
History & Physical Exam
IV (or iv)
Intravenously
KPS
Karnofsky Performance Scale
MTD
Maximum Tolerated Dose
ORR
Overall Response Rate or Objective Response Rate
OS
Overall Survival
PD
Progressive Disease
PFS
Progression Free Survival
PO (or p.o.)
Per os/by mouth/orally
RT
Radiotherapy/Radiation Therapy
SAE
Serious Adverse Event
SGOT
Serum Glutamic Oxaloacetic Transaminase
SPGT
Serum Glutamic Pyruvic Transaminase
TMZ
Temozolomide
TTFields
Tumor Treating Fields
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STUDY SCHEMA
Newly diagnosed Grade IV 
Glioma
RT: 5 days a week for a total 
of 6 weeks to a dose of 60 Gy
+
Nivolumab: 240mg IV Q2W
+
BMS-986205: PO QD
Unmethylated MGMT 
promoter 
N = up to 18 patients
RT Phase 
(6 weeks)
Maintenance Phase6
BMS-986205: + Nivolumab4
Phase I1
MTD
PD
Follow Up2
1.
Determination of MTD for MGMT unmethylated cohort will occur first, followed by determination of MTD for 
MGMT methylated cohort.
2.
Follow up: Patients will be contacted every 3 months either by clinic visit or by phone to monitor survival
3.
TMZ during Maintenance Phase will be given 200 mg/m2 QD for 5 days every 28 days for a total of 6 cycles.  
Nivolumab and BMS-986205 treatment will continue beyond 6 cycles as indicated.
4.
Beginning at Cycle 6 of the Maintenance Phase, nivolumab will be given at 480mg Q4W IV.
5.
Gd-MRI will occur every 8 weeks during Maintenance Phase beginning on C1D1.
6.
Patients will be given the option to begin TTFields treatment at the beginning of the Maintenance Phase.  
Patients who choose not to utilize TTFields will not be required to do so.
Screening (-28 days)
Post RT 
Phase 
(28 Days)
 BMS-986205 + Nivolumab
Newly diagnosed Grade IV 
Glioma
Methylated MGMT 
promoter 
N = up to 12 patients
RT: 5 days a week for a total 
of 6 weeks to a dose of 60 Gy.
+
TMZ: 75 mg/m2 TMZ PO QD
+
Nivolumab: 240mg IV Q2W
+
BMS-986205: PO QD
BMS-986205 + Nivolumab4 +TMZ3
PD
Follow Up2 
Gd-MRI5
Gd-MRI5
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STUDY SUMMARY
Title
Combination of checkpoint inhibition and IDO1 inhibition together with 
standard radiotherapy or chemoradiotherapy in newly diagnosed 
glioblastoma. A phase 1 clinical and translational trial.
Version
October 13, 2022
Study Design
This is a multi center, open-label, uncontrolled, Phase I study 
Study Center(s)
Northwestern University and Northwestern Memorial Healthcare (West 
Region)
Objectives
The primary objective of the study is to explore feasibility and toxicity of a 
novel combination of immunomodulating therapy together with standard 
radiotherapy in newly diagnosed glioblastoma patients. After 
determination of the MTD, this regimen will be explored for efficacy in 
patients with MGMT promoter unmethylated tumors.  It will also to be 
explored in conjunction with TMZ/RT → TMZ chemoradiotherapy in 
patients with MGMT promoter methylated tumors.
Sample Size
18-30 patients (explore 3 dose levels or a maximum of 18 patients with 
unmethylated tumors and 2 dose levels with up to 12 patients with 
methylated tumors.)
Diagnosis & Key 
Eligibility Criteria
Inclusion Criteria:

Newly diagnosed, histologically confirmed diagnosis of any 
grade IV glioma with documentation of MGMT methylation 
status. The histological diagnosis can be obtained either from a 
brain biopsy or from a neurosurgical resection of the tumor.

Tumor tissue specimens from the GBM surgery or biopsy for 
central pathology review and exploratory analysis of 
immunocorrelative studies, if available

For subjects who had undergone tumor resection, preoperative 
Gd-MRI and immediate postoperative Gd-MRI performed within 
<72 hours after surgery or biopsy is recommended. If CT scans 
were performed perioperatively, an MRI should be performed 
before initiation of study treatment.
Exclusion Criteria:

Patients with an active, known or suspected autoimmune 
disease.

History of recent prior malignancy.  Subjects with curatively 
treated cervical carcinoma in situ or basal cell carcinoma of the 
skin, or subjects who have been free of other malignancies for ≥2 
years are eligible for this study.
See section 3.0 for the full list of eligibility criteria.
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Treatment Plan
Patients with unmethylated MGMT promotor GBM will receive RT for 6 
weeks in combination with nivolumab (240mg) Q2W and BMS-986205 
PO QD.  
Following completion of RT, patients will enter the Maintenance Phase 
during which they will continue to receive nivolumab and BMS-986205.  
Beginning at Cycle 6, nivolumab dosing will change to 480mg Q4W.  In 
addition, patients will initiate TTFields approximately 4 weeks after the 
completion of RT.  Patients who choose not to utilize TTFields will not be 
required to do so.
Following the establishment of the phase 2 dose, another phase 1 cohort 
for patients with methylated MGMT promoter will be opened.  This cohort 
will add TMZ concomitant with RT as well as adjuvant TMZ to the study 
regimen. In addition, patients will initiate TTFields approximately 4 weeks 
after the completion of RT.  Patients who choose not to utilize TTFields 
will not be required to do so.
Treatment will continue until disease progression or unacceptable AEs.
Statistical Methodology
In this phase 1 trial, statistical analyses will be descriptive. Based on 
landmark analysis of historical control data for unmethylated tumors we 
estimate the 1-yr survival (OS12) at 50%. If this regimen proves safe and 
tolerable, further investigations in a randomized phase II trial will likely be 
proposed. 
Safety and tolerability 
The worst value of each hematological/biochemical category and 
Adverse Events will be identified and graded for each patient. 
Frequencies and percentages of each category will be tabulated per 
arm. A table with grade 3/4 frequencies and percentages will be 
provided. Summaries for Serious and Related Adverse Events will also 
be presented.
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1
INTRODUCTION – BACKGROUND & RATIONALE
1.1
Glioblastoma
Gliomas account for 40-70% of all primary brain tumors. Glioblastoma (GBM) is highly 
malignant infiltrating the brain extensively, and creating a local immunosuppressed 
microenvironment.  The clinical course of GBM is almost invariably fatal, with a median 
survival of only a few months if untreated. Treatment of these tumors is hampered by 
several factors, including genomic instability, which is common to many malignant 
tumors.  
The general treatment strategy for primary disease includes surgery, radiotherapy (RT), 
and chemotherapy with temozolomide (TMZ). Despite these available treatment options, 
people with GBM have poor prognoses, with a median survival time of 14-20 months and 
a 5-year survival rate of <10% (1). Major prognostic factors for survival are age and 
performance status at the time of diagnosis.
1.1.1
Standard treatment regimen in GBM
The standard of care for newly diagnosed GBM is based on the results of the 
phase III trial EORTC 26981-22981 & NCIC CE.3 with 573 randomized patients.  
This trial demonstrated that the addition of TMZ chemotherapy to RT increased 
median survival from 12 to 14.6 months, and 2-year survival rate from 10 to 
26%(2). 
This treatment regimen consists of TMZ (75 mg/m2 daily) administered 
concomitantly to RT for 6 weeks (60 Gy), followed by maintenance therapy of 6 
cycles TMZ (beginning 4 weeks after the end of RT; 150-200mg/m² for 5 days 
every 4 weeks). Results showed a hazard ratio for survival was 0.63 (95% 
confidence interval [CI] = 0.52, 0.75; log-rank P< 0.0001) indicating a 37% 
reduction in the risk of death for patients treated with RT/TMZ compared to RT 
alone as initial therapy. Median survival was 14.6 months (95% CI = 13.2, 16.8 
months) for RT/TMZ versus 12.1 months (95% CI = 11.2, 13.0 months) for RT 
alone. The 2-year survival rate was 26.5% (95% CI = 21.2%, 31.7%) for RT/TMZ 
compared with 10.4% (95% CI = 6.8%, 14.1%) for RT alone. Median PFS was 
6.9 months (95% CI = 5.8, 8.1 months) for RT/TMZ and 5.0 months (95% CI = 
4.2, 5.5 months) for RT alone. 
Safety data from EORTC/NCIC study confirmed a good tolerance and safety of 
the combination of TMZ plus RT.  During concomitant RT/TMZ, Grade 3 or 4 
neutropenia was documented in 12 (4%) subjects, and grade 3 or 4 
thrombocytopenia occurred in 9 (3%) subjects. Overall, 19 (7%) patients 
experienced any Grade 3 or 4 hematologic toxicity. During maintenance TMZ, 
14% of subjects experienced any Grade 3 or 4 hematologic toxicity, 4% 
developed Grade 3 or 4 neutropenia, and 11% developed Grade 3 or 4 
thrombocytopenia. During radiotherapy, severe infections were observed in 6 
(2%) patients in the RT arm and in 9 (3%) patients in the RT/TMZ arm; during 
adjuvant TMZ therapy, severe infections were reported in 12 (5%) patients.  
Toxicities related to TMZ are summarized in Table 1 (from Lukas & Mrugala, 
2017).
Glioblastoma with MGMT promoter methylation are likely to benefit from TMZ 
chemotherapy.   Patients with MGMT promoter unmethylated GBM are unlikely 
to benefit from TMZ chemotherapy (3). In turn, it is appropriate to limit TMZ use 
to the MGMT promoter methylated population (4).
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The utilization of TTFields, as described in the randomized phase II EF-14 trial, in 
addition to the standard of care as described above has been shown to further 
increase OS, PFS, and landmark survival in this patient population (5).  This has 
been shown without any impairment in health related quality of life with the 
addition of TTFields (6).  While TTFields are included in the NCCN guidelines as 
a level 1 recommendation, their utilization by patients with appropriate indications 
has not been universal.  However, the degree of compliance by those who elect 
to utilize TTFields has been high (7).  In turn, many contemporary trials for newly 
diagnosed glioblastoma leave the decision to patients.  This is a valid approach, 
particularly in light of the low toxicity profile of TTFields and low likelihood for 
overlapping toxicities with the investigational agents.
1.1.2
Immunosuppression and high-grade gliomas
Glioblastoma is associated with an immune suppressed tumor microenvironment. 
Two important contributors to this are the indoleamine 2,3 dioxygenase 1 (IDO) 
enzymatic pathway and the programmed death 1 (PD-1) and programmed death 
ligand 1 (PD-L1) interactions leading to T cell exhaustion (8, 9).
1.1.2.1 IDO1 expression correlates with worse GBM patient survival. 
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IDO1 is an inducible 
enzyme involved in 
converting 
tryptophan (Trp) into 
kynurenine (Kyn) 
(10, 11), which 
suppresses T-cell 
function and 
increases 
immunotolerance of 
tumor (12-14).  
IDO1 mRNA 
increases with 
glioma grade (Fig. 
1A), and high IDO1 
levels are 
associated with 
decreased overall 
survival (OS) in 
glioma patients (Fig. 
1B) (15). The IDO1 
gene has several 
IFNɣ response 
elements, and the 
tumor tropism of 
IFNɣ-producing T-cells appears to 
stimulate IDO1 expression in GBM (see 
experimental results below). Increased 
numbers of T-cells in GBM, as indicated 
by intratumoral T-cell marker detection, 
correlates with decreased patient 
survival (Fig. 2). 
1.1.2.2 Tumor-
infiltrating T-cells are primarily 
responsible for increased IDO1 
expression in human GBM.
Human T-cell tropism for intracranial 
GBM patient-derived xenografts (PDX) 
has been observed in humanized mouse 
tumor models, in which severely 
immunocompromised mice are engrafted with human immune cells and 
immune cell producing tissues, prior to engraftment with human tumor 
(16).  Results from depleting the humanized mice of CD4+ and CD8+ T-
cells show that the presence versus absence of these T-cells is directly 
correlated with tumor IDO1 mRNA abundance, as their depletion 
decreases intratumoral IDO1 mRNA levels (P<0.001, respectively: Fig. 
3A).
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Interestingly, human IDO1 mRNA is undetectable in intracranial GBM 
PDX isolated from T-cell-deficient mice. Expression of the T-cell-specific 
marker, CD3E, as well as the T-cell effector cytokine, IFNɣ, is readily 
detectable in intracranial tumors established in humanized mice, but is 
absent or decreased in the majority of engrafted GBM when humanized 
mice are depleted of human T-cells. We have demonstrated that IFNɣ 
potently induces IDO1 in GBM cells (Fig. 3B), and T-cells: GBM co-
cultures confirm that IDO1 is induced by activated T lymphocytes in an 
IFNγ-dependent manner (Fig. 3C; P<0.001). Taken together, these 
results indicate that tumor-infiltrating T-cells directly increase 
immunosuppressive IDO1 in GBM.
1.2
Intervention Background & Overview
1.2.1
BMS-986205
The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the degradation of 
tryptophan along the kynurenine pathway and is frequently expressed in human 
malignancies. In healthy humans, high IDO1 expression is found in the placenta, 
the mucosa of the female genital tract, the lungs, and the lymphoid organs (1). 
The activity of IDO1 induces an immunosuppressive microenvironment in tissues 
by inhibiting T-cell function through local depletion of the essential amino acid 
tryptophan and through generation of active kynurenine pathway metabolites (2). 
High IDO1 expression in cancers is correlated with more aggressive tumor 
progression and shorter patient survival time in most cancer types (3). Tumor 
IDO1 
trans
cript 
is 
eleva
ted in 
patie
nts 
with 
meta
static 
mela
noma 
and 
renal 
cell 
carci
noma 
(RCC
) 
after 
treat
ment 
with 
the 
anti-
progr
amm
ed 
death 
recep
tor 1 
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(PD1) antibody nivolumab (4, 5). In the mouse tumor model, IDO1 is a critical 
resistance mechanism in antitumor T-cell immunotherapy targeting the cytotoxic 
T lymphocyte antigen-4 (CTLA-4) with a neutralizing antibody (6). These 
observations suggest that IDO1 is a mechanism that contributes to tumor escape 
from host immune surveillance. Therefore, inhibition of IDO1 using 
pharmaceutical agents may diminish the immunosuppressive 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 and ipilimumab.  BMS-986205 
(FLX287 or F-1287) is a potent and selective oral IDO1 inhibitor. 
Comprehensive background information on non-clinical pharmacology, 
pharmacokinetics (PK) and toxicology can be found in the Investigator Brochure.
1.2.1.1 Pharmacokinetics of BMS-986205 Preclinical evaluations
BMS-986205 is a selective inhibitor of IDO1 without activity on IDO2 or 
TDO, other enzymes in the Trp metabolism pathway.   Once daily dosing 
is supported by preclinical studies.  PD has been demonstrated in in vitro 
models at single nM concentrations (17).  
Preclinical studies have not yet shown penetration of the blood brain 
barrier (BBB) by BMS-986205, however the BBB is a dynamic partial 
barrier which is deemed to evolve throughout the course of disease.  It is 
deemed that radiotherapy facilitates movement across the BBB.  
Additionally, the activity of immunotherapies in the non-target organ may 
have a favorable effect in the target organ.  Further, there is no data to 
suggest that IDO1 enzyme inhibitors must enter the brain for their 
synergistic effects with concurrent PD-1 blockade and radiotherapy. It is 
entirely possible that IDO1 enzyme inhibitors act solely on lymph node 
cells (outside of the brain) and that control the development and 
maturation of immune cells that subsequently are recruited to brain 
tumors (18).
1.2.1.2 Clinical evaluations.  
BMS-986205 is currently being investigated in an international multi-
center phase 1/2a trial.  The starting dose of BMS-986205 was 25 mg 
daily with the final dose of 400 mg daily.  In this study a BMS-986205 
monotherapy lead-in of two weeks was followed by combination therapy 
with BMS-986205 and nivolumab 240 mg IV every two weeks. The MTD 
was established at 200 mg based on the safety and tolerability profile 
and incidence of dose-limiting toxicities (DLTs).   Among DLT-evaluable 
subjects who completed a 2-week monotherapy lead-in of BMS-986205 
followed by 4 weeks of combination therapy with nivolumab, the following 
DLTs were observed: 0/7 at 25 mg BMS-986205, 0/8 at 50 mg, 1/9 at 
100 mg (Grade 3 autoimmune hepatitis leading to treatment 
discontinuation), 3/12 at 200 mg (Grade 3 fatigue and Grade 3 anemia 
leading to dose reduction, Grade 3 AST and ALT elevations, and Grade 
3 anemia leading to dose reduction), and 2/4 at 400 mg (initial Grade 2 
transaminases increased progressing to Grade 3, and Grade 2 fatigue 
and anemia leading to > 25% of BMS-986205 doses missed and 
requiring dose reduction). The BMS-986205 dose of 400 mg was the 
MAAD and exceeded the established target toxicity profile based on 
Bayesian Logistic Regression Method (38.8% posterior probability that 
the true DLT rate is in the range of excessive toxicity, exceeding the limit 
of 35%). Except for the transaminase elevation at the dose of 400 mg, all 
other DLTs occurred during the combination therapy period. Based on 
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these results, BMS-986205 at 200 mg is the MTD in combination with 
nivolumab.
Treatment-related adverse events (AEs) of all grades were seen in 
50.6% of patients receiving BMS-986205 plus nivolumab.  Only 12.3% of 
patients exhibited grade 3-4 treatment related AEs There has been 1 
treatment-related death due to myocarditis prior to the clinical data cutoff 
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.
Part 2 (Dose Expansion) is currently enrolling and is assessing the 
preliminary efficacy of BMS-986205 in combination with nivolumab in 
specific malignant disease populations. BMS-986205 is being 
administered at 100 mg QD in all cohorts. It is also administered at 200 
mg QD in select cohorts in order to obtain further safety, PK, and PD 
information among the BMS-986205 doses. Nivolumab is administered 
at either 240 mg Q2W or 480 mg every 4 weeks (Q4W).  
Pharmacokinetic studies reveal that human plasma concentrations of 
BMS-986205 exceed levels expected to inhibit IDO1 based upon the in 
vitro experiments.  At 25 mg daily, trough levels exceed the IC50.  At 50 
mg daily trough levels exceed the IC90.  Dose-dependent decreases in 
serum Kyn levels are also noted.  Approximately60% reduction on day 
15 in mean serum Kyn levels was noted in doses ≥100 mg daily.  There 
is also a dose-dependent decrease in intra-tumoral (non-CNS tumors) 
Kyn levels (19). 
1.2.1.3 Dose Justification
All participants randomized will receive BMS-986205 starting at a dose of 
50 mg PO QD in combination with nivolumab 240 Q2W (and beginning 
at cycle 6 of the maintenance phase, nivolumab dose will be 480mg 
Q4W). 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 maximum tolerated dose (MTD) established in 
dose escalation of BMS-986205 in combination with nivolumab, 
preliminary PK, PD, and safety data support the selection of 50 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.
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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.
1.2.1.4 Safety 
Preliminary analysis of safety results from Study CA017003, the first-in-
human, Phase 1/2a dose escalation and cohort expansion study in 
advanced malignant tumors have revealed a favorable safety profile. 
Treatment-related adverse events (TRAEs) have generally been of low 
grade and are manageable. Per Investigator Brochure v. 6 (01-29-2020), 
the most commonly reported TRAEs (in > 10% of participants) during 
combination therapy with nivolumab were fatigue (17.2%) and nausea 
(13.2%). Grade 3 and 4 TRAEs have been reported in approximately 
17% of participants receiving the combination. Treatment-related SAEs 
were reported in 9.4% of patients treated with BMS-986205 and 
nivolumab.There has been 1 treatment-related death due to myocarditis , 
which occurred during combination with nivolumab, and 2 additional 
deaths due to Stevens-Johnson syndrome and hepatic failure 
Furthermore, the 100 mg once daily (QD) dose of BMS 986205 in 
combination with nivolumab appears to have a safety profile similar to 
that reported for nivolumab monotherapy, except for anemia and 
methemoglobinemia, which may be related to p-chloroaniline production.
Metabolism of BMS-986205 produces a p-chloroaniline metabolite, which 
is associated with the formation of methemoglobin as well as with 
hemolytic anemia. As of 24-Oct-2019, there have been no clinically 
significant metHb events at the 100 mg dose level of BMS-986205, and 
the highest reported metHb value was 16% in a participant receiving 200 
mg of BMS-986205; no other participants 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 (1% and 0.3% of participants receiving combination 
therapy with nivolumab, respectively) and responded to dose holding, 
reductions, and other standard clinical measures. Entry criteria and 
monitoring parameters were developed in an attempt to reduce the risk 
of the occurrence and impact of methemoglobin-related toxicity. 
Participants with cytochrome b5 reductase and G6PD deficiencies are 
excluded due to the increased risk of methemoglobinemia and 
hemolysis, respectively.
*All information above references BMS-986205 Investigator Brochure v. 6 (01-
29-2020). Please refer to the most recent Investigator Brochure for a current 
listing of adverse events and toxicities.
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1.2.1.5 Efficacy
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, renal, triple negative breast, and endometrial 
cancers. Mature but preliminary aggregate data have been presented for 
bladder and cervical cancers as follows:
•
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 (n=15) and 20% for participants with 2 or more prior 
therapies (n=10). The ORR was 46.2% for PD-L1 positive 
participants (tumor PD-L1 expression ≥ 1%; n=13), and 22.2% for 
PD-L1 negative participants (tumor PD-L1 expression <1%; n=9).
•
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 (n=11) and 
29.1% for participants with 2 or more prior therapies (n=11). The 
ORR was 25.0% for PD-L1 positive participants (tumor PD-L1 
expression ≥ 1%; n=12), and 0% for PD-L1 negative participants 
(tumor PD-L1 expression < 1%; n=7).
Additional details can be found in the investigator’s brochure.
Study conduct.  Based on the nonclinical and clinical results available 
to date, the conduct of the study is regarded as justifiable at the planned 
dose ranges. The study shall be discontinued in the event of new 
findings that indicate that a relevant deterioration of the risk-benefit 
relationship is probable. 
This trial will be conducted in compliance with the protocol, International 
Conference on Harmonisation (ICH) Note for Guidance on Good Clinical 
Practice (GCP) (ICH, Topic E6, 1996) and applicable regulatory 
requirements.
1.2.2
Nivolumab
1.2.2.1 Mechanism of Action
Cancer immunotherapy rests on the premise that tumors can be 
recognized as foreign rather than as self and can be effectively attacked 
by an activated immune system. An effective immune response in this 
setting is thought to rely on immune surveillance of tumor antigens 
expressed on cancer cells that ultimately results in an adaptive immune 
response and cancer cell death. Meanwhile, tumor progression may 
depend upon acquisition of traits that allow cancer cells to evade 
immunosurveillance and escape effective innate and adaptive immune 
responses (20-22). Current immunotherapy efforts attempt to break the 
apparent tolerance of the immune system to tumor cells and antigens by 
either introducing cancer antigens by therapeutic vaccination or by 
modulating regulatory checkpoints of the immune system. T-cell 
stimulation is a complex process involving the integration of numerous 
positive as well as negative co-stimulatory signals in addition to antigen 
recognition by the T-cell receptor (TCR)(23). Collectively, these signals 
govern the balance between T-cell activation and tolerance. 
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PD-1 is a member of the CD28 family of T-cell co-stimulatory receptors 
that also includes CD28, CTLA 4, ICOS, and BTLA (24). PD-1 signaling 
has been shown to inhibit CD-28-mediated upregulation of IL-2, IL-10, IL-
13, interferon-γ (IFN-γ) and Bcl-xL. PD-1 expression also been noted to 
inhibit T cell activation, and expansion of previously activated cells. 
Evidence for a negative regulatory role of PD-1 comes from studies of 
PD-1 deficient mice, which develop a variety of autoimmune phenotypes 
(25). These results suggest that PD-1 blockade has the potential to 
activate anti-self T-cell responses, but these responses are variable and 
dependent upon various host genetic factors. Thus, PD-1 deficiency or 
inhibition is not accompanied by a universal loss of tolerance to self-
antigens.
In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (EC50 
0.39-2.62 nM), and inhibits the binding of PD-1 to its ligands PD-L1 and 
PD-L2 (IC50 ±1 nM). Nivolumab binds specifically to PD-1 and not to 
related members of the CD28 family such as CD28, ICOS, CTLA-4 and 
BTLA. Blockade of the PD-1 pathway by nivolumab results in a 
reproducible enhancement of both proliferation and IFN-γ release in the 
mixed lymphocyte reaction (MLR). Using a CMV re stimulation assay 
with human PBMC, the effect of nivolumab on antigen specific recall 
response indicates that nivolumab augmented IFN-γ secretion from CMV 
specific memory T cells in a dose-dependent manner versus isotype-
matched control. In vivo blockade of PD-1 by a murine analog of 
nivolumab enhances the anti-tumor immune response and result in 
tumor rejection in several immunocompetent mouse tumor models 
(MC38, SA1/N, and PAN02) (26).
1.2.2.2 Justification of Dose
The nivolumab dose of 240 mg every 2 weeks (Q2W) was selected 
based on clinical data and modeling and simulation approaches using 
population PK (PPK) and exposure-response analyses of data from 
studies in multiple tumor types (melanoma, non-small-cell lung cancer 
[NSCLC], and renal cell carcinoma [RCC]) where body weight 
normalized dosing (mg/kg) has been used.
PPK analyses have shown that the PK of nivolumab is linear with 
proportional exposure over a dose range of 0.1 to 10 mg/kg, and no 
differences in PK across ethnicities and tumor types were observed. 
Nivolumab clearance and volume of distribution were found to increase 
as the body weight increases, but less than proportionally with increasing 
weight, indicating that mg/kg dosing represents an over-adjustment for 
the effect of body weight on nivolumab PK. The PPK model previously 
developed using data from NSCLC subjects has recently been updated, 
using data from 1544 subjects from 7 studies investigating nivolumab in 
the treatment of melanoma, NSCLC, and RCC. In this dataset, the 
median (minimum - maximum) weight was 77 kg (35 - 160 kg) and thus, 
an approximately equivalent dose of 3 mg/kg for an 80 kg subject, 
nivolumab 240 mg Q2W was selected for future studies. To predict 
relevant summary exposures of nivolumab 240 mg Q2W, the PPK model 
was used to simulate nivolumab 3 mg/kg Q2W and 240 mg Q2W. In the 
simulations, the simulated patient populations consisted of 1000 subjects 
per treatment arm randomly sampled from aforementioned pooled 
database of cancer subjects. Because no differences in PK were noted 
across ethnicities and tumor types, these simulated melanoma and 
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NSCLC data will be applicable to subjects with other tumor types. The 
simulated measure of exposure of interest, time-averaged concentrations 
(Cavgss) for 240 mg Q2W are predicted to be similar for all subjects in 
reference to 80 kg subjects receiving 3 mg/kg Q2W.
Nivolumab is safe and well tolerated up to 10 mg/kg Q2W dose level. 
Adverse events have been broadly consistent across tumor types 
following monotherapy and have not demonstrated clear dose-response 
or exposure-response relationships. Additionally, the simulated median 
and 95th prediction interval of nivolumab summary exposures across 
body weight range (35 - 160 kg) are predicted to be maintained below 
the corresponding observed highest exposure experienced in nivolumab 
i.e., 95th percentile following nivolumab 10 mg/kg Q2W from clinical 
study CA209003. Thus, while subjects in the lower body weight ranges 
would have greater exposures than 80 kg subjects, the exposures are 
predicted to be within the range of observed exposures at doses (up to 
10 mg/kg Q2W) used in the nivolumab clinical program, and are not 
considered to put subjects at increased risk. For subjects with greater 
body weights, the simulated ranges of exposures are also not expected 
to affect efficacy, because the exposures predicted following 
administration of a 240 mg Q2W are on the flat part of the exposure-
response curves for previously investigated tumors, melanoma and 
NSCLC. Given the similarity of nivolumab PK across tumor types and the 
similar exposures predicted following administration of 240 mg flat dose 
compared to 3 mg/kg, it is expected that the safety and efficacy profile of 
240 mg nivolumab will be similar to that of 3 mg/kg nivolumab. Thus 
nivolumab 240 mg every 2 weeks over 30 minutes for the first 4 months 
will be used in this study.
At 6 months after initiating the Maintenance Phase, subjects will be 
switched from nivolumab 240 mg every 2 weeks to nivolumab 480 mg 
every 4 weeks (Q4W), which provides a more convenient dosing 
regimen for subjects. Based on PK modeling and simulations, 
administration of nivolumab 480 mg Q4W will be started after steady 
state is achieved with 240 mg Q2W and is predicted to provide Cavgss 
similar to 240 mg Q2W. While 480 mg Q4W is predicted to provide 
greater (approximately 20%) maximum steady state concentrations and 
lower (approximately 10%) steady state trough concentrations, these 
exposures are predicted to be within the exposure ranges observed 
exposures at doses up to 10 mg/kg Q2W used in the nivolumab clinical 
program, and are not considered to put participants at increased risk. 
Similar to the nivolumab 240 mg Q2W dosing regimen, the exposures 
predicted following administration of nivolumab 480 mg Q4W, are on the 
flat part of the exposure-response curves for previously investigated 
tumors, melanoma and NSCLC, and are not predicted to affect efficacy. 
Based on these data, nivolumab 480 mg Q4W is expected to have 
similar efficacy and safety profiles to nivolumab 240 mg Q2W.
 
1.2.3
Temozolomide
1.2.3.1 Pharmacokinetics
TMZ is rapidly and completely absorbed after oral administration; peak 
plasma concentrations occur in 1 hour. Food reduces the rate and extent 
of TMZ absorption. Mean peak plasma concentration and AUC 
decreased by 32% and 9%, respectively, and Tmax increased 2-fold 
(from 1.1 to 2.25 hours) when TMZ was administered after a modified 
high-fat breakfast.  TMZ is rapidly eliminated with a mean elimination 
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half-life of 1.8 hours and exhibits linear kinetics over the therapeutic 
dosing range. TMZ has a mean apparent volume of distribution of 0.4 
L/kg (%CV=13%). It is weakly bound to human plasma proteins; the 
mean percent bound of drug-related total radioactivity is 15%.
1.2.3.2 Metabolism and Elimination
TMZ is spontaneously hydrolyzed at physiologic pH to the active 
species, 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC) and to 
TMZ acid metabolite. MTIC is further hydrolyzed to 5-amino-imidazole-4-
carboxamide (AIC), which is known to be an intermediate in purine and 
nucleic acid biosynthesis and to methylhydrazine, which is believed to be 
the active alkylating species. Cytochrome P450 enzymes play only a 
minor role in the metabolism of TMZ and MTIC. Relative to the AUC of 
TMZ, the exposure to MTIC and ACI is 2.4% and 23%, respectively. 
About 38% of the administered TMZ total radioactive dose is recovered 
over 7 days; 37.7% in urine and 0.8% in feces. The majority of the 
recovery of radioactivity in urine is as unchanged TMZ (5.6%), AIC 
(12%), TMZ acid metabolite (2.3%), and unidentified polar metabolites(s) 
(17%). Overall clearance of TMZ is about 5.5 L/hr/m2.
1.2.3.3 Special Populations
Creatinine Clearance
Population pharmacokinetic analysis indicates that creatinine clearance 
over the range of 36-130 mL/min/m2 has no effect on the clearance of 
TMZ after oral administration. The pharmacokinetics of TMZ have not 
been studied in patients with severely impaired renal function (CLcr < 36 
mL/min/m2). Caution should be exercised when TMZ is administered to 
patients with severe renal impairment. TMZ has not been studied in 
patients on dialysis.
Hepatically Impaired Patients
In a pharmacokinetic study, the pharmacokinetics of TMZ in patients with 
mild to moderate hepatic impairment (Child’s-Pugh Class I-II) were 
similar to those observed in patients with normal hepatic function. 
Caution should be exercised when TMZ is administered to patients with 
severe hepatic impairment.
Gender
Population pharmacokinetic analysis indicates that women have an 
approximately 5% lower clearance (adjusted for body surface area) for 
TMZ than men. Women have higher incidences of Grade 4 neutropenia 
and thrombocytopenia in the first cycle of therapy than men.
Age
Population pharmacokinetic analysis indicates that age (range 19-78 
years) has no influence on the pharmacokinetics of TMZ. 
1.2.4
Tumor Treating Fields (TTFields)
1.2.4.1 Background
TTFields are a device which received FDA approval for the treatment of 
newly diagnosed GBM in 2015.  They are comprised of a set of arrays 
applied directly to the shaved scalp.  These arrays create low voltage 
medium-frequency (200 kHz) alternating electrical fields.  These 
alternating electrical fields have been shown in preclinical models to lead 
to decreased tumor cell proliferation and increased tumor cell death (27). 
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Preliminary data supports that there may be some additive effect when 
combined with PD-1 antibodies (28).
Treatment is typically initiated ~4 weeks after the completion of RT, at 
the time of the first adjuvant TMZ cycle.  The arrays are worn over the 
course of the day to maximize treatment exposure.  Patients may take 
breaks where arrays are taken off in addition to time periods when they 
are changing arrays (approximately every 3 days), bathing, etc.  
Treatment with TTFields is continued until no longer efficacious or no 
longer tolerable.
1.2.4.2 Efficacy
TTFields have demonstrated safety and efficacy in the treatment of 
recurrent GBM (29) and more recently newly diagnosed GBM (5).  The 
randomized phase III EF-14 trial demonstrated improved OS, PFS, and 
landmark survival extending to 5 years for the treatment group receiving 
TTFields in addition to the standard of care (5).  This was seen without 
any additional impairment in health related quality of life (6).  
1.2.4.3 Toxicity
The primary additional toxicity noted with TTFields were low grade 
(grade 1/2) cutaneous toxicities noted in approximately ½ of patients 
(30).  No additional toxicities were noted beyond those associated with 
standard temozlomide chemotherapy were noted in the phase 3 trial 
evaluating their use in newly diagnosed GBM patients (5).
1.3
Rationale for the Current Study
1.3.1
Summary of Findings from Previous Studies
1.3.1.1 Nonclinical Studies
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GBM immunotherapy requires a combinatorial approach. Brain-
penetrant IDO1 inhibitors have been tested in immunocompetent mice 
with syngeneic intracranial GBM. As a single agents they have shown no 
effect on outcome (Fig. 4). Consistent with these preclinical findings, 
initial clinical experience with other IDO inhibitors used as single agent 
did not exert clinical antitumor activity (31, 32).
Similarly, PD1 inhibition alone or radiotherapy alone, nor the combination 
of RT with PD1 affected tumor growth in the C57BL6-GL261 model. 
However, the triple combination of RT with simultaneous IDO1 and PD-1 
blockade greatly reduce the growth of 
intracranial GBM and improve the survival of 
engrafted mice, even curing some animals 
(Fig. 4). 
Preclinical results also show that the three-
agent combination therapy leads to increased 
intratumoral Trp, decreased Kyn, and a 
dramatic decrease in the Kyn/Trp ratio (Fig 5). 
Importantly, IDO1 mRNA expression is higher 
in treated tumors, confirming inhibition of 
IDO1 activity, rather than expression.
T-cell-driven IDO1 upregulation provides a 
novel therapeutic intervention strategy. A 
plausible explanation for the failure of single 
agent checkpoint inhibition in GBM is that the 
patient’s T-cells increase IDO1 activity (Fig. 
3), both systemically (Fig. 6) and within the 
tumor (Fig. 7). Experiments suggest that RT-
associated immune activation combined with 
PD-1 blockade and concomitant IDO1 
inhibition results in substantial survival benefit to immunocompetent mice 
with syngeneic intracranial tumor (Fig. 4).
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A model of T cell-driven IDO1 upregulation and therapeutic 
intervention strategy (Figure 8). Immunotherapy has yet to show a 
clinically measurable effect in GBM (Fig. 9). One reason for the lack of 
efficacy may be related to the enhancement of immunosuppressive IDO1 
expression (Figs. 1,2) in human GBM by tumor-infiltrating T cells (Fig. 3). 
IDO1 metabolism is increased peripherally (Fig. 6) and intratumorally 
(Fig. 7). Combination therapy experiments confirm that, the immune-
suppression inducing effects of radiotherapy and PD-1 blockade can be 
countered, at least in-part, by simultaneously administering an IDO1 
enzyme inhibitor (Figs. 4,5). Given that IDO1 inhibition is well-tolerated in 
patients, the data support a clinical trial combining RT with PD-1 and 
IDO1 blockade. 
1.3.1.2 Clinical Studies
Trp catabolism is altered in GBM patients and decreased by IDO1 
pathway inhibition. IDO1 expression is increased in GBM, leading to 
immunosuppression via increased 
production of Kyn (16, 33, 34). Since T-cell 
infiltration stimulates IDO1 expression, we 
investigated IDO1 in the circulating 
immune cells of patients. Fig. 5A shows 
that median OS for GBM patients with a 
high Kyn/Trp ratio is 40% less compared 
to GBM patients with lower ratios (Fig. 6B).
Single agent immunotherapy does not 
improve GBM patient survival. 
Checkpoint inhibitors have demonstrated 
promise in large phase III clinical trials for 
patients diagnosed with melanoma (35) 
non-small cell lung (36) and renal cell (37) 
cancers. While the combination of 
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nivolumab with radiotherapy and TMZ appears to be safe and well 
tolerated (38), a phase III clinical trial in recurrent GBM patients treated 
with nivolumab compared to bevacizumab has failed to demonstrate 
improved survival (Fig. 9) (39). Similarly, vaccine-based 
immunotherapeutic approaches, including rindopepimut and HSPPC-96 
tumor associated (8, 40), did not show improved outcomes in 
randomized clinical trials. There is a critical need to understand why 
these immunotherapies did not work in GBM patients despite supportive 
preclinical results and, more importantly, how to successfully apply 
immunotherapy treatments for this disease.
Trp catabolism can be 
monitored in GBM patients. 
In a clinical trial 
(NCT02052648) for treating 
recurrent GBM (rGBM) 
patients with the IDO1 
inhibitor indoximod, Trp 
metabolism was imaged 
pretreatment and on 
treatment via PET using α-
[11C]-methyl-L-Trp (AMT) 
(41). Figure 7 shows an 
example in which MRI 
confirmed the presence of 
rGBM in the left frontal lobe, 
with overlapping AMT-PET 
Trp prior to treatment with 
the IDO1 inhibitor. Two 
months after continuous 
indoximod, MRI indicated 
increased enhancement but 
also increased lesional Trp, 
which is indicative of 
decreased tumor Trp 
metabolism. This may be indicative of inhibition of the IDO-mediated 
conversion of Trp to Kyn.  This demonstrates that AMT-PET can be used 
to monitor tumor response to IDO1 inhibition.  However, it still requires 
further validation.
1.3.2
Clinical Trial Design
1.3.2.1 Introduction and Rationale
Patients newly diagnosed with GBM have a poor prognosis and the 
standard established by the Phase III EORTC/NCIC trial provides a 
clinically meaningful survival benefit for subjects newly diagnosed with 
GBM (2). However, tumor invariably recurs leading to patient death. 
Therefore a large, unmet need remains for developing new treatments 
based on the recently established treatment regimen.
The preclinical rationale for this three-agent combination has been 
outlined above. Patients with GBM lacking MGMT promoter methylation 
do not benefit from TMZ chemotherapy. This allows to withhold this 
immunosuppressive agent in favor of novel therapeutic agents (3). The 
combination of RT with immune checkpoint inhibitors has already proven 
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safe in large phase I-III clinical trials (NCT02667587; NCT03192943). 
This phase I prospective clinical trial will explore dose, safety and toxicity 
of concurrent RT, TTFields, the PD-1 mAb nivolumab and IDO1 enzyme 
inhibitor BMS-986205. Tumor tissue from initial resection and at 
recurrence (in patients undergoing repeat surgery) will be quantified for 
subtypes of tumor-infiltrating lymphocytes, PD1 expression, Trp and Kyn 
levels, Ki67 and TUNEL staining. 
1.3.2.2 Patient population and design
Patients with histologically confirmed newly diagnosed GBM with 
unmethylated MGMT gene promoter (MGMT status will be determined 
centrally by pyrosequencing) are eligible. Once the MTD and a 
recommended phase II dose have been established, a second cohort of 
patients with MGMT methylated tumors (GBM) also receiving 
concomitant TMZ will be explored. Other standard inclusion criteria 
include a Karnofsky performance status ≥70 and adequate 
hematological, kidney and liver function. Patients with a history of 
autoimmune disease are excluded. Patients should be on a minimal and 
stable dose of steroids, if needed at all. 
As of Protocol Amendment 10 (dated 9-03-2021), only IDH wildtype 
GBM is eligible (See Inclusion Criteria 3.1.2). Only IDH wildtype patients 
have been enrolled on the study. Preclinical modeling of this approach 
was studied exclusively within the study context of GBM IDH wildtype 
models.  In addition, limitation of the clinical trial to GBM IDH wildtype will 
allow for a more homogenous patient population providing greater clarity 
of the outcomes for the secondary and exploratory endpoints.
A classic 3+3 dose escalation will be used in this trial. Patients will 
receive concomitant RT (30x2 Gy, 60 Gy total), nivolumab (240 mg every 
2 weeks), and the IDO1 inhibitor (PO, QD). After completion of RT, 
patients will continue both nivolumab and IDO1 inhibitor combination, if 
tolerated until tumor progression.  The doses of radiation and nivolumab 
have been previously established and will remain constant, while the 
IDO1 inhibitor dose will be increased stepwise, depending on toxicity. 
The IDO inhibitor is currently being investigated in combination with 
nivolumab in a phase I trial of solid tumors not including GBM 
(NCT03192943). The MTD has been established at 200 mg in 
combination with nivolumab based on the safety and tolerability profile 
and incidence of dose-limiting toxicities (DLTs).   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 when utilized concurrently with nivolumab.  In 
the current study we will employ a starting dose of 50 mg QD as we are 
initiating BMS-986205 concurrently with nivolumab and RT.  If 0/3 
patients experience treatment-related dose-limiting toxicity (DLT), the 
dose will be escalated to the next level. If DLT toxicity is observed in 1/3 
patients, 3 additional patients will be enrolled at that dose. The MTD is 
defined as the dose for which at most 1 patient develops DLT; the 
recommended phase II dose would be the MTD. 
Once the recommended phase II dose has been established in patients 
with MGMT unmethylated tumors, and pending preliminary indications of 
safety and response to treatment in the unmethylated group, a cohort of 
patients with methylated MGMT gene promoter will be treated, starting 
one dose level below the recommended phase II dose and then 
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escalated up to the recommended phase II dose. These patients will also 
receive concomitant TMZ chemotherapy. Prior experience with another 
IDO1 inhibitor, indoximod, together with TMZ has shown good tolerance 
with no added toxicity (NCT02052648) (41). Nivolumab in conjunction 
with TMZ and RT also appears tolerable (38).  DLT will be established 
during the TMZ/RT phase, and separately for the maintenance phase 
(with a different TMZ schedule) after cycles 1 and 2.
Both cohorts of patients will receive TTFields beginning in the adjuvant 
phase approximately 4 weeks after completion of radiation.  
Approximately 30% of patients with newly diagnosed GBM are informed 
about TTFields and only 36% of these patients decide to pursue their 
utilization, despite the significant improvement in survival associated with 
their use (7).  Acknowledging that there is significant variability between 
neuro-oncology clinical practices as well as variability in patients’ 
acceptance of the utilization of TTFields, patients will be allowed to 
decline the use of TTFields.  It was felt that this approach is most 
representative of contemporary clinical practice.  It was also felt 
important to offer TTFields to all patients due to the survival advantage 
associated with their use.  As toxicity is minimal their addition should not 
substantially increase risk to patients.
The purpose of the current phase I study is to investigate the tolerability 
and activity of the combination of nivolumab with BMS-986205 with 
radiotherapy. For patients with MGMT promoter methylation TMZ, both 
concomitant with radiotherapy and adjuvant, will be included. The current 
study is an exploratory, uncontrolled, and open study.  A secondary 
endpoint is the overall survival. Survival is the preferred endpoint with 
delayed responses expected with immunotherapies. Overall survival will 
be calculated according to Kaplan-Meier with specific estimates 
examined at 12 months. 
 
As secondary endpoints the progression free survival and response rate 
will also be assessed. The evaluation of progression of disease will be 
based on radiological and neurological criteria as well as steroid use.  In 
addition, the influence of prognostic factors, like extent of surgery, 
performance status, or age will be addressed by subgroup analyses. In 
the case of major differences with regard to a number of prognostic 
factors, a matched-pair analysis might be performed with the EORTC 
data.
An independent review will be performed on all relevant Gd-MRI scans, 
and an independent pathologist will confirm the histopathological 
diagnosis.  Central pathologic review will occur only after trial enrollment.  
Patients with diagnoses other than glioblastoma will be censored in the 
efficacy analyses.
The planned treatment period was up to 2 years. Protocol Amendment 
10 (dated 9-03-2021), revised the treatment period so it is now for as 
long as the patient receives clinical benefit (for the study drugs BMS-
986205 & nivolumab). This change was made as a few patients were 
benefiting from the treatment and approaching the 2 year limit.  Patients 
will remain on treatment as long as they are not experiencing toxicity 
requiring removal from study or progression of disease.
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Antitumor effect of immunotherapeutic approaches may become evident 
and measurable only many months after initiation of therapy. Thus, 
occasionally initial tumor progression can be observed radiologically. 
Thus, patients with slowly progressing disease may continue therapy 
even in the presence of formal PD if the investigator believes that there 
is a benefit for the patient. Analyses based upon radiographic endpoints 
(i.e. response rate, PFS) will be performed utilizing the RANO and 
iRANO criteria (42).
A detailed clinical study report will be established within 8 months after 
inclusion of the last patient.
1.3.2.3 Anticipated Results and Interpretation
Based on our preclinical data, we anticipate durable responses and 
prolonged OS when treated with RT, TTFields, nivolumab and IDO1 
inhibitor compared with historical controls. We also expect GBM patients 
with MGMT methylation will experience improved OS when treated with 
TMZ/RT and TTFields combined with nivolumab/IDO1 inhibitor.
2
OBJECTIVES
2.1
Primary Objective
2.1.1
To determine the safety and tolerability of nivolumab in combination with BMS-
986205 and radiation in newly diagnosed MGMT promoter unmethylated 
glioblastoma and MGMT promoter methylated glioblastoma.
2.2
Secondary Objectives
2.2.1
Descriptive survival analyses (OS and OS12) in patients with MGMT 
unmethylated and MGMT methylated promoter.
2.2.2
PFS and PFS6 in patients with MGMT unmethylated and MGMT methylated 
promoter.
2.2.3
Radiographic response rates (RR) as determined by RANO and iRANO criteria in 
patients with MGMT unmethylated and MGMT methylated promoter.
2.3
Exploratory Objectives 
2.3.1
Determine the T-cell changes that occur in GBM treated with nivolumab in 
combination with BMS-986205 and radiation.
2.3.2
Correlate T-cell changes and IDO1 expression with patient outcomes.
2.3.3
Investigate GBM patient levels of distress, before, during, and after treatment 
with trimodal radiation, anti-PD-1 mAb and IDO1 enzyme inhibitor.
2.3.4
Assess whether tumor-associated α-[11C]-methyl-L-Trp (AMT) uptake on PET 
imaging is correlated with treatment response and other outcomes.
3
PATIENT ELIGIBILITY
The target population for this study is patients with newly diagnosed grade IV Glioma. This will be 
a multi-center trial conducted at Northwestern University Northwestern Memorial Healthcare 
(West Region) is a participating site.
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A total of 18-30 patients will be needed for this Phase I trial. Approximately 6 potentially eligible 
patients are seen per month, and it is anticipated that at least 2 per month will be accrued. 
Potential patients may be referred to the Principal Investigator (PI) at Northwestern University, Dr. 
Rimas Lukas, at (312) 695-0990.
Eligibility will be evaluated by the study team according to the following criteria. Eligibility waivers 
are not permitted. Subjects must meet all of the inclusion and none of the exclusion criteria to be 
registered to the study. Study treatment may not begin until a subject is registered. Please refer 
to Section 11 for complete instructions regarding registration procedures.
3.1
Inclusion Criteria
3.1.1
Patients must have a newly diagnosed histologically confirmed diagnosis of any 
grade IV Glioma with documentation of MGMT methylation status. The 
histological diagnosis can be obtained either from a brain biopsy or from a 
neurosurgical resection of the tumor.
Note: Study enrollment is to be within 6 weeks from diagnostic surgery or biopsy.
Note: Pyrosequencing will be performed to determine MGMT methylation status 
as SOC. MGMT methylation status from outside institution will be accepted for 
registration and will be confirmed at Northwestern Memorial Hospital.
3.1.2
Patients must have confirmed IDH wildtype glioblastoma per 
immunohistochemistry or next generation sequencing.
3.1.3
Patients must be age ≥ 18 years.
3.1.4
Patients must exhibit a Karnofsky performance score of ≥70% (See Appendix B).
3.1.5
Stable or decreasing dose of steroids for ≥7 days prior to registration. 
Note: Patients must be off of all steroids at the time of initiation of study 
treatment (D#1).
3.1.6
Patients must have adequate organ and bone marrow function at registration, as 
defined below: 
Absolute neutrophil count
≥1500/mm3
Platelets
≥100,000/mm3
Creatinine or creatinine 
clearance
≤1.5 times upper limit of 
normal or ≥ 60 mL/min
Hemoglobin
≥10 mg/dL
Blood transfusion allowed.
Total bilirubin
≤1.5 times upper limit of 
normal
AST(SGOT)/ALT(SPGT)
≤2.5 times above upper limit 
of normal
Alkaline phosphatase
≤2.5 times above upper limit 
of normal
3.1.7
Females of child-bearing potential (FOCBP) and males must agree to use 
adequate contraception prior to study entry, for the duration of study 
participation, and for 5 months following completion of therapy (See Appendix C). 
Should a female patient become pregnant or suspect she is pregnant while 
participating in this study, she should inform her treating physician immediately.
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Due to the potential interaction with study drug(s), contraceptions that use 
hormones are not considered to be highly effective for FOCBP participants in this 
study.
NOTE: A FOCBP is any woman (regardless of sexual orientation, having 
undergone a tubal ligation, or remaining celibate by choice) who meets the 
following criteria:

Has not undergone a hysterectomy or bilateral oophorectomy
Has had menses at any time in the preceding 12 consecutive months (and 
therefore has not been naturally postmenopausal for > 12 months)
3.1.8
Males who are sexually active with FOCBP must agree to follow instructions for 
method(s) of contraception (see Appendix C) 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). In addition, male participants must be willing to refrain 
from sperm donation during this time.
Male participants with partners who are FOCBP 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. This criteria applies to azoospermic males as 
well.
3.1.9
FOCBP must have a negative serum pregnancy test within 14 days of 
registration on study and within 24 hours of beginning study treatment.
3.1.10
Clinically normal cardiac function without history of ischemic heart disease in the 
past 6 months and not clinically significant 12 lead ECG (as determined by 
treating investigator).
3.1.11
Patients must have recovered from the effects of surgery, postoperative infection, 
and other complications before study registration.
3.1.12
Patients must have the ability to understand and the willingness to sign a written 
informed consent prior to registration on study.
3.2
Exclusion Criteria
3.2.1
Patients who have had chemotherapy for any cancer within 2 years prior to 
entering the study are not eligible.
3.2.2
Patients who have received brain radiation therapy (RT) are not eligible.
3.2.3
Patients may not be receiving any other investigational agents.  Patients may not 
have received an investigational agent within the past 30 days prior to the 
initiation of study treatment.
3.2.4
Patients with a condition requiring systemic treatment with either corticosteroids 
or other immunosuppressive medications are not eligible. 
Note: Inhaled or topical steroids, and adrenal replacement steroid doses ≥10 mg 
daily prednisone equivalent, are permitted in the absence of active autoimmune 
disease.
3.2.5
Patients with an active, known or suspected autoimmune disease are not eligible. 
Patients with type I diabetes mellitus, hypothyroidism only requiring hormone 
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replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring 
systemic treatment, or conditions not expected to recur in the absence of an 
external trigger are permitted to enroll.
3.2.6
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 are not eligible. All participants will be screened for 
methemoglobin levels prior to registration. 
3.2.7
Participants with a history of G6PD deficiency or other congenital or autoimmune 
hemolytic disorders are not eligible. All participants will be screened for G6PD 
levels prior to registration.
3.2.8
Participants with active interstitial lung disease (ILD) / pneumonitis or with a 
history of ILD / pneumonitis requiring steroids are not eligible.
3.2.9
Patients who have a history of allergic reactions attributed to compounds of 
similar chemical or biologic composition to nivolumab, temozolomide or BMS-
986205 are not eligible.
3.2.10
Patients who have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell 
co-stimulation or checkpoint pathways are not eligible.
3.2.11
Patients who have had prior treatment with BMS-986205 or any other IDO1 
inhibitors are not eligible.
3.2.12
Patients who have received 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 14 days prior to initiation of 
treatment are not eligible.
3.2.13
Patients who have an uncontrolled intercurrent illness including, but not limited to 
any of the following, are not eligible: 

Hypertension that is not controlled on medication

Ongoing or active infection requiring systemic treatment

Symptomatic congestive heart failure

Unstable angina pectoris

Cardiac arrhythmia

Psychiatric illness/social situations that would limit compliance with study 
requirements

Any other illness or condition that the treating investigator feels would 
interfere with study compliance or would compromise the patient’s safety or 
study endpoints
3.2.14
Female patients who are pregnant or nursing are not eligible.
3.2.15
Patients who have quantitative or qualitative G6PD assay results suggesting 
underlying G6PD deficiency are not eligible.
3.2.16
Patients who have blood methemoglobin > ULN, assessed in an arterial or 
venous blood sample or by co-oximetry are not eligible.
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3.2.17
Patients with a concurrent illness, including severe infection, which may 
jeopardize the ability of the subject to receive the procedures outlined in this 
protocol with reasonable safety are not eligible.
3.2.18
Concomitant use of strong inhibitors of CYP3A4/1A2 within 1 week or 5 half-lives 
(whichever is longer) or strong inducers of CYP3A4/1A2 within 2 weeks or 5 half-
lives (whichever is longer) is not permitted (Please refer to Section 4.5.2, and 
Appendix E).
3.2.19
Patients with a placement of Gliadel® wafer at surgery are not eligible.
3.2.20
Patients who are unable to undergo Gd-MRI are not eligible.
3.2.21
Patients with current known alcohol dependence or drug abuse are not eligible.
3.2.22
Patients with a history or presence of hypersensitivity or idiosyncratic reaction to 
methylene blue are not eligible.
3.2.23
Patients with a prior history of serotonin syndrome are not eligible.
3.2.24
Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). 
3.2.25
Patients who have any positive test result for hepatitis B virus or hepatitis C virus 
indicating presence of virus, e.g., Hepatitis B surface antigen (HBsAg, Australia 
antigen) positive, or Hepatitis C antibody (anti-HCV) positive (except if HCV RNA 
negative) are not eligible.
3.2.26
Patients with the presence of any familial, sociological or geographical condition 
potentially hampering compliance with the study protocol and follow-up schedule 
are not eligible; those conditions should be assessed with the patient before 
registration in the trial.
3.2.27
Patients with major medical illnesses or psychiatric impairments that in the 
investigator's opinion will prevent administration or completion of protocol therapy 
are not eligible.
4
TREATMENT PLAN
4.1
Overview
This is a multi center, open-label, uncontrolled, Phase I study conducted in subjects with 
newly diagnosed grade IV Glioma. 
Approximately 18-30 patients will be enrolled.  Up to 18 unmethylated MGMT patients will 
be enrolled initially using a classic 3+3 dose escalation design to determine MTD (see 
section 4.3).  Once the MTD for unmethylated MGMT patients is determined, a cohort of 
patients with methylated MGMT gene promoter will be treated, starting one dose level 
below the recommended MTD and then escalated up to the recommended MTD. These 
patients will also receive concomitant TMZ chemotherapy.
For both cohorts, there will be a 4-week screening period, after which subjects will begin 
study treatment. All patients will receive radiation therapy for 5 days a week for a total of 
6 weeks to a dose of 60 Gy.  Details of the radiation regimen can be found in section 
4.2.4.  Patients will also receive nivolumab at 240mg IV Q2W and BMS-986205 PO QD 
in combination with RT beginning on Day 1.  
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Patients will be treated with a dose escalation plan for BMS-986205 based on a 3+3 
study design.
Upon completion of RT, there will be a post RT phase (28 days) followed by a 
Maintenance Phase.  Patients will continue to receive nivolumab in combination with 
BMS-986205 during both the post RT and Maintenance Phases. Beginning at Cycle 6, 
nivolumab dosing will change to 480mg IV Q4W.
Nivolumab and BMS-986205 will be administered for the entire course of the trial, or until 
progression or unacceptable AEs. There is no particular order in which treatment should 
be administered.
Patients who have disease progression per iRANO criteria or clinical decline, may have 
the option to re-start treatment if they undergo standard of care surgery, and their tumor 
tissue shows on pathologic review that that there is no evidence of significant tumor and 
the changes on MRI were likely treatment related. The patient will be advised of the 
pathology results and that they may not derive any further benefit from re-starting 
therapy. The patient will need to re-sign the informed consent prior to starting therapy.
4.2
Treatment Administration
Treatment Administration Summary
Agent
Dose
Route
Schedule
Cycle Length
Supportive 
Therapies
BMS-986205
Phase I starting 
dose 50 mg (see 
4.3 for escalation)
PO
QD
As Needed
Nivolumab
240mg
480mg (Beginning 
at Cycle 6 of 
Maintenance 
Phase)
IV 
Q2W
Q4W 
(Beginning at 
Cycle 6 of 
Maintenance 
Phase)
As Needed
75 mg/m2 during 
RT
QD 
Temozolomide 
(in MGMT 
promoter 
methylated 
cohort)
200mg/m2 4 
weeks after 
completion of RT
PO
QD for 5 days 
every 4 weeks 
(for a total of 6 
cycles)
RT Phase: 6 
weeks
Maintenance 
Phase: 28 
Days
As Needed
TTFields
N/A
Directly 
applied 
to 
shaved 
scalp
Continuous 
with 
intermittent 
breaks as 
needed
28 days 
(TTFields to 
begin during 
Maintenance 
Phase)
As Needed
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4.2.1
BMS-986205
Treatment will be administered on an outpatient basis. Patients will receive a 
supply of BMS-986205 and will be instructed to take the dose at approximately 
the same time every day following a meal. Patients should avoid grapefruit and 
Sevile oranges and their juices due to the potential for CYP3A4 inhibition. Missed 
doses can be taken within 12 hours, otherwise patients should skip that dose and 
take the dose the following day.  BMS-986205 tablets may not be crushed.  
Patients will be instructed to swallow the tablets whole, in rapid succession, 
without chewing them. If vomiting occurs during the course of treatment, no re-
dosing of the patient is allowed before the next scheduled dose.  Patients will be 
given a drug diary and should bring back any pill containers to monitor 
compliance.
BMS-986205 will be administered daily during the radiation phase, during the 4 
week interval between radiation and the first post-radiation MRI, and will continue 
on the same schedule in the adjuvant phase.
The dose of BMS-986205 during the phase 1 trial will be delineated for each 
dosing cohort.
4.2.2
Nivolumab 
All patients in the study will receive nivolumab. Nivolumab will be administered IV 
every 2 weeks on Day 1 and Day 15 of each cycle (Day 1 is the same day as the 
1st dose of radiation).  Nivolumab will be infused over 30 minutes.  No 
premedication is required.  Nivolumab will be dosed at 240 mg per dose.
Nivolumab will be administered every 2 weeks during the radiation phase, during 
the 4 week interval between radiation and the first post-radiation MRI, and will 
continue on the same schedule in the Maintenance phase.
Participants should receive nivolumab at a dose of 240 mg as a 30 minute 
infusion on Day 1 and Day 15 of each treatment cycle until progression, 
unacceptable toxicity, withdrawal of consent, the study ends, or until Q4W dosing 
begins, whichever occurs first.  Beginning with at cycle 6 of the Maintenance 
Phase, participants should receive nivolumab at a dose of 480 mg as a 30 
minute infusion every 4 weeks (± 2 days) until progression, unacceptable toxicity, 
withdrawal of consent, or the study ends, whichever occurs first. 
There will be no dose escalations or reductions of nivolumab allowed. 
Participants may be dosed no less than 12 days from the previous dose during 
q2w cycles.
Participants should be carefully monitored for infusion reactions during nivolumab 
administration. If an acute infusion reaction is noted, participants should be 
managed according to Section 4.4.2.
4.2.3
Temozolomide
The dose of TMZ for MGMT methylated patients is from the standard of care as 
described in the EORTC/NCIC phase III trial.
4.2.3.1 Temozolomide During Concomitant Radiation Therapy
Only the MGMT promoter methylated cohorts will receive TMZ.  
They will receive it concomitantly with radiation and in up to 6 
maintenance cycles after radiation.
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TMZ will be administered continuously from day 1 ±2 days of 
radiotherapy to the last day of radiation at a daily (7 days a week) oral 
dose of 75 mg/m2 for a maximum of 49 days, as per standard practice. 
The dose will be determined using the body surface area (BSA) 
calculated at baseline. The BSA will be calculated from the height 
obtained at the pretreatment visit and the weight obtained at the visit 
immediately before the first day of treatment. Capsules of TMZ are 
available in 5, 20, 100, and 250 mg. The daily dose will be rounded to 
the nearest 5 mg, which is standard of care. The exact dose 
administered should be recorded in the medical record.  
Patients will be instructed to swallow the capsules whole, in rapid 
succession, without chewing them. If vomiting occurs during the course 
of treatment, no re-dosing of the patient is allowed before the next 
scheduled dose. The capsules should be taken on an empty stomach, 
therefore a minimum of 2 hours after a meal and with no food ingestion 
for 1 hour after TMZ administration.
Prophylaxis with a 5-HT3 antagonist is recommended prior to 
administration of the first few TMZ doses and should be administered 
orally 30 to 60 minutes before TMZ treatment.
4.2.3.2 Post-Radiation Temozolomide
Only the MGMT promoter methylated cohorts will receive post-
radiation TMZ.  
The start of the first maintenance cycle will be scheduled 28 days ± 3 
days after the last day of radiotherapy. The start of all subsequent 
maintenance cycles (2-6) will be scheduled every 4 weeks (28 days ± 2 
days) after the first daily dose of TMZ of the preceding cycle.  TMZ will 
be administered orally once per day for 5 consecutive days (days 1-5) of 
a 28-day cycle. The starting dose for the first cycle will be 200 
mg/m2/day. Prior to each treatment cycle with TMZ a complete blood 
count (CBC) will be obtained (within 72 hours prior to dosing).
The dose will be determined using the BSA calculated at the beginning 
of each treatment cycle. The BSA will be calculated from the height 
obtained at baseline and from the weight obtained at the visit 
immediately before each cycle. Capsules of TMZ are available in 5, 20, 
100, and 250 mg. The daily dose will be rounded to the nearest 5 mg. 
The exact dose administered should be recorded in the medical record.  
Patients will be instructed to swallow the capsules whole, in rapid 
succession, without chewing them. If vomiting occurs during the course 
of treatment, no re-dosing of the patient is allowed before the next 
scheduled dose. The capsules should be taken on an empty stomach, 
therefore a minimum of 2 hours after a meal and with no food ingestion 
for 1 hour after TMZ administration.
Antiemetic prophylaxis with a 5-HT3 antagonist is strongly recommended 
and should be administered 30 to 60 minutes before TMZ administration.
Duration of treatment.  Patients will be treated with post-radiation TMZ 
for 6 cycles unless there is evidence of tumor progression or treatment 
related toxicity.
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4.2.4
Radiation Therapy
4.2.4.1 Dose Specifications and Schedule
Radiotherapy must begin within ≤ 6 weeks (42 days) of surgery. A 
treatment fraction of 2Gy will be delivered daily, 5 days per week, for 6 
weeks, yielding a cumulative dose of 60Gy to the target volume.
4.2.4.2 Technical Factors
Treatment will be delivered with three-dimensional conformal 
radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) 
utilizing megavoltage machines capable of beam energies of at least 
6MV. Selection of photon-energies will depend on dose-distribution 
optimization. Source-to-axis distance (SAD) or source-to-skin distance 
(SSD) must be at least 80cm. IMRT methods may include fixed-gantry 
beam delivery, helical tomotherapy or volumetic modulated arc therapy 
(VMAT). Electron therapy is not permitted.
4.2.4.3 Localization, Simulation, and Immobilization
The patient shall be treated in a reproducible supine or other appropriate 
position utilizing a thermoplastic mask and headrest. A planning CT scan 
of the cranial contents (with ≤ 3.0mm slice thickness) will be fused with 
both pre- and post-operative MRI.
4.2.4.4 Treatment Planning/Target Volumes
Electronic fusion with the post-operative MRI is required for target 
volume definition while pre-operative imaging may be utilized for 
correlation and identification of tumor extent.
4.2.4.5 Initial Target Volume
For the first phase of treatment, gross tumor volume 1 (GTV1) will be 
defined to include: contrast enhancing disease + surgical cavity + 
surrounding edema. This will undergo a 2-cm uniform volumetric 
expansion to create clinical target volume 1 (CTV1), which may be 
reduced around natural barriers to tumor growth such as falx, skull, and 
ventricles, etc. Planning treatment volume 1 (PTV1) will be created to 
account for set-up and reproducibility errors by an additional expansion 
of 3 to 5 mm depending on localization method. This may not be reduced 
to modify organ at risk (OAR) dosing. The initial target volume will be 
treated to 46 Gy in 23 fractions. 
4.2.4.6 Boost Target Volume
For the second phase of treatment, GTV2 will be defined to include: 
contrast enhancing disease + surgical cavity. This will undergo a 2-cm 
uniform volumetric expansion to create CTV2, which may be reduced 
around natural barriers to tumor growth such as falx, skull, and 
ventricles, etc. PTV2 will be created to account for set-up and 
reproducibility errors by an additional expansion of 3 to 5 mm depending 
on localization method. This may not be reduced to modify OAR dosing. 
The boost target volume will be treated to 14 Gy in 7 fractions.
4.2.4.7 Dosing Guidelines
Dosing will be normalized such that 95% of the PTV (D95%) should be 
covered by 100% of the prescription dose. An acceptable variation is that 
of D95% being covered by 95% of the prescription dose. Dose 
homogeneity optimization should ensure that D10% is < 63Gy (variation 
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acceptable: 63-65.12Gy) and that D0.03cc ≤ 64 (variation acceptable: 
64-66Gy).
4.2.4.8 Dose Limitation to Critical Structures
The following OARs must be defined: (1) Lenses, (2) Retinae, (3) Optic 
nerves, (4) Optic chiasm, and (5) Brainstem. 
The optic nerves, optic chiasm and brainstem will undergo a uniform 
volumetric expansion by 3mm to create the corresponding planning risk 
volume (PRV) which shall be utilized for dose constraints. These OARs 
should adhere to the following maximal point dose constraints (defined 
as a volume greater than 0.03cc): lenses = 7Gy; retinae = 50Gy; optic 
nerves = 55Gy; optic chiasm = 55Gy, brainstem = 60Gy.
4.2.5
Tumor Treating Fields (TTFields)
TTFields will be initiated approximately 4 weeks after the completion of RT.  They 
will be initiated only after the post-RT MRI is completed.  Some delay between 
the completion of the post-RT MRI and initiation of TTFields will be allowable to 
allow for accommodation of the logistical aspects of initiating TTFields which are 
outside of the treating physicians’ control.
TTFields will be applied to the shaved scalp.  They will be reapplied as need 
(typically approximately every 3 days).  A cycle of TTFields will be defined as 28 
days.  If a patient utilizes TTFields for even a minimal amount of time during a 
cycle they will be recorded as having utilized TTFields for that respective cycle.  
Duration of therapy with TTFields will be indefinite, as long as there is no tumor 
growth and the TTFields prove tolerable.
If patients elect to refrain from utilizing TTFields they will be able to continue with 
on study treatment.
4.3
BMS-986205 Dose Escalation
The table below summarizes the dose levels. A dose level -1 is included in the event that 
level 1 is determined to be too toxic.
Dose Escalation Scheme
Dose Level
BMS-986205
# of Patients^
Level -1
25 mg
3-6
Level 1*
50 mg
3-6
Level 2
100 mg
3-6
*Starting dose level
^A minimum of 3 patients will be treated per cohort; a total of 
6 patients should be treated at whichever dose level 
is determined to be the MTD.
A standard “3+3” dose escalation design will be utilized. Initially, 3 patients will be 
enrolled at the starting dose (level 1), after which enrollment will be temporarily 
suspended until all 3 patients complete the DLT evaluation period (defined as the 
duration of RT (6 weeks)). Once all 3 patients complete the DLT period and toxicity data 
has been submitted, the Data and Safety Monitoring Committee (DSMC) will review the 
data and confirm the presence or absence of any DLTs (defined below). The following 
rules will be used at each dose level to determine whether or not to proceed to the next 
dose level:
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Dose 
Level
Dose
Number of 
patients
Number of 
DLTs
Outcome
0 or 1 of 3
Additional 3 slots will be added
3
2+ of 3
Study will be closed to further accrual and the 
regimen of BMS-986205 + Nivolumab will be 
considered too toxic at any dose
1 of 6
Dose level will be declared MTD
-1
25 mg
3-6
2+ of 6
Study will be closed to further accrual and the 
regimen of BMS-986205 + Nivolumab will be 
considered too toxic at any dose
0 of 3
Proceed to the next dose level
1 of 3
Additional 3 slots will be added
3
2+ of 3
De-escalation to level -1 will occur.
1 of 6
Escalation will proceed to the next level
1
50 mg
3-6
2+ of 6
De-escalation to level -1 will occur.
0 of 3
Additional 3 slots will be added.
1 of 3
Additional 3 slots will be added.
3
2+ of 3
The previous level will be declared the maximum 
tolerated dose (MTD)
1 of 6
Dose level will be declared MTD
2
100 mg
3-6
2+ of 6
Previous level will be declared the MTD.
NOTE: Whichever dose level is declared the MTD must have 6 total patients treated at 
that level, however this number could be expanded at discretion of PI and funding 
sponsor. For example, if 3 patients are treated at level 2 and 0 patients experience DLT, 
an additional 3 patients will enroll at that level (with 0 or 1 DLT observed in 6 total 
patients) in order to declare level 2 the MTD.  Further, if 2+ patients experience a DLT at 
dose level 2, additional 3 patients will be added to dose level 1 prior to being declared the 
MTD.
Note: intrapatient dose escalation will not be allowed.
4.3.1
Dose Limiting Toxicity
Dose Limiting Toxicities will be monitored for a period of 6 weeks. 
A Dose-Limiting Toxicity is defined below and considered possibly, probably, or 
definitely-related to BMS-986205 or the combination of BMS-986205 and 
nivolumab, excluding known TMZ-related hematological toxicities (in the MGMT 
promoter methylated cohorts treated with TMZ).  For certain events it may be 
difficult to attribute a toxicity exclusively to the investigational agent or the 
standard treatment, e.g. overlapping toxicity: nausea and vomiting or enhancing 
effects.  The AE will be described as detailed as possible and the investigators 
and BMS will subsequently attempt to identify events that apply specifically 
attributable to BMS-986205 and/or nivolumab. If patient experiences a dose-
limiting toxicity, they will be removed from the study.
4.3.1.1 Nonhematologic Dose-Limiting Toxicity (DLT):
Hepatic Nonhematologic DLT
Any of the following events will be considered a hepatic DLT:

Any ≥ Grade 3 elevation of AST, ALT, or total bilirubin

Grade 2 AST or ALT with symptomatic liver inflammation (e.g., 
right upper quadrant tenderness, jaundice, pruritus)

AST or ALT > 3× ULN and concurrent total bilirubin > 2× ULN 
without initial findings of cholestasis (elevated serum alkaline 
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phosphatase, e.g., findings consistent with Hy’s law or FDA 
definition of potential drug-induced liver injury [DILI])*
*Note that this special category of DLT uses ULN rather than Common 
Toxicity Criteria Grade for definition.
Nonhepatic Nonhematologic DLT
Any of the following events will be considered a nonhepatic 
nonhematologic DLT:

Grade 2 episcleritis, uveitis, or iritis

Any other Grade 2 eye pain or blurred vision that does not 
respond to topical therapy and does not improve to Grade 1 
severity within 2 weeks OR requires systemic treatment

Grade 2 myocarditis

Grade 3 pneumonitis, bronchospasm, neurologic toxicity, 
hypersensitivity reaction, or infusion reaction of any duration 
requires discontinuation

Any Grade 3 nondermatologic, nonhepatic, nonhematologic 
toxicity will be considered a DLT with the following specific 
EXCEPTIONS:

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

Grade 3 nausea, vomiting, or diarrhea that lasts less 
than 48 hours and either resolves spontaneously or 
responds to conventional medical intervention

Isolated Grade 3 elevation of amylase or lipase not 
associated with clinical or radiographic evidence of 
pancreatitis

Isolated Grade 3 fever not associated with hemodynamic 
compromise (e.g., hypotension, clinical or laboratory 
evidence of impaired end-organ perfusion)

Grade 3 endocrinopathy that is well-controlled by 
hormone replacement

Grade 3 tumor flare (defined as pain, irritation, or rash 
that localizes to site of known or suspected tumor)

Grade 3 fatigue

Grade 3 infusion reaction that returns to Grade 1 in less 
than 6 hours
Dermatologic DLT

Grade 3 rash if no improvement (i.e., resolution to ≤ Grade 1) 
after a 1- to 2-week infusion delay. Subjects who have not 
experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity.

Grade 4 rash of any duration

Grade 4 dermatologic toxicity

For all dermatologic DLTs, if the dermatologic toxicity is 
assessed as due to TTFields and not nivolumab, BMS-986205, 
or TMZ, TTFields will be on hold and systemic therapies can 
continue at the discretion of the treating physician and PI.
Hematologic DLT

Methemoglobin levels ≥ 15%
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
Grade 4 neutropenia ≥ 5 days in duration

Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with 
bleeding, or any requirement for platelet transfusion

Grade ≥ 3 febrile neutropenia for 48 hours

Grade ≥ 3 hemolysis (i.e., requiring transfusion or medical 
intervention such as steroids)

Grade 4 anemia not explained by underlying disease
Other DLT

Grade 3 or higher non-dermatologic, non-hepatic, non-
hematologic toxicity

Grade 4 lab abnormalities. With sufficient justification, you may 
specify that certain abnormalities will be excluded.
If one of the initial phase I subjects is withdrawn for reasons other than 
those mentioned above, the subject can be replaced.  Patients receiving 
a dose of BMS will be evaluable for toxicity. Another patient should be 
added if a patient withdraws study treatment prior to completing DLT 
period.
In addition to the above mentioned reasons for discontinuing the study, 
subjects will be monitored carefully for AEs related to the administration 
of nivolumab and BMS-986205, and the following early safety stopping 
rules will be applied:

The phase I component of the study will initially enroll only 
MGMT promoter unmethylated patients.  The cohort of MGMT 
promoter methylated patients will only begin accruing after a 
phase II dose of BMS-986205 has been established (See 
below).

During the phase I component of the study, the first 3 subjects in 
the MGMT promoter unmethylated cohort enrolled will be 
monitored with additional care for a period of 6 weeks (6 weeks 
of radiation). If no more than 1 Dose-Limiting Event occurs with 
the first 3 subjects during the 6-week observation period, subject 
enrollment is to continue. 

Once the phase II dose of BMS-986205 has been established in 
MGMT promoter unmethylated patients, 3 patients in the MGMT 
promoter methylated cohort will be treated at that dose.  If there 
is a Dose-Limiting Event, the cohort will be expanded by 3 
patients (i.e. total 3-6 patients at that dosing cohort). 

The phase II MGMT promoter unmethylated and MGMT 
promoter methylated cohorts will run simultaneously.  The 
MGMT promoter unmethylated phase II cohort will begin 
accruing once the phase I MGMT promoter unmethylated study 
has been completed and a phase 2 dose of BMS-986205 has 
been established.  The phase II MGMT promoter methylated 
cohort will begin accruing after the phase I MGMT promoter 
methylated study has been completed and a phase II dose of 
BMS-986205 has been established for the MGMT promoter 
methylated patients.
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4.4
Toxicity Management & Dose Delays/Modifications
Any patient who receives at least one dose of nivolumab or BMS-986205 will be 
evaluable for toxicity endpoints. Each patient will be assessed for the development of 
toxicity according to the timeframe referenced in the Schedule of Events table. Toxicity 
will be assessed according to Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0. 
As immunotherapies can be associated with delayed toxicities subjects will be queried 
regarding potential toxicities at each off study follow up call.  
Modifications should be made to the causing agent and other therapies may continue as 
permitted per protocol.
4.4.1
BMS-986205
The dosing cohorts of BMS-986205 is based upon the phase II dose determined 
in the phase I trial for solid tumors (NCT03192943) as discussed in Section 1.  
The MTD has been established at 200 mg in combination with nivolumab based 
on the safety and tolerability profile and incidence of dose-limiting toxicities 
(DLTs).  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. 
4.4.1.1 Holding Dose
BMS-986205 should be delayed for the following:

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 
4.4.1.2  Dose reduction
Doses of BMS-986205 should be reduced one dose level 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.
Note: dose can be reduced without being held.

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 investigator and in 
consultation with 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 
BMS-986205 if a subsequent dose reduction of BMS-986205 is required.
4.4.1.3 Methemoglobinemia
Detection of Methemoglobinemia
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.
Treatment of Methemoglobinemia Associated with BMS-986205
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 
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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.
4.4.1.4 Discontinuation of BMS-986205
BMS-986205 treatment should be permanently discontinued for the 
following:

Any event requiring discontinuation of nivolumab 

Any event requiring more than 1 dose reduction of BMS-986205 

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 >  12 weeks will result in 
the discontinuation of BMS 986205 only and participants may 
continue treatment with nivolumab

Any occurrence of serotonin syndrome
4.4.2
Nivolumab
The dose of nivolumab was determined based on nonclinical and clinical 
information as described in Section 1.2.  
There will be no dose modifications of nivolumab.  Nivolumab can be held up to 
12 weeks.  After 12 weeks, resumption of nivolumab will require discussion with 
PI.
Participants who require delay of nivolumab should be re-evaluated as clinically 
indicated, and resume nivolumab dosing at time of next cycle when re-treatment 
criteria are met.
Participants may resume treatment with study drug when the drug-related AE(s) 
resolve to grade ≤ 1 or baseline value, with the following exceptions:

Participants may resume treatment in the presence of grade 2 fatigue

Participants who have not experienced a grade 3 drug-related skin AE 
may resume treatment in the presence of grade 2 skin toxicity

For participants with grade 2 AST, ALT and/or total bilirubin 
abnormalities, dosing may resume when laboratory values return to 
grade 0-1  

Participants with persistent grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if 
discussed with, and approved by, the PI.

Participants with drug-related endocrinopathies adequately controlled 
with only physiologic hormone replacement may resume treatment.
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Please refer to the table below for further guidelines for holding/restarting 
therapy.
Dosing Guidelines for Drug-Related Adverse Events for Nivolumab
Toxicity
Severity
Dose Modification
Grade 2/3 diarrhea or colitis
Withhold dose1
Diarrhea/Colitis
Grade 4 diarrhea or colitis
Permanently discontinue
Grade 2 pneumonitis
Withhold dose1
Pneumonitis
Grade 3/4 pneumonitis
Permanently discontinue
Aspartate aminotransferase (AST)/or 
alanine aminotransferase (ALT) more 
than 3 and up to 5 times the upper 
limit of normal or total bilirubin more 
than 1.5 and up to 3 times the upper 
limit of normal
Withhold dose1
Hepatitis
AST or ALT more than 5 times the 
upper limit of normal or total bilirubin 
more than 3 times the upper limit of 
normal
Permanently discontinue
Grade 2/3 hypophysitis
Withhold dose1
Hypophysitis
Grade 4 hypophysitis
Permanently discontinue
Grade 2 adrenal insufficiency
Withhold dose1
Adrenal 
Insufficiency
Grade 3/4 adrenal insufficiency
Permanently discontinue
Grade 3 hyperglycemia
Withhold dose1
Type 1 Diabetes 
Mellitus
Grade 4 hyperglycemia
Permanently discontinue
Serum creatinine more than 1.5 and 
up to 6 times the upper limit of normal
Withhold dose1
Nephritis and 
Renal 
Dysfunction
Serum creatinine more than 6 times 
the upper limit of normal
Permanently discontinue
Grade 3 rash or suspected Stevens-
Johnson syndrome (SJS) or toxic 
epidermal necrolysis (TEN)
Withhold dose1
Skin
Grade 4 rash or confirmed SJS or 
TEN
Permanently discontinue
New-onset moderate or severe 
neurologic signs or symptoms
Withhold dose1
Encephalitis
Immune-mediated encephalitis
Permanently discontinue
Other Grade 3 adverse reaction:
First occurrence
Recurrence of same Grade 3 adverse 
reaction
Withhold dose1
Permanently discontinue
Life-threatening or Grade 4 adverse 
reaction
Permanently discontinue
Requirement for 10mg per day or 
greater prednisone or equivalent for 
more than 12 weeks
Permanently discontinue
Other
Persistent Grade 2 or 3 adverse 
reactions lasting 12 weeks or longer
Permanently discontinue
1.
 Resume treatment when adverse reaction returns to Grade 0 or 1.
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4.4.2.1 Treatment of Nivolumab-related Infusion Reactions
Since nivolumab contains only human immunoglobulin protein sequences, it is 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. 
However, if such a reaction were to occur, it might manifest with fever, chills, 
rigors, headache, rash, pruritus, arthralgias, hypotension, hypertension, 
bronchospasm, or other allergic-like reactions. Please refer to the table below for 
management of infusion reactions. 
Immunotherapy agents such as nivolumab are associated with AEs that can 
differ in severity and duration compared to other therapeutic classes of 
medications. Early recognition and management of AEs associated with 
nivolumab can mitigate severe toxicity. Corticosteroids are the primary therapy 
for drug-related AEs. Management algorithms have been developed to assist 
investigators in assessing and managing nivolumab associated AEs, which can 
be found in Appendix D of this protocol. The guidance provided in these 
algorithms should not replace the Investigator’s medical judgment.
 
Treatment recommendations are provided below and may be modified based on 
local treatment standards and guidelines, as appropriate: 
Nivolumab Infusion Reactions
NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Remain at bedside and monitor 
patient until recovery from 
symptoms. 
The following prophylactic 
pre-medications are 
recommended for future 
infusions: 

Diphenhydramine 50 
mg (or equivalent) 
and/or

Acetaminophen 325 
to 1000 mg at least 
30 minutes before 
additional nivolumab 
administrations
Grade 2
Moderate reaction requires 
therapy or infusion interruption 
but responds promptly to 
symptomatic treatment [eg, 
antihistamines, non-steroidal 
anti- inflammatory drugs, 
narcotics, corticosteroids, 
bronchodilators, IV fluids]; 
prophylactic medications 
indicated for < 24 hours
Stop the nivolumab infusion, begin 
an IV infusion of normal saline, and 
treat the patient with 
diphenhydramine 50 mg IV (or 
equivalent) and/or acetaminophen 
325 to 1000 mg; 
 
Remain at bedside and monitor 
patient until resolution of symptoms. 
Corticosteroid and/or bronchodilator 
therapy may also be administered 
as appropriate. If the infusion is 
interrupted, then restart the infusion 
at 50% of the original infusion rate; 
if no further complications ensue 
after 30 minutes, the rate may be 
increased to 100% of the original 
infusion rate. 
For future infusions, the 
following prophylactic pre-
medications are 
recommended: 

Diphenhydramine 50 mg 
(or equivalent) and/or

Acetaminophen 325 to 
1000 mg should be 
administered at least 30 
minutes before 
nivolumab infusions. 

If necessary, 
corticosteroids (up to 25 
mg of SoluCortef or 
equivalent) may be used.
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Nivolumab Infusion Reactions
NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
Monitor patient closely. If symptoms 
recur, then no further nivolumab will 
be administered at that visit.
Grades 3 or 4
Severe reaction, grade 3: 
prolonged [ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion]; 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae [eg, 
renal impairment, pulmonary 
infiltrates]. grade 4: Life-
threatening; pressor or 
ventilatory support indicated
Immediately discontinue nivolumab 
infusion. Begin an IV infusion of 
normal saline and treat the patient 
as follows: Recommend 
bronchodilators, epinephrine 0.2 to 
1 mg of a 1:1000 solution for 
subcutaneous administration or 0.1 
to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, 
and/or diphenhydramine 50 mg IV 
with methylprednisolone 100 mg IV 
(or equivalent), as needed. 
Patient should be monitored until 
the Investigator is comfortable that 
the symptoms will not recur. 
Nivolumab will be permanently 
discontinued. Investigators should 
follow their institutional guidelines 
for the treatment of anaphylaxis. 
Remain at bedside and monitor 
patient until recovery of the 
symptoms
In case of late-occurring 
hypersensitivity symptoms (eg, 
appearance of a localized or 
generalized pruritus within 1 week 
after treatment), symptomatic 
treatment may be given (eg, oral 
antihistamine or corticosteroids
No subsequent dosing
4.4.3
Combination Nivolumab and BMS-986205
4.4.3.1 Treatment Delay
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.  If determined by the treating 
investigator and PI to definitely be due to TTFields (device-
related) and unrelated to BMS-986205 and unrelated to 
nivolumab treatment with BMS-986205 and nivolumab may 
continue.  

Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin 
abnormalities

Grade 3 skin, drug-related AE.  If determined by the treating 
investigator and PI to definitely be due to TTFields (device-
related) and unrelated to BMS-986205 and unrelated to 
nivolumab treatment with BMS-986205 and nivolumab may 
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continue.  TTF would be held until the toxicity resolves to ≤grade 
1.

Grade 3 drug-related fatigue, nausea, vomiting, and anemia

Grade 3 drug-related laboratory abnormality, with the following 
exceptions:

Grade 3 lymphopenia or asymptomatic amylase or lipase 
elevations do not require dose delay

Grade > 3 AST, ALT, Total Bilirubin will require dose 
discontinuation 

Any AE, laboratory abnormality, or intercurrent illness which, 
in the judgment of the investigator, warrants delaying the 
dose of study medication
Participants may continue to receive Nivolumab during dose delays of 
BMS-986205 for elevations of methemoglobin and associated events, as 
well as QT prolongations. 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. See Section 4.4.1.2 for management of 
methemoglobinemia.
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.
4.4.3.2 Treatment Discontinuation 
Should the treating physician decide to discontinue treatment given 
suspicion for a drug-related side effect, the side effect should be 
attributed to one study drug to the best of the physician’s ability.  Based 
on attribution, patients may discontinue single study drug and continue 
other treatments if outside of DLT period for up to 12 weeks. 
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 the time frame permitted for dose delays 
OR requires systemic treatment

Any event requiring more than 1 dose reduction of BMS-986205 
requires discontinuation of BMS-986205 only

Any Grade 3 non-skin, drug-related AE lasting > 7 days or 
recurs, with the following exceptions for laboratory abnormalities, 
drug-related uveitis, pneumonitis, bronchospasm, neurologic 
toxicity, hypersensitivity reactions, infusion reactions, and 
endocrinopathies:
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
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, 
neurological toxicity, hypersensitivity reaction, or infusion 
reaction of any duration requires discontinuation.

Grade 3 drug-related endocrinopathies, adequately 
controlled with only physiologic hormone replacement do not 
require discontinuation. Adrenal insufficiency requires 
discontinuation regardless of control with hormone 
replacement.

Grade 3 drug-related laboratory abnormalities do not require 
treatment discontinuation except:

Grade 3 drug-related thrombocytopenia > 7 days or 
associated with bleeding requires discontinuation

Grade 3 drug-related AST, ALT or total bilirubin requires 
discontinuation*

Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x 
ULN
* In most cases of Grade 3 AST or ALT elevation, study treatment(s) will 
be permanently discontinued. If the investigator determines a possible 
favorable benefit/risk ratio that warrants continuation of study 
treatment(s), a discussion between the investigator and the PI Sponsor 
Medical Monitor/designee 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:

Grade 4 neutropenia < 7 days

Grade 4 lymphopenia or leukopenia or asymptomatic 
amylase or lipase

Isolated Grade 4 electrolyte imbalances/abnormalities that 
are not associated with clinical sequelae and are corrected 
with supplementation/appropriate management within 3 
calendar days of their onset

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 Sponsor Medical Monitor/designee.

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 > 12 weeks from 
the previous dose requires discontinuation, with the following 
exceptions:

Dosing delays to allow for prolonged steroid tapers to 
manage drug-related AEs are allowed.

Dosing delays lasting > 12 weeks from the previous dose 
that occur for non-drug-related reasons may be allowed if 
approved by the PI Sponsor Medical Monitor/designee.
Prior to re-initiating treatment in a participant with a dosing delay lasting 
> 10 weeks in which the prescribing physician believes that the patient 
may benefit from continuation of therapy, the PI/DSMC must be 
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consulted. Tumor assessments should continue as per protocol even if 
dosing is delayed. Periodic study visits to assess safety and laboratory 
studies should also continue every 4 weeks or more frequently if 
clinically indicated during such dosing delays.
For participants who delay BMS-986205 but continue Nivolumab, any 
dose delay of BMS-986205 lasting > 12 weeks will result in the patients 
being taken off study treatment.
In the case of pregnancy, the investigator must immediately notify the 
PI/QAM of this event via the NU CTO SAE Form. In most cases, the 
study drug will be permanently discontinued in an appropriate manner. 
Please contact the PI and DSMC within 24 hours of awareness of the 
pregnancy. If the investigator determines a possible favorable benefit/risk 
ratio that warrants continuation of study drug, a discussion with the PI 
must occur.
4.4.3.3 Resuming Treatment (BMS-986205 and Nivolumab)
Participants may resume treatment with study treatments when the drug-
related AE(s) resolve to

Grade < 1 or baseline value, with the following exceptions:
o
Participants may resume treatment in the presence of 
Grade 2 fatigue.
o
Participants who have not experienced a Grade 3 drug-
related skin AE may resume treatment in the presence 
of Grade 2 skin toxicity.

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.

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 if 
discussed with and approved by PI Sponsor Medical 
Monitor/designee.
Participants with drug-related endocrinopathies adequately controlled 
with only physiologic hormone replacement may resume treatment after 
consultation with BMS Medical
Monitor/designee. Adrenal insufficiency requires discontinuation 
regardless of control with hormone replacement.
For participants who have 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
4.4.4
Temozolomide
During either phase of temozolomide, there may be a need for a delay or 
discontinuation of TMZ or a reduction in dose. 
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4.4.4.1 Dose Reduction – Concomitant With Radiation 
Need for delay or discontinuation of TMZ administration or reduction in 
TMZ dose will be evaluated weekly according to hematologic and non-
hematologic AEs, as specified below. If the administration of TMZ has to 
be interrupted, the radiotherapy will proceed normally. Missed doses of 
TMZ will not be made up at the end of radiotherapy. The total number of 
days and total dose of TMZ will be recorded on the appropriate eCRF.
Note: If radiotherapy has to be temporarily interrupted for technical or 
medical reasons unrelated to the TMZ administration, then treatment 
with daily TMZ should continue. If radiotherapy has to be permanently 
interrupted then treatment with daily TMZ should stop.
4.4.4.2 Dose Reduction – Post-Radiation Treatment (Adjuvant)
Need for delay or discontinuation of TMZ administration or reduction in 
TMZ dose will be evaluated weekly according to hematologic and non-
hematologic AEs, as specified below. The total number of days and total 
dose of TMZ will be recorded on the appropriate eCRF.
Should adjuvant TMZ need to be delayed, BMS-986205 and Nivolumab 
may be continued as long as the treating investigator deems the AE not 
related to the specific drug.
4.4.4.3 Withhold TMZ treatment
If one or more of the following are observed:

ANC < 1.0 x 109/ L

Platelet count < 100 x 109/L

Grade 3 non-hematologic AE (except alopecia, nausea and 
vomiting while on maximal antiemetic therapy, and fatigue) 
Note: Any duration of grade 3 vomiting should require holding 
dose of TMZ (grade 3 vomiting requires tube feeding, TPN, or 
hospitalization).
TMZ treatment will be withheld until all of the following conditions are met:

ANC ≥ 1.0 x 109/L

Platelet count ≥ 100 x 109/L

Grade ≤ 1 non-hematologic AE (except alopecia, nausea and 
vomiting, and fatigue)
In case of hematologic AE as defined above, a complete blood count 
(CBC) should be performed at least twice weekly. In case of non-
hematologic AE, the patient should be assessed at least weekly with 
relevant laboratory test(s) and any other appropriate methods of 
evaluation. As soon as all of the above conditions are met, the 
administration of TMZ will resume at the same dose as used initially. A 
reduction in TMZ dose may also be appropriate per the investigator’s 
discretion (see section 4.4.4.5).
4.4.4.4 Discontinue TMZ treatment
If one or more of the following are observed:

ANC < 0.5 x 109/L (Grade 4)

Platelet count < 10 x 109/L (Grade 4)

Grade 3 or 4 non-hematologic AE (except alopecia, nausea and 
vomiting unless the patient has failed maximal antiemetic therapy, 
and fatigue)
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Note: Patients who experience Grade 3 or 4 nausea and vomiting 
and has failed maximal antiemetic therapy for up to 3 days will be 
discontinued from TMZ treatment.
4.4.4.5 Reduction in TMZ Dose
In the event of AEs of grade 3 or higher that are possibly, probably, or 
definitely related to TMZ or if the investigator deems it appropriate, a 
reduction in dose may be warranted. Investigator should use clinical 
judgement for decision to dose reduce TMZ. Guidance for dose 
reduction can be found in the following table.
Patient Temozolomide 
Dose Level
Temozolomide Dose 
Modification
Level 1 (starting dose): 200 
mg/m2 QD PO
↓ 150 mg/m2 QD PO
Level -1: 150 mg/m2 QD PO
↓ 100 mg/m2 QD PO
Level -2: 100 mg/m2 QD PO
↓ 75 mg/m2 QD PO
Level -3: 75 mg/m2 QD PO
↓ 50 mg/m2 QD PO
Level -4: 50 mg/m2 QD PO
Discontinue
4.4.5
Radiation Toxicity
Acute
Expected acute radiation-induced toxicities include hair loss, fatigue, and 
erythema or soreness of the scalp. Potential acute toxicities include nausea and 
vomiting as well as temporary aggravation of brain tumor symptoms such as 
headaches, seizures, and weakness. Reactions in the ear canals and on the ear 
should be observed and treated symptomatically; these reactions could result in 
short-term hearing impairment. Dry mouth or altered taste have been 
occasionally reported.
Early Delayed
Possible early delayed radiation effects include lethargy and transient worsening 
of existing neurological deficits occurring 1-3 months after radiotherapy 
treatment.
Late Delayed
Possible late delayed effects of radiotherapy include radiation necrosis, 
endocrine dysfunction, and radiation-induced neoplasms. In addition, 
neurocognitive deficits, which could lead to mental slowing and behavioral 
change, are possible. Permanent hearing impairment and visual damage are 
rare. Cataracts can be encountered.
4.4.5.1 Treatment Delays
Radiation will be delayed or interrupted if the platelet count is < 20,000 or 
if the patient’s treating physician notes a delay or interruption of the 
radiation would be in the patient’s best interest. Radiation will not begin 
or resume until the platelet count is ≥ 20,000. Hematologic toxicities 
should be rated on a scale of 0-5 as defined in the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 (See 
Appendix A).
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4.4.6
Tumor Treating Fields (TTFields)
Holding treatment
If patient develops grade 2 or 3 skin toxicity related to TTFields, TTFields will be 
held until this resolves to ≤grade 1 at which point they will be resumed per the 
treating physician’s discretion.  If patient develops grade 4 skin toxicity related to 
TTFields, TTFields will be held until this resolves to ≤grade 1.  At that point the 
decision regarding whether to resume will be made by the treating investigator 
and the PI.
4.5
Concomitant Medications/Treatments
Any concomitant medication or therapy that becomes necessary during the study and 
any changes in concomitant medication or therapy must be recorded in the 
corresponding section of the CRF, noting generic drug name, dose, duration, and 
indication.  
Prior chemotherapy, anticonvulsants, and systemic steroid use for treatment of GBM 
should be documented in the CRF.
Concomitant medications at study entry will be documented on the CRF. Subjects may 
take any concomitant medications, with the exception of those listed below.
4.5.1
Prohibited Concomitant Medication and Therapy

Chemotherapy
Chemotherapy after registration and prior to the first day of treatment on 
study or chemotherapy at any time during the study.  Use of a Gliadel® 
wafer is also excluded, when placed at surgery.

Investigational Agents
None within 4 weeks prior to the first day of treatment on study or at any 
time during the study. The exception to this are medications for quality of 
life improvement with no presumed efficacy in treating cancer.

Biological Agents
None within 4 weeks prior to the first day of treatment on study or 
biologic agents other than nivolumab at any time during the study.  

Strong inhibitors of CYP3A4 and/or CYP1A2 or strong inducers of 
CYP3A4 and/or CYP1A2 (See Appendix E)

Immunosuppressive agents

Immunosuppressive doses of systemic corticosteroids (exceptions apply)

Any concurrent anti-neoplastic therapy (i.e., chemotherapy, hormonal 
therapy, immunotherapy, extensive, 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 
4.5.2. 
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
Prophylactic antimicrobial therapy (Note: treatment for Pneumocystis 
carinii prophylaxis is allowed. See section 4.5.4.2)
4.5.2
Concomitant Medications/Treatments that are not recommended 
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 and 
should not be consumed while on study.

Concurrent use of moderate inhibitors or inducers of CYP3A4 and/or 
CYP1A2 may affect the systemic exposure of BMS-986205. See 
Appendix E 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. 

Caution is warranted when administering BMS-986205 to patients taking 
drugs that may be associated with QT prolongation. See Appendix F for 
a list of common medications associated with QT prolongation.

Caution is warranted when administering BMS-986205 to patients taking 
drugs that are patient to extensive intestinal efflux by P-gp/BCRP. See 
Appendix H for a list of common P-gp/BCRP substrates. 

In vitro solubility data indicate that BMS-986205 has decreased solubility 
with increasing pH. Until further data are available, patients should try to 
avoid taking proton pump inhibitors. H2 antagonists and short-acting 
antacid agents, such as Maalox® or TUMS®, 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 G). Dapsone, topical anesthetics, 
and antimalarial drugs are the most likely agents that may cause 
methemoglobinemia and these drugs should only be used after 
discussion with the PI.

BMS-986205 should be administered following a meal

Participants must be on a stable or decreasing dose of steroids ≤4mg of 
decadron for 7 days prior to initiating study treatment [not consent] and 
be off of all steroids at the time of initiation of study treatment (D#1).
4.5.3
Other Restrictions and Precautions
Use caution and monitor for symptoms of serotonin syndrome in participants 
receiving concurrent serotonergic psychiatric medications and/or tryptophan 
supplements.  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. BMS-986205 should be 
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discontinued in any participant who develops serotonin syndrome, whether 
considered related to BMS-986205 or not.
4.5.4
Permitted Concomitant Medication and Therapy for which specific dose 
requirements are necessary
The following medications are permitted with the indicated dosing requirements.
4.5.4.1 Anticonvulsants
These are allowed
4.5.4.2 Pneumocystis carinii prophylaxis
A prophylaxis against P. carinii (jiroveci) pneumonia is allowed during RT 
(and until 4 weeks thereafter) in all patients. Both corticosteroid therapy 
and continuous TMZ therapy induce lymphocytopenia. Subjects 
receiving any of these drugs or both concomitantly are at an increased 
risk for opportunistic infections. One of the following treatments should 
be considered:

Pentamidine inhaltations Once every 4 weeks

Trimethoprim-sulfamethoxazole (Bactrim forte®) 1 tablet/3x per 
week
Prophylaxis, while not mandated, should continue until subjects have 
fully recovered from any lymphocytopenia (CTC Grade ≤1), or have a 
CD4 count > 200/µL
4.5.4.3 Antiemetic
The prophylactic use of a 5-HT3-antagonsist is strongly recommended 
before the TMZ administration.
4.6
Duration of Therapy
Patients may continue to receive cycles of treatment  until any of the following occur:

Disease progression per iRANO

Development of an inter-current illness that prevents further administration of 
treatment

Unacceptable adverse event(s)

Patient decides to withdraw from either study treatment or the study as a whole

The treating investigator determines that the patient should be taken off treatment for 
any reason (i.e. changes in condition, inability to comply with study treatment or 
procedures)

Patient becomes pregnant
4.6.1
Continuation of Investigational Therapy 
Subjects who complete 34 weeks of treatment without progression will be offered 
the opportunity, in agreement with the responsible investigator, to continue 
therapy beyond Week 34 as long as it will be of benefit to the patient.
4.7
Duration of Follow Up
Once patients come off of treatment, they will return for a follow up visit 30 days (±3 
days) after last dose of treatment.  Patients removed from study for unacceptable 
treatment-related adverse event(s) will be followed until resolution or stabilization of the 
adverse event
Patients will be contacted every 3 months to monitor survival until patient’s withdraw 
consent or death.
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4.8
Removal of Subjects from Study Treatment and/or Study as a Whole
Patients can be taken off the study treatment and/or study as a whole at any time at their 
own request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation must be clearly 
documented on the appropriate eCRF and may include:

Patient voluntarily withdraws from treatment (follow-up permitted)

Patient withdraws consent (no follow-up permitted)

Patient is unable to comply with protocol requirements

Patient demonstrates disease progression 

Patient experiences unacceptable toxicity 

Treating physician determines that continuation on the study would not be in the 
patient’s best interest

Patient becomes pregnant 

Patient develops a second malignancy that requires treatment which would 
interfere with this study

Patient becomes lost to follow-up (LTF) 
In case of premature discontinuation of study drug by a subject, the investigations 
scheduled for the End of Treatment Visit should be performed, if possible.  In any case, 
the appropriate CRF section must be completed.  Subjects who fail to return for final 
assessments will be contacted by the site in an attempt to have them comply with the 
protocol.  Follow-up will include 2 telephone calls followed by a certified letter.  
It is important to obtain follow-up data on any subject withdrawn because of an AE or 
SAE.  Every effort must be made to undertake protocol-specified safety follow-up (see 
Section 7.3).  Upon occurrence of an intolerable AE, the Investigator will confer with 
BMS.
4.9
Patient Replacement
Any patient who signs consent and is registered for the trial but does not receive study 
treatment may be replaced.
Patients who withdraw from the study prior to completion of study treatment due to 
progression of disease (PD), unacceptable AEs, or death will not be replaced.
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5
STUDY PROCEDURES
5.1
Table 5-1: Study Procedures
 
* Unless otherwise noted.
1.
Includes vital signs (pulse, blood pressure) and height (baseline only) and weight.
2.
Vitals will be taken prior to each infusion with nivolumab (weeks 1, 3, and 5 of RT).
3.
To be performed on Day 1 of each week 1-6 during RT.
Screening
On Treatment
Off Treatment
RT
Post RT Phase
Maintenance Phase23
Cycle -1
Cycle 1+
Time Period
Baseline 
(-28 Days*)
Week 1
Day 1
Weeks 1-
6
Day 1 
(±2 
days)
Day 8 
(±2 
days)
Day 15 
(±2 days)
Day 21 
(±2 days)
Day 1 
(±2 days)
Day 8 
(±2 days)
Day 15 
(±2 days)
Day 21 
(±2 days)
EOT24
Follow-
up25
Assessment or Activity
Informed Consent
X
Medical history 
X
X
Physical exam1
X
X5
X2, 5
X
X
X
Review Concomitant 
Medications, Steroid use
X
X5
X5
X
X
X
KPS
X
X
X
X
X
Neurological Exam4
X
X4
X
Toxicity assessment
X5
X5
X
X
X
Gd-MRI
X
X
AMT PET (Optional)26
X
X26
X26
CBC with diff
X
X7,3
X3
X
X8
X
X8
X
Chemistry panel
X
X7,3
X3
X
X
X
TSH, free T3 and Free T4
X
X
X
Urinalysis
X
X7
X
G6PD
X
Methemoglobin
X
X
Pregnancy test9
X
X9
X
Focal RT10
X
X
EKG
X
Dispense BMS-98620511
X
X
Nivolumab12 
X
X12
X
X
Temozolomide13
X14
X14
TTFields16
Review Drug Diary
X
X
X
X
Questionnaire17
X
X
Tumor Tissue Collection
X18
X19
Blood Collection20
X--------------------X21
X
X
Stool Sample22
X--------------------X21
Survival status
See Table 5-2 for Maintenance Phase 
Procedures
X

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4.
Baseline exam to be performed within 28 days of registration.  Must be repeated on Day 1 of treatment if not within 7 days of beginning 
treatment.  The neurologic examination will include assessment of vision, speech, cranial nerves II through XII, and mental status as well as 
cerebellar, sensory, and motor function.
5.
To be performed every 2 weeks during RT beginning at Week 1 Day 1.  
6.
To be performed every 8 weeks beginning at cycle 1 of the Maintenance Phase. After 2 years of treatment, may be performed per treating 
investigator discretion.  An independent review will be performed on all relevant Gd-MRI scans, and an independent pathologist will confirm the 
histopathological diagnosis.
7.
If completed 72hrs prior to Week 1 Day 1 of RT, labs do not need to be repeated on Week 1 Day 1.
8.
CBC + diff only for MGMT Methylated Cohort on Days 8 and 21 of Cycles 1-6 in Maintenance Phase (can be done locally).  CBC + diff 
performed only on day 1 beginning at Cycle 7 of the Maintenance Phase.
9.
Serum test for females of child-bearing potential to be performed within 14 days of registration and repeated within 24 hours prior to first dose of 
study treatment, and every 4 weeks while on treatment.
10. A treatment fraction of 2Gy will be delivered daily, 5 days per week, for 6 weeks, yielding a cumulative dose of 60Gy to the target volume.
11. BMS-986205 will be dispensed to patients at Week 1 Day 1 and Week 5 Day 1 of RT, Day 1 of Post-RT Phase, and on Day 1 of each cycle 
during Maintenance Phase. Patients will be instructed to take the dose of study drug PO QD. 
12. Nivolumab will be administered Q2W (±2 days) at 240mg by IV (During RT: Weeks 1, 3 & 5.  During the Maintenance Phase: Days 1 and 15 of 
each cycle).  Beginning at Cycle 6 of the Maintenance Phase, nivolumab will be dosed at 480mg by IV Q4W (Day 1 of each cycle beginning at 
cycle 6).
13. TMZ only for MGMT promotor methylated cohort
14. TMZ will be administered continuously during RT phase at a daily oral dose of 75 mg/m2 for a maximum of 49 days, as per standard practice.  
15. Post RT, TMZ will be administered PO QD at 200 mg/m2 for 5 consecutive days (days 1-5) of a 28-day cycle beginning at Cycle 2 and continue 
for 6 cycles. 
16. Patients will be given the option to begin TTFields treatment at the beginning of the Maintenance Phase.  Patients who choose not to utilize 
TTFields will not be required to do so.
17. Patients will complete questionnaires at baseline/pretreatment (any time prior to Day 1 of RT), up to 1 week prior to each MRI follow-up (see 
footnote #5), and every 3 months during follow up.  Patients will receive paper forms to complete and return to the study team. Data from the 
paper forms will be entered into NOTIS by the study team. 
18. If available, tumor tissue specimens from the GBM surgery or biopsy must be available for central pathology review and exploratory analysis of 
immunocorrelative studies.
19. If a patient has progression of disease and undergoes further surgery, they will have the option of allowing fresh tissue to be analyzed.
20. Research blood (2 heparinized tubes with 10ml each) will be collected at baseline, on day 1 of post RT, and at each MRI time point (every 8 
weeks starting at cycle 1 day 1 of the Maintenance Cycle). Research blood will only be collected for up to 2 years of treatment, and the end of 
treatment visit.
21. Baseline sample can be collected at any time between consent and Week 1 Day 1 of RT prior to any treatment.
22. Optional stool sample collected at baseline and on C1D1 of maintenance phase.
23. In Maintenance Phase, 1 cycle = 28 Days.
24. End of treatment visit will occur 30 days (±3 days) of last dose of treatment.
25. Patients will be followed (either by routine clinic visit or by phone call) every 3 months until patients withdraws consent or death.
26. AMT PET is an optional study, and will be performed by Wayne State University Investigators, at the PET Center in the Children’s Hospital of 
Michigan. Scans will occur at baseline (prior to RT and systemic therapy but after standard of care surgery), 4 weeks after completing RT and 
systemic therapy (D1 of Maintenance phase), and at tumor progression or after 1 year of starting RT and systemic therapy. See Section 9.6 for 
more details.

NU Study Number: NU 18C02
BMS Study Number: CA017-075
Version Date: October 13, 2022 (Amendment 12)
52
5.2
Table 5-2: Study Procedures During Maintenance Phase
1.
Includes vital signs (pulse, blood pressure) and height (baseline only) and weight.
2.
Vitals will be taken prior to each infusion with nivolumab (weeks 1, 3, and 5 of RT).
3.
To be performed on Day 1 of each week 1-6 during RT.
4.
Baseline exam to be performed within 28 days of registration.  Must be repeated on Day 1 of treatment if not within 7 days of beginning 
treatment.  The neurologic examination will include assessment of vision, speech, cranial nerves II through XII, and mental status as well as 
cerebellar, sensory, and motor function.  
5.
To be performed every 2 weeks during RT beginning at Week 1 Day 1.  
On Treatment
Off Treatment
Maintenance Phase23
Cycle 1
Cycles 2-5
Cycle 6
Cycle 7+
Time Period
Day 1 
(±2 
days)
Day 8 
(±2 
days)
Day 15 
(±2 
days)
Day 21 
(±2 
days)
Day 1 
(±2 
days)
Day 8 
(±2 
days)
Day 15 
(±2 
days)
Day 21 
(±2 
days)
Day 1 
(±2 
days)
Day 8 
(±2 
days)
Day 15 
(±2 
days)
Day 21
(±2 
days)
Day 1 
(±2 
days)
EOT24
Follow-up25
Assessment or Activity
Informed Consent
Medical history 
Physical exam1
X
X
X
X
X
X
Review Concomitant 
Medications, Steroid use
X
X
X
X
X
X
KPS
X
X
X
X
X
X
Neurological Exam4
X
X
X
X
Toxicity assessment
X
X
X
X
X
X
Gd-MRI
X6
X6
X6
X6
AMT PET (Optional)26
X26
CBC with diff
X
X8
X
X8
X
X8
X
X8
X
X8
X8
X
Chemistry panel
X
X
X
X
X
X
TSH, Free T3, Free T4
X
X
X
X
Urinalysis
X
X
G6PD
Methemoglobin
X
X
X
X
Pregnancy test9
X
X
X
X
Focal RT10
EKG
X6
X6
X6
X6
Dispense BMS-98620511
X
X
X
X
Nivolumab12
X
X
X
X
X12
X
Temozolomide13
X14
X14
X15
TTFields16
X
Review Drug Diary
X
X
X
X
X
X
Questionnaire17
X17
X17
X17
X17
Tumor Tissue Collection
Blood Collection20
X20
X20
X20
X20
Stool Sample22
X
Survival status
See table 5-1 for Off 
Treatment 
Procedures

NU Study Number: NU 18C02
BMS Study Number: CA017-075
Version Date: October 13, 2022 (Amendment 12)
53
6.
To be performed every 8 weeks beginning at cycle 1 of the Maintenance Phase. After 2 years of treatment, may be performed per treating 
investigator discretion. An independent review will be performed on all relevant Gd-MRI scans, and an independent pathologist will confirm the 
histopathological diagnosis.
7.
If completed 72hrs prior to Week 1 Day 1 of RT, labs do not need to be repeated on Week 1 Day 1.
8.
CBC + diff only for MGMT Methylated Cohort on Days 8 and 21 of Cycles 1-6 in Maintenance Phase (can be done locally). CBC + diff performed 
only on day 1 beginning at Cycle 7 of the Maintenance Phase.
9.
Serum test for females of child-bearing potential to be performed within 14 days of registration and repeated within 24 hours prior to first dose of 
study treatment, and every 4 weeks while on treatment.
10. A treatment fraction of 2Gy will be delivered daily, 5 days per week, for 6 weeks, yielding a cumulative dose of 60Gy to the target volume.
11. BMS-986205 will be dispensed to patients at Week 1 Day 1 and Week 5 Day 1 of RT, Day 1 of Post-RT Phase and on Day 1 of each cycle 
during Maintenance Phase. Patients will be instructed to take the dose of study drug PO QD. 
12. Nivolumab will be administered Q2W (±2 days) at 240mg by IV (During RT: Weeks 1, 3 & 5.  During the Maintenance Phase: Days 1 and 15 of 
each cycle).  Beginning at Cycle 6 of the Maintenance Phase, nivolumab will be dosed at 480mg by IV Q4W (Day 1 of each cycle beginning at 
cycle 6).
13. TMZ only for MGMT promotor methylated cohort
14. TMZ will be administered continuously during RT phase at a daily oral dose of 75 mg/m2 for a maximum of 49 days, as per standard practice.  
15. Post RT, TMZ will be administered PO QD at 200 mg/m2 for 5 consecutive days (days 1-5) of a 28-day cycle beginning at Cycle 2 and continue 
for 6 cycles. 
16. Patients will be given the option to begin TTFields treatment at the beginning of the Maintenance Phase.  Patients who choose not to utilize 
TTFields will not be required to do so.
17. Patients will complete questionnaires at baseline/pretreatment (any time prior to Day 1 of RT), up to 1 week prior to each MRI follow-up (see 
footnote #5), and every 3 months during follow up.  Patients will receive paper forms to complete and return to the study team. Data from the 
paper forms will be entered into NOTIS by the study team.  
18. If available, tumor tissue specimens from the GBM surgery or biopsy must be available for central pathology review and exploratory analysis of 
immunocorrelative studies.
19. If a patient has progression of disease and undergoes further surgery, they will have the option of allowing fresh tissue to be analyzed.
20. Research blood (2 heparinized tubes with 10ml each) will be collected at baseline, on day 1 of post RT, and at each MRI time point (every 8 
weeks starting at cycle 1 day 1 of the Maintenance Cycle).Research blood will only be collected for up to 2 years of treatment, and the end of 
treatment visit.
21. Baseline sample can be collected at any time between consent and Week 1 Day 1 of RT prior to any treatment.
22. Optional stool sample collected at baseline and on C1D1 of maintenance phase.
23. In Maintenance Phase, 1 cycle = 28 Days.
24. End of treatment visit will occur 30 days (±3 days) of last dose of treatment.
25. Patients will be followed (either by routine clinic visit or by phone call) every 3 months until patients withdraws consent or death.
26.  AMT PET is an optional study, and will be performed by Wayne State University investigators, at the PET Center in the Children’s Hospital of 
Michigan. Scans will occur at baseline (prior to RT and systemic therapy but after standard of care surgery), 4 weeks after completing RT and 
systemic therapy (D1 of Maintenance phase), and at tumor progression or after 1 year of starting RT and systemic therapy. See Section 9.6 for 
more details.

NU Study Number: NU 18C02
BMS Study Number: CA017-075
Version Date: October 13, 2022 (Amendment 12)
54
6
ENDPOINT ASSESSMENT
6.1
Definitions
Clinical activity will be assessed by Gd-MRI, neurologic examination, and steroid use, as 
outlined in the following table.
6.1.1
Clinical Evaluation Criteria
iRANO
Clinical Activity Assessments
Clinical 
Status
Neuroimaging Gd-MRI
Neurologic Examination
Steroid Use
CR 1

Disappearance of all 
enhancing tumor, and

No new lesions.
Stable or improved compared 
to the most recent neurologic 
examination.
None
PR1

50% reduction in the 
sum of the products of the 
largest perpendicular 
diameters compared to 
the baseline sum,

No worsening of an 
evaluable lesion(s), and

No new lesions.
Stable or improved compared 
to the most recent neurologic 
examination

Same or lower dose 
compared to the dose at 
previous scan, and

Dose is stable for 
72 hours prior to each 
scan.
PD2

25% increase in the sum 
of the product of the 
largest perpendicular 
diameters compared to 
the smallest prior sum,

Worsening of an 
evaluable lesion(s), or

Any new lesion(s).
Worsening compared to the 
most recent neurologic 
examination3.
NA
SD
Neither response (CR or PR) nor PD 
1
To qualify as a CR or PR, all 3 criteria (neuroimaging, neurologic examination, and steroid use) must be met.  In 
addition, neuroimaging must be confirmed within 31 days  3 days.
2
Subjects with PD may remain in the study according to the criteria presented below.
3
Worsening overall performance and/or neurologic decline felt to be attributable to underlying disease despite lack 
of radiographic evidence of PD.  Such subjects may be classified as PD upon discussion between the 
Coordinating Investigator and the subject’s primary neuro-oncologist, if necessary.
Progressive Disease: Study treatment is to be discontinued at disease progression as 
determined by iRANO unless continuation is judged in the patient’s best interest by the 
treating physician (after agreement with the PI and BMS). The following iRANO criteria 
(42) are to be considered when making assessments of PD.

Repeat scan required to confirm radiographic PD for patients without significant 
clinical worsening

≥4 wks minimal time interval for confirmation of progression for patients without 
significant clinical decline

Further immunotherapy treatment allowed after initial radiographic progression

A new lesion does NOT define progression

Radiological or clinical deterioration to causes other than tumor progression 
(pseudoprogression) may warrant treatment discontinuation, and will not be 
considered PD
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NU Study Number: NU 18C02
BMS Study Number: CA017-075
Version Date: October 13, 2022 (Amendment 12)
55
RANO
Clinical Activity Assessments
Clinical 
Status
T1 gadolinium 
enhancing 
disease
T2/FLAIR
New 
Lesion
Corticosteroids
Clinical Status
Requirement 
for response
CR
None
Stable or ↓
None
None
Stable or ↑
All
PR
≥ 50% ↓
Stable or ↓
None
Stable or ↓
Stable or ↑
All 
SD
< 50% ↓ but < 
25% ↑
Stable or ↓
None
Stable or ↓
Stable or ↑
All
PD
≥ 25% ↑
↑
Present1
n/a
↓
Any1
1
Progression occurs when this criterion is present
↓ = decreased, ↑ = increased,
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease If PD is unclear based on white 
matter changes, patients may be kept on trial
6.2
Primary Endpoint
To determine the safety and tolerability of nivolumab in combination with BMS-986205 
and radiation in newly diagnosed MGMT promoter unmethylated glioblastoma and 
MGMT promoter methylated glioblastoma.
Any patient who has received a dose of therapy will be evaluable for this safety endpoint.
6.3
Secondary Endpoints
Patients who have completed the RT phase and have initiated treatment in Cycle 1 of the 
Maintenance Phase are evaluable.
6.3.1
Descriptive survival analyses (OS and OS12) in patients with MGMT 
unmethylated and MGMT methylated promoter.
One-year survival rate (probability of surviving 1 year or more from start of study 
treatment).
Median survival time (median time from start of study treatment to death).
6.3.2
PFS and PFS6 in patients with MGMT unmethylated and MGMT methylated 
promoter.
Six-month PFS rate (percentage of subjects who survived 6 months without 
disease progression)
Median time to disease progression (median time from first treatment on study to 
documented disease progression).
6.3.3
Radiographic response rates (RR) as determined by iRANO criteria in patients 
with MGMT unmethylated and MGMT methylated promoter.
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Radiographic response rates (RR) as determined by RANO criteria in patients 
with MGMT unmethylated and MGMT methylated promoter.
Response rate (percentage of subjects who achieve PR or CR according to the 
iRANO criteria).
Median duration of response (number of days from the first diagnosed PR or CR 
to PD), if applicable.
6.4
Exploratory Endpoints
6.4.1
Determine the T-cell changes that occur in GBM treated with nivolumab in 
combination with BMS-986205 and radiation.
6.4.2
Correlate T-cell changes and IDO1 expression with patient outcomes.
6.4.3
Investigate GBM patient levels of distress, before, during, and after treatment 
with trimodal radiation, anti-PD-1 mAb and IDO1 enzyme inhibitor using the 
‘Beck Depression Inventory’ (see Appendix K) and the ‘Emotional Distress-
Anxiety’ inventory of the PROMIS (see Appendix L) questionnaires.  
6.4.4
Correlation between AMT-PET responses and MRI responses, survival, and PFS 
in newly diagnosed MGMT promoter unmethylated and MGMT promoter 
methylated glioblastoma treated with nivolumab in combination with BMS-986205 
and radiation.
•
AMT-PET correlation with OS
•
AMT-PET correlation with radiographic response on MRI
•
Tumor immune-correlates
•
Serum immune-correlates
•
Molecular pathology correlates
Exploratory endpoints will be compared at baseline, with each MRI and at the 
end of treatment visit. Patients who have completed the RT phase and have 
initiated treatment in Cycle 1 of the Maintenance Phase are evaluable.
7
ADVERSE EVENTS
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) of the 
Robert H. Lurie Comprehensive Cancer Center of Northwestern University. The level of risk 
attributed to this study requires High Intensity Monitoring, as outlined in the DSMP. In addition, 
the study will abide by all safety reporting regulations, as set forth in the Code of Federal 
Regulations.  
7.1
Adverse Event Monitoring
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are reported in a 
routine manner at scheduled times during a trial (see Section 5 for time points). In 
addition, certain adverse events must be reported in an expedited manner to allow for 
optimal monitoring and patient safety and care. 
All patients experiencing an adverse event, regardless of its relationship to study drug, 
will be followed until: 

the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline; 

any abnormal laboratory values have returned to baseline; 
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
there is a satisfactory explanation other than the study drug for the changes 
observed; or

death.
7.2
Definitions & Descriptions
7.2.1
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an experimental intervention, whether or not related to 
the intervention. 
Recording of AEs should be done in a concise manner using standard, 
acceptable medical terms. In general, AEs are not procedures or measurements, 
but should reflect the reason for the procedure or the diagnosis based on the 
abnormal measurement. Preexisting conditions that worsen in severity or 
frequency during the study should also be recorded (a preexisting condition that 
does not worsen is not an AE). Further, a procedure or surgery is not an AE; 
rather, the event leading to the procedure or surgery is considered an AE.
If a specific medical diagnosis has been made, that diagnosis or syndrome 
should be recorded as the AE whenever possible.  However, a complete 
description of the signs, symptoms and investigations which led to the diagnosis 
should be provided. For example, if clinically significant elevations of liver 
function tests are known to be secondary to hepatitis, “hepatitis” and not 
“elevated liver function tests” should be recorded. If the cause is not known, the 
abnormal test or finding should be recorded as an AE, using appropriate medical 
terminology (e/g/ thrombocytopenia, peripheral edema, QT prolongation).
7.2.2
Severity of AEs
All non-hematologic adverse events will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The 
CTCAE v5 is available at 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm
If no CTCAE grading is available, the severity of an AE is graded as follows:

Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.  

Grade 2: Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living*.

Grade 3: Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self care activities of daily living**. 

Grade 4: Life-threatening consequences; urgent intervention indicated. 

Grade 5: Death related to AE
*Instrumental activities of daily living refer to preparing meals, shopping 
for groceries or clothes, using the telephone, managing money, etc.  
**Self care activities of daily living refer to bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not 
bedridden.
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NU Study Number: NU 18C02
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Version Date: October 13, 2022 (Amendment 12)
58
7.2.3
Serious Adverse Events (SAEs)
All SAEs, regardless of attribution, occurring from time of signed informed 
consent, through 100 days after the last administration of study drug, must be 
reported upon discovery or occurrence.
An SAE is defined in regulatory terminology as any untoward medical occurrence 
that:

Results in death.
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself.

Is life-threatening.
The patient was at risk of death at the time of the event; it does not refer to 
an event that hypothetically might have caused death if it were more severe.

Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours.

Results in persistent or significant disability or incapacity.

Is a congenital anomaly/birth defect.

Is an important medical event.
Any event that does not meet the above criteria, but that in the judgment of 
the investigator jeopardizes the patient, may be considered for reporting as a 
serious adverse event. The event may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition of “Serious 
Adverse Event”. 
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency.
Hospitalization
For reports of hospitalization, it is the sign, symptom or diagnosis which led 
to the hospitalization that is the serious event for which details must be 
provided.
Any event requiring hospitalization or prolongation of hospitalization that 
occurs during the study must be reported as a serious adverse event, except 
hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (e.g., 
social reasons such as pending placement in long-term care facility)

Hospitalizations for routine blood transfusions, hospitalization for an elective 
or diagnostic procedure, or surgery for a pre-existing condition that has not 
worsened, are not considered SAEs. (Emergency room visits that do not 
result with admission are not considered as SAEs).

Hospitalizations or prolongation of hospitalization for ≤24 hours.
7.2.4
Unanticipated Problems Involving Risks to Subject or Others
A UPIRSO is a type of SAE that includes events that meet ALL of the following 
criteria:

Is unanticipated in terms of nature, severity, or frequency

Places the research subject or others at a different or greater risk of harm

Is deemed to be at least possibly related to participation in the study.
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7.2.5
Overdose   
An overdose is defined as the accidental or intentional administration of any dose 
of a product that is considered both excessive and medically important. All 
occurrences of overdose must be reported as an SAE.
7.2.6
Pregnancy
In the case of pregnancy, the investigator must immediately notify the PI/QAM of 
this event via the NU CTO SAE Form. In most cases, the study drug will be 
permanently discontinued in an appropriate manner. Please contact the PI and 
DSMC within 24 hours of awareness of the pregnancy. 
7.3
Adverse Event Reporting
7.3.1
Routine Reporting
All routine adverse events, such as those that are expected, or are unlikely or 
definitely not related to study participation, are to be reported on the appropriate 
eCRF. Routine AEs will be reviewed by the Data and Safety Monitoring 
Committee (DSMC) according to the study’s phase and risk level, as outlined in 
the DSMP. 
7.3.2
Determining if Expedited Reporting is Required
This includes all events that occur within 100 days of the last dose of protocol 
treatment. Any event that occurs more than 100 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the agent(s) must 
also be reported accordingly.
1)
Identify the type of adverse event using the NCI CTCAE v 5.0.
2)
Grade the adverse event using the NCI CTCAE v 5.0.
3)
Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows:

Definite: AE is clearly related to the study treatment.

Probable: AE is likely related to the study treatment.

Possible: AE may be related to the study treatment.

Unlikely: AE not likely to be related to the study treatment.

Unrelated: AE is clearly NOT related to the study treatment.
4)
Determine the prior experience of the adverse event.
Expected events are those that have been previously identified as 
resulting from administration of the agent. An adverse event is 
considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in:

the current protocol

the drug package insert

the current Investigator’s Brochure
7.3.3
Expedited Reporting of SAEs/Other Events
Sponsor and Investigator will reconcile the clinical database SAE cases (case 
level only) transmitted to BMS Global Pharmacovigilance 
(Worldwide.Safety@bms.com). Frequency of reconciliation should be every 3 
months and 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.
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7.3.3.1 Reporting to the Northwestern University QAM/DSMC
All SAEs must be reported to the assigned QAM within 24 hours of 
becoming aware of the event. Completion of the NU CTO SAE Form, 
provided as a separate document, is required.
The completed form should assess whether or not the event qualifies as 
a UPIRSO. The report should also include:

Protocol description and number(s)

The patient’s identification number

A description of the event, severity, treatment, and outcome (if 
known)

Supportive laboratory results and diagnostics

The hospital discharge summary (if available/applicable)
All SAEs will be reported to, and reviewed by, the DSMC at their next 
meeting.
7.3.3.2 Reporting to the Northwestern University IRB

Any death of an NU subject that is unanticipated in nature and at 
least possibly related to study participation will be promptly 
reported to the NU IRB within 24 hours of notification. 

Any death of an NU subject that is actively on study treatment 
will be reported to the NU IRB within 5 working days of 
notification (regardless of whether or not the event is possibly 
related to study treatment)

Any death of a non-NU subject that is unanticipated and at least 
possibly related and any other UPIRSOs will be reported to the 
NU IRB within 5 working days of notification.
7.3.3.3 Reporting to the FDA 
The FDA will be notified within 7 calendar days of any SAE that is 
associated with study treatment, is unexpected, and is fatal or life-
threatening. The Principal Investigator will notify the FDA with the 
assistance of a Quality Assurance Monitor.
The FDA will be notified within 15 calendar days of any SAE that is 
associated with the study treatment, unexpected, and serious but not 
fatal or life-threatening. This includes any previous SAEs that were not 
initially deemed reportable, but are later determined to meet the criteria 
for reporting (i.e. by the DSMC).
All other SAEs will be reported on an annual basis as part of the annual 
FDA report.
7.3.3.4 Reporting to BMS
SAE reports (including pregnancy and death by any cause), regardless 
of attribution will be reported within 24 hours/1 business day to BMS 
Global Safety (using the NU CTO SAE Form and referencing the BMS 
study number, CA017-075). The assigned study coordinator will facilitate 
all reporting to BMS Global Safety and email QA a copy of the report 
upon completion. BMS Global Safety can be notified at:
Email Address: Worldwide.Safety@BMS.com
Fax: +1 609-818-3804
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7.3.3.5 Adverse Events of Special Interest (AEOSI)
Adverse events of special interest (AEOSI) requiring expedited 
regulatory reporting by the investigator have been defined. These are:
1.
Hemophagocytic lymphohistiocytosis (HLH; also known as 
histiocytosis haematophagic)
2.
Drug reaction with eosinophilia and systemic symptoms 
(DRESS) syndrome
3.
In addition, all potential DILI (drug induced liver injury) are to be 
expedited for regulatory reporting.
All AEOSIs, regardless of causal association, will be submitted to the 
FDA and BMS.
8
DRUG INFORMATION
8.1
BMS-986205
8.1.1
Other names 
N/a
8.1.2
Classification - type of agent
Selective IDO Inhibitor
8.1.3
Mode of action
BMS-986205 is a selective inhibitor of the IDO1 enzyme.  Inhibition of IDO1 
inhibits the conversion of Trp to the immunosuppressive kyn.
8.1.4
Storage and stability
BMS will provide BMS-986205 in open-label supplies to the trial site.  Study 
personnel will provide patients at the site with labeled bottles containing study 
drug.  Patients will be instructed to keep a log of the date and time which they 
take BMS-986205.
BMS-986205 must be carefully stored at the study site, safely and separately 
from other drugs.  
BMS-986205 tablets should be stored at 2°C to 30°C (36°F to 86°F) in a tightly-
closed container protected from light.
8.1.5
Protocol dose specifics
Patients will take BMS-986205 at prescribed dose PO once a day with meal.  If 
patients miss taking their dose by ≥12 hours they should skip that dose and take 
the dose the following day.  BMS-986205 tablets may not be crushed.
8.1.6
Preparation
No preparation is required.
8.1.7
Route of administration for this study
PO
8.1.8
Incompatibilities
There are no contraindications or limitations with concurrent medications.  Please 
refer to the current Investigator Brochure for up to date information.
Preliminary reaction phenotyping studies with human liver microsomes indicated 
that BMS-986205 was primarily metabolized by CYP3A4; therefore, the plasma 
concentrations of BMS-986205 may be affected by compounds that modulate the 
activity of this enzyme. Because of this, Concomitant use of strong inducers or 
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inhibitors of CYP3A4 is prohibited and moderate inducers or inhibitors of 
CYP3A4 should be used with caution.
BMS-986205 has a low potential to inhibit CYP1A2, CYP2B6, CYP2C8, 
CYP2C9, CYP2C19 and UGT1A1 in vivo, given the predicted Cmax at the 
projected efficacious dose and high plasma protein binding (> 99.9%). Results 
from in vitro results indicate BMS-986205 does not induce CYP1A2 and 
CYP2B6. Because most hormonal contraceptives are metabolized by CYP3A4, 
hormonal contraceptives may not be effective when co-administered with BMS-
986205. Therefore, further investigation on induction potential of CYP3A4 is 
warranted.
BMS-986205 has a low potential to inhibit human transporters including 
OATP1B1, OATP1B3, BSEP, MATE1 and OCT1 in vivo. BMS-986205 has been 
shown to be an inhibitor of P-gp/BCRP and could alter the absorption and 
distribution of compounds that are substrates of these transporters. As the 
potential for drug interactions exists, subjects will be prohibited from the use of 
strong inhibitors of CYP3A4 within 1 week or 5 half-lives (whichever is longer) or 
strong inducers of CYP3A4 within 2 weeks or 5 half-lives (whichever is longer) of 
starting BMS-986205. As grapefruit and Seville oranges and their juices can 
inhibit CYP3A4, they should be avoided while on study. Caution is warranted 
when administering BMS-986205 to subjects taking drugs that are highly 
dependent on CYP3A4 for metabolism or drugs that are subject to extensive 
intestinal efflux by P-gp/BCRP. In addition, as BMS-986205 exhibits pH-
dependent solubility, subjects should try to avoid taking proton pump inhibitors 
until further data are available. H2 antagonists and short-acting antacid agents, 
such as Maalox® or TUMS®, may be taken, but it is recommended that these not 
be taken 4 hours before or 4 hours after dosing of BMS-986205.
8.1.9
Availability & Supply 
BMS-986205 will be provided to the study site in individually labeled bottles in 3 
drug forms (25mg, 50mg and 100mg tablets).  These will be stored in the 
investigational pharmacy and will be provided to the patient on day of study visit 
on a monthly basis by the trial coordinator.
The information on the labels will be in accordance with all applicable regulatory 
requirements.  Each bottle label will state the drug name and the amount of the 
drug contained in the bottle, dose of each tablet, batch number, storage 
conditions, sponsor’s and manufacturer’s name, dosing instructions, and a notice 
that it is limited to investigational use. The vials will be numbered consecutively.  
The study and bottle number will be documented in the drug accountability log in 
the pharmacy. 
From the documentation on the study drug packaging, it shall be possible to 
retrace the composition and pharmaceutical quality according to the current 
Good Manufacturing Practice guidelines.     
A supply of BMS986205 may be ordered from by completing a Drug Request 
Form provided by BMS. The first request may take place upon screening of the 
first patient. Allow 5 business days for shipment of drug from BMS receipt of the 
Drug Request Form. Drug is protocol specific, but not patient specific. All drug 
product will be shipped by courier in a temperature-controlled container. It is 
imperative that only drug product designated for this protocol number be used for 
this study.
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Drug re-supply request form should be submitted electronically 10 business days 
before the expected delivery date.  Deliveries will be made Tuesday through 
Friday.  When assessing need for resupply, keep in mind the number of vials 
used per treatment dose, and that shipments may take 14 business days from 
receipt of request. Drug is not patient-specific. 
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.
8.1.10
Side effects
Among subjects receiving BMS-986205 at doses ranging from 25 to 400 mg, 201 
(50.6%) had treatment related AEs reported. The majority of these TRAEs were 
Grade 1 or Grade 2 in severity. The most common treatment related AEs 
(occurring in > 5% of subjects) occurring in this group were fatigue (14.1%), 
nausea (11.1%), decreased appetite (9.1%), AST increased (7.6%), and ALT 
increased (7.1%). Treatment related AEs reported in ≥ 2% of subjects are 
presented below.
Treatment related AEs Occurring in  2% of Subjects During BMS-986205 and 
Nivolumab Combination Treatment in Study CA017-003
Grade
Total
Preferred Term (%)
1
2
3
4
5
(N = 397)
Total subjects with AEs, regardless of 61 (15.4) 65 (16.4) 113 (28.5) 31 (7.8) 71 (17.9) 341 (85.9)
causality
Total subjects with a TRAE
86 (21.7)
65 (16.4)
43 (10.8)
6 (1.5)
1 (0.3)
201 (50.6)
Fatigue
33 (8.3)
21 (5.3)
2 (0.5)
0
0
56 (14.1)
Nausea
35 (8.8)
7 (1.8)
2 (0.5)
0
0
44 (11.1)
Decreased appetite
24 (6.0)
11 (2.8)
1 (0.3)
0
0
36 (9.1)
AST increased
17 (4.3)
6 (1.5)
7 (1.8)
0
0
30 (7.6)
ALT increased
10 (2.5)
13 (3.3)
5 (1.3)
0
0
28 (7.1)
Hepatobiliary disordersa
2 (0.5)
1 (0.3)
13 (3.3)
3 (0.8)
0
19 (4.8)
Pyrexia
14 (3.5)
2 (0.5)
0
0
0
16 (4.0)
Diarrhoea
11 (2.8)
4 (1.0)
1 (0.3)
0
0
16 (4.0)
Rash
11 (2.8)
3 (0.8)
2 (0.5)
0
0
16 (4.0)
Pruritus
15 (3.8)
0
0
0
0
15 (3.8)
Vomiting
13 (3.3)
2 (0.5)
0
0
0
15 (3.8)
Asthenia
7 (1.8)
5 (1.3)
0
0
0
12 (3.0)
Headache
9 (2.3)
2 (0.5)
0
0
0
11 (2.8)
Transaminases increased
7 (1.8)
2 (0.5)
1 (0.3)
1 (0.3)
0
11 (2.8)
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Anemia
3 (0.8)
3 (0.8)
4 (1.0)
0
0
10 (2.5)
Arthralgia
9 (2.3)
0
0
0
0
9 (2.3)
Infusion related reaction
3 (0.8)
6 (1.5)
0
0
0
9 (2.3)
Rash maculo-paular
4 (1.0)
2 (0.5)
2 (0.5)
0
0
8 (2.0)
Grade 3 treatment related AEs were reported in 43 (10.8%) subjects. Those 
occurring in > 2 subjects were AST increased (n = 7); ALT increased (n = 5); 
autoimmune hepatitis, hepatitis, and anemia (n = 4 each); hypophosphatemia (n 
= 3); and hepatocellular injury, pneumonitis, hyponatremia, lipase increased, 
rash, rash maculo-papular, fatigue, and nausea (n = 2 each). Grade 4 treatment 
related AEs were reported in 6 (1.5%) subjects and were autoimmune hepatitis 
(n = 2) and hepatitis acute, transaminases increased, gamma-
glutamyltransferase (GGT) increased, embolism, and dyspnea (n = 1 each). The 
Grade 4 dyspnea event was associated with myocarditis. Treatment related AEs 
leading to discontinuation of BMS-986205 or BMS-986205 and nivolumab during 
combination treatment were reported in 15 (3.8%) subjects and are presented 
below. The most commonly reported treatment related AEs leading to 
discontinuation were due to hepatobiliary events (1.5% of subjects).
Treatment related AEs Leading to Discontinuation During BMS-986205 and 
Nivolumab Combination Treatment in Study CA017-003
Preferred Term (%)
1
2
3
4
5
(N = 397)
Total subjects with an event
0
5 (1.3)
6 (1.5)
3 (0.8)
1 (0.3)
15 (3.8)
Pneumonitis
0
1 (0.3)
2 (0.5)
0
0
3 (0.8)
Autoimmune hepatitis
0
0
2 (0.5)
1 (0.3)
0
3 (0.8)
Hepatitis
0
0
1 (0.3)
0
0
1 (0.3)
Diarrhoea
0
1 (0.3)
0
0
0
1 (0.3)
Fatigue
0
1 (0.3)
0
0
0
1 (0.3)
Lethargy
0
1 (0.3)
0
0
0
1 (0.3)
Nausea
0
1 (0.3)
0
0
0
1 (0.3)
Uveitis
0
1 (0.3)
0
0
0
1 (0.3)
Liver injury
0
0
1 (0.3)
0
0
1 (0.3)
Rash
0
0
1 (0.3)
0
0
1 (0.3)
Embolism
0
0
0
1 (0.3)
0
1 (0.3)
Hepatitis acute
0
0
0
1 (0.3)
0
1 (0.3)
Myocarditis
0
0
0
0
1 (0.3)
1 (0.3)
Treatment-related SAEs were reported in 28 (7.1%) subjects treated with BMS-
986205 and nivolumab. The most commonly reported treatment-related SAEs 
were due to hepatobiliary events (3% of subjects).  An additional 2 SAEs of 
Hemophagic Lymphohistiocytosis (HLH) and Drug reaction with eosinophilia and 
systemic symptoms (DRESS) syndrome were reported after the clinical cutoff 
date (15-Nov-2017) and are being considered adverse events of special interest.
There were 101 deaths reported during combination treatment with BMS-986205 
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and nivolumab, the majority of which were due to reasons not related to study 
therapy: disease progression (n = 85), unknown causes (n = 2), other causes not 
related to treatment (n = 10; including episodes of septic shock/sepsis, lactic 
acidosis, infections, cardiac arrest, myocardial infarction, thrombolic event), and 
status indicating death (n = 3). 
There was 1 treatment-related death reported as of the 15-Nov-2017 clinical 
cutoff date due to Grade 5 myocarditis. Myocarditis was diagnosed based on lack 
of other positive diagnostic findings supporting an alternative diagnosis. In 
addition, there were another 2 treatment-related deaths reported after the clinical 
data cutoff date. A subject with diffuse large B cell lymphoma was treated with 
100 mg BMS-986205 and nivolumab 240mg Q2W, and developed mucositis and 
rash after 34 days of study treatment, which progressed to Grade 5 Stevens-
Johnson syndrome despite treatment with corticosteroids and infliximab. Another 
subject with non-small cell lung cancer was treated with BMS-986205 100 mg 
daily and nivolumab 480 mg every 4 weeks and developed grade 3 transaminitis 
and elevated bilirubin 141 days after study medications were initiated. He was 
treated with corticosteroids 1.5 mg/kg with subsequent addition of mycophenolic 
acid since the bilirubin did not respond to steroids alone. He died approximately 
25 days later of grade 5 hepatic failure.
8.1.11
Return and Retention of Study Drug
At the conclusion of the study, unused drug will be destroyed according to the 
institution’s drug destruction policy.
8.2
Nivolumab
8.2.1
Other names
ONO-4538, BMS-936558, or MDX1106, Opdivo
8.2.2
Classification
Human IgG4 anti-PD-1 monoclonal antibody
8.2.3
Mode of action
Nivolumab acts as an immunomodulator by blocking ligand activation of the 
programmed cell death 1 (PD-1) receptor on activated T cells anti-PD1.
8.2.4
Storage and stability
Nivolumab solution for infusion is a sterile, non-pyrogenic single-use, isotonic 
aqueous solution. Vials must be stored in a secure, limited-access location at 2 
to 8 degrees C (36 to 46 degrees F) and protected from light, freezing, and 
shaking. The product is a clear to opalescent solution, which may contain 
proteinaceous and extraneous particulates. 
Note: discard the vial if the solution is cloudy, discolored or contains 
extraneous particulate matter other than a few translucent-to-white, 
proteinaceous particles.
The product is intended for IV administration. The drug product can be further 
diluted with normal saline in IV containers made of polyvinyl chloride (PVC) or 
non-PVC material. Opened or accessed vials should be immediately used to 
prepare the infusion solution in the IV bag and the infusion solution should be 
immediately administered.
After preparation, store the Nivolumab infusion either:

at room temperature for no more than 8 hours from the time of 
preparation. This includes room temperature storage of the infusion in 
the IV container and time for administration of the infusion or
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
under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 
hours from the time of infusion preparation.

Do not freeze.
8.2.5
Protocol dose
Nivolumab will be given at 240mg Q2W.  At the beginning of Cycle 6 of the 
Maintenance Phase, nivolumab will be given at 480mg Q4W.
8.2.6
Preparation and administration

Nivolumab should be prepared in a laminar flow hood or safety cabinet using 
standard precautions for the safe handling of intravenous agents applying 
aseptic technique.

Visually inspect the drug product solution for particulate matter and 
discoloration prior to administration. Discard if solution is cloudy, if there is 
pronounced discoloration (solution may have a pale-yellow color), or if there 
is foreign particulate matter other than a few translucent-to-white amorphous 
particles.

Mix by gently inverting several times. Do not shake.

Aseptically withdraw the required volume of nivolumab solution into a 
syringe, and dispense into an IV bag.

If multiple vials are needed for a subject, it is important to use a separate 
sterile syringe and needle for each vial to prevent problems such as dulling of 
needle tip, stopper coring, repeated friction of plunger against syringe barrel 
wall.

Do not enter into each vial more than once. Do not administer as an IV push 
or bolus injection. 

When the dose is based on patient weight (ie, mg/kg), nivolumab injection 
can be infused undiluted (10 mg/mL) or diluted with 0.9% Sodium Chloride 
Injection, USP or 5% Dextrose Injection, USP to protein concentrations as 
low as 0.35 mg/mL. 

When the dose is fixed (eg, 240 mg, 480mg), nivolumab injection can be 
infused undiluted or diluted so as not to exceed a total infusion volume of 160 
mL.
8.2.7
Route of administration
Intravenous infusion. Do not administer as an IV push or bolus injection. 
Administer nivolumab 240 mg as an intravenous infusion over 30 (-10/+15) 
minutes through a 0.2-micron to 1.2-micron pore size, low-protein binding 
(polyethersulfone membrane) in-line filter.  Beginning at Cycle 6 of the 
Maintenance Phase, nivolumab will be given at 480mg as an intravenous 
infusion over 30 (-5/+15) minutes. At the end of the infusion period, flush the line 
with a sufficient quantity of approved diluents. Nivolumab injection is to be 
administered as an IV infusion. 
8.2.8
Incompatibilities
No incompatibilities between nivolumab injection and polyvinyl chloride (PVC), 
DEHP (di[2-ethylhexyl]phthalate), non-PVC/non-DEHP (di[2-ethylhexyl]phthalate) 
IV components, or glass bottles have been observed. Nivolumab should not be 
infused concomitantly in the same intravenous line with other medicinal products.
8.2.9
Availability & Supply
Nivolumab will be supplied by the study as 100 mg/Vial (10 mg/mL) clear to 
opalescent, colorless to pale yellow liquid in 10-cc Type 1 flint glass vials 
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stoppered with butyl stoppers and sealed with aluminum seals.  May contain 
particles. 
A supply of nivolumab may be ordered from by completing a Drug Request Form 
provided by BMS. The first request may take place upon screening of the first 
patient. Allow 5 business days for shipment of drug from BMS receipt of the Drug 
Request Form. Drug is protocol specific, but not patient specific. All drug product 
will be shipped by courier in a temperature-controlled container. It is imperative 
that only drug product designated for this protocol number be used for this study.
Drug re-supply request form should be submitted electronically 10 business days 
before the expected delivery date.  Deliveries will be made Tuesday through 
Friday.  When assessing need for resupply, keep in mind the number of vials 
used per treatment dose, and that shipments may take 14 business days from 
receipt of request. Drug is not patient-specific. 
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.
8.2.10
Side effects
Related side effects reported in subjects receiving nivolumab alone were:
Very Frequent – Expected to occur in more than 20% of people (more than 20 
out of 100 people): Fatigue (50%), Dyspnea (38%), Musculoskeletal pain (36%), 
Rash (21%), Increased AST (28%), Increase alkaline phosphatase (22%), 
Hyponatremia (25-38%) 
Frequent - Expected to occur in 10% to 20% of people (10 to 20 out of 100 
people): Pruritus (19%), Cough (17%), URI (11%), Peripheral edema (10%), 
Increased ALT (16%), Hyperkalemia (15%)
Not Frequent – Expected to occur in less than 10% of people (less than 10 out 
of 100 people): ventricular arrhythmia, iridocyclitis, infusion related reactions, 
increased amylase, increased lipase, dizziness, peripheral and sensory 
neuropathy, exfoliative dermatitis, erythema multiforme, vitiligo, psoriasis
Deaths thought to be related to nivolumab when given alone were reported in 
approximately 0.5% of subjects treated (approximately 1 out 200 people).
For the most recent safety update, please refer to the current Investigator’s 
Brochure or Study Agent Prescribing Information.
8.2.11
Monitoring of dose administration
Participants are seen by their study doctor and research nurse before each dose 
of nivolumab (every 2 weeks or every 4 weeks beginning at Cycle 6 of the 
Maintenance Phase). Safety evaluations at this time include a physical exam, 
vital signs, performance status assessment, and safety laboratory tests. The 
study team will continuously monitor participants for treatment side effects. 
Participants are instructed to inform their study doctor right away if they notice or 
feel anything different so the study doctor can check for side effects. The study 
doctor may be able to provide treatment for side effects. The study doctor may 
temporarily hold the study drug to reduce side effects. The study doctor will 
permanently stop the study drug if side effects are too severe and/or long lasting. 
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All participants will be followed for side effects for 12 weeks from their last dose 
of nivolumab.
8.2.12
Return and Retention of Study Drug Monitoring of dose administration
The clinical study team will be responsible for keeping accurate records of the 
clinical supplies received from suppliers. Upon completion or termination of the 
study, all unused and/or partially used investigational product will be destroyed at 
the site per institutional policy. It is the Investigator’s responsibility to arrange for 
disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept.
8.3
Temozolomide
8.3.1
Other names 
TMZ, Temodar, Temodal
8.3.2
Classification - type of agent
Alkylating Agent
8.3.3
Mode of action
TMZ is an alkylating chemotherapy which adds methyl groups to key locations on 
DNA including the O6 guanine, N7 guanine, and N3 adenine, which proves 
cytotoxic to tumor cells.  Activity of the DNA repair enzyme methylguanine 
methyltransferase (MGMT) markedly decreases the efficacy of TMZ.  MGMT 
activity is controlled by methylation of its promoter, with unmethylated patients 
gleaning minimal benefit, at best, from TMZ (3).
8.3.4
Storage and stability
The capsules are packaged in amber glass bottles and should be stored at 25°C. 
Temperature excursions between 15 and 30°C are permissible. Refer to the 
commercially labeled bottles for expiration dating.
8.3.5
Protocol dose specifics
Only patients in the MGMT methylated promotor cohort will take TMZ.  
During radiation therapy (the first 6 weeks of treatment) subjects in the MGMT 
promoter methylated cohorts will also receive an oral (p.o.) daily dose of 75 
mg/m2 TMZ.  
Four weeks after the end of RT therapy, subjects will continue with concomitant, 
maintenance TMZ at a dose of 200 mg/m2 daily for 5 days every 4 weeks for a 
total of 6 cycles.
8.3.6
Preparation
TMZ will be obtained commercially from the patient’s local or specialty pharmacy.
8.3.7
Route of administration for this study
PO
8.3.8
Incompatibilities
TMZ is contraindicated in patients who have a history of a hypersensitivity 
reaction to any of its components or to DTIC.
8.3.9
Availability & Supply 
As TMZ is being obtained commercially it will not be stored at the investigational 
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site.
8.3.10
Side effects
Hematologic: Thrombocytopenia, leukopenia, myelodysplastic syndrome
Gastrointestinal: Nausea, vomiting, anorexia
Hepatic: Elevated liver enzymes (reversible)
Skin: Rash
Neurologic: Convulsions, weakness on one side of the body, abnormal 
coordination, paralysis
Other: Constipation, diarrhea, stomatitis, fatigue, decreased performance status, 
headache
8.3.11
Nursing implications
Patients will be instructed to swallow the capsules whole, in rapid succession, 
without chewing them. If vomiting occurs during the course of treatment, no re-
dosing of the patient is allowed before the next scheduled dose. The capsules 
should be taken on an empty stomach, therefore a minimum of 2 hours after 
eating and with no food consumption for at least 1 hour after temozolomide 
administration. 
8.4
Tumor Treating Fields
8.4.1
Other names
Optune, NovoTTF™-200A System (Optune delivers Tumor Treating Fields [TTF])
8.4.2
Classification
Medical Device-Tumor Treating Fields (TTF).
8.4.3
Mode of action
Tumor treating fields mechanism of action: (A) Disruption of the formation of the 
mitotic spindle in metaphase, and (B) Positive dielectrophoresis during 
anaphase.
The antimitotic effect of TTFields Therapy might be expected to damage the 
replication of rapidly dividing normal cells within the body (bone marrow, small 
intestine mucosa).
The TTFields Device is a portable battery-operated device that produces 
TTFields within the human body using surface electrodes (transducer arrays). 
The NovoTTF Therapy is delivered to the patient by means of surface transducer 
arrays that are electrically insulated, so that resistively coupled electric currents 
are not delivered to the patient. All the treatment parameters are pre-set by 
Novocure so there are no electrical output adjustments available to the patient. 
The patient must learn to apply and change transducer arrays and change and 
recharge depleted device batteries and to connect to an external electrical outlet.
8.4.4
Storage and Stability
The device and all related all related equipment will be stored at the patient’s 
home at room temperature.
8.4.5
Protocol dose
TTField treatment will be offered to the patient at the beginning of the 
Maintenance Phase. All patients will be required to shave their heads to initiate 
array placement and TTField therapy. Array placement will be performed based 
on the transducer array map calculated during treatment planning.
8.4.6
Preparation and administration
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Treatment with the device will be continuous with breaks allowed for personal 
needs (eg. showering, array exchange). Patients must use the device for at least 
18 hours a day on average.
Treatment Planning: Transducer array layout will be determined based on the 
location of the patient’s tumor(s) on MRI. NovoTALTM software supplied by 
Novocure for layout planning may be used by study investigators who previously 
received training by a Novocure representative and wish to use it on this trial. All 
other investigators will be required to send the baseline MRI scans to Novocure 
for NovoTAL array layout planning within one day of submitting the prescription 
and an array layout will be supplied prior to treatment start. The investigator may 
modify the transducer array layout at any time during the trial based on 
radiological data analysis and clinical considerations.
Patient training: Patients on the study will be trained on the technical aspects of 
using the device by a Novocure Device Support Specialist either in their home or 
at the investigator’s office, as dictated by the investigator. Patients will receive an 
instructional call from Novocure prior to training to highlight important items such 
as the need to shave the head and to answer any technical or logistics questions 
the patient or caregiver may have.
8.4.7
Route of administration
Tumor treating fields through transducer arrays electrodes on bare scalp.
8.4.8
Incompatibilities

Patients with active implanted medical device, a skull defect (such as, 
missing bone with no replacement), a shunt or bullet fragments. Examples of 
active electronic devices include deep brain stimulators, spinal cord 
stimulators, vagus nerve stimulators, pacemakers, defibrillators, and 
programmable shunts.

Patients with known to be sensitive to conductive hydrogels like the gel used 
on electrocardiogram (ECG) stickers or transcutaneous electrical nerve 
stimulation (TENS) electrodes.

Patients with programmable VP shunts and patients with vagal nerve 
stimulators.
8.4.9
Contraindications
Do not use Optune if you have an active implanted medical device, a skull defect 
(i.e., missing bone with no replacement) or bullet fragment(s).  Examples of 
active electronic devices include deep brain stimulators, spinal cord stimulators, 
vagus nerve stimulators, pacemakers, defibrillators, and programmable shunts.  
Use of the Optune together with implanted electronic devices has not been 
tested and may theoretically lead to malfunctioning of the implanted device.  Use 
of the Optune together with skull defects or bullet fragments has not been tested 
and may possibly lead to tissue damage or render the Optune ineffective. 
Do not use the Optune if you are known to be sensitive to conductive hydrogels 
like the gel used on electrocardiogram (ECG) stickers or transcutaneous 
electrical nerve stimulation (TENS) electrodes.  In this case, skin contact with the 
electrode gel used with the Optune may commonly cause increased redness and 
itching, and rarely may even lead to severe allergic reactions such as shock and 
respiratory failure.
8.4.10
Availability & Supply
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Patients will receive the Optune device through a commercial prescription 
process.
8.4.11
Side effects
Treatment with the Optune is not expected to cause any serious side effects. 
However, it is possible that treatment may cause any of the following: 

Local warmth and tingling “electric” sensation beneath the transducer 
array 

Allergic reaction to the adhesive or to the gel 

Skin irritation or skin breakdown 

Infection at the sites of transducer array contact with the skin 

Transducer array overheating leading to pain and/or local skin burns 

Headache 

Fatigue 

Malaise 

Muscle twitching 

Fall, if the system interferes with walking 
8.4.12
Nursing Implications
Patients should only use Optune under the supervision of a physician properly 
trained in use of the device. All technical training on the device will be done by a 
Novocure representative called a Device Support Specialist. He/she will deliver 
the equipment directly to the patient and train the patient and any caregivers on 
the all the practicalities of using the device. An instructional manual regarding the 
device will be provided to the patient. All medical management will be done by 
the PI and nursing staff. While using Optune, the following skin care guidelines 
should be closely adhered to:

If the skin beneath the transducer arrays is inflamed, a high potency topical 
steroid should be prescribed to the patient. The patient or caregiver should 
apply the ointment after removing the arrays, removing remaining array 
adhesive from the skin with baby oil and cleaning the skin with medical 
alcohol. The ointment should be left on the skin for at least 30 minutes prior 
to washing the skin with a mild soap and applying a new set of arrays.

At each array replacement, the new set of arrays should be shifted by 
approximately 2 cm compared to the previous layout so that the array discs 
are placed between the areas of skin irritation. At the next array replacement, 
the arrays should be shifted back to their original location. 

If the epidermis is breached (skin erosions, punctate lesions, cuts, open 
sores etc.) an antibiotic ointment (e.g. mupirocin) should be prescribed and 
used in place of the topical steroid treatment. Any evidence of infection 
should result in bacterial cultures being taken.

There will be no “dose” adjustments to the device for adverse events.

Reasons for breaks in treatment for longer than 24 hours will be documented 
in the CRFs. The maximum duration of treatment break allowed for adverse 
events related to NovoTTF Therapy is 8 weeks (9 weeks for patients who 
switch to the 3–week treatment schedule after Cycle 4).
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9
CORRELATIVES/SPECIAL STUDIES
Patients must provide a sample of tumor tissue from GBM surgery or biopsy at baseline, if 
available (no minimum requirement).  If patient undergoes surgery following disease progression, 
providing tumor tissue for analysis is optional. Patients will undergo a blood draw at baseline, 
every 8 weeks during the Maintenance Phase beginning at Cycle 1 Day 1, and at the End of 
Treatment Visit.  An optional stool sample may be collected at baseline and at Cycle 1 Day 1 of 
the Maintenance Phase.
Correlative Samples - Details for Lab Manual 
Correlative study 
(sample type)
e.g. 
Pharmacokinetics 
(blood)
Archival Tissue
Fresh Tissue
Blood
Blood 
Stool
Mandatory or 
Optional
Optional 
Optional
Mandatory
Mandatory
Optional
Timing (+/- windows)
Baseline and If 
patient undergoes 
surgery following 
disease 
progression
If patient 
undergoes 
surgery following 
disease 
progression
Baseline (prior to first 
dose of study 
treatment), on day 1 
of post RT, and every 
8 weeks during the 
Maintenance Phase 
beginning on Cycle 1 
Day 1 (±2 days), and 
at the end of 
treatment visit.
Baseline (prior to first 
dose of study 
treatment), on day 1 
of post RT, and every 
8 weeks during the 
Maintenance Phase 
beginning on Cycle 1 
Day 1 (±2 days), and 
at the end of 
treatment visit.
Baseline (prior to first 
dose of study 
treatment) and Cycle 
1 Day 1 of 
Maintenance Phase
Volume Needed 
(blood only)
n/a
n/a
10 ml
10 ml
n/a
Tube type needed 
(blood only)
n/a
n/a
Sodium Heparinized 
tubes
Sodium Heparinized 
tube
n/a
Tissue thickness 
and/or # slides 
(tissue only)
5um, 10 slides
n/a
n/a
n/a
Processing center 
(e.g. PCF-CTU)
PCF-CTU & CNS 
Tumor Tissue 
bank
CNS Tumor 
Tissue bank
CNS Tumor Tissue 
bank
CNS Tumor Tissue 
bank
PCF-CTU
Sample 
handling/processing 
instructions
PCF-CTU will 
obtain archival 
tissue samples 
and will deliver to 
CNS Tumor Bank
Samples will be 
delivered to Kristen L 
Lauing, PhD in Dr. 
Derek Wainwright’s 
laboratory.
Samples will be 
delivered to Kristen L 
Lauing, PhD in Dr. 
Derek Wainwright’s 
laboratory
Globe Scientific Self-
Standing Transport 
Tube with Screw Cap 
and Spoon
Storage needs
Stored at –20°C in 
Wainwright 
Labuntil analysis
Stored at –20°C in 
Wainwright 
Labuntil analysis
Stored at –80°C in 
CNS Tumor Bank 
until analysis
Stored at –80°C in 
CNS Tumor Bank 
until analysis
Stored at –80°C in 
PCF-CTU until 
analysis
Analysis center
Wainwright Lab
Cardinal 
Bernardin Cancer 
Center
Loyola University 
Chicago, Health 
Sciences Division
2160 S. First 
Ave., Bldg. 112, 
Rooms 208 and 
210
Maywood IL 
60153
Wainwright Lab
Cardinal 
Bernardin Cancer 
Center
Loyola University 
Chicago, Health 
Sciences Division
2160 S. First 
Ave., Bldg. 112, 
Rooms 208 and 
210
Maywood IL 
60153
Wainwright Lab
Cardinal Bernardin 
Cancer Center
Loyola University 
Chicago, Health 
Sciences Division
2160 S. First Ave., 
Bldg. 112, Rooms 208 
and 210
Maywood IL 60153
Wainwright Lab
Cardinal Bernardin 
Cancer Center
Loyola University 
Chicago, Health 
Sciences Division
2160 S. First Ave., 
Bldg. 112, Rooms 208 
and 210
Maywood IL 60153
Wainwright Lab
Cardinal Bernardin 
Cancer Center
Loyola University 
Chicago, Health 
Sciences Division
2160 S. First Ave., 
Bldg. 112, Rooms 208 
and 210
Maywood IL 60153
Assay methodology
tryptophan/kynure
nine levels and for 
gene expression 
profile analysis
tumor-infiltrating 
lymphocytes 
(TIL),
evaluation of 
activated peripheral 
lymphocytes
Peripheral blood 
analysis for gene 
expression, 
tryptophan 
metabolism and 
cytokine abundance
high-throughput next-
generation Illumina 
MiSeq sequencing 
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9.1
Sample Collection Guidelines
Please refer to the Laboratory Manual for instructions on Sample Collection.
9.2
Sample Processing, Storage, and Shipment
Please refer to the Laboratory Manual for instructions on sample processing, storage and 
shipment.
9.3
Assay Methodology
9.3.1
Tissue
Tumor tissue removed at surgery will be used to extract tumor-infiltrating 
lymphocytes (TIL), myeloid cells including macrophages, microglia, DCs, 
MDSCs, as well as CD45highCD3- cells that do not possess traditionally-defined 
characteristics, tryptophan/kynurenine levels and for gene expression profile 
analysis. In addition, fresh frozen and formalin fixed paraffin embedded tissue will 
be banked for analysis. Extracted TILs will be used to evaluate the tumor 
infiltrative lymphocyte population by flow cytometry and paraffin embedded tissue 
will be used to evaluate TILs in situ by immunohistochemistry. If a patient has 
progression of disease and undergoes further surgery, they will have the option 
of allowing tissue to be analyzed for the above.
9.3.2
Blood
Blood, prior to, and after treatment initiation, will be collected for baseline 
evaluation of activated peripheral lymphocytes.  Once patients are off study, 
there will be an optional blood draw during surgery, prior to restarting treatment 
and on the day of each MRI scan with extraction and banking of peripheral blood 
leukocytes (PBL). 
PBLs and plasma will be separated with SepMate isolation tubes.
PBLs obtained prior to drug administration will be studied by flow cytometry to 
identify relative populations of CD8 T cells (CD3+, CD8+, PD1+/-), CD4 T cells 
(CD3+, CD8+, PD1+/-), regulatory T cells (CD4+, CD25+, FoxP3+), and 
suppressive monocytes (CD45+, CD11b+, PD-L1+).  Repeat assessment of PBL 
markers will be determined by flow cytometry of subsequent samples taken on 
the day of surgery, post operatively and then on MRI days. Additionally, TILs 
extracted from patient tissue will be evaluated for relative populations of activated 
CD8 T cells (CD3+, CD8+, IFN-g+, PD1+/-), activated CD4 T cells (CD3+, 
CD8+,  IFN-g+, PD1+/-), regulatory T cells (CD4+, CD25+, FoxP3+), and 
suppressive monocytes (CD45+, CD11b+, CD163+, PD-L1+). Double-labeled 
tissue immunofluorescence can also be performed on FFPE sections to obtain 
immune effector cell counts, reported as # cells / 10 hpf. Optimized labeling 
schemes include: CD8/IFN-g, CD4/IFN-g, CD8/PD-1, CD4/PD-1, CD68/PD-L1, 
and GFAP/PD-L1 (to identify PD-L1 + tumor cells). Banked PBLs, TILs and FFPE 
tissue from prior patients treated without the study drug will serve as comparative 
controls.
PBLs will also undergo gene expression analysis for IDO1, PD-L1, among other 
immunomodulatory factors that may change during treatment.
Plasma will be collected and stored for downstream analysis of tryptophan and 
kynurenine levels via HPLC, as well as for serum catecholeamine and cytokine 
levels including epinephrine (43), norepinephrine (43), and cortisol (44), as well 
as stress-related cytokines, MCP-1(45) and IL-6.
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9.3.3
Stool
An optional stool sample will be collected at baseline and at the beginning of the 
Maintenance Phase (Cycle 1 Day 1) to study the effect of the microbiome on 
outcomes with this immunotherapeutic approach.  
9.3.4
Characterize tumor and immune response to RT, PD-1 mAb and IDO 
enzyme inhibition in GBM patients.
Preclinical results show a marked survival advantage in GBM-bearing mice 
treated with a combination of RT and PD-1/IDO1 inhibition, with some mice even 
experiencing cure of tumor. Analyses of circulating and intratumoral immune cells 
will be performed. Orthotopic PDX models will be established.
Clinical trial correlative analyses. GBM tissue and blood samples from the 
operating room and clinic will be collected and processed for: (i) standard 
neuropathological and immunohistochemical analyses (Biospecimen Core), for ii) 
genomic and transcriptomic profiling of analytes from frozen material (Tempus, 
Chicago, IL), and (iii) immunocorrelative and targeted molecular analyses 
(Wainwright laboratory). As patients have been selected initially for resectability 
of their tumors and will be closely followed, we estimate that approx. 30 to up to 
50% of patients may undergo repeat surgery at tumor progression. This will allow 
for paired comparison of the initial tumor samples with their respective recurrent 
tumors developing under therapy.
9.4
Specimen Banking
Samples will be stored in the Wainwright Lab.  Please see the Lab Manual for specific 
instructions regarding specimen banking.
9.5
Patient Questionnaires
These questionnaires will investigate GBM patient levels of distress, before, during, and 
after treatment with trimodal radiation, anti-PD-1 mAb and IDO1 enzyme inhibitor. 
Biobehavioral stressors may mitigate the benefits of trimodal immunotherapy. Both 
patient-reported and physiologic stress measures will be investigated. Patients will 
complete online questionnaires using the Patient-Reported Outcomes Measurement 
Information System (PROMIS) to evaluate psychosocial and behavioral factor impact 
before, during, and after immunotherapeutic treatment. Blood levels for epinephrine, 
norepinephrine, cortisol, and stress-associated cytokines, in addition to T cell and 
monocyte expression and localization for glucocorticoid and catecholamine receptors, will 
be evaluated, before, during, and after treatment.
This project will use a non-randomized pre-test and post-test design, with participants 
serving as their own controls for assessing psychosocial and biobehavioral measures. 
Sampling will be obtained at baseline/pretreatment (any time prior to Day 1 of RT), 1 week 
prior to each MRI follow-up, and every 3 months during follow up. Patient email addresses 
will be requested at time of consent.  A paper copy of the questionnaires will be available 
if needed (see appendices K and L).
The following patient report measures will be used:

‘Beck Depression Inventory’ as well as the ‘Emotional Distress-Anxiety’ inventory of 
the PROMIS measure. The PROMIS measures are a series of open access 
questionnaires used to evaluate general or specific areas of health and well-being. 
They are well validated and precise. Specific profile domains of emotional distress, and 
anxiety will be used to target known problems in the brain tumor population and 
minimize the burden of form completion. Each form can be completed in the privacy 
and comfort of a participant’s home. Patients will be given a paper form for the PROMIS 
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measures. When completed, the data from the form will be entered into a secure 
NOTIS database by the study team. Paper forms will be secured in a locked room with 
access given to authorized study personnel only.  Report data will be downloaded by 
the study team and reviewed with the patient during the visit.

Blood draws will be obtained and separated into sera and blood cells for quantification 
of:
o
Distress-associated hormones including epinephrine (43), norepinephrine 
(43), and cortisol (44), as well as stress-related cytokines, MCP-1(45) and IL-
6(44).
o
Glucocorticoid receptor and beta adrenergic receptor expression level in/on 
CD8+ cytolytic T cells, CD4+FoxP3- helper T cells, and CD4+CD25+FoxP3+ 
immunosuppressive regulatory T cells, and CD3- monocytes. 
9.6
AMT-PET Study
AMT-PET will be offered to all patients in the study (participation is optional), and we 
estimate performing PET imaging in about half of the patients, both prior to treatment and 
after RT + nivolumab + BMS-986205 +/- temozolomide combination therapy. A baseline 
AMT-PET will be performed after surgery or biopsy when histologic diagnosis has been 
established and before starting RT and systemic therapy. Follow up AMT-PET will be 
performed approximately 4 weeks after the completion of combined RT + IDOi + anti-PD-
1 antibody. This imaging study will be correlated with the 4 week post-radiation MRI. After 
1 year or at tumor progression another AMT-PET may be performed. The quantitative or 
semi-quantitative PET-response after the end of radiotherapy (+ nivolumab and BMS-
986205) will be correlated with patient outcome.
9.6.1
AMT-PET
AMT is an analog of Trp, and AMT-PET quantifies intratumoral Trp metabolism 
based on the amount of radiolabeled AMT in tumor. Importantly, unlike 
alternative amino acid PET tracers, AMT is not incorporated into protein. Both 
contrast-enhancing and non-enhancing gliomas have increased AMT uptake, 
and increased trapping in glioma tissue is associated with elevated elevated 
IDO1, as confirmed by surgical resection of tumor and accompanying IHC, 
following treatment. Detailed volumetric analysis has demonstrated that 
increased AMT uptake on PET is not confined to the area of contrast 
enhancement in high-grade gliomas, and often extends to non-enhancing tissue 
subsequently shown to have tumor cell infiltration (proven by targeted biopsy and 
analysis of biopsied tissue). AMT-PET can accurately differentiate RT injury from 
tumor recurrence. The study described is being performed to assess whether 
tumor-associated α-[11C]-methyl-L-Trp (AMT) uptake on PET imaging is 
correlated with treatment response and survival outcomes.
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9.6.2
AMT-PET Scanning Protocol
PET studies will be performed using the GE Discovery STE PET/CT scanner, 
located in the PET Center, Children’s Hospital of Michigan, Wayne State 
University, Detroit. The scanner has a 15 cm field of view and generates 47 
image planes with a slice thickness of 3 mm. The reconstructed image resolution 
is 7.5 ± 0.4 mm (isotropic), and images from this scanner will be iteratively 
reconstructed (2 iterations, 16 subsets, 8 mm axial smoothing). The AMT tracer 
is synthesized using a standard method.  The procedure for AMT PET scanning 
has also been described previously. In brief, patients will fast for 6 hours prior to 
AMT PET. This decreases risk of aspirating gastric contents, and also ensures 
stable plasma Trp and large neutral amino acid levels during the study. In 
females of child-bearing age, a urine pregnancy test will be performed before 
scanning. A venous line will be established for injection of AMT (0.1 mCi/kg) as a 
slow bolus. A second venous line will be established for collection of timed blood 
samples (0.5 mL/sample, collected at 0, 20, 30, 40, 50 and 60 min after AMT 
injection). Blood radioactivity data will be used for Patlak graphical analysis.
In order to quantify AMT, cardiac volume will first be quantified via a 5-minute 
computerized tomography (CT) scan, using very low power (10mA, 80 keV) for 
attenuation correction. Following injection of AMT, a 20-minute dynamic PET 
scan of the heart will be performed (sequence: 12x10 s, 3x60 s, and 3x300 s) in 
2D-mode in order to obtain the left ventricular (LV) blood input function. 
Continuation of the blood input function beyond the initial 20 minutes is then 
achieved using venous blood samples obtained during brain scanning. Twenty-
five minutes after tracer injection, a 5-minute CT scan of the brain will be followed 
by a 35-min dynamic emission PET scan of the brain (7 x 5 minutes) in high-
sensitivity 3D mode. Measured attenuation correction will be applied to the AMT 
PET images of the heart, whereas computed attenuation correction will be used 
to correct the brain images. Plasma will be isolated from a blood sample by 
centrifugation, and plasma samples will be counted in a NaI well counter cross-
calibrated to the PET scanner in order to obtain the blood input function.
PET scans will be collected digitally, both raw images and processed images 
(color-coded, co-registered with MRI). These scans will be mailed by the Wayne 
State University Study Team on a CD to the NU study team at this address:
c/o Rimas Lukas, MD
710 N. Lake Shore Drive
Abbott Hall 1114
Chicago, IL 60611
Co-registration of PET and MRI image volumes 
Multimodal image co-registration and analysis will be done by 3D Slicer software 
(www.slicer.org). Images will be co-registered with pre- and post-contrast axial 
T1 MR images, T2 and FLAIR images (acquired at Northwestern or local 
institution within 7 days of planned AMT-PET and transferred for Dr. Juhasz’s 
access at WSU) using the Fast Rigid Registration module. Fused images will be 
automatically resliced and resampled. MRI abnormalities (T2/FLAIR, T1 post-
gadolinium) will be delineated semi-automatically, and the volumes of interest 
(VOI) will be used as regions for quantitative assessment of AMT uptake and 
kinetic parameters.
Quantitative assessment of AMT tumor uptake
The AMT uptake in VOIs, defined on MRI will be characterized in the following 
ways: 1) Standardized uptake values (SUVs): the SUV calculation relates tracer 
concentration in tissue to the dose injected and the subject's mass (SUV= tissue 
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concentration in ROI [uCi/cc]/injected dose per weight [mCi/kg]). Since all 
subjects receive the same injected dose based upon weight (0.1 mCi/kg), the 
SUV images will be directly obtained by averaging the last four frames of the 
dynamic brain image sequence during which time there is the highest metabolic 
product. 2) Patlak analysis: In order to quantify unidirectional AMT uptake and 
metabolism in tumors non-invasively, a Patlak graphical analysis will be 
performed using the LV arterial input function and the dynamic brain sequence (7 
x 5 min consecutive frames starting 25 min post-injection). The Patlak graphical 
analysis is based on a well-validated equation described in previous studies and 
provides the following parameters: K-complex, VD, and k3. In case of irreversible 
trapping of Trp metabolites, the slope parameter (k3VD) corresponds to the 
previously described K-complex, reflecting the unidirectional uptake of tracer into 
tissue. In the case of AMT, the value of the K-complex is thought to be 
proportional to the Trp metabolism via the Kyn pathway in tumor tissue (or 
serotonin in non-tumoral brain). In order to distinguish the effects of Trp transport 
from Trp metabolism, the intercept of the Patlak plot, termed VD' (=eVD), and the 
ratio between slope and intercept termed k3' (= k3/e) will be also assessed.
Comparison of AMT kinetic parameters between baseline and follow-up 
AMT-PET images 
Baseline and follow-up (on treatment) AMT-PET images will be co-registered, 
together with corresponding (clinically acquired) MR images. VOIs created on the 
baseline images will be transferred to the post-treatment images to make sure 
that AMT uptake and kinetic parameters will be measured repeatedly in the same 
tumor volume for comparison. AMT SUV and kinetic parameters (K, VD, k3) will 
be calculated from the post-treatment PET images, and compared to 
corresponding baseline values.
All exploratory analyses will be considered hypothesis generating only and formal 
statistical significance will not be assessed.
9.6.3
Patient Reimbursement for Travel
Participants will be compensated for travels costs, including automobile mileage, 
airfare, hotel and taxi fees, and meals. The maximum amount of money that can 
be reimbursed per patient is $750 per each AMT-PET performed. 
Reimbursement will be given in the form of a check. Participants will be 
instructed to keep all their receipts in order to receive reimbursement.
Free parking is available at the Children’s Hospital of Michigan. Participants will 
be given a handout with directions and a map to CHM and areas to park around 
the hospital.
9.6.4
Communication Plan
If there is an eligible patient, the NU study team will contact the Wayne State 
University Investigator (Dr. Juhasz Csaba). The PET Center will need a signed 
NU consent form, eligibility verification for the AMT PET study (includes clinical 
and imaging records), and patient contact information. This information will be 
provided by the NU study team via encrypted email.
Dr. Juhasz will inform Angela Wigeluk (Lead technologist) and her colleagues 
(PET Center staff), who will check the PET schedule and give possible dates for 
the scan. 
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Once the AMT-PET scan is scheduled by the PET Center staff, a technologist or 
a nurse from the WSU PET Center will call the patient to confirm the 
appointment, and give instructions and directions to the PET Center.
Patients will complete an additional PET consent form at the CHM PET Center 
before the scan.
PET images will be sent electronically from Dr. Juhasz’s office to NU 
investigators after image processing. The images will be mailed on CDs to the 
address listed in Section 9.6.2.
Angela Wigeluk is the primary contact for the PET Center and can be contacted 
by patients if there are any questions about the AMT PET study. Her contact 
information and the other PET Center/WSU study contacts are listed in Section 
9.6.5.
Communication Plan Diagram
9.6.5
Wayne State University PET Center Personnel and Contact Information
Investigator
Lead Technologist
Csaba Juhasz, MD, PhD
Angela Wigeluk
Phone: 313-966-5136
Phone: 313-993-3849
Email: csaba.juhasz@wayne.edu
Email: wigeluka@karmanos.org
Regulatory Coordinator
PET Center 
Lynda Ferguson
Children’s Hospital of Michigan
Phone: 313-993-0006
3901 Beaubien St.
Email: fergusol@karmanos.org
Detroit, MI 48201
Fax: 313-966-9228
10 STATISTICAL CONSIDERATIONS
10.1
Study Design/Study Endpoints
In this phase 1 trial, statistical analyses will be descriptive. Based on landmark analysis of 
historical control data for unmethylated tumors we estimate the 1-yr survival (OS12) at 
50%. For methylated tumors the prognosis is somewhat more favorable, and a benefit 
may only be observed after > 2 years. All statistical analyses of data from this cohort 
including survival will be considered descriptive and exploratory.
10.1.1
Primary Variable
Phase I
• Safety
• Dosing
10.1.2
Secondary Variables
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• 1-year survival rate (probability of surviving 1 year or more from start of 
study treatment).
• Median survival time (median time from time of first treatment to death).
• Response rate (percentage of subjects who achieve PR or CR according 
to the iRANO criteria).
• Response rate (percentage of subjects who achieve PR or CR according 
to the RANO criteria).
• Median duration of response (number of days from the first diagnosed PR 
or CR to PD or death), if applicable.
• 6-month PFS rate (probability of disease progression or death from any 
cause occurring 6 months or later from start of study treatment)
• Median time to disease progression (median time from first treatment on 
study to documented disease progression or death from any cause).
10.1.3
Safety Variables
• Incidence and type of AEs
• Vital signs 
• Laboratory values
• Neurologic exam
• KPS
10.1.4
Further Variables of Interest
• Tumor immune-correlates
• Serum immune-correlates
• Molecular pathology correlates
• Patient distress correlates
• AMT-PET correlation with overall survival
• AMT-PET correlation with radiographic response on MRI
• AMT-PET correlation with tumor and serum immune-correlates
10.2
Analysis sets
10.2.1
Intention-to-treat (Full analysis set)
The intention-to-treat population includes all subjects who have received at least 
1 i.v. administration of nivolumab or one oral dose of BMS-986205.  
10.2.2
Per protocol
The per protocol population includes all intention-to-treat subjects who meet the 
following criteria:  
• Complete 12 months of infusion with nivolumab and 12 months of oral BMS-
986205 unless drug is discontinued due to disease progression, death, or 
study drug related unacceptable AEs in which case the subject will not be 
required to complete 12 months of treatment.
• Do not miss more than 2 consecutive doses of nivolumab or 4 consecutive 
weeks of BMS-986205 and do not miss a total of 7 doses of nivolumab or 
30 doses of BMS-986205 during the first 12 months of the study or prior to 
disease progression, death, or study drug related unacceptable adverse 
events whichever occurs first. 
Subjects who do not meet the above criteria may continue in the study but are 
considered not evaluable.  Subjects with major protocol violations that would 
likely affect the clinical activity of study drug may also be excluded from the per 
protocol population.  Such decision should be made prior to database lock and 
the primary analysis.  
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10.2.3
Safety
The safety population includes all subjects who have received at least 1 i.v. 
administration of nivolumab or one oral dose of BMS-986205, which is same as 
the intention-to-treat population.
10.2.4
Subgroups
Following subgroups will be analyzed descriptively:
• Age, (Patients <65 years old and patients ≥65 years old)
• performance score,
• extent of resection, if applicable.
10.3
Sample Size and Accrual
We will recruit 18-30 patients in this Phase I study depending on dose findings. 
Based on landmark analysis of historical control data for unmethylated tumors we 
estimate the 1-yr survival (OS12) at 50%. For methylated tumors the prognosis is 
somewhat more favorable, and a benefit may only be observed after > 2 years. All 
statistical analyses of data from this cohort including survival will be considered 
descriptive and exploratory.
10.4
Data Analyses Plans
All statistical analyses pertaining to the proposed studies will be performed under the 
supervision of Dr. Denise Scholtens, PhD (Associate Director of Biostatistics for the 
RHLCCC Quantitative Data Sciences Core). In general, for continuous variables, data will 
be presented as mean (SD) or mediation (range, interquartile range) and categorical 
variables will be summarized with tables of frequencies and counts. Exploratory overall 
survival and PFS curves will be generated via Kaplan-Meier method.  Statistical analyses 
will be performed using R-3.6.1 (https://cran.r-project.org/). 
10.4.1
General considerations
Analyses of primary and secondary target variables will be performed using the 
intention-to-treat and the per protocol populations, with the intention-to-treat 
population being the primary analysis set.  All analyses of safety and tolerability 
will be performed using the safety population.
Point estimates and the 95% confidence interval will be provided for all primary 
and secondary target variables.  Safety and tolerability data will be summarized 
descriptively using tables of frequencies and counts.
Handling of drop outs and missing data
Subjects who terminated the study prior to the 12-month time point will be 
considered failure to achieve 12-month survival.  For response rate calculations, 
the best response during the observed period will be used.
For time-to-event analyses, missing data will be treated as censored at the time 
of last follow-up if the event (death or progression) is not observed.
Analyses of the safety data will be performed using all observed data.  
MGMT unmethylated and methylated groups
All statistical analyses will be performed separately for MGMT unmethylated and 
methylated patient groups
10.4.2
Primary analysis
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The primary analyses for this Phase I study will be descriptive. Dose-limiting 
toxicities will be monitored as described above to conduct of the 3+3 design.  All 
dose-limiting toxicities and adverse events will be tabulated.
10.4.3
Secondary analyses
Survival time is defined as the number of days between date of study enrollment 
and date of death.  Subjects for whom death is not observed will be censored at 
the time when the subject is last known to be alive.  The survival curve will be 
plotted using the Kaplan-Meier method.  Median survival time and the 95% 
confidence interval will be presented for each study group and 1-year overall 
survival will be estimated.  The 95% confidence intervals will be obtained by 
Greenwood’s formula.  
Tumor response will be reported as CR, PR, SD, PD, or unknown (UNK) 
according to the iRANO criteria and RANO criteria (42).  A responder is defined 
as a subject whose best response during the study is either complete (CR) or 
partial (PR).  The response rate will be calculated as the percentage of 
responders, and similarly, the 95% confidence interval will be calculated using 
the exact binomial method, if data allow.
Time to disease progression is defined as the number of days between date of 
study enrollment and date of first assessment of PD during the study or until 
death from any cause, whichever occurs first.  Subjects without disease 
progression and are alive will be censored at the time when the subject is last 
known to be non-progressing.  Similar to overall survival analyses, the Kaplan-
Meier curve will be plotted and median time to disease progression and the 95% 
confidence interval will be calculated. 6-month progression free survival will also 
be estimated.  Since tumor assessment will only be performed periodically (every 
8 weeks), the Kaplan-Meier estimate (estimated probability that a subject is 
progression-free at a specific time) and its 95% confidence interval will be 
provided at the end of each 8-week period. 
For subjects who achieve PR or CR during the study, duration of objective 
response measures the number of days from the first objective assessment of 
PR or CR to PD or death from any cause following a confirmed PR or CR.  
Subjects who achieve PR or CR but for whom subsequent PD is not observed 
during the study will be censored at the time when the subject is last known to be 
non-progressing.  Each duration and censoring information will be provided in a 
data listing.
10.4.4
Exploratory analyses
Exploratory analyses will include non-parametric Spearman correlations and 
95%CIs between tumor immune correlates, serum immune correlates and 
molecular pathology correlates. Non-parametric summaries of continuous 
variables by categorical groups, or contingency tables for comparisons of 
categorical variables will also be used. 
In addition, non-parametric summaries of patient distress measures with clinical 
outcomes will also be explored using either Spearman correlations or non-
parametric summaries of continuous measures across groups, as appropriate.
While sample size may preclude formal interpretation of results, correlations 
between AMT-PET responses and MRI responses with time-to-event outcomes 
will be explored using Cox proportional hazards regression models. If 
appropriate, we will include the use of time-varying covariates in these models to 
allow for changes in response status over time.  Exploratory analyses evaluating 
correlations between AMT-PET responses and tumor and serum-immune 
correlates will also be performed.
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10.4.5
Safety analyses
Drug safety and tolerability will be evaluated by descriptively summarizing AEs, 
laboratory assessments, vital signs, and ECG assessments using tables of 
frequencies and counts for categorical variables and means (sds) or medians 
(ranges, interquartile ranges) for continuous variables.
11 STUDY MANAGEMENT
11.1
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol.
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki.
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB approved consent form.
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the 
informed consent discussion.
11.2
Amendments
The Principal Investigator will formally initiate all amendments to the protocol and/or 
informed consent. All amendments will be subject to the review and approval of the 
appropriate local, institutional, and governmental regulatory bodies, as well as by BMS. 
11.3
Registration Procedures
For potential patients for this phase I study, study teams are asked to inform the QAM of 
the date and time that the patient will need to be registered 
(croqualityassurance@northwestern.edu).  
BEFORE a patient can be treated on study, please complete and submit the following 
items to confirm eligibility and receive an identification number:

Patient’s signed and dated informed consent form (upload to NOTIS and keep 
original hard copy in a secure location/study chart)

Eligibility checklist (signed and dated by the treating physician – upload to 
NOTIS)

Eligibility eCRF (complete in NOTIS)

Copy of the pathology report (upload to NOTIS)
The QAM will review all source documentation required to confirm eligibility that is readily 
available in the patient’s electronic medical record (EMR).  Any information that is not 
available in the EMR must be de-identified and emailed to the QAM. Once the QAM 
confirms the patient is eligible, he or she will register the patient, assign a subject 
identification number, provide a cohort assignment, and send a confirmation of 
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registration to involved personnel. Registration will then be complete and the patient may 
begin study treatment. 
11.4
Data Submission
Once a subject is confirmed and registered to the study, eCRFs should be submitted 
according to the study procedure table.  Generally, all data for phase I patients during the 
time period patients are evaluated for Dose Limiting Toxicities (DLTs) must be submitted 
on a weekly basis. 
11.5
Instructions for Participating Sites
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Trials Office at Northwestern University (as applicable):

Completed feasibility assessment(s) to verify site’s capacity to support a 
Northwestern sponsored trial

Signed copy of Northwestern University’s Data Participating Site 
Acknowledgement which details data submission guidelines

Draft consent form for review and approval prior to submission to the local IRB

A copy of the official IRB approval letter for the protocol and informed consent

A copy of the IRB approved informed consent

Pertinent credentials (CVs, MLs, CITI & GCP Training and FDFs) for the local PI 
and any sub-investigators who will be involved in the study at the site

Form FDA 1572 appropriately filled out and signed with appropriate supporting 
certifications
Additional activities may be required prior to site activation (i.e. contract execution, study-
specific training, and delegation of authority log). Full requirements will be outlined in the 
study start-up packet upon successful completion of a feasibility assessment. 
11.6
Data Collection and Record Keeping
We will take measures to minimize the unauthorized release of confidential information. 
All personal identifying information will be removed from the clinical database, specimens 
tracking systems, as well as the headers of the raw NGS data files. They will be replaced 
with the unique study number generated through the Northwestern Oncology Trial 
Information System (NOTIS). A key will be established that links the unique study number 
to the patient's name and medical record number. That key will only be accessible to 
study personnel with access to the protocol in NOTIS. This will allow the combination, 
only when needed, of data from various sources e.g. combining genetic information with 
clinical (i.e. response to treatment, survival, etc.). 
NOTIS will be used to develop the case report forms (CRFs) and to populate them with 
data.  The study coordinator at each participating institution will be responsible for 
entering data into NOTIS. All sites will be trained by a member of the Northwestern 
University study team to use NOTIS.  
11.7
Data Management and Monitoring/Auditing
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) 
of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please 
refer to NOTIS for additional information). The level of risk attributed to this study requires 
high-intensity monitoring, as outlined in the DSMP. The assigned QAM, with oversight 
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from the Data and Safety Monitoring Committee, will monitor this study in accordance 
with the study phase and risk level. 
11.8
Adherence to the Protocol
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol. 
11.8.1
Emergency Modifications
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval. 
For any such emergency modification implemented, an IRB modification form 
must be completed within 5 business days of making the change, and the QAM 
must be notified within 24 hours of such change. 
11.8.2
Other Protocol Deviations
All other deviations from the protocol must be reported to the assigned QAM 
using the appropriate form.
A protocol deviation is any unplanned variance from an IRB approved protocol 
that: 

Is generally noted or recognized after it occurs.

Has no substantive effect on the risks to research participants.

Has no substantive effect on the scientific integrity of the research plan 
or the value of the data collected.

Did not result from willful or knowing misconduct on the part of the 
investigator(s). 
A protocol deviation may be considered an instance of Promptly Reportable Non-
Compliance (PRNC) if it:

Has harmed or increased the risk of harm to one or more research 
participants.

Has damaged the scientific integrity of the data collected for the study.

Results from willful or knowing misconduct on the part of the 
investigator(s).

Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies.
11.9
Investigator Obligations
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The PI is responsible for personally overseeing the treatment of all study 
patients. The PI must assure that all study site personnel, including sub-investigators and 
other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion.
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected, entered onto the appropriate eCRFs, and submitted 
within the study-specific timeframes. Periodically, monitoring visits may be conducted and 
the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. The study may also be subject to routine audits by the 
Audit Committee, as outlined in the DSMP. 
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11.10
Publication Policy
All potential publications and/or data for potential publications (e.g. manuscripts, 
abstracts, posters, clinicaltrials.gov releases) must be approved in accordance with the 
policies and processes set forth in the Lurie Cancer Center DSMP. For trials that require 
high intensity monitoring, the assigned QAM will prepare a preliminary data summary (to 
be approved by the DSMC) no later than 3 months after the study reaches its primary 
completion date (the date that the final subject is examined or receives an intervention for 
the purposes of final data collection for the primary endpoint). If the investigator’s wish to 
obtain DSMC-approved data prior to this point (or prior to the point dictated by study 
design), the PI must send a written request for data to the QAM which includes 
justification. If the request is approved, data will be provided no later than 4 weeks after 
this request approval. The data will be presented to the DSMC at their next available 
meeting, and a final, DSMC-approved dataset will be released along with any DSMC 
decisions regarding publication. The investigators are expected to use only DSMC-
approved data in future publications. The investigators should submit a copy of the 
manuscript to the biostatistician to confirm that the DSMC-approved data are used 
appropriately.  Once the biostatistician gives final approval, the manuscript may be 
submitted to external publishers.
11.11
Discontinuation of Study
Although BMS has every intention of completing the study, BMS reserves the right to 
discontinue the study at any time for clinical or administrative reasons.  Reasons for 
terminating the study may include:

Occurrence of intolerable drug-related AEs unknown to date with respect to their 
nature, severity, and duration.

Unexpected incidence of known AEs.

Medical or ethical reasons affecting the continued performance of the study.

Difficulties in the recruitment of subjects.

Cancellation of drug development.
In case of early study discontinuation investigators will be recompensated for expenses 
incurred.
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following primary treatment: relationships with depression, fatigue, and disability. Brain, behavior, and 
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Lutgendorf SK, Sood AK, Lopez-Berestein G. Adrenergic regulation of monocyte chemotactic protein 1 
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APPENDICES
Appendix A: Common Terminology Criteria for Adverse Events V5.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting. 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm)
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Appendix B: Karnofsky Performance Scale (KPS)
Points
Description
100
Normal, no complaints, no evidence of disease
90
Able to carry on normal activity
80
Normal activity with effort; some signs or symptoms of disease
70
Cares for self; unable to carry on normal activity or to do active work
60
Requires occasional assistance but is able to care for most of his/her needs
50
Requires considerable assistance and frequent medical care
40
Disabled; requires special care and assistance
30
Severely disabled; hospitalization indicated.  Death not imminent
20
Very sick; hospitalization necessary; active support treatment necessary
10
Moribund; fatal processes progressing rapidly
0
Dead
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Appendix C: Female Participants of Child Bearing Potential Definitions and Methods of 
Contraception
Female of Child Bearing Potential (FOCBP)
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 FOCBP

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 FOCBP participants in Arms, which include BMS986205 IDO.
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 BMS986205 IDO: Combined (estrogen- and progestogen-
containing) hormonal contraception associated with inhibition of ovulationb 

oral 

intravaginal 

transdermal 
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
Not in Arms, which include BMS986205 IDO. Progestogen-only hormonal contraception 
associated with inhibition of ovulationb 

oral 

injectable 
Highly Effective Methods That Are User Independent 

Not in Arms, which include BMS986205 IDO. Implantable progestogen-only hormonal 
contraception associated with inhibition of ovulation b

Not in Arms, which include BMS986205 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 FOCBP 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. 

FOCBP participants who choose complete abstinence must continue to have pregnancy tests, 
as specified in Section 2. 

Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the FOCBP participants chooses to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may 
reduce the efficacy of the contraceptive method.  Hormonal contraception is permissible only 
when there is sufficient evidence that the IMP and other study medications will not alter 
hormonal exposures such that contraception would be ineffective or result in increased 
exposures that could be potentially hazardous.  In this case, alternative methods of 
contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of 
contraception in the absence of definitive drug interaction studies when hormone exposures 
from intrauterine devices do not alter contraception effectiveness. The absence of such 
interactions is not known for BMS-986205 when administered with nivolumab. Therefore, 
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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.
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 D: Management Algorithms

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Appendix E: CYP3A4, CYP2B6 and CYP1A2 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/DrugInteractionsLabeling/ucm0
93664.htm
Table 1:
Classification of In Vivo Inhibitors of CYP Enzymes
CYP Enzymes
Strong Inhibitorsa
 5-fold Increase in AUC
or > 80% Decrease in CL
Moderate Inhibitorsb
 2 but < 5-fold Increase in 
AUC or 50-80% Decrease 
in CL
Weak Inhibitorsc
 1.25 but < 2-fold Increase 
in AUC or 20-50% 
Decrease in CL
CYP3A
Boceprevir, clarithromycin, 
conivaptan, grapefruit juice,d 
indinavir, itraconazole, 
ketoconazole, 
lopinavir/ritonavir, 
mibefradil,e nefazodone, 
nelfinavir, posaconazole, 
ritonavir, saquinavir, 
telaprevir, telithromycin, 
voriconazole
Amprenavir, aprepitant, 
atazanavir, ciprofloxacin, 
darunavir/ritonavir, 
diltiazem, erythromycin, 
fluconazole, fosamprenavir, 
grapefruit juice,d imatinib, 
verapamil
Alprazolam, amiodarone, 
amlodipine, atorvastatin, 
bicalutamide, cilostazol, 
cimetidine, cyclosporine, 
fluoxetine, fluvoxamine, 
ginkgo,f goldenseal,f 
isoniazid, nilotinib, oral 
contraceptives, ranitidine, 
ranolazine, 
tipranavir/ritonavir, zileuton
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.
Table 2:
Classification of In Vivo Inducers of CYP Enzymes
CYP Enzymes
Strong Inducers
 80% Decrease in AUC
Moderate Inducers
50-80% Decrease in AUC
Weak Inducers
20-50% Decrease in AUC
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Table 2:
Classification of In Vivo Inducers of CYP Enzymes
CYP Enzymes
Strong Inducers
 80% Decrease in AUC
Moderate Inducers
50-80% Decrease in AUC
Weak Inducers
20-50% Decrease in AUC
CYP3A
Avasimibe,a carbamazepine, 
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 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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Version Date: October 13, 2022 (Amendment 12)
107
Appendix F: Medications Associated with QT Prolongation
The list below is not meant to be all inclusive. Please consult individual drug labels for further information.
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Appendix G: 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) and in individuals with glucose-6-phosphate dehydrogenase deficiency, it may 
induce acute hemolysis that can further decrease oxygen delivery to the tissues. Furthermore, in high doses, 
methylene blue can also increase methemoglobinemia.
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Appendix H: 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/DrugInteractionsLabeling/ucm080499.h
tm
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Appendix I: BMS-986205 and Nivolumab Dose Delay Criteria
Table 1:
BMS-986205 and Nivolumab Dose Delay and Reduction
Situation
Nivolumab 
delay
BMS-986205 
delay
BMS-986205 
Reduction after 
Delay
Grade 2 non-skin, drug-related AE, except fatigue, 
nausea, vomiting and anemia
Yes
Yes
No
Grade 2 drug-related creatinine, AST, ALT and/or 
Total Bilirubin abnormalities
Yes
Yes
No
Grade 3 skin, drug-related AE
Yes
Yes
No
Grade 3 drug-related laboratory abnormality 
(exceptions apply, consult protocol)
Yes
Yes
No
Grade 3 drug-related fatigue, nausea, vomiting, 
and anemia
Yes
Yes
Yes
Methemoglobin  15% or any clinically significant 
elevation with associated Gr 3 AE not attributable 
to another etiology
No
Yes
Yes
QTcF > 500 msec (and > 60 msec above baseline)
No
Yes
Yes
Other lower grade AEs (in consultation with MM)
Possibly
Possibly
Possibly
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Appendix J: BMS-986205 Diagnostic Criteria for HLH and DRESS Syndrome
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IRB #: STU00209583-CR0006 Approved by NU IRB for use on or after 1/14/2025 through 1/13/2026.

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IRB #: STU00209583-CR0006 Approved by NU IRB for use on or after 1/14/2025 through 1/13/2026.

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IRB #: STU00209583-CR0006 Approved by NU IRB for use on or after 1/14/2025 through 1/13/2026.

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Appendix K: Beck's Depression Inventory Questionnaire
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IRB #: STU00209583-CR0006 Approved by NU IRB for use on or after 1/14/2025 through 1/13/2026.

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IRB #: STU00209583-CR0006 Approved by NU IRB for use on or after 1/14/2025 through 1/13/2026.

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IRB #: STU00209583-CR0006 Approved by NU IRB for use on or after 1/14/2025 through 1/13/2026.

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Appendix L: PROMIS Emotional Distress - Anxiety
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PROMIS Item Bank v1.0 – Fatigue – Short Form 6a
FATIGUE – SHORT FORM 6A
Please respond to each question or statement by marking one box per row.
During the past 7 days…
Not at all
A little bit
Somewhat
Quite a bit
Very much
HI7
AN3
FATEXP41
FATEXP40
FATEXP35
I feel fatigued .............................................
I have trouble starting things because I am 
tired............................................................
In the past 7 days…
How run-down did you feel on average? ...
How fatigued were you on average? ..........
How much were you bothered by your 
fatigue on average?.....................................

1

1

1

1

1

2

2

2

2

2

3

3

3

3

3

4

4

4

4

4

5

5

5

5

5
FATIMP49
To what degree did your fatigue interfere 
with your physical functioning? .................

1

2

3

4

5
16 May 2016
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PROMIS Item Bank v1.0 – Sleep Disturbance – Short Form 8b
Sleep Disturbance – Short Form 8b
Please respond to each item by marking one box per row.
In the past 7 days...
Not at all
A little bit
Somewhat
Quite a bit
Very much
Sleep108
My sleep was restless..................................

1

2

3

4

5
 
Sleep115
I was satisfied with my sleep ......................

5

4

3

2

1
Sleep116
My sleep was refreshing .............................

5

4

3

2

1
Sleep44
I had difficulty falling asleep ......................

1

2

3

4

5
In the past 7 days…
Never
Rarely
Sometimes
Often
Always
Sleep87
I had trouble staying asleep.........................

1

2

3

4

5
Sleep90
I had trouble sleeping..................................

1

2

3

4

5
Sleep110
I got enough sleep .......................................

5

4

3

2

1
In the past 7 days…
Very poor
Poor
Fair
Good
Very good
Sleep109
My sleep quality was ..................................

5

4

3

2

1
3 May 2016
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PROMIS® Item Bank v2.0 – Physical Function – Short Form 10b
Physical Function – Short Form 10b
Please respond to each question or statement by marking one box per row.
 
Without 
any 
difficulty
With a 
little 
difficulty
With some 
difficulty
With 
much 
difficulty
Unable to 
do
PFA11 
Are you able to do chores such as 
vacuuming or yard work?..........................

5

4

3

2

1
 
PFA56
Are you able to get in and out of a car? .....

5

4

3

2

1
PFA21
Are you able to go up and down stairs at a 
normal pace? ..............................................

5

4

3

2

1
PFA53
Are you able to run errands and shop? .......

5

4

3

2

1
PFA9
Are you able to bend down and pick up 
clothing from the floor?..............................

5

4

3

2

1
PFB28r1
Are you able to lift 10 pounds (5 kg) 
above your shoulder? .................................

5

4

3

2

1
Not at all
Very little
Somewhat
Quite a lot
Cannot do
PFA1
Does your health now limit you in doing 
vigorous activities, such as running, lifting 
heavy objects, participating in strenuous 
sports?.........................................................

5

4

3

2

1
PFA6
Does your health now limit you in bathing 
or dressing yourself? ..................................

5

4

3

2

1
PFB3
Does your health now limit you in putting 
a trash bag outside? ....................................

5

4

3

2

1
PFB44
Does your health now limit you in doing 
moderate activities, such as moving a 
table, pushing a vacuum cleaner, bowling, 
or playing golf? ..........................................

5

4

3

2

1
12 June 2018
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PROMIS - Ca Item Bank v1.0 - Emotional Distress - Anxiety
In the past 7 days…
Never
Rarely
Sometimes
Often
Always
EDANX30
I felt worried .............................................

1

2

3

4

5
EDANX46
I felt nervous..............................................

1

2

3

4

5
EDANX51
I had trouble relaxing.................................

1

2

3

4

5
EDANX54
I felt tense ..................................................

1

2

3

4

5
EDANX41
My worries overwhelmed me ....................

1

2

3

4

5
EDANX03
It scared me when I felt nervous................

1

2

3

4

5
EDANX48
Many situations made me worry ...............

1

2

3

4

5
EDANX09
I had unpleasant thoughts that wouldn't 
leave my  mind ..........................................

1

2

3

4

5
EDANX39
I worried about dying ................................

1

2

3

4

5
24 June 2016
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Appendix M: Summary of Changes
Amendment 1 – October 18, 2018
Sections(s) Affected
Prior Version
Amendment 1 
Changes
Rationale
Cover Page;
Funded by BMS
Funded by the 
Department of 
Neurosurgery, 
Northwestern 
University
BMS is no longer 
funding study
Cover Page; Study 
Schema; Study Summary; 
Section 1.3.2 (Clinical Trial 
Design); Section 2 
(Objectives); Section 3 
(Patient Eligibility); Section 
4.1 (Treatment Overview); 
Section 4.2 (Treatment 
Administration); Section 
4.2.1 (BMS-986205); 
Section 4.2.2 (Nivolumab); 
Section 4.2.3 
(Temozolomide); Section 
4.3 (BMS-986205 Dose 
Escalation); Section 6.2 
(Primary Endpoint); Section 
6.3 (Secondary Endpoints); 
Section 10 (Statistical 
Considerations); Section 
11.3 (Registration 
Procedures); Section 11.4 
(Data Submission)
Study written as a 
Phase I/IIa 
Study written as a 
Phase I only
Due to the change in 
funding, this study 
will move forward as 
a Phase I only.  
Plans for Phase II 
portion to be opened 
separately.
Section 3 (Patient Eligibility)
“Approximately 5 
potentially eligible 
patients are seen 
per month, and it is 
anticipated that at 
least 1 per month 
will be accrued”
“Approximately 6 
potentially eligible 
patients are seen per 
month, and it is 
anticipated that at 
least 2 per month will 
be accrued”
Estimate of patient 
recruitment has 
been updated.
Section 3.1.6 (Inclusion 
Criteria); Section 3.2.4 
(Exclusion Criteria)
n/a
Addition of restrictions 
for steroids use while 
on study treatment.
There is emerging 
data supporting 
abrogation of benefit 
of immunotherapies 
in patients treated 
with steroids.  It was 
felt by the 
neurooncology 
community at a 
recent NRG meeting 
that it would be very 
reasonable to 
include additional 
restrictions for 
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patients on steroids.
Section 5 (Study 
Procedures)
AMT-PET to be 
performed only in 
Phase II portion of 
the study
AMT-PET will be 
performed in current 
study, which is only 
Phase I
Optional AMT-PET 
will be performed 
during Phase I.
Amendment 2 – January 14, 2018
Sections(s) Affected
Prior Version
Amendment 2 
Changes
Rationale
Cover page
IND Holder: pending
IND Holder: Rimas 
Lukas, MD
Administrative 
change
Section 1.2.1 (BMS-
986205); Section 8.1.10 
(Side Effects)
Language 
describing ongoing 
clinical trials for 
BMS-986205
Updates to information 
for ongoing clinical 
trials for BMS-986205
Additional 
background 
information is 
available regarding 
BMS-986205
Section 1.3.2. (Clinical Trial 
Design); Section 4.6.1 
(Continuation of 
investigational Therapy)
“Planned treatment 
period is indefinite”
“Planned treatment 
period is up to 2 years”
BMS recommends 
nivolumab treatment 
up to 2 years.
Section 3.1.10 (Inclusion 
Criteria)
n/a
Referenced the 
pregnancy test 
required within 24 
hours prior to 
beginning study 
treatment
Included 
requirement that 24 
hour pregnancy test 
is required prior to 
beginning study 
treatment.
Section 4.3 (BMS-986205 
Dose Escalation)
n/a
Added “Further, if 2+ 
patients experience a 
DLT at dose level 2, 
additional 3 patients 
will be added to dose 
level 1 prior to being 
declared the MTD.”
Included additional 
clarification on how 
DLTs will be 
managed prior to 
determining MTD.
Section 4.3.1 (Dose 
Limiting Toxicity); Section 
4.4.3.3 (Resuming 
Treatment); Section 6.1 
(Definitions); Section 7.3.3 
(Expedited Reporting of 
SAEs/Other Events); 
Section 8.1.4 (Storage and 
Stability)
Referred to “the 
funding sponsor”
Refer to “BMS”
BMS is no longer 
financially 
supporting this trial, 
so the language 
needed to be 
changed
Section 4.3.1.1 
(nonhematologic DLT)
“Details will be 
established in a 
protocol amendment 
after establishing the 
recommended 
phase II dose in the 
unmethylated 
patient population.”
Removed statement 
about amending the 
protocol
Referencing a future 
amendment to 
update the MGMT 
promoter 
unmethylated Phase 
II dose is not 
needed.
Section 4.4 (Toxicity 
Management & Dose 
Delays/Modifications)
“Any patient who 
receives at least one 
dose of nivolumab 
and BMS-986205 
will be evaluable for 
“Any patient who 
receives at least one 
dose of nivolumab or 
BMS-986205 will be 
evaluable for toxicity 
Clarify that a patient 
who receives one 
dose of either drug 
will be evaluable for 
toxicity
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toxicity endpoints”
endpoints”
Section 4.4.2.1 (Dose 
Reduction)
n/a
Removed typo
Corrected type error 
in protocol
Section 4.4.2.1 (Dose 
Reduction); Section 4.4.3.3 
(Resuming Treatment)
Referenced BMS-
986205 placebo
Removed reference to 
BMS-986205 placebo
Corrected error.  No 
placebo is being 
used in this trial.
Section 4.4.2 (Nivolumab)
• Bilirubin >1.5 - 3.0 
x ULN
•Alkaline 
Phosphatase >2.5 - 
5.0 x UL
• Grade 2 Bilirubin 
>1.5 - 3.0 x ULN
• Grade 2 Alkaline 
Phosphatase >2.5 - 
5.0 x ULN
• Grade 2 AST/ALT
Clarified and 
updated criteria for 
delaying nivolumab 
administration based 
on BMS comments.
n/a
Added “any event 
requiring more than 1 
dose reduction of 
BMS-986205 requires 
discontinuation of 
BMS-986205 only”
Clarification that 
patients may 
continue to take 
nivolumab on study 
if BMS-986205 is 
discontinued.
Section 4.4.3.2 (Treatment 
Discontinuation)
“For participants 
who delay BMS-
986205 but continue 
Nivolumab, any 
dose delay of BMS-
986205 lasting > 12 
weeks will result in 
the discontinuation 
of both BMS-
986205 and 
Nivolumab”.
“For participants who 
delay BMS-986205 but 
continue Nivolumab, 
any dose delay of 
BMS-986205 lasting > 
12 weeks will result in 
the patients being 
taken off study 
treatment.”
Patients who 
discontinue BMS-
986205 and 
nivolumab will be 
taken off study 
treatment.
Section 4.5.2 (Concomitant 
Medications/Treatments 
that are not recommended)
n/a
Added “Caution is 
warranted when 
administering BMS-
986205 to participants 
taking drugs that are 
highly dependent on 
CYP3A4 or CYP2B6 
for metabolism.”
Additional 
information provided 
by BMS on CYP 
restrictions
Section 4.5.2 (Concomitant 
Medications/Treatments 
that are not recommended); 
Section 4.5.4 (Permitted 
Concomitant Medication 
and Therapy for which 
specific dose requirements 
are necessary)
n/a
Added clarification to 
steroid use 
“Participants must be 
on a stable or 
decreasing dose of 
steroids ≤4mg of 
decadron for 7 days 
prior to initiating study 
treatment [not 
consent] and be off of 
all steroids at the time 
of initiation of study 
treatment (D#1).”
To align with steroid 
restrictions in 
inclusion criteria
Section 4.5.3 (Other 
Restrictions and 
Precautions”
n/a
Included additional 
information on 
serotonin syndrome
Additional 
information provided 
by BMS
Section 5 (Study 
n/a
Included X for 
As indicated by 
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Procedures)
pregnancy test during 
RT therapy
footnote 5, 
pregnancy test will 
be performed every 
4 weeks while on 
treatment, including 
during RT.
Section 6.3.1 (Secondary 
Endpoints); Section 10.1.2 
(Secondary Variables)
Indicate timeframe 
for collected data 
from “time of study 
enrollment”
Indicate timeframe for 
collected data from 
“start of study 
treatment”
Correction of error.  
Data for survival will 
be collected starting 
at the time of 
treatment initiation.
Section 7.3.3.4 (Reporting 
to BMS)
n/a
“SAE reports 
(including pregnancy 
and death by any 
cause),…”
Must inform BMS of 
pregnancy while on 
study treatment
Section 7.3.3.5 (Adverse 
Events of Special Interest 
(AEOSI))
n/a
Included information 
on AEOSI (HLH and 
DRESS)
Per BMS, additional 
AEOSI require 
expedited reporting.
Section 8.1.9 (Availability 
and Supply)
n/a
Additional information 
on ordering BMS 
986205 
Administrative 
change to provide 
clarification on drug 
ordering.
Section 8.2.6 (Preparation 
and administration)
“When the dose is 
fixed (eg, 240 mg, 
480mg), nivolumab 
injection can be 
infused undiluted or 
diluted so as not to 
exceed a total 
infusion volume of 
120 mL.”
“When the dose is 
fixed (eg, 240 mg, 
480mg), nivolumab 
injection can be 
infused undiluted or 
diluted so as not to 
exceed a total infusion 
volume of 160 mL.”
Update from 
nivolumab IB.
Section 8.2.9 (Availability 
and Supply)
“The initial order 
should be limited to 
20 vials”
Removed restriction 
limiting order to 20 
vials
Per BMS, not 
needed in protocol.
Section 10.3 (Sample Size 
and Accrual)
“We will recruit 18-
30 patients in this 
Phase I study 
depending on dose 
findings in the 
Phase I study.”
“We will recruit 18-30 
patients in this Phase I 
study depending on 
dose findings.”
Removed text due to 
redundancy
Appendix C
“Guidance for 
collection of 
Pregnancy 
Information and 
outcome of 
pregnancy on the 
Pregnancy 
Surveillance Form is 
provided in Section 
9.2.5 and the 
Appendix for 
Adverse Events 
and Serious 
Adverse Events 
Definitions and 
“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.”
Clarify the location 
of pregnancy 
surveillance form
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128
procedures for 
Evaluating, Follow-
up and Reporting.”
Appendix D
n/a
Included introductory 
language on 
management 
algorithms previously 
included in Appendix I
Formatting error 
corrected for clarity.
Appendix E
CYP3A4 and 
CYP2B6 Guidance
CYP3A4, CYP2B6 and 
CYP1A2 Guidance
Updated guidance 
based on 
information from 
BMS
Appendix I
n/a
BMS-986205 and 
Nivolumab Dose Delay 
Criteria
Updated information 
provided by BMS
Appendix J
n/a
BMS-986205 
Diagnostic Criteria for 
HLH and DRESS 
syndrome
Updated information 
provided by BMS
Amendment 3 -- For Internal Use
SRC acknowledgement of FDA and IRB protocol changes
Amendment 4 - September 19, 2019
Sections(s) Affected
Prior Version
Amendment 4 
Changes
Rationale
Cover page; Study 
Schema; Study Summary; 
Section 1.1 (Glioblastoma 
and Anaplastic 
Astrocytoma); Section 
1.3.1.1 (Nonclinical 
Studies); Section 1.3.2.2 
(Patient population and 
design); Section 2.1 
(Primary Objective); 
Section 3.1.1 (Inclusion 
Criteria); Section 4.1 
(Overview)
Study opened to 
patients with newly 
diagnosed 
glioblastoma
Study opened to 
patients with newly 
diagnosed 
glioblastoma and 
anaplastic 
astrocytoma
To facilitate accrual 
which allow the 
study to progress 
more quickly into a 
randomized phase 2 
trial.
List of Abbreviations
n/a
Include AA (anaplastic 
astrocytoma) and 
TTFields (tumor 
treating fields)
Administrative 
update
Study Schema; Study 
Summary; Section 1.1.1 
(Standard treatment 
regimen in GBM); Section 
1.2.4 (Tumor Treating 
Fields); Section 1.3.2.2 
(Patient population and 
design); Section 1.3.2.1 
(Introduction and 
Rationale); Section 1.3.2.3 
(Anticipated Results and 
Interpretation); Section 
3.2.22 (Exclusion Criteria); 
Section 4.2 (Treatment 
Optune (TTFields) 
therapy not 
permitted
Optune (TTFields) is 
permitted beginning at 
Day 1 of the 
Maintenance Phase
Make Optune 
available to patients 
who would like to 
participate
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Administration); Section 
2.4.5 (Tumor Treating 
Fields); Section 4.3.1.1 
(Nonhematologic Dose-
Limiting Toxicity (DLT):
Hepatic Nonhematologic 
DLT); Section 4.4.3.1 
(Treatment Delay); Section 
4.4.6 (Tumor Treating 
Fields); Section 4.5.1 
(Prohibited Concomitant 
Medication and Therapy); 
Section 8.4 (Tumor 
Treating Fields)
Section 1.1.2 
(Immunosuppression and 
high-grade gliomas)
Section title 
“Immunosuppressio
n and GBM”
Section title: 
”Immunosuppression 
and high-grade 
gliomas”
To reference both 
GBM and AA
Section 1.2.1.3 (Dose 
Justification)
Starting dose of 
BMS-986205 listed 
as 100mg
Starting dose of BMS-
986205 listed as 50mg
Corrected error.
Section 1.3.2.2 (Patient 
population and design)
“Analyses based 
upon radiographic 
endpoints (i.e. 
response rate, PFS) 
will be performed 
utilizing the iRANO 
criteria”
“Analyses based upon 
radiographic endpoints 
(i.e. response rate, 
PFS) will be performed 
utilizing the RANO 
and iRANO criteria”
Both RANO and 
iRANO will be used 
for response 
analysis.
Section 2.3.3 (Exploratory 
Objectives); Section 5 
(study Procedures); Section 
6.4.3 (Exploratory 
Endpoints); Section 9.5 
(Patient Questionnaires); 
Appendix K (Beck’s 
Depression Inventory 
Questionnaire); Appendix L 
(PROMIS Emotional 
Distress - Anxiety)
n/a
Include an exploratory 
objective “Investigate 
GBM/AA patient levels 
of distress, before, 
during, and after 
treatment with trimodal 
radiation, anti-PD-1 
mAb and IDO1 
enzyme inhibitor.
Included an 
objective to analyze 
patient levels of 
distress using the 
PROMIS 
questionnaires.
Section 3.1.1 (Inclusion 
Criteria)
“Study enrollment is 
to be within 5 weeks 
from diagnostic 
surgery or biopsy.”
“Study enrollment is to 
be within 6 weeks 
from diagnostic 
surgery or biopsy.”
Increase window to 
allow for more 
patient availability
Section 3.1.2 (Inclusion 
Criteria); Section 3.1.3 
(Inclusion Criteria)
Inclusion criteria: 
Tumor tissue 
specimens from the 
GBM surgery or 
biopsy for central 
pathology review 
and exploratory 
analysis of 
immunocorrelative 
studies, if available 
(no minimum 
requirement). 
Criteria removed.
Both criteria were 
removed as they are 
not requirements for 
study enrollment, 
only 
recommendations.
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130
For subjects who 
had undergone 
tumor resection, 
preoperative Gd-
MRI and immediate 
postoperative Gd-
MRI performed 
within <72 hours 
after surgery or 
biopsy is 
recommended. If CT 
scans were 
performed 
perioperatively, an 
MRI should be 
performed before 
initiation of study 
treatment.
Section 3.1.9 (Inclusion 
Criteria)
“Clinically normal 
cardiac function 
without history of 
ischemic heart 
disease in the past 6 
months and normal 
12 lead ECG.”
“Clinically normal 
cardiac function 
without history of 
ischemic heart disease 
in the past 6 months 
and not clinically 
significant 12 lead 
ECG (as determined 
by treating 
investigator).”
Clarification to allow 
for treating physician 
discretion
Section 3.2.1 (Exclusion 
Criteria)
“Patients who have 
had chemotherapy 
within 2 years prior 
to entering the study 
are not eligible.”
“Patients who have 
had chemotherapy for 
any cancer within 2 
years prior to entering 
the study are not 
eligible.”
Clarification
Section 3.2.9 (Exclusion 
Criteria)
“Patients with a 
history of recent 
prior malignancy are 
not eligible.  
Subjects with 
curatively treated 
cervical carcinoma 
in situ or non-
melanoma basal cell 
carcinoma of the 
skin, or subjects 
who have been free 
of other 
malignancies for ≥2 
years are eligible for 
this study.”
Removed criteria
Exclusion criteria 
3.2.1 was clarified to 
cover all previous 
cancer diagnoses so 
this was redundant. 
Section 3.2.12 (Exclusion 
Criteria)
“Patients who have 
received treatment 
with botanical 
preparations (e.g., 
herbal supplements 
“Patients who have 
received treatment 
with botanical 
preparations (e.g., 
herbal supplements or 
Allow for washout 
period to be from 
time of treatment.
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Version Date: October 13, 2022 (Amendment 12)
131
or traditional 
Chinese medicines) 
intended for general 
health support or to 
treat the disease 
under study within 
14 days prior to 
registration are not 
eligible.”
traditional Chinese 
medicines) intended 
for general health 
support or to treat the 
disease under study 
within 14 days prior to 
initiation of 
treatment are not 
eligible.”
Section 3.2.24 (Exclusion 
Criteria)
“Note: testing for 
HIV must be 
performed at sites 
where mandated 
locally”
Removed note
This is a single 
institution study and 
HIV testing is not 
mandated at 
Northwestern.
Section 4.3 (BMS-986205 
Dose Escalation)
“BMD-986205”
“BMS-986205”
Corrected typing 
error.
Section 4.3.1.1 
(Nonhematologic Dose-
limiting Toxicity (DLT)); 
Section 4.4.3.1 (Treatment 
Delay)
n/a
Include information for 
DLTs specific to 
TTFields
Clarify DLTs due to 
TTFields will not 
delay other 
treatments.
Section 4.4.3.2 (Treatment 
Discontinuation)
A dosing delay 
lasting > 10 weeks 
from previous dose
A dosing delay lasting 
> 12 weeks from 
previous dose
Corrected error.
Section 4.5.1 (Prohibited 
Concomitant Medication 
and Therapy)
All Prophylactic 
antimicrobial therapy 
prohibited
Prophylactic 
antimicrobial therapy 
(Note: treatment for 
Pneumocystis carinii 
prophylaxis is allowed. 
See section 4.5.4.2)
Clarify restrictions 
with Prophylactic 
antimicrobial therapy
Section 4.6 (Duration of 
Therapy)
n/a
Disease progression 
by iRANO
Clarify that therapy 
will continue until 
disease progression 
as determined by 
iRANO criteria.
One table for study 
procedures
Study procedures for 
Maintenance Phase 
have been moved into 
a separate table.
Tables have been 
split to provide 
clarity on timing of 
procedures to be 
performed.
n/a
Footnote numbers 
were updated
Format update
n/a
Footnote 18: clarify 
that blood will be 
collected at each MRI 
time point, which is 
“every 8 weeks 
starting at cycle 1 day 
1)
Clarification of 
timing
Section 5 (Study 
Procedures)
n/a
Footnote 5 was added 
to clarify timing of 
toxicity assessment, 
physical exam and 
conmeds during RT 
phase
Included for clarity.
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Version Date: October 13, 2022 (Amendment 12)
132
n/a
Added footnote 13 to 
clarify TMS will only be 
in MGMT promotor 
methylated cohort
Included for clarity.
n/a
Added to footnote 8 
that beginning at cycle 
7 of Maintenance 
Phase, CBC +diff will 
be performed only on 
day 1
Once MGMT 
promotor methylated 
patients complete 
TMZ, they will no 
longer need 
additional CBC+diff
Section 5 (Study 
Procedures); Section 9 
(Correlatives/Special 
Studies)
n/a
Added footnote 21 to 
allow baseline 
research blood and 
stool samples can be 
collected any time 
after consent and prior 
to any study treatment.
Extended the 
window for blood 
collection to reduce 
deviations.
Section 5.1 (Study 
Procedures)
n/a
Included “Post RT 
Phase” in procedure 
table
Post RT Phase was 
referenced in the 
protocol, however 
was not included in 
the procedure table.
Section 8.1.9 (Availability & 
Supply); Section 8.2.9 
(Availability & Supply)
n/a
Included instructions 
for the end of study 
period from BMS
Required language 
from BMS (moved 
from section 8.4)
Section 9 
(Correlatives/Special 
Studies)
n/a
Table of correlative 
collection information 
has been updated to 
reflect the involvement 
of Pathology Core 
Facility for collecting 
archival tissue 
samples and stool 
samples.
Updates to sample 
collection.
Section 9.3.2 (Blood)
n/a
Additional information 
on analysis of blood 
samples
Clarification of 
analysis plans
Section 10.4.1 (Data 
Analyses Plans)
“Statistical analyses 
will be performed 
using R-3.4.3”
“Statistical analyses 
will be performed 
using R-3.6.1”
Software Update
Section 10.4.4 (Exploratory 
Analyses)
Explanation the 
analyses of AMT-
PET exploratory 
analyses
Explanation of 
analyses of 
questionnaires and 
correlative studies. 
Analyses plans have 
been updated based 
on the change to 
study endpoints.
Amendment 5– December 16, 2019
Sections(s) Affected
Prior Version
Amendment 5 
Changes
Rationale
Coverpage
Jeffery Raizer listed 
as Sub-I
Jeffery Raizer 
removed from Sub-I 
list
Administrative 
change
Table 5-2 (Study 
Procedures During 
Maintenance Phase)
n/a
“X” added in columns 
for maintenance cycle 
for the following rows: 
MRI, EKG, 
Administrative 
update for clarity 
and to match table 
with current 
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Version Date: October 13, 2022 (Amendment 12)
133
temozolomide, 
questionnaire, and 
correlative blood. 
footnotes
Appendix
n/a
Inserted 4 missing 
pages of Emotional 
Distress-Anxiety 
questionnaire in 
appendix of protocol. 
Questionnaires are in 
Redcap for patients 
completion.
Inserted missing 
pages, correction of 
administrative error. 
Amendment 6 – May 1, 2020
Sections(s) Affected
Prior Version
Amendment 6 
Changes
Rationale
n/a
Added Dr. Csaba 
Juhasz MD, PhD from 
Wayne State 
University to Lab Co-
Investigators
Added optional 
AMT-PET study to 
the Protocol per PI 
request.
Dr. Juhasz and his 
PET Center team 
will perform the 
AMT-PET scans and 
analyze/send data to 
NU for this optional 
exploratory study. 
Both contrast-
enhancing and non-
enhancing gliomas 
have increased AMT 
uptake. This study 
will assess whether 
AMT uptake on PET 
imaging is correlated 
with treatment 
response and other 
outcomes.
Cover Page;
Biostatistician: 
Denise Scholtens, 
PhD
Biostatistician: Hui 
Zhang, PhD
Dr. Scholtens is no 
longer part of the 
Division of 
Biostatistics.
1.2.1.4 Safety
The most commonly 
reported TRAEs (in 
> 10% of 
participants) during 
combination therapy 
with nivolumab were 
fatigue (14.1%) and 
nausea (11.1%). 
Grade 3 TRAEs 
have been reported 
in approximately 
11% of participants 
receiving the 
combination and 
treatment-related 
Per Investigator 
Brochure v. 6 (01-29-
2020), the most 
commonly reported 
TRAEs (in > 10% of 
participants) during 
combination therapy 
with nivolumab were 
fatigue (17.2%) and 
nausea (13.2%). 
Grade 3 and 4 TRAEs 
have been reported in 
approximately 17% of 
participants receiving 
the combination. 
Updated the 
numbers per IB v. 6 
(01-29-2020). 
Removed outdated 
dates per Pharma 
sponsor feedback.
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SAEs in 
approximately 7%. 
There has been 1 
treatment-related 
death due to 
myocarditis prior to 
the clinical data 
cutoff date (15-Nov-
2017), which 
occurred during 
combination with 
nivolumab, and 2 
additional deaths 
due to Stevens-
Johnson syndrome 
and hepatic failure, 
which occurred after 
the clinical data 
cutoff date. (pg 23 
IB)
Treatment-related 
SAEs were reported in 
9.4% of patients 
treated with BMS-
986205 and 
nivolumab.There has 
been 1 treatment-
related death due to 
myocarditis , which 
occurred during 
combination with 
nivolumab, and 2 
additional deaths due 
to Stevens-Johnson 
syndrome and hepatic 
failure Furthermore, 
the 100 mg once daily 
(QD) dose of BMS 
986205 in combination 
with nivolumab 
appears to have a 
safety profile similar to 
that reported for 
nivolumab 
monotherapy, except 
for anemia and 
methemoglobinemia, 
which may be related 
to p-chloroaniline 
production.
Metabolism of BMS-
986205 produces a 
p-chloroaniline 
metabolite, which is 
associated with the 
formation of 
methemoglobin as 
well as with 
hemolytic anemia. 
As of 15-Nov-2017, 
there have been no 
clinically significant 
metHb events at the 
100 mg dose level of 
BMS-986205, and 
the highest reported 
metHb value was 
16% in a participant 
receiving 200 mg of 
BMS-986205; no 
other participants 
had reported metHb 
levels over 10%, 
none have required 
Metabolism of BMS-
986205 produces a p-
chloroaniline 
metabolite, which is 
associated with the 
formation of 
methemoglobin as well 
as with hemolytic 
anemia. As of 24-Oct-
2019, there have been 
no clinically significant 
metHb events at the 
100 mg dose level of 
BMS-986205, and the 
highest reported 
metHb value was 16% 
in a participant 
receiving 200 mg of 
BMS-986205; no other 
participants had 
reported metHb levels 
over 10%, none have 
required specific 
treatment for 
Updated the data 
per IB v. 6 (01-29-
2020).
Added a footnote to 
explain that the data 
in the above 
paragraphs are 
based on IB v. 6 
(01-29-2020), and 
that the most current 
version of the IB 
should be consulted.
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135
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 
participants 
receiving 
combination therapy 
with nivolumab, 
respectively) and 
responded to dose 
holding, reductions, 
and other standard 
clinical measures. 
Entry criteria and 
monitoring 
parameters were 
developed in an 
attempt to reduce 
the risk of the 
occurrence and 
impact of 
methemoglobin-
related toxicity. 
Participants with 
cytochrome b5 
reductase and 
G6PD deficiencies 
are excluded due to 
the increased risk of 
methemoglobinemia 
and hemolysis, 
respectively.
methemoglobinemia, 
and there have been 
no treatment 
discontinuations due 
to 
methemoglobinemia. 
Anemia and hemolytic 
anemia have also 
occurred infrequently 
(1% and 0.3% of 
participants receiving 
combination therapy 
with nivolumab, 
respectively) and 
responded to dose 
holding, reductions, 
and other standard 
clinical measures. 
Entry criteria and 
monitoring parameters 
were developed in an 
attempt to reduce the 
risk of the occurrence 
and impact of 
methemoglobin-
related toxicity. 
Participants with 
cytochrome b5 
reductase and G6PD 
deficiencies are 
excluded due to the 
increased risk of 
methemoglobinemia 
and hemolysis, 
respectively.
*All information above 
references BMS-
986205 Investigator’s 
Brochure v. 6 (01-29-
2020). Please refer to 
the most recent 
Investigator Brochure 
for a current listing of 
adverse events and 
toxicities.
1.3.1.2 Clinical Studies
Added Figure 7 and 
clinical information on 
AMT-PET in GBM 
patients.
Added clinical 
information to 
provide rationale for 
optional AMT-PET 
study.
2.3 Exploratory Objectives, 
2.3.4
n/a
Added exploratory 
objective 2.3.4 
“Assess whether 
tumor-associated α-
[11C]-methyl-L-Trp 
Added an objective 
for AMT-PET.
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(AMT) uptake on PET 
imaging is correlated 
with treatment 
response and other 
outcomes. “
4.4.1.1 Holding Dose
QTcB > 500 msec 
confirmed by at least 
1 repeat ECG and at 
least 60 msec above 
baseline
QTcF> 500 msec 
confirmed by at least 1 
repeat ECG and at 
least 60 msec above 
baseline
Changed to QTc 
Fridericia’s formula 
(was previously 
Bazett’s) to be 
consistent with the 
rest of the Protocol.
4.4.1.2 Dose reduction
QTcB > 500 msec 
confirmed by at least 
1 repeat ECG and at 
least 60 msec above 
baseline
QTcF > 500 msec 
confirmed by at least 1 
repeat ECG and at 
least 60 msec above 
baseline
Changed to QTc 
Fridericia’s formula 
(was previously 
Bazett’s) to be 
consistent with the 
rest of the Protocol.
4.4.2 Nivolumab
Nivolumab 
administration 
should be delayed 
for the following (in 
addition to the table 
below) until 
resolution to ≤ grade 
1 or baseline:
•Grade 2 non-skin, 
drug-related adverse 
events (including 
below), with the 
exception of fatigue
•Grade 2 Bilirubin 
>1.5 - 3.0 x ULN
•Grade 2 Alkaline 
Phosphatase >2.5 - 
5.0 x ULN
•Grade 2 AST/ALT
•Grade 3 skin, drug-
related adverse 
event
•Grade 3 drug-
related laboratory 
abnormality, with the 
following exceptions: 
o
Grade ≥ 3 
lymphopenia or 
asymptomatic 
amylase or 
lipase elevation 
does not require 
dose delay
o
Grade ≥ 3 AST, 
ALT, total 
bilirubin will 
require dose 
N/A
Deleted this section. 
The bulleted 
language for the 
nivolumab 
monotherapy dose 
modification 
contradicted some 
of the guidelines for 
the nivolumab 
combination therapy 
dose modifications. 
The pharma sponsor 
clarified that this 
section should be 
deleted, and that the 
table below (on 
page 38) should be 
followed in it’s place.
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discontinuation 
o
Grade ≥ 3 
cardiac toxicity, 
neurotoxicity, or 
pneumonitis will 
require dose 
discontinuation
n/a
Added “AMT PET 
(Optional)26” as an 
assessment, marked 
at screening, EOT, 
and follow-up.
See rationale for 
AMT-PET above.
n/a
Added “TSH, free T3, 
and Free T4” at 
baseline, Post RT 
Phase D1, and EOT.
Per pharma sponsor 
feedback, thyroid 
function tests are 
necessary for safety 
monitoring.
n/a
Added footnote 26.
The footnote was 
added to describe 
when/where AMT-
PET will be 
performed.
n/a
Added Blood 
Collection at D1 of 
Post RT Phase.
Added per Dr. Derek 
Wainwright’s 
request (lab 
investigator). Dr. 
Wainwright would 
like to see how the 
patient’s blood 
counts respond to 
radiation.
Table 5-1: Study 
Procedures
Footnote 20: 
Research blood (2 
heparinized tubes 
with 10ml each) will 
be collected at 
baseline and at each 
MRI time point 
(every 8 weeks 
starting at cycle 1 
day 1 of the 
Maintenance Cycle) 
and at the end of 
treatment visit.
Footnote 20: 
20.Research blood (2 
heparinized tubes with 
10ml each) will be 
collected at baseline, 
on day 1 of post RT,  
and at each MRI time 
point (every 8 weeks 
starting at cycle 1 day 
1 of the Maintenance 
Cycle) and at the end 
of treatment visit.
See rationale for 
additional blood 
sample above.
n/a
Added “AMT PET 
(Optional)26” as an 
assessment, marked 
at Day 1
See rationale for 
AMT-PET above.
b/a
Added “TSH, Free T3, 
Free T4” to every 
cycle D1.
Per pharma sponsor 
feedback, thyroid 
function tests are 
necessary for safety 
monitoring.
Table 5-2: Study 
Procedures During 
Maintenance Phase
n/a
Added footnote 26.
The footnote was 
added to describe 
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when/where AMT-
PET will be 
performed.
Footnote 20: 
Research blood (2 
heparinized tubes 
with 10ml each) will 
be collected at 
baseline and at each 
MRI time point 
(every 8 weeks 
starting at cycle 1 
day 1 of the 
Maintenance Cycle) 
and at the end of 
treatment visit.
Footnote 20: 
20.Research blood (2 
heparinized tubes with 
10ml each) will be 
collected at baseline, 
on day 1 of post RT,  
and at each MRI time 
point (every 8 weeks 
starting at cycle 1 day 
1 of the Maintenance 
Cycle) and at the end 
of treatment visit.
See rationale for 
additional blood 
sample above
6.4 Exploratory Endpoints, 
6.4.4
n/a
Added Endpoint 6.4.4: 
Correlation between 
AMT-PET responses 
and MRI responses, 
survival, and PFS in 
newly diagnosed 
MGMT promoter 
unmethylated and 
MGMT promoter 
methylated 
glioblastoma treated 
with nivolumab in 
combination with 
BMS-986205 and 
radiation.

AMT-PET 
correlation with OS

AMT-PET 
correlation with 
radiographic 
response on MRI

Tumor immune-
correlates

Serum immune-
correlates

Molecular 
pathology 
correlates
See rationale for 
adding AMT-PET 
study above.
7.2.3 Serious Adverse 
Events (SAEs)
n/a
Added a 
Hospitalization 
section:
Hospitalization
For reports of 
hospitalization, it is the 
sign, symptom or 
diagnosis which led to 
the hospitalization that 
is the serious event for 
which details must be 
This section was 
added to clarify 
when a 
hospitalization is an 
SAE and when it 
isn’t. This helps 
prevent reporting 
previously planned 
surgical and routine 
procedures (i.e. a 
craniotomy) as an 
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BMS Study Number: CA017-075
Version Date: October 13, 2022 (Amendment 12)
139
provided.
Any event requiring 
hospitalization or 
prolongation of 
hospitalization that 
occurs during the 
study must be 
reported as a serious 
adverse event, except 
hospitalizations for the 
following:
•Hospitalizations not 
intended to treat an 
acute illness or 
adverse event (e.g., 
social reasons such as 
pending placement in 
long-term care facility)
•Hospitalizations for 
routine blood 
transfusions, 
hospitalization for an 
elective or diagnostic 
procedure, or surgery 
for a pre-existing 
condition that has not 
worsened, are not 
considered SAEs. 
(Emergency room 
visits that do not result 
with admission are not 
considered as SAEs).
•Hospitalizations or 
prolongation of 
hospitalization for ≤24 
hours.
SAE.
7.3.3.3 Reporting to the 
FDA
N/A
Added the following 
line:
The Principal 
Investigator will notify 
the FDA with the 
assistance of a Quality 
Assurance Monitor.
Per pharma sponsor 
feedback, clarified 
that the FDA will be 
notified by the PI 
with assistance from 
a QAM.
7.3.3.5 Adverse Events of 
Special Interest (AEOSI)
N/A
Added the following 
line: 
All AEOSIs, regardless 
of causal association, 
will be submitted to the 
FDA and BMS.
Per pharma sponsor 
feedback, clarified 
that all AEOSIs will 
be submitted to the 
FDA and BMS. This 
confusion was 
because the section 
had defined events 
of special interest 
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140
that required 
expedited regulatory 
reporting. This does 
not mean we will not 
report AEOSIs 
beyond the three 
listed in this section 
that are of “special 
interest.”
9 
CORRELATIVES/SPECIAL 
STUDIES, Correlative 
Samples – Details for Lab 
Manual
Under “Timing and 
Blood”:
Baseline (prior to 
first dose of study 
treatment) and every 
8 weeks during the 
Maintenance Phase 
beginning on Cycle 
1 Day 1 (±2 days), 
and at the end of 
treatment visit.
Under “Timing and 
Blood”:
Baseline (prior to first 
dose of study 
treatment), on day 1 
of post RT,  and every 
8 weeks during the 
Maintenance Phase 
beginning on Cycle 1 
Day 1 (±2 days), and 
at the end of treatment 
visit.
See rationale above 
for adding additional 
blood sample on D1 
of post RT.
9.6 AMT-PET Study
n/a
Added section 9.6 to 
describe the AMT-PET 
study including the 
scanning protocol, 
description of AMT, 
timing of assessments, 
communication plan 
between NU and 
WSU, WSU personnel 
contact info,  and 
patient 
reimbursement.
See rationale above 
for AMT-PET study.
10.1.4 Further Variables of 
Interest
n/a
Added three additional 
variables of interest: 
-AMT-PET correlation 
with overall survival
-AMT-PET correlation 
with radiographic 
response on MRI
-AMT-PET correlation 
with tumor and serum 
immune-correlates
See rationale above 
for AMT-PET study.
10.4.4 Exploratory analyses
n/a
Added analysis plan 
for AMT-PET (third 
paragraph in section).
See rationale above 
for AMT-PET study.
TITLE PAGE, LIST OF 
ABBREVIATIONS, STUDY 
SCHEMA, STUTDY 
SUMMARY TITLE (Title 
Objectives, Diagnosis & 
Key Eligibility Criteria, 
Treatment Plan), 1.1 
Glioblastoma and 
Anaplastic Astrocytoma,  
Mentioned 
Astrocytoma or “AA”
Removed astrocytoma 
or AA.
All references to 
astrocytoma cohort 
were removed. The 
pharma sponsor 
(BMS) requested we 
remove this cohort 
for two reasons: 1. 
The protocol 
primarily supports 
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BMS Study Number: CA017-075
Version Date: October 13, 2022 (Amendment 12)
141
1.2.3.3 Special Populations 
(Age), 1.3.1.1 GBM/AA 
immunotherapy requires a 
combinatorial 
approach,1.3.2.2 Patient 
population and design, 
2.1.1 Primary Objective, 
Exploratory Objectives 
2.3.1 and 2.3.3, Inclusion 
Criteria 3.1.1, 4.1 Overview
GBM, as all the 
preclinical and 
clinical data are 
based on GBM 
models and there 
isn’t much data in 
support of AA 
patients.  
2. Due to small 
sample size 
inclusion of another 
subset population 
introduces 
heterogeneity into 
the study, which 
could limit 
interpretability of the 
study results.  
Throughout Protocol
Editorial changes 
such as protocol 
version date, page 
numbers, formatting, 
TOC updates, etc 
were made 
throughout.
Amendment 7 – July 24, 2020
Sections(s) Affected
Prior Version
Amendment 7 
Changes
Rationale
Title Page
Added the West 
Region of NM with Dr. 
Sean Grimm as the 
Lead Investigator. 
The West Region 
will be added as an 
outside site to this 
study.
Tables 5-1 Study 
Procedures and 5-2 Study 
Procedures in 
Maintenance Phase
Footnote 17: 
Patients will 
complete 
questionnaires at 
baseline/pretreatme
nt (any time prior to 
Day 1 of RT), 1 
week prior to each 
MRI follow-up (see 
footnote #5), and 
every 3 months 
during follow up.  
Patients will receive 
a link to complete 
questionnaires 
online via RedCAP.
Footnote 17:
Patients will receive 
paper forms to 
complete and return to 
the study team. Data 
from the paper forms 
will be entered into 
NOTIS by the study 
team.   
Due to technical 
issues with 
REDCap, paper 
form questionnaires 
will be used. Paper 
forms will be 
secured in a locked 
room. Data from the 
paper forms will be 
entered into NOTIS.
Table 9 
Correlative/Special 
Studies
Previous address:
300 E Superior 
Street
Tarry Bldg 2-725
Updated Address for 
Dr. Wainwright’s lab:
303 E Superior St
Simpson-Querrey 6-
Dr. Wainwright’s lab 
was moved to a new 
location.
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BMS Study Number: CA017-075
Version Date: October 13, 2022 (Amendment 12)
142
Chicago, IL 60611
Lab Phone: (312) 
503-5168; Office 
Phone: (312) 503-
3161
500
Chicago, IL 60611
Lab Phone: 312-503-
5168
Analysis center for 
all specimens 
previously said:
Wainwright Lab
300 E Superior 
Street
Tarry Bldg 2-725
Chicago, IL 60611
Lab Phone: (312) 
503-5168; Office 
Phone: (312) 503-
3161
Updated Address to: 
 
303 E Superior St
Simpson-Querrey 6-
500
Chicago, IL 60611
Lab Phone: 312-503-
5168
Dr. Wainwright’s lab 
was moved to a new 
location, with a new 
address.
9.5 Questionnaires
When completed, 
the form data will be 
immediately 
uploaded into a 
secure REDCap 
database. Patients 
who do not have 
access to email, or 
do not wish to 
complete measures 
by email link, will be 
offered the 
opportunity to 
complete the 
measures on arrival 
into the clinic, prior 
to evaluation by the 
physician. Report 
data will be 
downloaded by the 
study team and 
reviewed with the 
patient during the 
visit.
Patients will be given a 
paper form for the 
PROMIS measures. 
When completed, the 
data from the form will 
be entered into a 
secure NOTIS 
database by the study 
team. Paper forms will 
be secured in a locked 
room with access 
given to authorized 
study personnel only.  
Report data will be 
downloaded by the 
study team and 
reviewed with the 
patient during the visit.
See rationale above.
Throughout Protocol
Editorial Changes 
(formatting, 
grammar, updates to 
Protocol 
Amendment version 
and date, etc).
Amendment 8 – November 18, 2020
Sections(s) Affected
Prior Version
Amendment 8 
Changes
Rationale
4.1 Overview
Added the following 
To allow patients 
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BMS Study Number: CA017-075
Version Date: October 13, 2022 (Amendment 12)
143
paragraph:
Patients who have 
disease progression 
per iRANO criteria or 
clinical decline, may 
have the option to re-
start treatment if they 
undergo standard of 
care surgery, and their 
tumor tissue shows on 
pathologic review that 
that there is no 
evidence of significant 
tumor and the 
changes on MRI were 
likely treatment 
related.  The patient 
will be advised of the 
pathology results and 
that they may not 
derive any further 
benefit from re-starting 
therapy. The patient 
will need to re-sign the 
informed consent prior 
to starting therapy.
who may have 
experienced 
pseudo-progression 
(treatment-related 
inflammation) to re-
start treatment.
4.4.2 Nivolumab
Removed DSMC from 
this paragraph:
There will be no dose 
modifications of 
nivolumab.  Nivolumab 
can be held up to 12 
weeks.  After 12 
weeks, resumption of 
nivolumab will require 
discussion with 
PI/DSMC.
Per DSMC 
feedback, asked to 
remove them from 
this paragraph as 
they do not provide 
waivers.
Amendment 9 – August 16, 2021
New NM West Region PI, fixing NM West Region info on the title page, and adding 
Multicenter language that was omitted in error.
Sections(s) Affected
Prior Version
Amendment 9 
Changes
Rationale
TITLE PAGE
.
Added the bolded and 
underlined text:
Participating 
Northwestern
Medicine Network 
Site:
Northwestern 
Memorial Healthcare 
(West Region)
Participating 
Added new PI Dr. 
Gondi, to replace Dr. 
Grimm who is no 
longer at NM.
Also corrected the 
title page 
information to clearly 
show which West 
Region location is 
participating (only 
Warrenville).
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Version Date: October 13, 2022 (Amendment 12)
144
Northwestern 
Memorial Healthcare 
Location:
•Northwestern 
Medicine Cancer 
Center Warrenville
4405 Weaver 
Parkway
Warrenville, IL 60555
Phone: 630-352-5450
Northwestern 
Memorial Healthcare 
Principal 
Investigator:
Vinai Gondi, MD
Director of Research 
& Education 
Northwestern 
Medicine Proton 
Center
Co-Director, Brain & 
Spine Tumor Center
Northwestern 
Medicine Cancer 
Center Warrenville
4405 Weaver 
Parkway
Warrenville, IL 60555
Phone: (630) 352-
5350
Email: 
vinai.gondi@nm.org
STUDY SUMMARY
Added the bolded and 
underlined text:
Study Center(s):
Northwestern 
University and 
Northwestern 
Memorial Healthcare 
(West Region)
Added West Region 
as a participating 
center. Erroneously 
considered West 
Region as part of 
Northwestern 
University in 
previous 
Amendments.
3 PATIENT ELIGIBILITY
Added the bolded and 
underlined text and 
deleted the 
strikethrough text:
This will be a multi 
single-center trial 
conducted at 
Northwestern 
University. 
Northwestern 
Added West Region 
as a participating 
center. Erroneously 
considered West 
Region as part of 
Northwestern 
University in 
previous 
Amendments.
IRB #: STU00209583-CR0006 Approved by NU IRB for use on or after 1/14/2025 through 1/13/2026.

NU Study Number: NU 18C02
BMS Study Number: CA017-075
Version Date: October 13, 2022 (Amendment 12)
145
Memorial Healthcare 
(West Region) is a 
participating site.
4 TREATMENT PLAN
4.1 Overview
Added the bolded and 
underlined text:
This is a multisingle 
center, open-label, 
uncontrolled, Phase I 
study conducted in 
subjects with newly 
diagnosed grade IV 
Glioma.
Erroneously 
considered West 
Region as part of 
Northwestern 
University in 
previous 
Amendments
5 STUDY PROCEDURES. 
5.1 Table 5-1: Study 
Procedures, 5.2 Table 5-2: 
Study Procedures During 
Maintenance Phase
Added the bolded and 
underlined text:
Footnote 11. BMS-
986205 will be 
dispensed to patients 
at Week 1 Day 1 and 
Week 5 Day 1 of RT, 
Day 1 of Post-RT 
Phase, and on Day 1 
of each cycle during 
Maintenance Phase. 
Patients will be 
instructed to take the 
dose of study drug PO 
QD.
Omitted Day 1 of 
Post-RT phase from 
the footnote, in 
error. It was marked 
on the study 
calendar.
11.5 Instructions for 
Participating Sites
Added the bolded and 
underlined text:
Before the study can 
be initiated at any 
site, the following 
documentation must 
be provided to the 
Clinical Trials Office 
at Northwestern 
University (as 
applicable):
•Completed 
feasibility 
assessment(s) to 
verify site’s capacity 
to support a 
Northwestern 
sponsored trial
•Signed copy of 
Northwestern 
University’s Data 
Participating Site 
Acknowledgement 
which details data 
submission 
Erroneously 
considered West 
Region as part of 
Northwestern 
University in 
previous 
Amendments. 
Added instructions 
for participating sites 
since the West 
Region should be 
considered a 
participating site.
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Version Date: October 13, 2022 (Amendment 12)
146
guidelines
•Draft consent form 
for review and 
approval prior to 
submission to the 
local IRB
•A copy of the 
official IRB approval 
letter for the protocol 
and informed 
consent
•A copy of the IRB 
approved informed 
consent
•Pertinent 
credentials (CVs, 
MLs, CITI & GCP 
Training and FDFs) 
for the local PI and 
any sub-
investigators who 
will be involved in 
the study at the site
•Form FDA 1572 
appropriately filled 
out and signed with 
appropriate 
supporting 
certifications
Additional activities 
may be required 
prior to site 
activation (i.e. 
contract execution, 
study-specific 
training, and 
delegation of 
authority log). Full 
requirements will be 
outlined in the study 
start-up packet upon 
successful 
completion of a 
feasibility 
assessment.
Throughout Protocol
Editorial Changes 
(formatting, 
grammar, updates to 
Protocol 
Amendment version 
and date, etc).
Amendment 10 – September 3, 2021
Sections(s) Affected
Prior Version
Amendment 10 
Changes
Rationale
IRB #: STU00209583-CR0006 Approved by NU IRB for use on or after 1/14/2025 through 1/13/2026.

NU Study Number: NU 18C02
BMS Study Number: CA017-075
Version Date: October 13, 2022 (Amendment 12)
147
SCHEMA, Treatment Plan
Deleted the 
strikethrough text:
Treatment will 
continue for up to 2 
years until disease 
progression or 
unacceptable AEs.
Patients will be 
allowed to continue 
treatment until they 
no longer receive 
clinical benefit. This 
decision was made 
because two 
patients on study 
are deriving clinical 
benefit from the 
study drugs, and are 
approaching the two 
year limit.
1.3.2.2 Patient Population 
and Design
Added the bolded and 
underlined text:
As of Protocol 
Amendment 10 
(dated 9-03-2021), 
only IDH wildtype 
GBM is eligible (See 
Inclusion Criteria 
3.1.2). Only IDH 
wildtype patients 
have been enrolled 
on the study. 
Preclinical modeling 
of this approach was 
studied exclusively 
within the study 
context of GBM IDH 
wildtype models.  In 
addition, limitation of 
the clinical trial to 
GBM IDH wildtype 
will allow for a more 
homogenous patient 
population providing 
greater clarity of the 
outcomes for the 
secondary and 
exploratory 
endpoints.
The patients that 
have been enrolled 
on the study happen 
to be all IDH 
wildtype. The PI 
requested we make 
this an inclusion 
criteria, as a 
homogenous patient 
population will make 
the endpoints 
clearer. 
Deleted the 
strikethrough text and 
added the bolded and 
underlined text:
The planned treatment 
period wasis up to 2 
years. Protocol 
Amendment 10 
(dated 9-03-2021), 
revised the treatment 
period so it is now 
for as long as the 
Patients will be 
allowed to continue 
treatment for as long 
as they receive 
clinical benefit. This 
decision was made 
because two 
patients on study 
are deriving clinical 
benefit from the 
study drugs, and are 
approaching the two 
year limit.
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BMS Study Number: CA017-075
Version Date: October 13, 2022 (Amendment 12)
148
patient receives 
clinical benefit (for 
the study drugs 
BMS-986205 & 
nivolumab). This 
change was made as 
a few patients were 
benefiting from the 
treatment and 
approaching the 2 
year limit.  Patients 
will remain on 
treatment as long as 
they who are not 
experiencing toxicity 
requiring removal from 
study or progression of 
disease will remain on 
study treatments.
3.1 Inclusion Criteria
Added the bolded and 
underlined:
3.1.2
Patients must 
have confirmed IDH 
wildtype 
glioblastoma per 
immunohistochemist
ry or next generation 
sequencing.
See rationale above.
4.6 Duration of Therapy
Deleted the 
strikethrough text:
Patients may continue 
to receive cycles of 
treatment for up to 2 
years or until any of 
the following occur:
See rationale above.
4.6.1 Continuation of 
Investigational Therapy
Deleted the 
strikethrough text:
Subjects who 
complete 34 weeks of 
treatment without 
progression will be 
offered the 
opportunity, in 
agreement with the 
responsible 
investigator, to 
continue therapy 
beyond Week 34 as 
long as it will be of 
benefit to the patient 
up to 2 years.
See rationale above
5.1 + 5.2 Study Procedures
Deleted strikethrough 
text, added bolded and 
Clarified that some 
procedures may not 
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BMS Study Number: CA017-075
Version Date: October 13, 2022 (Amendment 12)
149
underlined text:
Footnote 6: To be 
performed every 8 
weeks beginning at 
cycle 1 of the 
Maintenance Phase. 
After 2 years of 
treatment, may be 
performed per 
treating investigator 
discretion.  An 
independent review 
will be performed on 
all relevant Gd-MRI 
scans, and an 
independent 
pathologist will confirm 
the histopathological 
diagnosis.
Footnote 20: Research 
blood (2 heparinized 
tubes with 10ml each) 
will be collected at 
baseline, on day 1 of 
post RT, and at each 
MRI time point (every 
8 weeks starting at 
cycle 1 day 1 of the 
Maintenance Cycle). 
Research blood will 
only be collected for 
up to 2 years of 
treatment, and the 
end of treatment 
visit. and at the end of 
treatment visit.
be repeated after 2 
years of treatment 
(research blood). 
Also clarified that 
EKG and tumor 
imaging after 2 
years will be 
performed per 
investigator 
discretion (does not 
need to follow 8 
week schedule).
Throughout Protocol
Editorial Changes 
(formatting, 
grammar, updates to 
Protocol 
Amendment version 
and date, etc).
Amendment 11 – February 22, 2022
Sections(s) Affected
Prior Version
Amendment 11 
Changes
Rationale
TITLE PAGE & Throughout
Protocol Version 
Date: September 3, 
2021 (Amendment 
10)
Protocol Version Date: 
February 22, 2022
Administrative 
revision
4.4 Toxicity Management & 
Dose Delays/Modifications
“No dose reduction 
will be made, but 
delay or 
discontinuation of 
“Need for delay or 
discontinuation of TMZ 
administration or 
reduction in TMZ dose 
Option to reduce 
TMZ dose is now 
available
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Version Date: October 13, 2022 (Amendment 12)
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TMZ administration 
will be decided 
weekly…”
will be evaluated 
weekly…”
4.4.4 Temozolomide
[not present]
“During either phase of 
temozolomide, there 
may be a need for a 
delay or 
discontinuation of TMZ 
or a reduction in 
dose.”
Option to reduce 
TMZ dose is now 
available
4.4.4.1 Dose Reduction – 
Concomitant With Radiation
“No dose reduction 
will be made, but 
delay or 
discontinuation of 
TMZ administration 
will be decided 
weekly according to 
hematologic and 
non-hematologic 
AEs, as specified 
below.” 
“Need for delay or 
discontinuation of TMZ 
administration or 
reduction in TMZ dose 
will be evaluated 
weekly according to 
hematologic and non-
hematologic AEs, as 
specified below.” 
Option to reduce 
TMZ dose is now 
available for 
treatment 
concomitant with 
other drugs
4.4.4.2 Dose Reduction – 
Post-Radiation Treatment 
(Adjuvant)
[not present]
“Need for delay or 
discontinuation of TMZ 
administration or 
reduction in TMZ dose 
will be evaluated 
weekly according to 
hematologic and non-
hematologic AEs, as 
specified below. The 
total number of days 
and total dose of TMZ 
will be recorded on the 
appropriate eCRF.
Should adjuvant TMZ 
need to be delayed, 
BMS-986205 and 
Nivolumab may be 
continued as long as 
the treating 
investigator deems the 
AE not related to the 
specific drug.”
Option to reduce 
TMZ dose is now 
available for 
adjuvant treatment
4.4.4.3 Withhold TMZ 
Treatment
“In case of non-
hematologic AE, the 
patient should be 
assessed at least 
weekly with relevant 
laboratory test(s). As 
soon as all of the 
above conditions are 
met, the 
administration of 
TMZ will resume at 
the same dose as 
used initially.”
“In case of non-
hematologic AE, the 
patient should be 
assessed at least 
weekly with relevant 
laboratory test(s) and 
any other appropriate 
methods of evaluation. 
As soon as all of the 
above conditions are 
met, the administration 
of TMZ will resume at 
the same dose used 
Option to reduce 
TMZ dose is now 
available
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initially. A reduction in 
TMZ dose may also be 
appropriate per the 
investigator’s 
discretion (see section 
4.4.4.5).”
4.4.4.5 Reduction in TMZ 
Dose
[not present] 
“In the event of AEs of 
grade 3 or higher that 
are possibly, probably, 
or definitely related to 
TMZ, a reduction in 
dose may be 
warranted. Guidance 
for dose reduction can 
be found in the 
following table.”
[table; includes 
information on dose 
de-escalation starting 
with a baseline dose of 
200 mg/m2 QD PO]
Specifying 
information on TMZ 
dose reduction
Amendment 12 – October 13, 2022
Sections(s) Affected
Prior Version
Amendment 12 
Changes
Rationale
TITLE PAGE & Throughout
Protocol Version 
Date: February 22, 
2022
Protocol Version Date: 
October 13, 2022
Administrative 
revision
TITLE PAGE
Lab Co-
Investigators:
Derek A. 
Wainwright, PhD
Department of 
Neurosurgery
Northwestern 
University
Lab Co-
Investigators:
Derek A. Wainwright, 
PhD
Department of 
Neurosurgery
Loyola University
Wainwright lab is 
relocating to Loyola 
University
9 Correlatives/Special 
Studies
Wainwright Lab
303 E Superior St
Simpson-Querrey 6-
500
Chicago, IL 60611
Lab Phone: 312-
503-5168
Wainwright Lab
Cardinal Bernardin 
Cancer Center
Loyola University 
Chicago, Health 
Sciences Division
2160 S. First Ave., 
Bldg. 112, Rooms 208 
and 210
Maywood IL 60153
Wainwright lab is 
relocating to Loyola 
University
IRB #: STU00209583-CR0006 Approved by NU IRB for use on or after 1/14/2025 through 1/13/2026.