Conditions: Metastatic Colorectal Cancer
Keywords: Metastatic colorectal cancer colon cancer microsatellite stable
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 13
Healthy volunteers: no

Brief summary:
This is a single arm Phase Ib/II, open label, safety, pharmacokinetic, pharmacodynamics and efficacy study of ONC201 in combination with Opdivo (Nivolumab) in adult patients with metastatic colorectal cancer, for whom no standard therapy is available. This study will enroll adult patients with metastatic colorectal cancer who progressed after at least two lines of therapy.

Detailed description:

Arms:
arm 1: 625mg ONC201 Cycle 1 Day -7 dose then once week arm 2: 500 mg ONC201 Cycle 1 Day -7 dose then once week arm 3: 375 mg ONC201 Cycle 1 Day -7 dose then once week arm 4: 240mg IV flat dose q 2 weeks

Interventions: intervention 1: Dose level 1 ONC201 625mg intervention 2: Dose level 2 ONC201 500mg intervention 3: Dose level 3 ONC201 375mg
Intervention descriptions: intervention 1: ONC201 625mg + Nivolumab 240mg IV flat dose intervention 2: ONC201 500mg + Nivolumab 240mg IV flat dose intervention 3: ONC201 375mg + Nivolumab 240mg IV flat dose

Protocol document:
Prot_SAP_ICF_000.pdf: 
Page 1 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
 
 
 
 
BrUOG 379: A Phase Ib/II Single Arm Study of ONC201 plus Nivolumab in Microsatellite 
Stable (MSS) metastatic colorectal cancer (mCRC) patients 
 
 
Principal Investigator:  
 
Khaldoun Almhanna, MD, MPH 
 
 
 
     
 
Brown University Oncology Research Group 
 
 
 
 
 
 
 
 
 
Study Monitor & Central coordinating group: 
Brown University Oncology Research 
Group  
 
 
Original Version and date:     
 November 11, 2018 
 
IND:   
 
 
 
143357 
 
BMS Protocol Number:  
  
CA209-79E 
 
Amendment #1: 7/22/19 
Amendment #2: 3/3/2020 
Amendment #3: 10/26/2020 
 
 
 
 
 
 
 


Page 2 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
Contents 
 ..................................................................................................................................................... 1 
PROTOCOL SYNOPSIS ........................................................................................................ 7 
1 
INTRODUCTION .................................................................................................................... 9 
2 
Study population ....................................................................................................................... 9 
 
Background .................................................................................................................... 10 
2.1.1 
Opdivo (nivolumab) Anti-PD1 ............................................................................... 10 
2.1.2 
ONC201 .................................................................................................................. 10 
 
Clinical Studies .............................................................................................................. 22 
2.2.1 
Safety of ONC201................................................................................................... 22 
2.2.2 
Dosage and Administration of Opdivo (Nivolumab).............................................. 28 
2.2.3 
Safety of Opdivo (Nivolumab) ............................................................................... 28 
 
Rationale......................................................................................................................... 34 
2.3.1 
Rationale for combination of ONC201 with anti-PD1 Opdivo (Nivolumab)......... 34 
3 
OBJECTIVES AND ENDPOINTS ........................................................................................ 35 
 
Objectives – Phase Ib ..................................................................................................... 35 
3.1.1 
Phase Ib: Primary Objective ................................................................................... 35 
3.1.2 
Phase Ib: Secondary Objectives .............................................................................. 35 
 
Objectives – Phase II ...................................................................................................... 35 
3.2.1 
Phase II: Primary Objectives .................................................................................. 35 
3.2.2 
Phase II: Secondary Objectives .............................................................................. 35 
4 
STUDY DESIGN ................................................................................................................... 35 
 
Overview ........................................................................................................................ 35 
 
Study Design .................................................................................................................. 36 
 
Number of Patients ......................................................................................................... 37 
 
Duration of Study ........................................................................................................... 37 
5 
ELIGIBILITY CRITERIA ..................................................................................................... 38 
 
Inclusion ......................................................................................................................... 38 
 
Exclusion ........................................................................................................................ 39 
 
Contraception ................................................................................................................. 41 
 
Inclusion of Women and Minorities............................................................................... 41 


Page 3 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
Patient Registration ............................................................................................................ 41 
 .............................................................................................................................................. 41 
6 
STUDY TREATMENTS ........................................................................................................ 42 
 
Biopsy & Tissue: ............................................................................................................ 42 
 
Treatment Regimen ........................................................................................................ 42 
 
New cycle requirements (cycle 2-on) (Refer to sections 6.4, 6.5 and 6.6 before dosing)
 
45 
 
Determination of the MTD and RP2D ........................................................................... 46 
6.4.1 
Dose Limiting Toxicity (DLT) definition ............................................................... 46 
6.4.2 
DLT definitions phase Ib: ....................................................................................... 47 
6.4.3 
Dose de-escalation: ................................................................................................. 48 
 
ONC 201 Dose Delays/Holds Phase II: Dose Delays, Reductions and Interruptions for 
toxicities that are deemed related (some causality) to ONC201 During the Phase II Portion of 
the Study:................................................................................................................................... 49 
 
Dose delays for Nivolumab Phase Ib and Phase II: ....................................................... 49 
6.6.1 
Nivolumab Removal from study:............................................................................ 51 
6.6.2 
Treatment of Nivolumab Infusion Reactions: ......................................................... 52 
6.6.3 
Immune-Related Adverse Events (irAEs) General Definition, Monitoring, and 
Management .......................................................................................................................... 54 
6.6.4 
Immune-mediated Endocrinopathy ......................................................................... 54 
6.6.5 
Immune-mediated enterocolitis .............................................................................. 55 
6.6.6 
Immune-mediated hepatitis and pancreatitis .......................................................... 56 
6.6.7 
Renal Adverse Events ............................................................................................. 57 
6.6.8 
Immune-mediated dermatitis .................................................................................. 57 
6.6.9 
Fatigue..................................................................................................................... 57 
6.6.10 
Fever ....................................................................................................................... 58 
6.6.11 
Other immune-mediated AEs (eg, ocular, joint, myocardial, pericardial) – See 
Appendix ............................................................................................................................... 58 
 
Permitted and Prohibited concomitant medications and interventions .......................... 58 
6.7.1 
Permitted Supportive/Ancillary Care and Concomitant Medications .................... 59 
6.7.2 
Prohibited therapies ................................................................................................ 59 
7 
Drug Supply ONC201 ............................................................................................................ 60 


Page 4 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
7.1.1 
Formulation, packaging and storage ....................................................................... 60 
7.1.2 
Drug accountability ................................................................................................. 61 
7.1.3 
Destruction and Return ........................................................................................... 61 
7.1.4 
Administration ........................................................................................................ 62 
7.1.5 
Drug ordering .......................................................................................................... 62 
 
ONC201 Dose Modifications for phase II (see section 6.5) .......................................... 62 
 
Concomitant Medications ONC201 ............................................................................... 63 
7.3.1 
Drug Interactions .................................................................................................... 63 
 
Nivolumab Drug Supply: ............................................................................................... 63 
7.4.1 
PHARMACEUTICAL INFORMATION ............................................................... 63 
7.4.2 
Description .............................................................................................................. 63 
7.4.3 
Form ........................................................................................................................ 64 
7.4.4 
Storage and Stability ............................................................................................... 64 
7.4.5 
Compatibility .......................................................................................................... 64 
7.4.6 
Handling .................................................................................................................. 65 
7.4.7 
Availability ............................................................................................................. 65 
7.4.8 
Preparation .............................................................................................................. 65 
7.4.9 
Nivolumab Administration ..................................................................................... 65 
7.4.10 
Nivolumab Ordering ............................................................................................... 66 
7.4.11 
Accountability ......................................................................................................... 67 
7.4.12 
Destruction and Return ........................................................................................... 67 
8 
STUDY PROCEDURES ........................................................................................................ 68 
9 
Criteria for Taking a Participant Off Protocol Therapy .......................................................... 73 
10 Efficacy Evaluations ............................................................................................................... 74 
11 BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ............................................. 83 
 Pharmacokinetic Evaluations ......................................................................................... 83 
11.1.1 
Background ............................................................................................................. 84 
11.1.2 
Biomarkers in Blood: PD samples .......................................................................... 84 
11.1.3 
CfDNA: ................................................................................................................... 85 
11.1.4 
Biomarkers in Tumor Biopsy.................................................................................. 86 
12 ADVERSE EVENT REPORTING:  LIST AND REPORTING REQUIREMENTS ............ 87 


Page 5 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 Expected Toxicities ........................................................................................................ 88 
 Expected list of toxicities ONC201:............................................................................... 89 
 Adverse Event Characteristics ....................................................................................... 90 
 Definitions ...................................................................................................................... 90 
12.4.1 
Attribution of the AE: ............................................................................................. 91 
12.4.2 
Serious Adverse Events (SAE) Definition .............................................................. 91 
12.4.3 
Events requiring reporting as an Important Medical Event: ................................... 92 
Monitoring of Adverse Events and Period of Observation ....................................................... 93 
 BRUOG ADVERSE EVENT REPORTING REQUIREMENTS ................................. 93 
12.5.1 
Pregnancies ............................................................................................................. 93 
12.5.2 
Serious Adverse Event Reporting Procedures ........................................................ 94 
12.5.3 
Types of Report: Guidelines for sites to report:...................................................... 96 
 BrUOG Responsibility Regarding Reporting: ............................................................... 97 
 IND Annual Reports, for IND study only ...................................................................... 99 
 Adverse event updates/IND safety reports ..................................................................... 99 
13 REGULATORY CONSIDERATIONS .................................................................................. 99 
 Protection of Human Subjects ........................................................................................ 99 
 Compliance with the Protocol and Protocol Revisions: ................................................. 99 
 Protocol amendments or changes in study conduct: .................................................... 100 
14 DATA MONITORING / QUALITY ASSURANCE/ RECORD RETENTION ................. 100 
 Good Clinical Practice: ................................................................................................ 100 
 Patient Confidentiality: ................................................................................................ 101 
 Protocol Compliance: ................................................................................................... 101 
 On-site Audits: ............................................................................................................. 101 
 Drug Accountability: .................................................................................................... 101 
 Premature Closure of the Study: .................................................................................. 101 
 Record Retention: ......................................................................................................... 102 
15 DATA SAFETY AND MONITORING BOARDS .............................................................. 102 
16 DATA ANALYSIS/STATISTICAL METHODS ................................................................ 103 
 Sample Size Determination for Phase I........................................................................ 103 
 Safety Analysis ............................................................................................................. 103 


Page 6 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
16.2.1 
Early Stopping Rule for Safety for Phase II study ................................................ 104 
 Efficacy Analysis for Phase II ...................................................................................... 104 
 Primary Analysis for Phase II ...................................................................................... 105 
17 REFERENCES ..................................................................................................................... 106 
APPENDIX A Eligibility CHECKLIST ..................................................................................... 110 
Appendix B ................................................................................................................................. 114 
Appendix C: Performance Status ................................................................................................ 135 
APPENDIX D I-O AE ALGORITHMS ..................................................................................... 136 
Appendix E: FDA MedWatch Reporting Checklist for site to submit with report .................... 144 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 7 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
 
 
 
 
PROTOCOL SYNOPSIS 
 
Title:  
BrUOG 379: Phase Ib/II investigator-initiated, single arm study of ONC201 plus 
Nivolumab in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) 
patients 
 
Drugs: 
ONC201 (Oncoceutics) 
 
 
Nivolumab; Opdivo (BMS) 
 
Phase:  
Ib/II 
 
Rationale for combination of ONC201 with anti-PD1 Opdivo (Nivolumab): 
The combination of ONC201 with anti-PD-1 therapy resulted in more potent in vivo tumor 
suppression with the combination versus anti-PD-1 therapy alone 
 
Hypothesis: We hypothesize that ONC201 is a novel mCRC therapy that acts through TRAIL 
innate immune and cell mediated NK, and T cell signaling to inhibit tumor growth and metastases, 
and that anti-tumor effects (disease control, prolonged PFS > 2 mo) will be observed in patients 
who receive ONC201 in combination with Nivolumab. 
 
Objectives: 
 
Primary: 
 
Phase Ib: Primary Objective 
1) Determine the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose 
(RP2D) of ONC201 when administered orally in combination with Opdivo (Nivolumab) 
in patients with microsatellite stable metastatic colon cancer who progressed after at least 
2 lines of therapy 
 
 
Phase Ib: Secondary Objectives 
1) 
Evaluate the overall safety profile of orally-administered ONC201 in combination with 
Opdivo (Nivolumab) using CTCAE version 5.0 
2) 
Evaluate the pharmacokinetic (PK) profile of orally-administered agent ONC201 in 
combination with Opdivo (Nivolumab) 


Page 8 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
3) 
Assess the pharmacodynamic effects of orally-administered agent ONC201 
4)         Assess the efficacy of ONC201 and nivolumab.  
 
 
 
 
 
Phase II:  
 
Primary Objective: 
 
1) 
Determine progression free survival (PFS) of orally-administered ONC201 in 
combination with Opdivo (Nivolumab) 
2) 
Determine the response rate to ONC201 in combination with Opdivo (Nivolumab), as 
assessed using the Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1, in 
patients with microsatellite stable metastatic colorectal cancer 
 
Secondary Objectives: 
 
1) 
Confirm safety of phase II dose of ONC201 in combination with Opdivo (Nivolumab) 
using CTCAE version 5.0 
 
2) 
Assess preliminary overall survival associated with ONC201 and Opdivo (Nivolumab) in 
patients with microsatellite stable metastatic colorectal cancer 
3) 
Correlate clinical outcome with tumor & blood biomarkers including cancer stem cells, 
signaling intermediates and inhibitors, NK cells, TRAIL, granzyme, perforin, and M30. 
 
Study Period: 
The maximum duration of treatment will be 12 months unless it is determined that a patient 
would derive benefit from continued therapy beyond 12 months, as determined by the 
investigator. The study is expected to be completed over an approximate 3.5-year period  
 
Study Design:  
 
This is a single arm Phase Ib/II, open label, safety, pharmacokinetic (PK), pharmacodynamics 
(PD) and efficacy study of ONC201 in combination with Opdivo (Nivolumab) in adult patients 
with metastatic colorectal cancer who progressed after at least 2 lines of chemotherapy. 
 
This is a phase Ib/II study that will enroll patients with microsatellite stable (MSS) metastatic 
colorectal cancer (mCRC) 
 
Phase Ib Dose Level ONC201 (625 mg PO weekly) plus Nivolumab (240 mg IV Q2 weeks). 


Page 9 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
Phase II Stage at Recommended Phase II Dose (RP2D). 
 
Planned Enrollment 
 
Phase Ib: Approximately 6 patients 
 
Phase II: A total of 34 patients will be treated at the RP2D (including 6 patients from the Phase 
IB treated at the RP2D and 28 patients from phase II). Interim safety analysis after 12 patients 
accrued at the RP2D, interim efficacy analysis after 17 patients.) 
 
Eligibility Criteria: 
 
Inclusion: Patients aged ≥ 18 years must have a histologically/cytologically -confirmed primary 
MSS colorectal tumors who progressed after at least 2 lines of treatment 
 
Exclusion: Patients with symptomatic brain metastases. Patients with inflammatory and 
autoimmune diseases or other medical disease in which Nivolumab is contraindicated. Patients 
with prior ONC201 will be excluded. 
Randomization: 
 
This is a single arm study with no randomization. All enrolled patients will receive the study 
drugs. 
 
Correlative Studies 
 
Pre- and post-treatment biopsies are mandatory to evaluate tumor infiltration of NK, T cells, 
cancer stem cells. Tumor biopsies will be used to evaluate integrated stress response (ISR), TNF-
related apoptosis-inducing ligand (TRAIL), DR5, granzyme, perforin, cell death, cell 
proliferation. PD-1 and PD-L1 testing will all be performed.  
1 
INTRODUCTION 
The Phase I portion of the study will determine the maximum tolerated dose (MTD) and/or 
recommended Phase II dose (RP2D) of ONC201, when given in combination with Nivolumab to 
patients with microsatellite stable (MSS) advanced metastatic colorectal cancer (mCRC) who 
progressed on at least two lines of therapy. Identification of the MTD and/or RP2D will assist in 
the design of the Phase II portion. The Phase II study will assess efficacy and refine safety 
assessments of the drug combination.  
 
2 
Study population 
 


Page 10 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
This trial will enroll adult patients with advanced mCRC who progressed after at least 2 lines of 
therapy. ONC201 is an investigational agent. Nivolumab (Opdivo) has been approved in patients 
with microsatellite instability-high (MSI-H) or mismatch repair (MMR)-deficient mCRC. 
 
 
Background 
2.1.1 Opdivo (nivolumab) Anti-PD1 
 
In the tumor microenvironment, program death -1(PD-1) and its ligand PD-L1 and PDL-2 perform 
a vital role in tumor progression and survival by escaping tumor neutralizing immune surveillance. 
Binding of the PD-1 ligands, to the PD-1 receptor inhibits T cell proliferation and cytokine 
production. Upregulation of PD-1 ligands in cancer contributes to inhibition of active T-cell 
immune surveillance. 
 
Opdivo (nivolumab) is a humanized monoclonal antibody that binds to the PD-1 receptor and 
blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the 
immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, 
blocking PD-1 activity resulted in decreased tumor growth in several malignancies.  
 
In the recent years, FDA granted approval of Nivolumab as a single agent or in combination in 
several malignancies: including treatment (as a single agent or in combination with ipilimumab) 
of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic 
colorectal cancer (CRC) in adults and pediatric patients, treatment of recurrent or metastatic 
squamous cell carcinoma of the head and neck in patients with disease progression on or after 
platinum-based therapy, treatment of hepatocellular carcinoma (HCC) in patients who have been 
previously treated with sorafenib, treatment of classical Hodgkin lymphoma (cHL) in adult 
patients that have relapsed or progressed following autologous hematopoietic stem cell transplant 
(HSCT) and brentuximab vedotin, or after 3 or more lines of systemic therapy that included 
autologous HSCT, adjuvant treatment of melanoma with involvement of lymph nodes or 
metastatic disease following complete resection, treatment (as a single agent) of unresectable or 
metastatic melanoma, treatment of metastatic non-small cell lung cancer (NSCLC) that has 
progressed on or after platinum-based chemotherapy, treatment (as a single agent) of advanced 
renal cell cancer (RCC) in patients who have received prior anti-angiogenic therapy, treatment of 
intermediate or poor risk, previously untreated advanced RCC (in combination with ipilimumab), 
Treatment of metastatic small cell lung cancer (SCLC) in patients with progression after 
platinum-based chemotherapy and at least one other line of therapy, treatment of locally 
advanced or metastatic urothelial carcinoma in patients with disease progression during or 
following a platinum-containing therapy  
2.1.2 ONC201 
ONC201 (TIC10) is a first-in-class small molecule that activates the integrated stress response 
(ISR) in tumor cells that leads to downstream anticancer effects that include inactivation of pro-


Page 11 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
survival Akt and ERK signaling along with induction of the TRAIL pathway (Allen et al., 2013). 
The efficacy of ONC201 has been consistently demonstrated in numerous in vitro and in vivo 
experiments (subcutaneous, orthotopic, and transgenic) by multiple institutions. Despite its strong 
cytotoxicity in tumor cells, ONC201 does not induce cell death in normal cells. In vivo studies 
indicate that the safety margin (ratio of therapeutic dose to lowest dose with a mild adverse event) 
of ONC201 is at least 10-fold in rats and dogs in GLP toxicology studies. The profile of ONC201 
is well suited for an oncology product: preclinical efficacy with infrequent administration, broad-
spectrum activity independent of mutations or disease type, orally active, compelling safety 
profile, combines synergistically and safely with many approved therapies, highly active by 
employing a combination of established anti-tumor/pro-apoptotic pathways, highly stable, water 
soluble, and can penetrate the blood-brain barrier. In summary, preclinical studies suggest that 
ONC201 is an orally active antitumor agent with a remarkably benign safety profile given its 
broad-spectrum activity demonstrated in a variety of aggressive cancer models.  
2.1.2.1 Preclinical Efficacy 
ONC201 induces broad-spectrum cell death in tumor cells harboring diverse mutations in genes 
such as p53, KRAS, Raf, EGFR and others that render resistance to chemotherapies and targeted 
agents. ONC201 induces caspase-mediated apoptosis in cancer cell lines and exhibits broad-
spectrum cytotoxicity in vitro. ONC201 has demonstrated single agent anti-tumor effects in several 
solid tumor models (Figure 1) that include subcutaneous and orthotopic colon cancer, 
subcutaneous triple-negative breast cancer, subcutaneous non-small cell lung cancer, 
subcutaneous and orthotopic intracranial glioblastoma, and immunocompetent lymphoma 
transgenic mouse models. ONC201 exhibits promising anticancer activity that has been 
demonstrated in a wide range of malignancies in preclinical models (e.g. glioblastoma multiforme, 
triple-negative breast cancer, colorectal cancer and non-small cell lung cancer) that include 
subcutaneous, orthotopic, and transgenic models. Beyond solid tumors, ONC201 has also 
demonstrated striking efficacy in tumor types such as multiple myeloma, including cells with 
bortezomib resistance, that are highly sensitive to induction of ER stress. Therefore, the 
development of ONC201 will be broad given the current need for new treatment options and the 
wealth of preclinical information that was generated in preclinical settings in various disease 
settings with the study drug.  


Page 12 of 145 
 
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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
Figure 1: ONC201 antitumor activity in subcutaneous xenografts.   
Subcutaneous xenografts in athymic nude mice receiving a single dose of ONC201 (100 
mg/kg, IP). Data shown is approximately 1 week following single dose administration and is 
relative to the tumor size on the day of administration. 
Preclinical efficacy studies revealed that ONC201 has peak efficacy when administered at 25 
mg/kg orally once every two weeks. To begin to estimate the safety margin of ONC201 in vivo, 
exploratory exaggerated dosing studies were conducted in mice. ONC201 was administered IP to 
cohorts of mice as a single dose either as an IP bolus or fractionated IP dose. The single bolus dose 
was well tolerated up to 220 mg/kg. At 250 mg/kg, single rapidly administered IP doses of 
ONC201 caused labored breathing, dyspnea, and death. A dose of 250 mg/kg ONC201 
administered IP and divided into four equivalent doses was well-tolerated. The preclinical efficacy 
of ONC201 in mice was achieved at doses as low as 12.5 mg/kg with maximal efficacy observed 
in at least one model at 25 mg/kg. Administering ONC201 twice a week in nude mice at 25 mg/kg 
caused a mild reversible skin rash following two weeks of administration that was not observed 
with weekly administration. 
2.1.2.2 Mechanism of Action (MOA) 
ONC201 was identified through a phenotypic screen as a small molecule that induces p53-
independent upregulation of TRAIL gene transcription in tumor cells. A series of gene expression 
profiling and cell signaling investigations have unraveled signaling pathways that are engaged in 
tumor cells following ONC201 treatment.  


Page 13 of 145 
 
Protocol- BrUOG 379 
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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
ONC201 appears to activate the integrated stress response (ISR), which is the same signaling 
pathway activated by ER stress-inducing compounds such as proteasome inhibitors (e.g. 
bortezomib). When the ISR is activated by ER stress-inducing compounds, the pathway is often 
referred to as the ER stress response. ONC201 causes an early-stage increase in the 
phosphorylation of eIF2-alpha at serine 51, which results in attenuation of protein translation and 
upregulation of the transcription factor ATF4 (Figure 2: Proposed model of ONC201 MOA in 
tumor cells). ATF4 up regulates CHOP, which is also a transcription factor that regulates several 
apoptosis-related genes such as the TRAIL-receptor DR5. ATF4 and CHOP upregulate expression 
of TRB3, which interacts directly 
with Akt to decrease its kinase 
activity. TRB3 also serves as a 
scaffold protein in the MAPK 
signaling pathway that can negatively 
regulate this pathway. Decreased 
levels of phospho-MEK, -ERK, and –
Akt have been documented in 
response to ONC201. The decreased 
ERK and Akt kinase activity results 
in less phosphorylated Foxo3a, which 
is a transcription factor that regulates 
both the TRAIL and DR5 genes. 
Dephosphorylated Foxo3a undergoes 
nuclear translocation and activation 
in response to ONC201.  
In summary, ONC201 appears to activate the ISR that attenuates protein translation and activates 
ATF4, which causes induction of genes that lead to apoptosis. ATF4 and CHOP also downregulate 
Akt and ERK activity that cooperatively induce complementary downstream apoptotic effects. 
Preliminary evidence suggests that ONC201 may not activate eIF2-alpha through PERK. This 
distinct mechanism may explain the lack of cross-resistance between ONC201 and other ER stress-
inducing agents such as bortezomib. In addition, ONC201 has enhanced antitumor efficacy in 
combination with bortezomib that may be explained by engaging parallel stimuli that lead to an 
enhanced activation of the ISR in tumor cells.  
 
ONC201/TIC10 inhibition of Akt and ERK oncogenic pro-survival kinases leads to Foxo3a 
and TRAIL gene transactivation and toxicity to freshly isolated patient-derived CRC cells  
We discovered that ONC201, as a single chemical entity, is a dual inhibitor of p-Akt and p-ERK 
in human CRC cell lines (Figure 3; Allen et al., 2013). The inhibition of Akt and ERK leads to 
dephosphorylation of Foxo3a on different target sites for these kinases (Figure 3), nuclear 
translocation of Foxo3a (Allen et al., 2013, and direct transcriptional upregulation of the TRAIL 
gene both in cell lines and in vivo (Allen et al., 2013). 
Figure 2: Proposed model of ONC201 MOA in tumor cells 


Pa ge 1 4  of 1 4 5  
 
Pr ot oc ol - Br U O G 3 7 9  
C O N FI D E N TI A L  
Dates: 1 1/ 0 4/ 2 0 1 8, 1 1/ 1 1/ 1 8, 1 1/ 1 6/ 1 8, 1 1/ 2 4/ 1 8, 1 1/ 3 0/ 1 8, 1 2/ 2/ 1 8, 1 2/ 6/ 1 8, 1 2/ 7/ 1 8, 1 2/ 1 0/ 1 8, 1/ 8/ 1 9 B M S 
re vie w, 1/ 9/ 1 9, 1/ 1 3/ 1 9, 1/ 1 5/ 1 9, 1/ 1 6/ 1 9, 1/ 1 7/ 1 9, 1/ 2 0/ 1 9, 1/ 2 2/ 1 9, 2/ 4/ 1 9, 2/ 1 9/ 1 9, 3/ 1 9/ 1 9, A M # 1 7/ 2 2/ 1 9, B M S 
re vie w 8/ 2 3/ 1 9, A M # 2 3/ 3/ 2 0, B M S a p pr o ve d 4/ 1/ 2 0, O nc oce utics a p pr o ve d 4/ 2 4/ 2 0, A M # 3 1 0/ 2 6/ 2 0 2 0, B M S 
a p pr o ve d 1/ 5/ 2 1, O nc oce utics a p pr o ve d 3/ 3 0/ 2 1  
 
  
Fi g ure 3. O N C 2 0 1/ TI C 1 0 is a d u al i n hi bit or of A kt a n d E R K pr o-s ur vi v al 
ki n ases t o i n d uce T R AI L t hr o u g h F o x o 3 a.  West er n bl ot a n al ysis of H C T 1 1 6 
p 5 3-/- cells treate d wit h O N C 2 0 1/ TI C 1 0 ( 2. 5, 5, a n d 1 0 M) f or 7 2 h o urs. 
A d diti o nal e x peri me ntal details as well as m ore detaile d a nal ysis of F o x o 3a a n d 
T R AI L i n a d diti o nal cell li nes ca n be f o u n d i n All e n et al., 2 0 1 3. 
  
 
 
O N C 2 0 1 sti m ulates T R AI L pr o d u cti o n o n t he cell s urface a n d dis pla ys t o xicit y 
t o war ds fres h h u ma n C R C cells ( Fi g ure 4; Alle n et al., 2 0 1 3). We h a ve d e m o nstrate d t hat F o x o 3a 
a n d T R AI L are critical t o t he a nti -t u m or effects of O N C 2 0 1 b ot h i n cell c ult ure a n d i n vi v o ( Alle n 
et al., 2 0 1 3).  
Fi g ure  4.  O N C 2 0 1  sti m ul ates  T R AI L  e x pressi o n  o n  t he  cell  
s urf ace a n d dis pl a ys t o xicit y t o w ar ds fres hl y is ol ate d h u m a n C R C 
cells. Pa nel  4 A  (left  pa nel).  O N C 2 0 1/ TI C 1 0 -i n d uce d  cell  s urface  
T R AI L e x pressi o n i n fres hl y res ecte d c ol o n ca ncer cells ( 1 0 M, 7 2 
h o urs).  Data  ar e  e x presse d  as  me dia n  fl u ores ce nce  i nte nsit y.  All  
pri mar y p atie nt s peci me ns were o btai ne d i n acc or da nce wit h I R B -
a p pr o ve d pr ot oc ols. Sa m ples were recei ve d i m me diatel y after resecti o n, ma n uall y di geste d i n 
c o m plete D M E M m e dia, filtere d wit h a 1 0 0 -m n yl o n mes h, a n d pl ate d at 2 x 1 0 5 cells/ ml i n 
c o m plete D M E M. Pa nel 4 B ( Ri g ht Pa nel). Cell via bilit y assa y of pri mar y c ol o n ca ncer cells fr o m 
pa nel A treate d wit h D M S O, O N C 2 0 1/ TI C 1 0 ( 0. 6, 1. 2 5, 2. 5, 5, 1 0, a n d 2 0 M fr o m t o p t o 
b ott o m).  
 
O N C 2 0 1/ TI C 1 0 i n d uces a n i nte gr ate d stress res p o nse i n v ol vi n g A T F 4 a n d C H O P le a di n g t o 
u pre g ul ati o n  of  T R AI L  de at h  rece pt o r 5  ( D R 5) o n  t u m or cell s. We f urt her u nc o v ere d a 
criticall y i m p orta nt as pect of t he mec ha nis m of acti o n of O N C 2 0 1 t hat a p pears t o b e me diate d 
t hr o u g h a P E R K-i n d e pe n de nt i nte grat e d stress res p o nse ( Kli ne et al., Sci. Si g., i n press, 2 0 1 6). O ur 
e x peri me nts re veale d t hat O N C 2 0 1 i n d uces A T F 4 a n d C H O P ( Fi g ure 5) a n d t hat d ual k n oc k d o w n 
of A T F 4 a n d C H O P i n hi bits t he u pre g ulati o n of D R 5 o n t he s urface of h u ma n C R C cells ( Fi g ure 
5). F urt her e x peri me nts de m o nstrate d t hat O N C 2 0 1 effects are me diate d t hr o u g h t he eI F 2 -al p ha 
ki nases P K R a n d H RI t h at ar e r e q uire d f or A T F 4 i n d ucti o n b y O N C 2 0 1 ( Kli ne et al., Sci. Si g., i n 
press, 2 0 1 6). 
 
Fi g ure 5. O N C 2 0 1/ TI C 1 0 i n d uces a n i nte gr ate d stress res p o nse i n v ol vi n g A T F 4 a n d C H O P.  


Pa ge 1 5  of 1 4 5  
 
Pr ot oc ol - Br U O G 3 7 9  
C O N FI D E N TI A L  
Dates: 1 1/ 0 4/ 2 0 1 8, 1 1/ 1 1/ 1 8, 1 1/ 1 6/ 1 8, 1 1/ 2 4/ 1 8, 1 1/ 3 0/ 1 8, 1 2/ 2/ 1 8, 1 2/ 6/ 1 8, 1 2/ 7/ 1 8, 1 2/ 1 0/ 1 8, 1/ 8/ 1 9 B M S 
re vie w, 1/ 9/ 1 9, 1/ 1 3/ 1 9, 1/ 1 5/ 1 9, 1/ 1 6/ 1 9, 1/ 1 7/ 1 9, 1/ 2 0/ 1 9, 1/ 2 2/ 1 9, 2/ 4/ 1 9, 2/ 1 9/ 1 9, 3/ 1 9/ 1 9, A M # 1 7/ 2 2/ 1 9, B M S 
re vie w 8/ 2 3/ 1 9, A M # 2 3/ 3/ 2 0, B M S a p pr o ve d 4/ 1/ 2 0, O nc oce utics a p pr o ve d 4/ 2 4/ 2 0, A M # 3 1 0/ 2 6/ 2 0 2 0, B M S 
a p pr o ve d 1/ 5/ 2 1, O nc oce utics a p pr o ve d 3/ 3 0/ 2 1  
 
Pa nel 5 A ( Left Pa nel). H C T 1 1 6 c ol orectal ca ncer cells were treate d wit h i n dicate d c o nce ntrati o ns 
of O N C 2 0 1 f or 2 4 h o urs. Wester n bl ot a nal ys es of A T F 4 a n d A T F 4 tra nscri pti o nal tar gets were 
perf or me d .  Res ults  i n dicate  O N C 2 0 1-i n d uce d  A T F 4  p at h wa y  u pre g ul ati o n.  Pa nel  5 B  ( Ri g ht  
Pa nel). H C T 1 1 6 cells w ere tra nsf ecte d wit h scra m ble d (scr) or A T F 4 a n d C H O P si R N A f or 2 4 
h o urs. S u bse q ue ntl y, cells were treat e d wit h 5 M O N C 2 0 1 a n d R N A w as is olate d fr o m t he cells 
after i n dicate d tr eat me nt peri o ds ( 0, 2 4, or 4 8 hr). q P C R a nal ys es f or D R 5 m R N A ( n or malize d 
o ver G A P D H m R N A) e x pressi o n were perf or me d. Bars i n dicate relati ve e x pressi o n of D R 5 i n 
treate d cells v ers us cells t hat wer e tr a nsfecte d wit h scra m ble d si R N A (scr) a n d were treate d o nl y 
wit h ve hicle. Res ults i n dicate t hat O N C 2 0 1 -i n d uce d D R 5 m R N A e x pressi o n is de pe n de nt o n 
A T F 4/ C H O P.  
 
O N C 2 0 1/ TI C 1 0 i n hi bits C R C ste m cells, c ol o n os p here gr o wt h a n d C R Cs i niti ate d b y c a ncer 
ste m cells ( C S Cs) i n vi v o i n mice. Gi ve n t he i m p orta nce of C S Cs t o t u m or rela pse a n d dr u g 
resista nce, we i n vesti gat e d w het her O N C 2 0 1 ca n i m pact o n C S C -li ke cells i n C R C m o dels. O ur 
res ults re veale d t hat O N C 2 0 1 s u p presses C S C-li ke cells ( b ot h A L D H + a n d C D 1 3 3 +) i n c ult ure d 
C R C cell li nes w hereas 5 -F U d oes n ot ( Pra b h u et al., 2 0 1 5). We f urt her s h o we d t hat O N C 2 0 1 
i n hi bits C R C c ol o n os p here gr o wt h a n d s u p presses t u m or gr o wt h f oll o wi n g i m pla ntati o n of s orte d 
C R C ste m cells i n vi v o i n mice ( Fi g ur e 6; Pra b h u et al., 2 0 1 5).  
 
 
 
Fi g ure
 6.
 
O N C 2 0 1/ TI C 1 0 
i n hi bits
 C R C
 
c ol o n os p here gr o wt h a n d C R Cs i niti ate d b y c a ncer ste m cells ( C S Cs) i n vi v o i n mice.  Pa nel 
6 A ( Left m ost Pa nel). O N C 2 0 1/ TI C 1 0 pre v e nts c ol o n os p here f or mati o n. D L D 1 a n d S W 4 8 0 cells 
( 1 0, 0 0 0 cells/ well) were plate d f or c ol o n os p here f or mati o n i n t he prese n ce of D M S O or 1 0 µ M 
O N C 2 0 1/ TI C 1 0. C ol o n os p heres ( > 6 0 µ m) were c o u nte d at 9 6 h. Pa nel 6 B ( Sec o n d Pa n els fr o m 
Left). Re prese nt ati ve i ma ge ( 1 0 X ma g nificati o n) f or D L D 1 cells i n pa nel 6 A. Eac h di visi o n o n t he 
scale  is  1 0  µ m. Pa nel  6 C  ( T hir d  Pa nel  fr o m  Left).  O N C 2 0 1/ TI C 1 0  pre ve nts  C S C -me diate d 
x e n o graft t u m or gr o wt h.  S orte d D L D 1 Al defl u or( +) cells were s u bc uta n e o usl y i njecte d i nt o t he 
ri g ht a n d left fla n k of at h y mic n u d e mice. U p o n t u m or f or mati o n, mice w ere a d mi nistere d eit her 
ve hicle or O N C 2 0 1/ TI C 1 0 5 0 m g/ k g (i. p.). ( N = 7 per gr o u p) D os es (i n di cate d b y tria n gle) we re 
a d mi nistere d p ost -t u m or i m pla ntati o n o n da y 7, 1 4 a n d 2 2. T u m or gr o wt h was m o nit ore d wee kl y 
u ntil t he e n d p oi nt. Data is prese nte d as mea n ± sta n dar d err or of mea n. * i n dicates p < 0. 0 5.  Pa n el 
6 D ( Ri g ht m ost Pa nels).  
 
O N C 2 0 1 precli nic al d ose i nte nsific ati o n de m o nstr ates p ote nt a nti-t u m o r a n d a nti-met ast asis 
eff ects i n m o use m o dels le a di n g t o desi g n of a d ose i nte nsific ati o n tri al.  Gi ve n t he o bser ve d 
safet y of O N C 2 0 1 i n t he FI H trial, we i n vesti gate d w het her i ncrease d d ose a n d fre q u e nc y of dr u g 
a d mi nistrati o n mi g ht e n h a nce a nti -t u m or efficac y. We f o u n d e vi de nce t hat i ncreasi n g dr u g d osi n g 
fr o m 2 5 t o 5 0 a n d t o a 1 0 0 m g/k g  e n ha n ce d a nti -t u m or efficac y ( Fi g ure 7).  


Page 16 of 145 
 
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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
 
Figure 
7. 
ONC201 
preclinical 
dose 
intensification 
demonstrates potent anti-tumor and anti-metastasis effects in mouse models. ONC201 exerts 
a frequency-of-dose effect when administered at 100 mg/kg during various timelines. Six-week 
old female athymic nude mice where inoculated with 1.5x106 of HCT116 p53-/- cells (upper 
graph) or HT29 (lower graph) in panel A (Leftmost Panels). The middle panel (Panel B) shows 
western blot results demonstrating partial or more complete pathway signaling suppression 
depending on dose intensity as indicated or as a function or more frequent dosing (tumors were 
harvested at 4 weeks). The right most panel (Panel C) shows metastasizing HT29-luc 
(bioluminescence imaging not shown). Mice were injected in both flanks and tumors where 
allowed to grow to ~175 mm3 volume before being treated with ONC201. Tumor volume was 
assessed through caliper measurements every 3 days and monitored by bioluminescence imaging 
every week (bioluminescence imaging not shown). The percent tumor growth was established 
based on final volume of the vehicle-treated mice. HT29 xenograft-bearing mice were sacrificed 
at 30 days, and HCT116 p53-/- xenograft-bearing mice were sacrificed when tumor volume 
reached 20 mm in diameter or at 10 weeks. Histology and Hematoxylin-Eosin staining was 
confirmed by pathologist. (N=6 tumors, 2 tumors per each of 3 mice per cohort). 
 
2.1.2.3 Preclinical rationale for combination of ONC201 with Opdivo (Nivolumab)  
 
ONC201 induces CD3+/NK cell accumulation 
We have noted what we consider to be an interesting observation that ONC201-treated tumors 
appear to contain an NK/CD3+ cellular infiltration, and that NK cell accumulation can be detected 
in the peripheral blood of ONC201-treated mice (Figure 8). 


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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
Figure 8. ONC201 induces CD3+/NK cell accumulation. A) CD3+ staining using mouse/human 
CD3+ in athymic nude mice. The mice were inoculated with 1.5 x 106 HT29 CRC cells and were 
treated with ONC201 at the doses indicated in mg/kg per 1 week or 2 weeks as indicated. Mice 
were treated when the xenografted tumors were 200 mm3 and they were sacrificed on day 35. 
Tumors were harvested and embedded in paraffin, sectioned and stained as described. B) NK1.1 
IHC staining using mouse specific NK1.1 (PK136) antibody in athymic nude mice. The mice were 
inoculated as described in panel A, but the example shown here they were treated with 100 mg/kg 
of ONC201 every 3 weeks and tumors were again harvested at 35 days.  C) Flow cytometry 
analysis of NK1.1 cells in untreated and ONC201 (100 mg/kg) C57/BL6 mice through orbital 
bleed performed in a non-tumor bearing mouse. Blood was sampled at 24 hrs after drug 
administration. Dead cells and CD11b cells (B-cells) were gated out from this analysis.  
Potent CRC growth inhibition in mice from combination of ONC201 and anti-PD1 
The combination of ONC201 with anti-PD-1 therapy resulted in more potent in vivo tumor 
suppression with the combination versus anti-PD-1 therapy alone (Figure 9). 
 
Figure 9. ONC201 in combination with anti-PD1. Relative tumor volume after 4 weeks in CT26 
tumors in Balb/c mice treated with vehicle, 100 mg/kg ONC201, anti-PD-1, or ONC201 + anti-
PD-1. 
2.1.2.4 Nonclinical Safety/Toxicology Studies in Animals 
In rats and dogs ONC201 was better tolerated when administered orally compared to 
intravenously. In rat non-GLP studies, the No-Observed Adverse Effect Level (NOAEL) was 225 
mg/kg with oral administration compared to 100 mg/kg with a 2 hour infusion and 50 mg/kg with 


Page 18 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
a 30 minutes infusion. Non-GLP clinical observations in rodents included decreased activity, 
altered gait, and mortality. In dog non-GLP studies, the NOAEL in doses was at least 120 mg/kg 
with oral administration and clinical observations were limited to emesis and changes in fecal 
consistency. The non-GLP studies only evaluated clinical observations, weight gain, food 
consumption and gross findings at necropsy.  In general, the toxicology/safety studies indicate that 
the acute toxicities associated with ONC201 are limited to the day of administration and are 
reversible.  
 
In GLP dog studies, the NOAEL was at least 42 mg/kg. Observations were limited to decreased 
activity, decreased food consumption, emesis, salivation, and/or soft, stool or mucous feces. In rat 
GLP studies, the NOAEL was at least 125 mg/kg. Observations included decreased activity, 
decreased food consumption, decreased body weight, and abnormal stance and gait. Minor changes 
in serum chemistries were noted, largely in the 225 mg/kg rat cohort, which included slight 
increases in cholesterol and chloride.  The significance of these findings is unknown as other 
clinical chemistry and histology did not corroborate this observation (e.g. liver findings). Rats 
receiving 125 or 225 mg/kg ONC201 had mild edema and inflammation that was primarily 
submucosal in the stomach and was completely resolved by day 19. 
2.1.2.4.1 Non-GLP Safety Studies 
Non-GLP studies were conducted in rats and dogs to assess clinical observations and body weight 
with ONC201.  
 
Non-GLP toxicology studies in rats 
The ability of rats to tolerate ONC201 by intravenous administration was explored as a function 
of infusion time. Clinical observations with intravenous administration included decreased 
activity, salivation, abnormal gait and stance, labored respiration, pale skin, nasal discharge, 
prostration during the dose, mild body twitching, and red discharge from the mouth.  
The NOAEL following administration of ONC201 to Sprague-Dawley rats by a 30-minute 
intravenous infusion was 50 mg/kg.  The NOAEL following administration of ONC201 to 
Sprague-Dawley rats by a 2-hour intravenous infusion was 100 mg/kg. Administration of 100 
mg/kg ONC201 by intravenous infusion over 30 minutes resulted in the death of one male rat. 
Administration of 200 mg/kg ONC201 by a 2-hour infusion resulted in the death of both animals 
during the infusion period. Following these observations, the tolerance of oral ONC201 was 
explored given the potential to lower acute toxicity by lowering the maximal concentration (Cmax). 
Clinical observations with oral exaggerated doses of ONC201 included decreased activity, 
abnormal gait and stance, prostration, irregular respiration, moderate twitching, red discharge on 
the muzzle, scant feces, hunched posture, not eating, piloerection, and skin cold to touch.  The 
NOAEL following administration of ONC201 to Sprague-Dawley rats by oral gavage was 225 
mg/kg.   
 
Non-GLP toxicology studies in dogs  
In parallel to non-GLP toxicology studies in rats, the ability of beagle dogs to tolerate ONC201 


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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
was explored. No deaths were observed at any doses in dogs. The NOAEL following the 30-minute 
intravenous infusion of ONC201 to beagle dogs is considered to be at least 33.3 mg/kg.  The 2 
hour-intravenous infusion of 16.7 mg/kg ONC201 was not associated with any clinical signs of 
toxicity. Therefore, the NOAEL following a 2 hour-intravenous infusion of ONC201 to beagle 
dogs is considered to be greater than 16.7 mg/kg, though higher doses were not explored as the 
oral route was selected for further development based on observations in rats. The NOAEL with 
oral ONC201 was considered to be at least 120 mg/kg in dogs. Clinical observations at doses of 
66.7 to 120 mg/kg were limited to emesis and changes in fecal consistency. 
2.1.2.4.2 GLP Toxicology and Safety Studies 
Single Dose Oral Toxicity Study in Dogs (GLP)  
A GLP study was performed to evaluate the toxicity and toxicokinetics of ONC201 following a 
single oral dose to Beagle dogs followed by a 2-day or an 18-day recovery period. Dogs received 
a single dose of 0, 4.2, 42, or 120 mg/kg by oral gavage. There was no mortality observed in this 
study. There were no definitive ONC201-related effects on group mean body weight or body 
weight gain, EKG rhythm or morphology, mean heart rate or arterial blood pressure, urinalysis, 
hematology parameters, coagulation parameters, clinical chemistry parameters, erythrocyte 
morphology, gross findings on necropsy, changes in absolute or organ to body or organ to brain 
weights.  
 
Although not statistically significant, there were some dose-related decreases in group mean food 
consumption for the first week following dosing. The 120 mg/kg females had statistically 
significantly decreased group mean food consumption compared to the vehicle control group on 
Days 14, 15 and 18. There were no clinical signs of toxicity noted following a single dose of 4.2 
mg/kg ONC201.  At a dose of 42 mg/kg and 120 mg/kg, some dogs had clinical observations at 
approximately 1-hour post-dose including decreased activity, emesis, salivation, and/or soft, loose 
or mucous feces. Of uncertain relationship to ONC201 administration was the unusual finding of 
mononuclear cell inflammation in the blood vessels of the brain, which was multifocal and mild 
in one high dose female at Day 3, multifocal and minimal in one high dose female at Day 19, and 
minimal and focal in one control female at Day 19. Similar findings were not noted in any male 
animal. 
 
Based on the results of this study, the NOAEL following oral administration of ONC201 at single 
doses of 4.2, 42 or 120 mg/kg to Beagle dogs is considered to be at least 42 mg/kg. 
Single Dose Oral Toxicity and Toxicokinetic Study in Rats with a 19-Day Recovery (GLP) 
A GLP study was performed to evaluate the toxicity of ONC201 following a single oral dose in 
Sprague-Dawley rats with necropsy after a 2-day or an 18-day recovery period. Rats received 0, 
12.5, 125, or 125 mg/kg ONC201 by oral gavage.  
There was no mortality observed in this study. There were no definitive ONC201-related effects 
on coagulation parameters, clinical chemistry parameters, gross findings at necropsy. There were 
no clinical signs of toxicity noted at single doses up to 125 mg/kg ONC201.  There were no 
ONC201-related statistically significant changes in hematology parameters or clinical chemistries 


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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
outside of the historical control range for these values.  
 
At a dose of 225 mg/kg, clinical signs of toxicity were limited on the day of dose administration 
to one out of twenty males and one out of twenty females that showed signs of decreased activity 
and abnormal gait and stance.  The male was also noted to have increased respiration.  All were 
normal by Day 2. No ONC201 related changes were noted during the functional observational 
battery (CNS activity) performed on Day 1 between 1 and 2 hr post-dose with the exception of one 
225 mg/kg female noted as having decreased activity. A statistically significant decrease in group 
mean body weight gain was noted on Day 7 for the 225 mg/kg males. A statistically significant 
decrease in group mean food consumption was noted on Day 7 for the 225 mg/kg males.  
On Day 3 the 225 mg/kg females also had increased glucose, cholesterol, sodium and chloride. 
Sodium and chloride were statistically significantly increased for the 125 mg/kg females. Only 
cholesterol and chloride were outside historical control ranges for this laboratory on day 19. As 
the increase in cholesterol was only noted for the females and no corresponding liver findings were 
observed, the significance of this finding is unknown. Though within normal historical control 
values for these laboratories, chloride remained increased for the 225 mg/kg males while 
cholesterol remained increased for the 225 mg/kg females.   
 
Changes in brain and liver weights were noted but did not occur in a dose-dependent manner and 
no microscopic changes were noted for in these organs for the high dose females. These changes 
were considered incidental and unrelated to treatment. At the Day 3 necropsy, ONC201-related 
minimal to mild edema and/or mixed cell inflammation was present in the non-glandular stomach 
of 225 mg/kg males and females.  This edema and inflammation was primarily submucosal, 
although in some animals the inflammation involved the serosa or mesentery.  Two males and one 
female had minimal focal ulceration of the overlying squamous epithelium. Similar stomach 
findings were seen in 125 mg/kg animals, with a lower incidence than in 225 mg/kg. There was 
complete resolution of all stomach lesions at the Day 19 necropsy, indicating full recovery.   
Based on the results of this study, the NOAEL following oral administration of ONC201 at single 
doses of 12.5, 125 or 225 mg/kg to Sprague-Dawley rats is considered to be at least 125 mg/kg. 
Evaluation of the Effect of ONC201 Dihydrochloride on Respiratory Function Following Single-
Dose Administration in Rats (GLP) 
 
A GLP study was performed to determine the potential effects of ONC201 dihydrochloride on 
respiratory function in rats following a single oral gavage administration. Twenty-four (6/group) 
male rats received 0, 12.5, 125, or 225 mg/kg ONC201 by oral gavage and were monitored in 
plethysmographic chambers. The oral administration of ONC201 dihydrochloride at 12.5 and 125 
mg/kg did not induce any biologically relevant effects on respiratory rate, tidal volume or minute 
volume in conscious male rats.  A marginal to moderate transient decrease in respiratory rate and 
minute volume was observed following the oral administration of ONC201 dihydrochloride at 225 
mg/kg, which resolved by 2 hours. 
 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
2.1.2.5 Pharmacokinetic Studies 
The measured half-life of ONC201 in mice is ~6 hours with intravenous administration as 
measured by an HPLC-UV assay. In rats, exposure to ONC201 was dose-dependent and 
approximately dose-proportional. Exposure to ONC201 was slightly greater in female rats after a 
single oral gavage dose. Plasma t1/2 ranged from 2.3 to 8.4 hours in 7 of 8 profiles.  Clearance 
ranged from 7.5 to 23.5 L/hr/kg in 7 of 8 profiles.  Volume of distribution ranged from ~49 to 
~103 L/kg in 6 of 8 profiles.  
 
In dogs, exposure to ONC201 following oral gavage dosing at 4.2, 42, and 120 mg/kg ONC201 
was dose-dependent and increased with greater ONC201 dose levels. Exposure to ONC201 was 
similar in male and female dogs with the observation that all mean male Cmax and AUC values 
were slightly greater than those corresponding female values. Elimination of ONC201 from plasma 
was similar between the mid and high dose levels; mean t1/2 ranged from 4.6 to 7.8 hours. Mean 
t1/2 following the low dose of 4.2 mg/kg was ~1 hour [the half-life determined for dogs in the low 
dose group may represent more of a distribution phase half-life rather than the terminal plasma 
elimination half-life]. Overall elimination of ONC201 was greater following the low dose.   
In a Phase I dose-escalation clinical trial of ONC201 in patients with advanced solid tumors, the 
pharmacokinetics of single agent ONC201 was determined by LC-MS-MS analysis of plasma 
collected in the first cycle of therapy within 21 days of drug administration (Fig 2.3). While dose 
escalation involved single patient cohorts, systemic exposure to ONC201, as determined by AUC 
and Cmax, appeared to saturate at a dose of 375 mg. PK parameters are summarized for patients 
who received the RP2D in Table 2.1. For the top dose cohort, the mean Cmax was 3312 (SD 2133) 
ng/mL, which occurred on average 1.8 hours following administration.  The mean Vz was 381 
(SD 164) L, consistent with a large distributive volume.  Mean AUC was 26.3 (SD 10.8) h.μg/mL, 
and mean CL/F was 27.19 (SD 10.95) L/h.  The mean t1/2 was 9.62 (SD 1.76) hours.  
 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
Table 1: Mean ONC201 pharmacokinetic parameters determined in patients receiving 625 mg 
ONC201 every three weeks 
Generally, CL/F was observed to be variable but consistent across all the dose groups. There were 
no apparent relationships between drug CL/F and patient sex and age. Noticeable, shallow trends 
were observed with patient weight and BSA. An overall increase in CL/F was observed as weight 
and BSA increased. Although a slight upward trend was observed, there was no strong correlation 
between CL/F and CLCR.  
 
Stronger correlations were observed with the distributive volume estimate (VZ) and patient weight 
and BSA.  A pronounced increase in VZ was observed with increasing patient weight.  A greater 
than 2-fold increase in VZ is predicted from this trend with an increase in weight from 50 to 100 
kg.  A similar trend was observed between VZ and BSA. Trends of decreasing exposure with 
increasing weight were observed in plots of Cmax/Dose and AUC/Dose versus patient weight.  
Weight normalized CL/F was plotted versus dose, showing a similar trend to un-normalized CL/F, 
but with significantly less variability across patients in the 625 mg dose group.  
 
Clinical Studies 
2.2.1  Safety of ONC201 
The clinical safety of ONC201 has been evaluated in a Phase I clinical trial; An open-label, dose-
escalation Phase I trial of single agent ONC201was conducted in patients with advanced refractory 
solid tumors who had exhausted or refused standard treatment options. The primary objective of 
this study was to determine the maximal tolerated dose (MTD) and to determine the recommended 
Phase II dose (RP2D) of oral ONC201 and to evaluate the safety and tolerability of the drug. 
Secondary objectives were to study the pharmacokinetics and pharmacodynamics of ONC201 and 
preliminary assessment of anti-tumor efficacy.  
An accelerated dose escalation design was used to reduce the number of patients treated at 
potentially sub-therapeutic dose. Ten evaluable (aged 47-80 years) patients received oral ONC201 
once every 3 weeks at five dose levels ranging from 125 to 625 mg. The study design included 
only one patient per cohort until any patient experiences a grade 2 adverse event during the first 
cycle of treatment, defined as 21 days. Five dose levels (125 mg, 250 mg, 375 mg, 500 mg, 625 
mg) were evaluated. Enrollment at each subsequent dose level required that all patients enrolled 
at the prior dose level completed Cycle 1 dosing and were evaluated 21 days later to assess safety 
and had no grade toxicity.  
 
On average, patients received 3.1 doses of ONC201. Nine out of ten patients completed at least 2 
cycles, 4 patients completed at least four cycles, and one patient received six cycles and remains 
on therapy. 625 mg was the highest dose administered and was determined to be the RP2D that 
surpassed the absorption saturation threshold by two dose levels.  The only adverse event during 
the dose escalation phase that was possibly attributed to ONC201 was a low-grade fever. No Grade 
>1 drug-related toxicities were observed. Explorative laboratory studies and physical exams did 
not reveal any drug-related abnormalities. Similarly, cardiovascular assessments revealed no drug-


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
related effects.  (Stein MN et al. Clin Cancer research 2017) 
 
Clinical efficacy was observed in some patients; Patient #3, a 72-year-old with advanced clear cell 
endometrial cancer, had a mixed objective response with >50% decrease in lymphadenopathy 
(10/11 afflicted lymph nodes responded) after 2 doses. Patient #4, a 62-year-old male with renal 
cancer and bone metastases with debilitating pain in the clavicle, experienced relief from his 
clavicular pain. Patient #6, a 69-year-old patient with prostate adenocarcinoma, has received 8 
doses of ONC201 and has stable disease. Patient #8, a 71-year old colon cancer patient had stable 
disease for at least 12 weeks with 4 doses of ONC201 (Figure 10).  
 
 
 
Figure 10. Stable disease over 12 weeks in the patient with mCRC who received Q 3-week 
ONC201 in first-in-human study. 
 
A 47-year-old male with appendiceal cancer (patient #2) had biochemical response with CA27.29 
declining from 30 units to 20 units (normal range) after 4 doses of ONC201. Given the 
heterogeneity of the tumor types in the enrolled patients, no widely used biomarker was available 
to uniformly assay all patient samples. Since most solid tumors express cytokeratin-18, the serum 
M30 assay was selected to detect a caspase-cleaved form of cytokeratin-18 (Demiray et al; 2006). 
Induction of the M30 assay for apoptosis was noted in 67% of patients treated at the RP2D with a 
range of 1.25- to 4-fold increase.  
 
Eighteen patients were enrolled in the expansion phase, patients received 625mg of ONC 201 
orally every 3 weeks. On the basis of these clinical observations in the dose escalation phase, the 
expansion phase enriched for endometrial and prostate cancer patients. A 90-year-old prostate 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
cancer patient had a rapid shrinking of his primary tumor and metastatic bone lesion (∼25%) after 
two doses of 625 mg ONC201. Waterfall analysis of the 28 patients on a lesion-by-lesion basis 
revealed tumor regressions in prostate and endometrial cancer patients that involved lymph nodes, 
bone, and lung lesions). An endometrial cancer patient experienced stable disease for 42 weeks 
and exhibited sustained regression of her metastatic lung lesion. The only adverse events among 
these 18 patients that were attributed as possibly related to ONC201 were nausea in 1 patient, 
emesis in 1 patient, and increased serum amylase in 2 patients. All of these adverse events were 
grade 1 and reversed rapidly. In a phase II study of ONC 201 in patients with recurrent 
glioblastoma was recently reported. Seventeen patients with recurrent, bevacizumab-naïve, 
IDH1/2 WT glioblastoma were enrolled. Patients received 625mg ONC201 every three weeks. 
Median OS was 41.6 weeks with OS of 71% and 53%. At 6 and nine weeks respectively.  Seven 
of 17 patients are alive. PFS6 was 11.8% with two patients remaining on study who continue to 
receive ONC201 for >12 months. One of these patients had a durable objective response with a 
secondary glioblastoma possessing a H3.3 K27M mutation, exhibiting regression by 85% in one 
lesion and 76% in the second lesion. The second patient who continues to receive ONC201 for 
>12 months remains disease-free after enrolling on this trial following a re-resection. No drug-
related SAEs or treatment discontinuation due to toxicity occurred. Plasma PK at 2 hours’ post-
dose was 2.6 ug/mL, serum prolactin induction was observed as a surrogate marker of target 
engagement, and DRD2 was expressed in all evaluated archival tumor specimens. (Arrillaga-
Romany I et al. oncotarget) 
 
Additional clinical studies of ONC201 are currently enrolling or being initiated, including a Phase 
I clinical trial in multiple myeloma, a Phase I/II trial in relapsed/refractory acute leukemias and 
high-risk myelodysplastic syndrome, a Phase I/II trial in advanced non-Hodgkin’s lymphoma  
 
In a currently enrolling phase II study of ONC 201 in patients with relapsed NHL, the first patient 
treated with ONC201 had relapsed/refractory mantle cell lymphoma with gastrointestinal 
manifestations; after the first post-treatment evaluation, patient had a striking response with almost 
complete eradication of disease (Figure 11). After only two doses of 125mg ONC201 (1/5th of the 
RP2D) spaced three weeks apart, the tumor disappeared from the colon and only small foci of 
residual disease were found on rectal biopsy. DRD2 expression was detected at baseline biopsy. 
Patient continue to be in   complete remission based on recent endoscopy. Additionally, a 22-year 
old patient with recurrent glioblastoma (unmethylated MGMT, H3.3 mutant) had a confirmed 
objective response with 625 mg ONC201 every three weeks resulting in an 82% reduction in 
overall tumor size and continues treatment with a durable response for over 1 year (Figure 12). 
Peripheral blood samples from patients who received ONC201 treatment showed a 2-10 fold 
increase in the number of activated TRAIL-secreting NK cells after ONC201 treatment up to three 
days after treatment (Figure 13).  
 
 
 
Figure 11: Rectal biopsy of relapsed/refractory MCL patient with cyclin D1 at (A) baseline 


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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
and (B) after 3 doses of 125mg ONC201 once every 3 weeks. DRD2 expression at baseline in 
rectal biopsy shown in (C). Patient currently in complete remission based on recent 
endoscopy.  
 
 
 
 
 
Figure 
12: 
Partial 
response in recurrent 
glioblastoma 
patient 
with 625mg ONC201 
every 3-weeks. 
 
Figure 13: NK cells are increased in peripheral blood of patients following treatment with 
ONC201. Percentage of NK cells in PBMCs (left) and percentages of NK cells expressing 
Granzyme B (right) following 625 mg weekly ONC201 administration. 
In addition, a 68-year-old male with advanced colon cancer was treated with 375 mg ONC201 on 
an every 3-week schedule.  
 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
Another 68-year-old patient with metastatic KRAS/NRAS wild type, APC and p53 mutant colon 
cancer who progressed on 3 lines of therapy was treated with ONC201 monotherapy at 625 mg 
PO Q 3 weeks  
The patient had 2 doses of ONC201 and came off-therapy because of disease progression. (Figure 
14 and Table 2).  
 Follow up scans after treatment discontinuation surprisingly showed a continued mixed response 
 
 
 
Figure 14. CT scans showing initial increase in the largest lesion in patient with mCRC treated with ONC201. A 
subsequent CT taken ~7 weeks later before the patient had any further treatment showed stable disease. Other lesions (see 
Table 2) showed regression. This patient received a total of two doses of ONC201 for progressive pretreated mCRC (on a 
Q3 week schedule). The patient's initial staging scan suggested progressive disease and patient was taken off study on 
January 24. Table 2 shows 5 lesions that appeared larger on 1/24/17 vs 12/6/17. 
 
 
Table 2. Mixed response in the subsequent 7 
weeks after patient came off of the ONC201 trial. 
 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
with some lesions that decreased (4 of 11 measured lesions) and large lesions that remained stable 
(3 of 11 lesions). There were some lesions that slightly increased (3 of 11 lesions) and there was 
one new lesion. See Table 2 for lesion sizes. 
  
Preclinical data suggesting a potent ONC201 dose intensification effect coupled with suppression 
of metastases, an NK cell infiltration, and a potent preclinical tumor suppression in patients with 
mCRC. This supports dose intensification to potentially lead to a better response in patients with 
mCRC. In addition, the somewhat delayed response is consistent with the hypothesis that ONC201 
has an immune stimulatory effect that may last beyond the immediate PK and PD anti-tumor 
effects. Further evidence for this mechanism will be pursued in the proposed clinical trial. 
 
More recent clinical trial data in prostate cancer shows evidence of increased granzyme B in post-
treatment biopsies (unpublished, Mark Stein et al.). Since tumor biopsies were not available for 
most patients in phase 1 ONC201 monotherapy studies, immune cytokine and effector profiling 
was conducted from serum samples using a multiplex cytokine (unpublished, Mark Stein et al.). 
A broad induction of immune cytokines and effector molecules was observed amongst patients 
treated with ONC201, in particular among patients who experienced at least stable disease by 
RECIST for 12 or more weeks. Examining the kinetics of this response revealed that maximum 
immune cytokine induction tended to occur within the first two cycles, while maximum effector 
induction tended to occur beyond cycle 2 (unpublished, Mark Stein et al.). Examination of the 
serum samples from previously reported patients treated on the once every three-week schedule 
revealed a similarly broad immune cytokine and effector molecule induction (unpublished, Mark 
Stein et al.). The magnitude of induction was generally lower than that of patients who received 
ONC201 once weekly, though this did not reach statistical significance (unpublished, Mark Stein 
et al.). Patients who had a >50% induction in serum perforin, a cytolytic protein found in granules 
of cytotoxic T lymphocytes (CTLs) and NK cells19, upon ONC201 administration had a 
significantly longer progression-free survival (P=0.011; HR=0.3211) (unpublished, Mark Stein et 
al.). 
 
Based on the expected delayed immune response and immune stimulatory effect of intense dose 
ONC 201, We now propose this phase I/II study of the combination of ONC201 plus Nivolumab 
in patients with microsatellite stable advanced metastatic colorectal cancer.  
 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
2.2.2 Dosage and Administration of Opdivo (Nivolumab) 
 
Based on FDA labeling and investigator brochure provided by the manufacturer dosage and 
administration of Opdivo (Nivolumab) for microsatellite instability-high (MSI-H) or mismatch 
repair deficient (dMMR) metastatic colorectal cancer is 240 mg every 2 weeks administered as an 
intravenous infusion over approximately 30 minutes. 
2.2.3 Safety of Opdivo (Nivolumab) 
 
The clinical safety of Opdivo (Nivolumab) has been evaluated in in multiple clinical trials for the 
treatment of multiple human cancers and is approved by FDA to be used alone or with other drugs 
to treat a number of pediatric and adult cancers. 
 
Based on FDA labeling and investigator brochure provided by the manufacturer the most common 
adverse reactions (≥20%) in patients as a single agent were fatigue, rash, musculoskeletal pain, 
pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, 
arthralgia, upper respiratory tract infection, pyrexia, headache, and abdominal pain.  
 
Immune-Mediated Adverse Reactions See Appendix D 
 
Based on FDA labeling and investigator brochure provided by the manufacturer the following 
adverse reactions have been reported: 
 
• Immune-Mediated Pneumonitis  
• Immune-Mediated Colitis  
• Immune-Mediated Hepatitis  
• Immune-Mediated Endocrinopathies  
• Immune-Mediated Nephritis and Renal Dysfunction  
• Immune-Mediated Skin Adverse Reactions  
• Immune-Mediated Encephalitis  
• Other Immune-Mediated Adverse Reactions  
• Infusion Reactions  
• Complications of Allogeneic HSCT after Opdivo  
 
The below is the adverse reactions discussed in greater detail: 
 
Immune-Mediated Pneumonitis 
In patients receiving Opdivo as a single agent, immune-mediated pneumonitis occurred in 3.1% 
(61/1994) of patients. The median time to onset of immune-mediated pneumonitis was 3.5 months 
(range: 1 day to 22.3 months). Immune-mediated pneumonitis led to permanent discontinuation of 
Opdivo in 1.1%, and withholding of Opdivo in 1.3% of patients. Approximately 89% of patients 
with pneumonitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
day) for a median duration of 26 days (range: 1 day to 6 months). Complete resolution of symptoms 
following corticosteroid taper occurred in 67% of patients. Approximately 8% of patients had 
recurrence of pneumonitis after re-initiation of Opdivo. 
 
Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for 
symptoms of pneumonitis. 
 
Management 
Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for moderate 
(Grade 2) or more severe (Grade 3-4) pneumonitis, followed by corticosteroid taper. Permanently 
discontinue Opdivo for severe (Grade 3) or life-threatening (Grade 4) pneumonitis and withhold 
Opdivo until resolution for moderate (Grade 2) pneumonitis [see Dosage and Administration]. 
 
Immune-Mediated Colitis 
In patients receiving Opdivo as a single agent, immune-mediated colitis occurred in 2.9% 
(58/1994) of patients; the median time to onset was 5.3 months (range: 2 days to 20.9 months). 
Immune-mediated colitis led to permanent discontinuation of Opdivo in 0.7% and withholding of 
Opdivo in 1% of patients. Approximately 91% of patients with colitis received high-dose 
corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 23 days 
(range: 1 day to 9.3 months). 
 
Four patients required addition of infliximab to high-dose corticosteroids. Complete resolution 
occurred in 74% of patients. Approximately 16% of patients had recurrence of colitis after re-
initiation of Opdivo. 
 
Management  
Monitor patients for signs and symptoms of colitis. Administer corticosteroids at a dose of 1 to 2 
mg/kg/day prednisone equivalents followed by corticosteroid taper for severe (Grade 3) or life-
threatening (Grade 4) colitis. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone 
equivalents followed by corticosteroid taper for moderate (Grade 2) colitis of more than 5 days 
duration; if worsening or no improvement occurs despite initiation of corticosteroids, increase dose 
to 1 to 2 mg/kg/day prednisone equivalents. 
 
Withhold Opdivo for moderate or severe (Grade 2 or 3) colitis. Permanently discontinue Opdivo 
for life-threatening (Grade 4) or for recurrent colitis upon re-initiation of Opdivo 
[see Dosage and Administration]. 
 
Immune-Mediated Hepatitis 
In patients receiving Opdivo as a single agent, immune-mediated hepatitis occurred in 1.8% 
(35/1994) of patients; the median time to onset was 3.3 months (range: 6 days to 9 months). 
Immune-mediated hepatitis led to permanent discontinuation of Opdivo in 0.7% and withholding 
of Opdivo in 1% of patients. All patients with hepatitis received high-dose corticosteroids (at least 


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Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
40 mg prednisone equivalents) for a median duration of 23 days (range: 1 day to 2 months). Two 
patients required the addition of mycophenolic acid to high-dose corticosteroids. Complete 
resolution occurred in 74% of patients. Approximately 29% of patients had recurrence of hepatitis 
after re-initiation of Opdivo. 
 
Management 
Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer 
corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid 
taper for severe (Grade 3) or life-threatening (Grade 4) transaminase elevations, with or without 
concomitant elevation in total bilirubin. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day 
prednisone equivalents for moderate (Grade 2) transaminase 
elevations. 
 
Immune-Mediated Endocrinopathies 
 
Hypophysitis 
In patients receiving Opdivo as a single agent, hypophysitis occurred in 0.6% (12/1994) of 
patients; the median time to onset was 4.9 months (range: 1.4 to 11 months).  
 
Hypophysitis led to permanent discontinuation of Opdivo in 0.1% and withholding of Opdivo in 
0.2% of patients. Approximately 67% of patients with hypophysitis received hormone replacement 
therapy and 33% received high-dose corticosteroids (at least 40 mg prednisone equivalents per 
day) for a median duration of 14 days (range: 5 to 26 days). 
 
Management 
Monitor patients for signs and symptoms of hypophysitis. Administer hormone replacement as 
clinically indicated and corticosteroids at a dose of 1 mg/kg/day prednisone equivalents followed 
by corticosteroid taper for moderate (Grade 2) or greater hypophysitis. Withhold Opdivo for 
moderate (Grade 2) or severe (Grade 3). Permanently discontinue Opdivo for life-threatening 
(Grade 4) hypophysitis [see Dosage and Administration]. 
 
Adrenal Insufficiency 
In patients receiving Opdivo as a single agent, adrenal insufficiency occurred in 1% (20/1994) of 
patients and the median time to onset was 4.3 months (range: 15 days to 21 months). Adrenal 
insufficiency led to permanent discontinuation of Opdivo in 0.1% and withholding of Opdivo in 
0.5% of patients. Approximately 85% of patients with adrenal insufficiency received hormone 
replacement therapy and 25% received high-dose corticosteroids (at least 40 mg prednisone 
equivalents per day) for a median duration of 11 days (range: 1 day to 1 month). 
 
Management 
Monitor patients for signs and symptoms of adrenal insufficiency. Administer corticosteroids at a 
dose of 1 to 2 mg/kg/day prednisone equivalents followed by a corticosteroid taper for severe 


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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
(Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Withhold Opdivo for moderate 
(Grade 2) and permanently discontinue Opdivo for severe (Grade 3) or life-threatening (Grade 4) 
adrenal insufficiency [see Dosage and Administration]. 
 
Hypothyroidism and Hyperthyroidism  
In patients receiving Opdivo as a single agent, hypothyroidism or thyroiditis resulting in 
hypothyroidism occurred in 9% (171/1994) of patients; the median time to onset was 2.9 months 
(range: 1 day to 16.6 months). Approximately 79% of patients with hypothyroidism received 
levothyroxine and 4% also required corticosteroids. Resolution occurred in 35% of patients.  
 
Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving Opdivo as a single agent; the 
median time to onset was 1.5 months (range: 1 day to 14.2 months). Approximately 26% of 
patients with hyperthyroidism received methimazole, 9% received carbimazole, 4% received 
propylthiouracil, and 9% received corticosteroids. Resolution occurred in 76% of patients 
 
Management 
Monitor thyroid function prior to and periodically during Opdivo treatment. Administer hormone-
replacement therapy for hypothyroidism. Initiate medical management for control of 
hyperthyroidism. There are no recommended dose adjustments of Opdivo for hypothyroidism or 
hyperthyroidism.  
 
Type 1 Diabetes Mellitus  
In patients receiving Opdivo as a single agent, diabetes occurred in 0.9% (17/1994) of patients 
including two cases of diabetic ketoacidosis. The median time to onset was 4.4 months (range: 15 
days to 22 months). 
 
Management 
Monitor for hyperglycemia. Withhold Opdivo in cases of severe (Grade 3) hyperglycemia until 
metabolic control is achieved. Permanently discontinue Opdivo for life-threatening (Grade 4) 
hyperglycemia [see Dosage and Administration].  
 
Immune-Mediated Nephritis and Renal Dysfunction  
In patients receiving Opdivo as a single agent, immune-mediated nephritis and renal dysfunction 
occurred in 1.2% (23/1994) of patients; the median time to onset was 4.6 months (range: 23 days 
to 12.3 months). Immune-mediated nephritis and renal dysfunction led to permanent 
discontinuation of Opdivo in 0.3% and withholding of Opdivo in 0.8% of patients. All patients 
received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median 
duration of 21 days (range: 1 day to 15.4 months). Complete resolution occurred in 48% of 
patients. No patients had recurrence of nephritis or renal dysfunction after re-initiation of Opdivo. 
 
Management 
Monitor patients for elevated serum creatinine prior to and periodically during treatment. 


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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by 
corticosteroid taper for life-threatening (Grade 4) increased serum creatinine. Administer 
corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents for moderate (Grade 2) or 
severe (Grade 3) increased serum creatinine, if worsening or no improvement occurs, increase 
dose of corticosteroids to 1 to 2 mg/kg/day prednisone equivalents.  
Withhold Opdivo for moderate (Grade 2) or severe (Grade 3) increased serum creatinine. 
Permanently discontinue Opdivo for life-threatening (Grade 4) increased serum creatinine [see 
Dosage and Administration].  
 
Immune-Mediated Skin Adverse Reactions  
In patients receiving Opdivo as a single agent, immune-mediated rash occurred in 9% (171/1994) 
of patients; the median time to onset was 2.8 months (range: <1 day to 25.8 months). Immune-
mediated rash led to permanent discontinuation of Opdivo in 0.3% and withholding of Opdivo in 
0.8% of patients. Approximately 16% of patients with rash received high-dose corticosteroids (at 
least 40 mg prednisone equivalents per day) for a median duration of 12 days (range: 1 days to 8.9 
months) and 85% received topical corticosteroids. Complete resolution occurred in 48% of 
patients. Recurrence of rash occurred in 1.4% of patients who resumed Opdivo after resolution of 
rash. 
 
Management 
Opdivo can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic 
epidermal necrolysis (TEN), some cases with fatal outcome. For symptoms or signs of SJS or 
TEN, withhold Opdivo and refer the patient for specialized care for assessment and treatment. If 
SJS or TEN is confirmed, permanently discontinue Opdivo [see Dosage and Administration].  
 
For immune-mediated rash, administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone 
equivalents followed by a corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) 
rash. Withhold Opdivo for severe (Grade 3) rash and permanently discontinue Opdivo for life-
threatening (Grade 4) rash.  
 
Immune-Mediated Encephalitis  
In patients receiving Opdivo as a single agent, encephalitis occurred in 0.2% (3/1994). Fatal limbic 
encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of Opdivo 
and administration of corticosteroids. In the other two patients, encephalitis occurred post-
allogeneic HSCT [see Warnings and Precautions]. 
 
Management 
Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation 
with a neurologist, brain MRI, and lumbar puncture.  
 
Withhold Opdivo in patients with new-onset moderate to severe neurologic signs or symptoms and 
evaluate to rule out infectious or other causes of moderate to severe neurologic deterioration. If 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
other etiologies are ruled out, administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone 
equivalents for patients with immune-mediated encephalitis, followed by corticosteroid taper. 
Permanently discontinue Opdivo for immune-mediated encephalitis [see Dosage and 
Administration].  
 
 
Other Immune-Mediated Adverse Reactions  
Opdivo can cause other clinically significant and potentially fatal immune-mediated adverse 
reactions. Immune-mediated adverse reactions may occur after discontinuation of Opdivo therapy. 
For any suspected immune-mediated adverse reactions, first, exclude other causes and based on 
the severity of the adverse reaction, permanently discontinue or withhold Opdivo, administer high-
dose corticosteroids, and if appropriate, initiate hormone-replacement therapy. Upon improvement 
to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider 
restarting Opdivo after completion of corticosteroid taper based on the severity of the event [see 
Dosage and Administration].  
 
Across clinical trials of Opdivo administered as a single agent or in combination with ipilimumab, 
the following clinically significant immune-mediated adverse reactions, some with fatal outcome, 
occurred in less than 1.0% of patients receiving Opdivo: myocarditis, rhabdomyolysis, myositis, 
uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia 
rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic 
inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing 
lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, aplastic anemia, 
pericarditis, and myasthenic syndrome.  
 
If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-
Koyanagi-Harada-like syndrome, which has been observed in patients receiving Opdivo or Opdivo 
in combination with ipilimumab and may require treatment with systemic steroids to reduce the 
risk of permanent vision loss.  
 
Infusion Reactions 
In patients receiving Opdivo as a 60-minute intravenous infusion, infusion-related reactions 
occurred in 6.4% (127/1994) of patients. In a study assessing the pharmacokinetics and safety of 
a more rapid infusion, in which patients received Opdivo as a 60-minute intravenous infusion or a 
30-minute intravenous infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% 
(10/369) patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, 
respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, 
permanent discontinuation or withholding of Opdivo. 
 
Management 
Opdivo can cause severe infusion reactions, which have been reported in less than 1.0% of patients 
in clinical trials. Discontinue Opdivo in patients with severe or life-threatening infusion reactions. 


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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions [see 
Dosage and Administration]. 
 
Embryo-Fetal Toxicity  
Based on its mechanism of action and data from animal studies, Opdivo can cause fetal harm when 
administered to a pregnant woman. In animal reproduction studies, administration of nivolumab 
to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased 
abortion and premature infant death. Advise pregnant women of the potential risk to a fetus. Advise 
females of reproductive potential to use effective contraception during treatment with an Opdivo-
containing regimen and for at least 5 months after the last dose of Opdivo [see Use in Specific 
Populations in the drug packaging insert]  
 
Rationale  
ONC201 is a first-in-class small molecule with consistent antitumor activity in difficult-to-treat 
cancers as demonstrated using in vitro, ex vivo, and in vivo models. The mechanism of action of 
ONC201 appears to involve the activation of the ISR that causes a downstream inactivation Akt 
and ERK signaling as well as induction of the pro-apoptotic TRAIL pathway. The efficacy of 
ONC201 has been demonstrated in numerous solid and liquid tumor cell lines and patient sample 
that are refractory to chemotherapy and targeted therapies. ONC201 is effective in tumor cells 
harboring diverse mutations in genes such as p53, KRAS, Raf, EGFR and others that render 
resistance to chemotherapy and targeted therapies. Colon cancer has been selected for evaluation 
in this trial based on preclinical efficacy as well as the mechanism of action of ONC201 that 
involves engagement of the ISR, inactivation of Ras signaling, and induction of the TRAIL 
pathway that should be effective in these tumors based on preclinical and clinical evidence.   
2.3.1 Rationale for combination of ONC201 with anti-PD1 Opdivo (Nivolumab) 
The combination of ONC201 with anti-PD-1 therapy resulted in more potent in vivo tumor 
suppression with the combination versus anti-PD-1 therapy alone (Figure 15). (Wagner et al. J 
Clin Invest. 2018) 
 
Figure 15. ONC201 in combination with anti-PD1. Relative tumor volume after 4 weeks in CT26 
tumors in Balb/c mice treated with vehicle, 100 mg/kg ONC201, anti-PD-1, or ONC201 + anti-
PD-1. 


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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
3 
OBJECTIVES AND ENDPOINTS 
 
Objectives – Phase Ib 
3.1.1 Phase Ib: Primary Objective 
2) Determine the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose 
(RP2D) of ONC201 when administered orally in combination with Opdivo (Nivolumab) 
in patients with microsatellite stable metastatic colon cancer who progressed after at least 
2 lines of therapy 
3.1.2 Phase Ib: Secondary Objectives 
1) Evaluate the overall safety profile of orally-administered ONC201 in combination with 
Opdivo (Nivolumab) using CTCAE version 5.0. 
2) Evaluate the pharmacokinetic (PK) profile of orally-administered agent ONC201 in 
combination with Opdivo (Nivolumab) 
3) Assess the pharmacodynamic effects of orally-administered agent ONC201 
4) Assess preliminary efficacy of ON201 and Opdivo 
 
Objectives – Phase II 
3.2.1 Phase II: Primary Objectives 
1) Determine progression free survival (PFS) of orally-administered ONC201 in combination 
with Opdivo (Nivolumab) 
2) Determine the response rate to ONC201 in combination with Opdivo (Nivolumab), as 
assessed using the Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1, in 
patients with microsatellite stable metastatic colorectal cancer 
3.2.2 Phase II: Secondary Objectives 
1) Confirm safety of phase II dose of ONC201 in combination with Opdivo (Nivolumab) 
using CTCAE version 5.0 
2) Assess preliminary overall survival associated with ONC201 and Opdivo (Nivolumab) in 
patients with microsatellite stable metastatic colorectal cancer 
3) Correlate clinical outcome with tumor & blood biomarkers including cancer stem cells, 
signaling intermediates and inhibitors, NK cells, TRAIL, granzyme, perforin, and M30. 
 
4 
STUDY DESIGN 
 
Overview 
This is a single arm Phase Ib/II, open label, safety, pharmacokinetic, pharmacodynamics and 
efficacy study of ONC201 in combination with Opdivo (Nivolumab) in adult patients with 
metastatic colorectal cancer, for whom no standard therapy is available. This study will enroll adult 
patients with microsatellite stable metastatic colorectal cancer who progressed after at least two 
lines of therapy.  
 


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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
Study Design 
In the phase IB portion of the trial, the safety of the combination of ONC201 and nivolumab will 
be established in cohorts of 3-6 patients using a dose de-escalation design. Once the recommended 
phase 2 dose (RP2D) is determined, phase II will be initiated so a total of 34 patients will be treated 
at the RP2D.  
 
Throughout the study, AEs, SAEs, laboratory values, vital signs, physical examination findings, 
ECOG performance status, and EKGs will be obtained to evaluate the combination treatment arms. 
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE), version 5.0.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The maximum duration of treatment will be 12 months unless it is determined that a patient 
would derive benefit from continued therapy beyond 12 months, as determined by the 
investigator. Follow-up for all patients will be approximately 6 months.  
 
The study is expected to be completed over an approximate 3.5-year period 
 
Archival tissue available from prior surgery or biopsy will be collected for future testing. There is 
a required pre-treatment biopsy which will occur post consent and prior to run-in dose of ONC-
201 (D-7). A second research biopsy will be performed post cycle 2, at approximately 8 weeks 
and to coincide with the first imaging. If patients progress at that time they will come off study. If 
Dosing phase Ib and II: 
An initial dose of ONC201 will be given -7 
days prior to cycle 1, day1 
Cycle = 4 weeks (28 days) 
• ONC201 weekly day 1 
• Nivolumab 240mg IV q2 weeks day 1 
and 15 over approximately 30 minutes, 
with ONC201 
Phase IB: 
 
Dose de-escalation, cohorts of 3-6 
patients to determine RP2D 
 
(PK, PD, tumor biopsies) 
 
 
Phase II: 
 
28 additional patients at RP2D 
 
(PD and tumor biopsies) 
 RP2D 


Page 37 of 145 
 
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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
the patient has not progressed, a third research biopsy will be performed at the time of progression, 
if progression occurs during the study treatment or follow-up time period. 
 
Dose-limiting toxicities (DLTs) are defined below in section 6.4.2.  
 
Serial blood samples to measure plasma concentrations of ONC201, and potentially relevant 
biomarkers, will be collected at pre-specified time points as indicated in the respective Schedule 
of evaluations table.  
 
Number of Patients  
It is anticipated that 6 evaluable patients in the Phase IB and an additional 28 patients in Phase II 
will be enrolled into this study. Enrollment is estimated to occur over the course of 2 years with 
study completion occurring over approximately 3.5 years. Because a 3 + 3 dose de-escalation 
design will be used, the actual sample size will depend on the number of cohorts and the number 
of patients enrolled in phase Ib.  
 
Duration of Study 
A cycle is defined as q 4 weeks (28 days). Nivolumab and ONC201 will start on day 1 of each 
cycle (following an initial dose of ONC 201 on day -7).  ONC201 will be given weekly day 1, and 
Nivolumab will be given q 2 weeks at a flat dose of 240mg IV over an approximate 30-minute 
infusion. See treatment section for details.  
 
Dosing will continue until disease progression, unacceptable toxicity per patient or treating 
physician, or the patient discontinues for any other reason.  
 
The maximum duration of treatment will be 12 months unless it is determined that a patient 
would derive benefit from continued therapy beyond 12 months, as determined by the 
investigator. Follow-up for all patients will be approximately 6 months.  
 
The study is expected to be completed over an approximate 3.5-year period 
 
When patients discontinue study treatment, they should return to the study site 30 days (+1 week) 
and 100 days (+1 week) after administration of the last treatment (Nivolumab or ONC201, 
whichever is last) to complete the safety assessment visit and procedures. 
 
The study will be completed in approximately 3.5 years, taking into account approximately 2 years 
of enrollment, 12 months of treatment and approximately 6 months of follow-up, on average. 


Page 38 of 145 
 
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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
5 
ELIGIBILITY CRITERIA 
 
Inclusion 
1. Patients must have a histologically/cytologically -confirmed MSS primary colorectal 
adenocarcinoma tumor, with confirmation of being microsatellite stable. 
2. Radiographic or clinical evidence of metastatic disease that has progressed after at least 2 
prior regimens. Prior bevacizumab, cetuximab, trifluridine and tipiracil, or regorafenib is 
allowed, prior FOLFIRI and FOLFOX treatment is required. (Treatment with a 
FOLFIRINOX regimen will count as 2 regimens). Prior treatment does not have to have 
been in the metastatic setting. 
3. Patients must have measurable disease by RECIST criteria 
4. All patients must have a tumor(s) located in an area that that can be biopsied as confirmed 
by treating physician 
5. All patients must submit representative tissue from their malignancy if it is confirmed there 
is enough tissue from prior surgery or most recent biopsy. This can consist of archival 
tumor samples or tissue collected at biopsy to prove recurrence. In both cases, samples 
should consist of a formalin-fixed paraffin embedded (FFPE) tumor tissue block or at least 
20 unstained slides (charged) of 4 uM thickness sent to the lab address outlined in section 
11.1.4. Tissue located outside of Lifespan Cancer Institute hospitals must be confirmed as 
requested from outside organization or that it was received from outside organization prior 
to enrollment.   
6. All previous therapies for cancer, including radiotherapy, major surgery and investigational 
therapies must be discontinued for ≥ 14 days before the first dose of ONC201 (D-7 run in). 
7. All clinically significant adverse events related to any prior therapy must have resolved to 
Grade ≤ 1 Common Terminology Criteria for Adverse Events (CTCAE v5.0), except 
alopecia or parameters defined in this eligibility list. 
8. Age ≥ 18 years. 
9. ECOG performance status ≤ 2. 
10. Adequate organ and marrow function as defined below: 
a. Absolute neutrophil count ≥1,000/mm3 without growth factor use ≤ 7 days 
prior to treatment (this is Day -7) 
b. Platelets 
 
 
≥75,000/mm3 without platelet transfusion ≤ 7 days 
prior to treatment (this is Day -7) 
c. Hemoglobin  
 
>8.0 mg/dL without red blood cell transfusion ≤ 7 
days prior to treatment (this is Day -7) 
d. Total serum bilirubin 
 
<1.5 X upper limit of normal (ULN) 


Page 39 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
e. AST (SGOT)/ALT (SGPT) 
 
≤2 X ULN; ≤ 5 X ULN if liver 
dysfunction is felt to be secondary to tumor burden within 14 days prior to 
treatment (this is Day -7)  
f. Serum creatinine ≤ 1.5 X ULN (OR creatinine clearance ≥ 60 mL/min/1.73 m2) 
within 14 days prior to treatment (this is Day -7) 
g. Serum or urine pregnancy test (for females of childbearing potential) negative 
≤7 days of treatment (this is Day -7) 
11. Ability to understand and the willingness to sign a written informed consent document 
and comply with the study scheduled visits, treatment plans, laboratory tests and other 
procedures. 
12. Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception from time of consent and for the duration of study treatment 
through 5 months after the last dose of study treatment (ONC201 or Nivolumab, whichever 
is last) The decision of effective contraception will be based on the judgment of the 
principal investigator or a designated associate. 
13. Patients must agree to the required tumor biopsies to enroll in the trial. Pre-treatment 
biopsies can occur any time post consent and prior to run-in ONC201 dose, a second biopsy 
will be required at the end of cycle 2 to assess response biomarkers, a final biopsy is 
included at the time of progression to assess for resistance mechanisms. Only 2 biopsies 
will be required for patients who initially progress at time of 2nd biopsy. 
 
Exclusion 
1. Patients with symptomatic brain metastases are excluded. Patients with asymptomatic and 
treated CNS metastases may participate in this trial. The patient must have completed any 
prior treatment for CNS metastases > 28 days prior to registration, including radiotherapy 
or surgery. Steroids for the treatment of brain metastasis are not permitted. 
2. Patients with prior treatment with ONC201 or who have had prior therapy with nivolumab or 
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 immune check point pathways will be excluded 
3. Active inflammatory gastrointestinal disease such as severe chronic diarrhea (unless 
related to underlying malignancy), gastrointestinal perforation, or intra-abdominal abscess 
within 6 months prior to study registration. Gastroesophageal reflux disease under 
controlled treatment with proton pump inhibitors is allowed. 
4. Pregnant or breast feeding. 
5. Current active treatment in another clinical study (treatment trial) within 14 days of D-7. 


Page 40 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection 
requiring IV antibiotics, hepatitis, active rheumatologic or collagen vascular disease, 
symptomatic congestive heart failure, unstable angina pectoris, clinically significant 
cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements.  
 
NOTE: Participants with active or a history of Hepatitis B or C infection as follows: 
 
Active hepatitis B (positive hepatitis B surface antigen [HBsAg] or hepatitis C virus 
(HCV) (positive HCV RNA) are not eligible to participate.  
HBV carriers or those participants requiring antiviral therapy are not eligible to 
participate. 
Participants positive for HCV antibody are eligible only if PCR is negative for HCV 
RNA. If PCR is positive, they are not eligible to participate. 
Past HBV infection or resolved HBV infection are may be eligible on this trial provided 
the following criteria are met prior to randomization: Positive for hepatitis B core 
antibody (HBcAb), the absence of hepatitis B surface antigen (HBsAg), and no detectable 
HBV DNA in serum.  
7. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS)-related illness. (testing is not required for eligibility). 
8. Any of the following in the previous 3 months: myocardial infarction, severe/unstable 
angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, 
cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism 
as defined by treating physician.  
9. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or study drug administration, 
or may interfere with the interpretation of study results, or in the judgment of the 
investigator would make the patient inappropriate for entry into the study. 
10. Participants with an active, known or suspected autoimmune disease. Participants with 
type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin 
disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger are permitted to 
enroll. 
11. Participants with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 
14 days of day 1 of treatment. Inhaled or topical steroids, and adrenal replacement steroid 
doses > 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease 
12. Patients with a history of other invasive malignancies, with the exception of non-melanoma 
skin cancer are excluded if there is any evidence of other malignancy being present within 
the last three years (2 years for invasive breast cancer). However, patients with a 
malignancy that is non-likely to require treatment, as per the treating physician, in the next 


Page 41 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
2 years, such as a completely resected, early stage breast cancer, or other malignancies 
treated with curative intent are eligible. Patients are also excluded if their previous cancer 
treatment contraindicates this protocol therapy. 
13. Prior treatment with immunotherapy for any cancer, including immune checkpoint 
inhibitors or anti-CTLA4 agents 
14. Participants who have received a live / attenuated vaccine within 30 days of first treatment. 
 
Contraception 
During the study, fertile female patients must take precautions to prevent pregnancy since the 
effects of the study medication on the fetus are unknown. Male patients with partners of 
childbearing potential must take precautions to prevent pregnancy of the partner since the effects 
of this drug on sperm are unknown. These restrictions should remain in force for 5 months from 
the last dose of investigational agent (Nivolumab or ONC201) for WOCBP and for 7 months from 
the last dose of investigational agent (Nivolumab or ONC201). Drug interaction studies with oral 
contraceptives have not been performed, so barrier methods of contraception or abstinence should 
be considered. The definition of effective contraception should be in agreement with local 
regulation and based on the judgment of the principal investigator or a designated associate. A 
suggested definition of adequate contraception is the use of double barrier contraception (e.g., 
condom plus spermicide in combination with a female condom, diaphragm, cervical cap or 
intrauterine device). 
 
Inclusion of Women and Minorities 
 
Women and Men of all races and ethnic groups are eligible for this trial. 
 
Patient Registration 
Details of patient’s study participation should be documented in clinic/file notes. This project 
will leverage the Lifespan REDCap instance for making electronic health data accessible for 
research purposes. REDCap was developed by Vanderbilt University with collaboration from a 
consortium of institutional partners as a software toolset and workflow methodology for 
electronic collection and management of research and clinical trial data. The REDCap platform 
is a secure, web-based application flexible enough to be used for a variety of types of research, 
provides an intuitive interface for users to enter data, and enforces real time validation rules 
(with automated data type and range checks) at the time of entry. This platform provides an 
intuitive data manipulation interface, custom reporting capabilities, audit trail functionality, and 
real-time data monitoring/querying of participant records. REDCap has multiple data export 
options to common statistical packages (SPSS, SAS, Stata, R/S-Plus). The investigator will 
electronically sign the REDCap case reports prior to DSMB review and at the end of follow-up, 
to indicate that, to his/her knowledge, they are complete and accurate. 
 
All support data must be sent in for registration only. It is the treating physician’s responsibility 
to review all data submitted to the BrUOG Central Office for accuracy and completeness and 
he/she must electronically sign the off-study form. Sites are to be sure that elements to support 


Page 42 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
all inclusion and exclusion criteria are submitted and that all assessments from the study 
procedures calendar (section 8) are submitted for registration.  
 
All patients will be registered through the Brown University Oncology Research Group Central 
Office. Eligibility Checklist with supporting documentation, and the signed Patient Consent 
Form must be emailed to the BrUOG Central Office to allow for registration and prior to patient 
treatment. Registrations should be planned such that the BrUOG office has a full 2 business days 
to review all registration packets, prior to the scheduled date of treatment (D-7). 
 
 
6 
STUDY TREATMENTS 
 
 
Biopsy & Tissue: 
 
There are 3 specimens anticipated for collection, a pre-BrUOG 379 treatment biopsy and a mid-
treatment biopsy- both of which are required. If the patient does not progress at time of 2nd 
biopsy, there is a required 3rd biopsy to occur at time of progression (if patient progresses during 
treatment/follow-up time period) 
 
All collected specimens will be stored in the laboratory of Dr. Wafik El-Deiry for correlative 
testing for future exploratory analyses to assess biomarkers associated with treatment using 
nivolumab and ONC201 in metastatic colon cancer.   
 
Archival Tissue: All patients must submit representative tissue from their malignancy if it is 
confirmed there is enough tissue from prior surgery or most recent biopsy. This can consist of 
archival tumor samples or tissue collected at biopsy to prove recurrence. In both cases, samples 
should consist of a formalin-fixed paraffin embedded (FFPE) tumor tissue block or at least 20 
unstained slides (charged) of 4 uM thickness sent to the lab address located in section 11.1.4.  
Tissue located outside of Lifespan Cancer Institute hospitals must be confirmed as requested 
prior to enrollment.  
 
Treatment Regimen 
This is a single arm study with no randomization. All enrolled patients will receive the study drugs. 
 
All patients will receive a dose of ONC201 prior to starting cycle 1, 7 days (-7 days) prior to cycle 
1 day 1 and prior to beginning the combination therapy.  
 
Each cycle is 4 weeks long (28 days). Nivolumab: For cycle 1 day 1 in phase Ib and phase II, only 
a +2 day window is allowed. 
 


Page 43 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
Treatment will be administered on an outpatient basis. No investigational or commercial agents 
or therapies other than those described below may be administered with the intent to treat the 
participant's malignancy. 
 
The treatment dose of nivolumab is 240 mg. No dose reductions or escalations will be allowed 
for nivolumab. Dosing delays and modifications are described in Section 6.3-6.5 (DLT, Dosing 
Delays/Dose Modifications).  
 
The maximum duration of treatment will be 12 months unless it is determined that a patient 
would derive benefit from continued therapy beyond 12 months, as determined by the 
investigator. Follow-up for all patients will be approximately 6 months.  
 
The study is expected to be completed over an approximate 3.5-year period 
 
If nivolumab is permanently discontinued due to toxicity, and the patient has had stable or 
responding disease, then ONC201may be resumed when toxicity resolves to grade <1. If the 
patient develops recurrent grade >3 toxicity while on single agent ONC201 after stopping 
nivolumab then ONC201 will be permanently stopped and the patient removed from protocol 
treatment.   
 
(The rationale for continuing single agent ONC201 is to gather additional information of the 
efficacy of ONC201 in colon cancer. As described in section 2.1.2.1 ONC201 has activity in colon 
cancer cell lines. As described in section 2.2.1, in the phase I study, one patient with metastatic 
colon cancer that had progressed after multiple lines of standard therapy, had prolonged stable 
disease with ONC201. Since preliminary studies of ONC201 have demonstrated a promising 
toxicity profile, it may be helpful to continue ONC201 in stable/responding patients if nivolumab 
is stopped for immune toxicities.) 
 
 
If ONC201 is permanently discontinued due to toxicity then nivolumab will be stopped and 
patients will be removed from study treatment.  
 
 
When Nivolumab and ONC201 are both due, if administration of nivolumab is delayed based on 
section 6.6, ONC201 may be given alone, as long as the patient meets criteria for ONC201 dosing. 
If it is day 1 of a cycle, please also refer to section 6.3. 
 
 
 
 
Nivolumab Description 


Page 44 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length=4 
weeks 
Nivolumab 
No premedication or 
hydration necessary. 
Subjects should be 
carefully monitored, as 
per institutional policy, 
for infusion reactions 
during nivolumab 
administration.  
240 mg 
IV over 
approximately 30 
minutes 
Day 1 
Dosing: Q 
14 days 
(2 weeks 
+/- 2 days) 
For cycle 
1 day 1 a 
+ 2 day 
window 
only is 
allowed 
 
There will be no dose reductions for Nivolumab. All patients should continue to meet treatment 
parameters required at eligibility, unless as otherwise specified below.  
 
Nivolumab is to be administered as an approximate 30-minute IV infusion. For details on 
prepared drug storage, preparation, and administration, please refer to the Nivolumab 
Investigator Brochure (IB). The nivolumab infusion must be promptly followed by a 
saline flush to clear the line of nivolumab. 
 
Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 1.2-micron 
pore size, low-protein binding polyethersulfone membrane in-line filter at 240 mg. It is not to be 
administered as an IV push or bolus injection. 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 1 mg/mL. Care must be taken to assure sterility of the prepared 
solution as the product does not contain any antimicrobial preservative or bacteriostatic agent.  
 
ONC201: dose de-escalation will proceed according to a standard 3 + 3 design. Dosing is to be 
given day 1 of each week and is to occur with Nivolumab dosing when each drug is to be given 
on the same day. There is a +/- 2-day window.  
 
On days when ONC201 and nivolumab are administered on the same day, ONC201 should be 
administered within (<) 30 minutes after completion of nivolumab 
 
If drug cannot be given within the required time-frame, utilizing the window, then the dose is 
considered missed and is not made up.  
 
All patients will ingest ONC201 capsules in front of research clinical staff during cycle 1. 
 
ONC201 will be taken in front of research staff in cycle 1. Patients are to bring ONC201 drug into 
clinic day -7, day 1, day 8, day 15, day 22. 


Page 45 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
Example Phase Ib:  
 
Run-in Day -7: January 7, 2019 ONC201 dose 1 
Cycle 1 day 1: January 14, 2019 Nivolumab and ONC201 dose 2 (+ 2-day window allowed, both 
drugs to be given together) 
Cycle 1 week 2: January 21, 2019 ONC201 dose 3 (+/- 2-day window allowed) 
Cycle 1 week 3: January 28, 2019 Nivolumab and ONC201 dose 4 (+/- 2-day window allowed, 
both drugs to be given together) 
Cycle 1 week 4: February 4, 2019 ONC201 dose 5 (+/- 2-day window allowed) 
End of cycle 1 
 
Dose de-escalation schedule for phase 1b trial ONC201: 
 
Doses in table are exact flat doses. Doses are not adjusted for body weight.  
 
Dose Level 
Dose of ONC201* (mg) every week, day 1 (to 
occur with Nivolumab dosing when both 
drugs are due) 
Level 1 (starting dose level) 
625mg 
Level 2 
500mg 
Level 3 
375mg 
 
 
The starting dose schedule of ONC201 will be 625 mg administered once every 1 week, which has 
been established to be safe in the first-in-human trial in advanced solid tumors (Stein et al, JCO, 
under review). 
 
Dose limiting Toxicities (DLTs): 
 
DLTs will be assessed in the phase Ib portion of the trial. DLTs will be collected during the run-
in (dose 1 of ONC201), cycle 1 and prior to dosing cycle 2 day 1. All patients in a cohort must be 
assessed for DLTs through pre-dosing cycle 2 day 1 prior to the next cohort being opened. 
 
 
 
New cycle requirements (cycle 2-on) (Refer to sections 6.4, 6.5 and 6.6 before 
dosing) 
 
A new course of treatment (cycle) with ONC201 and Nivolumab should not begin until the 


Page 46 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
following criteria are met.  
• Platelets > 75000/mcl  
• Granulocytes (ANC) >1000/mcl 
• Recovery from other clinically significant, treatment related non-hematologic toxicities to 
< Grade 2     
When Nivolumab and ONC201 are both due, if a patient is unable to receive Nivolumab based on 
section 6.6, ONC201 may be given alone, as long as the patient meets criteria for ONC201 dosing. 
If it is day 1 of a cycle, please also refer to section 6.3. 
 
Determination of the MTD and RP2D 
 
Dose limiting Toxicities (DLTs): 
DLTs will be assessed in the phase Ib portion of the trial. DLTs will be collected during the run-
in (dose 1 of ONC201), cycle 1 and prior to dosing cycle 2 day 1. All patients in a cohort must be 
assessed for DLTs through pre-dosing cycle 2 day 1 prior to the next cohort being opened. 
 
Dose Definitions (MAD, MTD, RP2D) 
The maximally tolerated dose (MTD) is defined as the dose frequency schedule above which the 
absolute observed DLT rate is > 25%. The MTD is equivalent to the anticipated recommended 
phase 2 dose (RP2D).  
 
However, the final RP2D may also be influenced by pharmacokinetic information, additional 
emerging toxicity data, pharmacodynamic data, or practical dosing (capsule load) information. 
The RP2D will never exceed the MTD. 
The MAD, or maximally administered dose, is estimated to be 625 mg (5 capsules) given weekly, 
beginning day -7 (phase Ib) and day 1 (phase II).  
6.4.1 Dose Limiting Toxicity (DLT) definition  
Toxicity will be evaluated according to the NCI CTCAE, version 5.0.  
 
DLTs will be collected during the run-in (dose 1 of ONC201), cycle 1 and prior to dosing cycle 2 
day 1. All patients in a cohort must be assessed for DLTs through pre-dosing cycle 2 day 1 prior 
to the next cohort being opened.  
 
If, however a patient experiences one of the below toxicities after cycle 2 or in the phase II 
portion it will not be considered a DLT, however: hold treatment (both drugs), once the toxicity 
reduces to a grade 1 or less, dose reduce (ONC201) and resume treatment, even though it will no 
longer be defined as a DLT. 
A DLT will be defined as any of the following AEs that are attributed to the study drugs 
(Nivolumab or ONC201): 
 


Page 47 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
If a patient experiences a DLT, hold treatment (both drugs) until the adverse event reduces to a 
grade 1 or less and resume ONC201 at 1 dose level reduction. Nivolumab is not to be dose reduced.  
 
If nivolumab is permanently discontinued due to toxicity, and the patient has had stable or 
responding disease, then ONC201may be resumed when toxicity resolves to grade <1. If the 
patient develops recurrent grade >3 toxicity while on single agent ONC201 after stopping 
nivolumab then ONC201 will be permanently stopped and the patient removed from protocol 
treatment.   
 
  
6.4.2  DLT definitions phase Ib: 
(Run-in Day -7, cycle 1 and pre-cycle 2), Events occurring in cycles 2-12+ in phase Ib or in 
phase II will be not be considered a DLT however both treatments must be held and once 
toxicity reduces to grade 1 or less, dose reduce ONC201: 
 
Hematologic: 
• Grade 4 neutropenia that persists for >7 consecutive days 
• Febrile neutropenia (defined as neutropenia ≥ Grade 3 and a body temperature 38.5°C) 
• Grade ≥ 3 neutropenic infection 
• Grade 4 thrombocytopenia (platelets <25,000 cells/mm3) or Grade ≥ 3 thrombocytopenia 
with bleeding 
 
Non-hematologic: 
 
• Any other treatment related, clinically significant Grade ≥ 3 toxicity not classified under 
CTCAE blood or bone marrow with the exception of grade 3 nausea, vomiting, or 
diarrhea in patients who have received optimal treatment with antiemetics or anti-
diarrheals and who do not downgrade to a grade 1 within 72 hours; Grade 4 (life 
threatening) diarrhea or vomiting will be  considered DLTs, irrespective of the duration 
of the event. alopecia is not a DLT 
• Delay of > 2 weeks secondary to a treatment related AE that is deemed possibly or 
definitely related to either drug  
• Failure to receive at least 80% of the planned dose on ONC201 due to treatment related 
AEs (ONC201) in cycle 1 (5 doses ONC201 with run-in).  
 
Although toxicities may be observed at any point during treatment, only those occurring during 
the defined DLT observation window of treatment that are considered DLTs will guide dose de-
escalation decisions, expansion of a dose level, or evaluation of intermediate dose levels. 
 
Patients will be monitored through all cycles of therapy for treatment-related toxicities, and all 
toxicities, including those occurring in beyond the DLT observation window, will be documented.  


Page 48 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
6.4.3 Dose de-escalation: 
Dose de-escalation will proceed by a 3+3design. Cohorts will be de-escalated in successive cohorts 
of 3 to 6 patients.  
 
Patients failing to complete the first 4 weeks of treatment for reasons other than toxicity (e.g., lost 
to follow up, patient withdrawal, progression) will be replaced for the purpose of meeting the 
primary objective of this study.  
 
Starting with the treatment of 3 patients at the planned dose cohorts described previously, the 
administration of ONC201 will follow traditional 3 + 3 dose de-escalation rules summarized 
below: 
1. Dose level 1: Enroll 3 patients.  
2. If 0 of 3 patients experience a DLT, 3 additional patients will be enrolled at that same dose 
cohort to confirm safety. If < 1 (no patients) of these 6 subjects encountered a DLT, then 
this dose level will be declared to be the MTD. This dose level will be expanded to treat 
34 patients in phase II. 
3. If 1 of 3 patients experience a DLT, 3 additional patients will be enrolled at that same 
dose cohort. If 2 or more of the 3-6 subjects within a cohort encounter a DLT, then the 
MTD has been exceeded and de-escalation will proceed to the next dose level (dose level 
2 etc.). Only 2 dose reductions of ONC201 will be allowed. 


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CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
 ONC 201 Dose Delays/Holds Phase II: Dose Delays, Reductions and Interruptions 
for toxicities that are deemed related (some causality) to ONC201 During the Phase II 
Portion of the Study: 
Adverse 
Event 
Dose Adjustment 
Grade 1 
and 2 
• No change in dose 
Grade 3 
Hold ONC201 
Resumption of ONC201 may continue as outlined below: 
• First occurrence: Hold ONC201 until ≤ Grade 1. Resume ONC201 at one 
dose frequency cohort lower 
• Second occurrence: Hold ONC201 until ≤ Grade 1. Resume ONC201 at one 
dose frequency cohort lower with ~ half the number of capsules administered 
followed by the administration of the other half of the capsules 6-12 hours 
later 
• Third occurrence: Off protocol therapy 
Grade 4 
• Off protocol therapy 
 
If, however a patient experiences a “DLT toxicity” after cycle 2 or in the phase II portion it will 
not be considered a DLT, however: hold treatment (both drugs), once the toxicity reduces to a 
grade 1 or less, dose reduce (ONC201) and resume treatment, even though it will no longer be 
defined as a DLT. 
 
On a day when Nivolumab and ONC201 are both due, if a patient is unable to receive Nivolumab 
based on section 6.6, ONC201 may be given alone, as long as the patient meets criteria for 
ONC201 dosing. If it is day 1 of a cycle, please also refer to section 6.3. 
 
Dose delays for Nivolumab Phase Ib and Phase II: 
 
Non-Immune mediated: All clinically significant (grade 3 or higher) hematologic and non-
hematologic toxicities felt to have some causality to nivolumab must resolve to < grade 2 
(excluding weight loss, weight gain, and alopecia) or to baseline prior to a patient receiving a 
subsequent dose (of Nivolumab). Any dose of nivolumab not administered will be skipped and 
not made up if outside of the +/- 2-day window.  
 
 
Immune mediated: Adverse events (both serious and non-serious) associated with 
nivolumab may represent immunologic etiology.  
 


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Protocol- BrUOG 379 
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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
Nivolumab must be held for suspected immune-mediated toxicities or severe/life-threating 
AEs of particular interest as outlined in section below and immune-related toxicities in 
Appendix D. Please review both Sections (6.6 (below) and Appendix D) prior to infusion of 
nivolumab in any patient in whom immune-mediated toxicity is suspected.   
 
If the investigator is unsure if a particular toxicity at least possibly represents an immune 
mediated toxicity to nivolumab, the treating physician should follow section 6.5 (this section) 
and appendix D and treat as immune mediated, until it is confirmed as not being immune 
mediated. Consultation with BrUOG is suggested in such situations. BrUOG will share 
information about the situation with the BrUOG Reviewer and provide the site guidance, as 
available. 
 
Except on day 1 of a cycle, when Nivolumab and ONC201 are both due, if a patient is unable to 
receive Nivolumab based on section 6.6, ONC201 may be given alone, as long as the patient meets 
criteria for ONC201 dosing. If it is day 1 of a cycle, please also refer to section 6.3. 
 
Prior to treatment of either arm or either drug, the following criteria must be met as they pertain 
to related (to either or both drugs) immune mediated events: 
 
• ANC < grade 3 (must be > 500). 
 
-Febrile neutropenia or neutropenia < 500 cells/mm³ (grade 4).  
-If Grade 4 neutropenia persists for greater than one week, the patient is required 
to come off study. 
• Hyperthyroidism or Hypothyroidism: grade will be based on patient symptoms, not solely 
on whether suppression or supplementation is indicated. 
 Grade 1 asymptomatic 
o Grade 2 symptomatic, limiting instrumental ADLs 
o Grade 3 severely symptomatic, limiting self-care ADLs, hospitalization indicated 
o Grade 4 Life threatening consequences, intervention indicated. Requires patient to 
come off study 
o Grade 5 death 
 
Patients meeting criteria of Grade 2 or greater must resolve to Grade 1, be on stable hormone 
therapy, and complete steroid taper (if indicated). Of note, a patient who meets grade 1 criteria, 
but who is on a stable dose of hormone therapy, is allowed to receive treatment on study.  
 
• Diarrhea and enterocolitis< grade 2 
 
 
Grade 2: delay until < grade 1 and resume at discretion of treating MD 
 
 
Grade 3 or 4: Patient off study 
• Transaminase and Bilirubin < grade 2 
 
 
Grade 2: Hold until < grade 1 and increase monitoring as per table 


Page 51 of 145 
 
Protocol- BrUOG 379 
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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
Grade 3 or 4: remove from study, see appendix D for details on grade 3 
• Lipase and amylase < grade 4 
 
 
Grade 2 with findings of pancreatitis: hold until resolved 
Grade 3 or 4: Lipase or amylase elevations only patient may continue on 
study with monitoring 
Grade 3 or 4 pancreatitis or worsening DM: remove from study 
• Neurological events (inclusive of neuropathy if not present at baseline) < grade 2 
Grade 2: Hold until < grade 1. If steroids needed, remove from study 
 
 
 
Grade 3 or 4: remove from study 
• Pneumonitis < grade 1 
 
Grade 1: Consider delay of treatment, but may proceed with treatment at 
the discretion of the treating physician.   
Grade 2: Delay until < grade 1. Consider steroids (see Appendix D, 
Pulmonary AE Management Algorithm). If not improving after 2 weeks or 
worsening symptoms, treat as Grade 3 or 4. If improving, taper steroids 
over at least 1 month once symptoms return to or near baseline and resume 
protocol treatment.  
Grade 3 or 4: remove from study 
• Creatinine < grade 2 
 
Grade 2 and 3: Hold until < grade 1. Consider steroid treatment (see 
Appendix D, Renal AE Management Guideline).  
 
 
 
Grade 2 or 3 for > 7 days: treat as a grade 4 
 
 
 
Grade 4: remove from study 
• Skin rash (all types) and oral lesions < grade 2 
 
 
 
Grade 3: Hold until < grade 1 
 
 
 
Grade 4: remove from study 
• Fatigue < grade 2 
Grade 3: Hold until < grade 2 if within 7 days. If persists >7 days, remove 
from study.  
 
 
Grade 4: remove from study 
• Fever < grade 2 
 
 
Grade 2, 3: hold until < grade 1 
 
 
Grade 4: remove from study 
6.6.1  Nivolumab Removal from study: 
 
Patients must discontinue nivolumab permanently for the following:  
 
• Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period 
OR requires systemic treatment 


Page 52 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
• Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding   
• Any treatment delay resulting in no nivolumab dosing for > 6 weeks.  
• Grade 4 drug-related endocrinopathy adverse events such as adrenal insufficiency, ACTH 
deficiency, hyper- or hypothyroidism, or glucose intolerance, hypophysitis. 
• > Grade 3 or 4 hepatic AEs * see appendix D for details 
• > Grade 4 skin toxicity (per Appendix D can delay or discontinue for grade 3. Must come 
off, as per this bullet for grade 4 skin) 
• ALL OTHER treatment related grade 3/4 treatment related events with the following 
exceptions: 
  
 Grade 4 neutropenia ≤ 7 days;  
 Grade 4 lymphopenia or leukopenia;  
 isolated Grade 4 electrolyte imbalances/abnormalities that are not 
associated with clinical sequelae and are corrected with supplementation/ 
appropriate management within 72 hours of their onset;  
 Grade 3 hepatic AEs that return to Grade 2 or less within 5 days; of note, 
this overrides Appendix D 
 Skin toxicity < grade 3 that improves with steroid therapy. NOTE: Any 
rash consistent with Stevens-Johnson Syndrome or Toxic Epidermal 
Necrolysis requires permanent discontinuation of nivolumab.  
 Grade 3 renal toxicity (as per Appendix D) 
 
6.6.2 Treatment of Nivolumab Infusion Reactions:  
 
Nivolumab 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, hypo- or hypertension, bronchospasm, or other symptoms of allergic-
like reactions.  
 
All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met. Infusion 
reactions should be graded according to NCI CTCAE 5.0 guidelines. 
 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate: 
 
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated) 
 
Remain at bedside and monitor subject until recovery from symptoms. The following prophylactic 
pre-medications are recommended for future infusions: diphenhydramine 50 mg (or equivalent) 


Page 53 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
and/or acetaminophen 325 to 1000 mg at least 30 minutes before additional nivolumab 
administrations. 
 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [e.g., antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for 24 
hours). 
 
Stop the infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen 325 to 1000 mg; remain at 
bedside and monitor subject until resolution of symptoms. Corticosteroid or bronchodilator 
therapy may also be administered as appropriate. If the infusion is interrupted, then restart the 
infusion at 50% of the original infusion rate when symptoms resolve; if no further complications 
ensue after 30 minutes, the rate may be increased to 100% of the original infusion rate. Monitor 
subject closely. If symptoms recur, then no further nivolumab will be administered at that visit. 
Administer diphenhydramine 50 mg IV, and remain at bedside and monitor the subject until 
resolution of symptoms. The amount of study drug infused must be recorded on the case report 
form (CRF). The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg should be 
administered at least 30 minutes before additional administrations. If necessary, corticosteroids 
(recommended dose: up to 25 mg of IV hydrocortisone or equivalent) may be used. 
 
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [i.e., not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[e.g., renal impairment, pulmonary infiltrates]). Grade 4: (life threatening; pressor or ventilatory 
support indicated).  
 
Immediately discontinue infusion. Begin an IV infusion of normal saline, and treat the subject as 
follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 solution for 
subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV 
administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or 
equivalent), as needed. Subject should be monitored until the investigator is comfortable that the 
symptoms will not recur. Nivolumab will be permanently discontinued. Investigators should 
follow their institutional guidelines for the treatment of anaphylaxis. Remain at bedside and 
monitor subject until recovery from symptoms.  
 
In the case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given (e.g., 
oral antihistamine, or corticosteroids). 


Page 54 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
6.6.3 Immune-Related Adverse Events (irAEs) General Definition, Monitoring, and 
Management 
 
For the purposes of this protocol, an immune-related adverse reaction irAE is defined as an 
adverse reaction of unknown etiology associated with drug exposure and consistent with an 
immune phenomenon. Efforts should be made to rule out neoplastic, infectious, metabolic, toxin 
or other etiologic causes prior to labeling an event an irAEs.  Serologic, immunologic, and 
histologic (biopsy) data should be used to support the diagnosis of an immune-related toxicity. 
Suspected immune-related adverse reactions must be documented on an AE or SAE form.  
 
Overall, immune-related AEs commonly start within 3 to 10 weeks from initiation of therapy and 
are in most cases successfully managed by delaying doses, discontinuing dosing, and/or through 
administering symptomatic or immunosuppressive therapy, including corticosteroids, as 
mentioned below.  Immune-related AEs generally resolved within days to weeks in the majority 
of subjects. 
 
Patients should be informed of and carefully monitored for evidence of clinically significant 
systemic immune-mediated adverse reactions (e.g., systemic lupus erythematosus-like diseases) 
or organ specific immune-mediated adverse reaction (e.g., rash, colitis, uveitis, hepatitis or 
thyroid disease). If an immune-mediated adverse reaction is noted, appropriate work-up 
(including biopsy if possible) should be performed, and steroid therapy may be considered if 
clinically necessary.   
 
It is unknown if systemic corticosteroid therapy has an attenuating effect on nivolumab activity. 
If utilized, corticosteroid therapy should be individualized for each patient. For example, prior 
experience suggests that colitis manifested as ≥ grade 3 diarrhea requires corticosteroid 
treatment. If an irAE is documented, in general, delay protocol therapy and initiate 
corticosteroids earlier to obtain resolution with the possibility for resuming protocol therapy 
rather than waiting for higher grade events. 
 
Investigators should as a rule evaluate suspected adverse effects early, and with any suspicion, 
erring on the side of caution by withholding drug and instituting appropriate treatment as 
indicated in the management tables and following event specific guidelines. 
6.6.4  Immune-mediated Endocrinopathy  
 
Agents such as nivolumab can cause inflammation of endocrine organs including thyroid 
(Hashimoto’s thyroiditis with positive antibodies) and adrenal glands, hypophysitis, 
hypopituitarism, and resulting thyroid and adrenal insufficiency, low ADH, prolactin, FSH, LH.  
Hyperthyroid with Graves’ disease and positive antibody has been reported.  Patients may 
present with subtle and nonspecific symptoms.  The most common clinical presentation includes 
headache and fatigue.  Symptoms may also include visual field defects, behavioral changes, and 


Page 55 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
electrolyte disturbances including hyponatremia and hypotension.  Adrenal crisis as a cause of 
the patient’s symptoms should be excluded.  Based on the available data with known outcome, 
most of the subjects symptomatically improved with hormone replacement therapy.  
 
Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency 
(including adrenal crisis), and hyper- or hypothyroidism.  Headache is often the first symptoms 
of hypophysitis.  Patients may present with fatigue, headache, mental status changes, loss of 
libido, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which 
may resemble other causes such as brain metastasis or underlying disease.  Unless an alternate 
etiology has been identified, signs or symptoms of endocrinopathy should be considered 
immune-mediated and drug withheld pending evaluation.  Patients may demonstrate both central 
(hypophysitis) and peripheral adrenal and thyroid insufficiency.  Evaluation of hypophysitis 
should include pituitary MRI.  
 
In this study, TSH will be performed at baseline prior to initial treatment.  TSH levels, clinical 
chemistries and clinical assessment is to be performed using the schedule below, with further 
evaluation as clinically indicated.  Monitoring TSH may allow early detection of pituitary 
dysfunction and hypophysitis. Clinical monitoring of symptoms may be equally or more 
sensitive as an initial presentation.  In a limited number of patients, hypophysitis was diagnosed 
by imaging studies through enlargement of the pituitary gland.   
 
Please see Appendix D (Endocrinopathy Management Algorithm) for guidelines on managing 
adverse events. 
6.6.5  Immune-mediated enterocolitis 
 
The clinical presentation of GI immune-related AEs included diarrhea, increase in the frequency 
of bowel movements, abdominal pain, or hematochezia, with or without fever. However, 
inflammation may occur in any part of the GI tract including esophagitis and gastritis.  Fatalities 
due to GI perforation have been reported in clinical trials of Ipilimumab in particular. Patients 
should be carefully monitored for GI symptoms that may be indicative of immune-related colitis, 
diarrhea, or GI perforation.  Diarrhea or colitis occurring after initiation of nivolumab therapy 
should be evaluated to exclude infectious or alternate etiologies. In clinical trials, immune-
related colitis was associated with evidence of mucosal inflammation, with or without 
ulcerations, and lymphocytic infiltration. 
Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, 
mucus or blood in stool, with or without fever) and bowel perforation (such as peritoneal signs 
and ileus).  In symptomatic patients, rule out infectious etiologies and consider endoscopic 
evaluation to establish etiology and for persistent or severe symptoms.  C.difficile toxin has been 
detected in several patients with colitis and may be an independent entity or may co-exist with 
ipilimumab induced inflammatory colitis.  
 


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Protocol- BrUOG 379 
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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
Permanently discontinue nivolumab in patients with severe enterocolitis (see table below), and 
initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of methylprednisolone IV or IV 
equivalent. Upon improvement to grade 1 or less, initiate corticosteroid taper and continue to 
taper over at least one month. In clinical trials, rapid corticosteroid tapering of ipilimumab has 
resulted in recurrence or worsening symptoms of enterocolitis in some patients receiving 
ipilimumab. Patients have been treated with anti-TNF agents (e.g., infliximab) for persistent 
colitis not responding to steroids.  
 
Please note autoimmune pancreatitis may cause abdominal pain and should be included in all 
evaluations. Enteritis may occur occasionally with other autoimmune events including hepatitis, 
pancreatitis, and endocrine insufficiency, which should be evaluated as clinically indicated. 
 
Please refer to the GI Adverse Event Management Algorithm in Appendix D for guidance on 
toxicity management. 
6.6.6 Immune-mediated hepatitis and pancreatitis 
 
Hepatic immune-related AEs are mostly clinically silent and manifested as transaminase or 
bilirubin laboratory abnormalities.  Fatal hepatic failure has been reported in clinical trials of 
ipilimumab.  Serum transaminase, bilirubin and lipase levels must be evaluated before each 
protocol directed therapy infusion as early laboratory changes may be indicative of 
emerging immune-related hepatitis/ pancreatitis and elevations in liver function tests 
(LFTs) may develop in the absence of clinical symptoms.  Increase in LFT or total bilirubin 
should be evaluated to exclude other causes of hepatic injury, including infections, disease 
progression, or other medications, and monitored until resolution.  Liver biopsies from patients 
who had immune-related hepatotoxicity have shown evidence of acute inflammation 
(neutrophils, lymphocytes, and macrophages).  
 
Monitor levels of hepatic transaminases, bilirubin, and lipase and assess patients for signs and 
symptoms of hepatotoxicity/pancreatitis before each protocol directed therapy infusion.  In 
patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of 
liver function test monitoring until resolution.  Please see the Hepatic Adverse Management 
Guideline in Appendix D for further guidance. 
 
The management of pancreatitis is given below. 
Pancreatitis 
Amylase/Lipase  
Management/Next Dose for Nivolumab  
Grade 1 
Continue protocol therapy and monitor. Asymptomatic lipase/amylase 
elevation, continue protocol therapy and monitor patient clinically. 
Grade 2 
For amylase/lipase elevations only, continue protocol therapy and 
monitor patient clinically. For radiographic findings consistent with 
pancreatitis, hold protocol therapy until resolved. 


Page 57 of 145 
 
Protocol- BrUOG 379 
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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
Pancreatitis 
Amylase/Lipase  
Management/Next Dose for Nivolumab  
 
Grade 3 
Discontinue protocol therapy for development of Grade 3 pancreatitis or 
for new or worsening DM. Evaluate for co-existing 
hepatitis/cholecystitis.   For amylase/lipase elevations only, continue 
protocol therapy and monitor patient clinically.  
Grade 4 
Discontinue protocol therapy for development of Grade 4 pancreatitis or 
for new or worsening DM.   For amylase/lipase elevations only, 
continue protocol therapy and monitor patient clinically. Consider 
imaging if no improvement or worsening. 
 
 Pneumonitis 
 
Distinguishing inflammatory pneumonitis is often a diagnosis of exclusion for patients who do 
not respond to antibiotics and have no causal organism identified including influenza.  Most 
patients with respiratory failure or hypoxia will be treated with steroids, see Opdivo package 
insert for further information.  Bronchoscopy may be required and analysis of lavage fluid for 
lymphocytic predominance may be helpful.  Patients with new lung nodules should be evaluated 
for sarcoid like granuloma.  Consider recommending seasonal influenza killed vaccine for all 
patients. 
Please refer to Appendix D for management of pulmonary adverse events.  
6.6.7  Renal Adverse Events 
 
Please refer to Appendix D for management of renal adverse events.  
6.6.8  Immune-mediated dermatitis 
 
Skin immune-related AEs presented mostly frequently as a rash and/or pruritus.  Some subjects 
reported vitiligo associated with nivolumab administration.  Fatal toxic epidermal necrolysis has 
been reported in clinical trials of ipilimumab. Monitor patients for signs and symptoms of 
dermatitis such as rash and pruritus.  Unless an alternate etiology has been identified, signs or 
symptoms of dermatitis should be considered immune-mediated.  For further information, refer 
to Appendix D for management of skin adverse events. 
6.6.9  Fatigue 
 
Fatigue is the most common adverse event associated with immune checkpoint therapy.  Grade 2 
or greater fatigue should be evaluated for associated or underlying organ involvement including 
pituitary, thyroid, hepatic, and/or muscle (CPK) inflammation. 
 


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Protocol- BrUOG 379 
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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
FATIGUE  
Management/Next Dose for Nivolumab  
Grade 1 
Continue protocol therapy 
Grade 2 
Continue protocol therapy 
Grade 3 
Hold protocol therapy.  Resume protocol therapy if ≤ Grade 2 within 7 
days. 
Grade 4 
Discontinue protocol therapy 
6.6.10 Fever 
 
Patients with fever should be evaluated as clinically appropriate.  Patients may experience 
isolated fever during infusion reactions or up to several days after infusion.  Evaluation over the 
course of 1-2 weeks should be done for other autoimmune events that may present as fever. 
 
Fever  
Management/Next Dose for Nivolumab  
Grade 2 
Hold protocol therapy until < grade 1.  Then resume protocol therapy  
Grade 3 
Hold protocol therapy until < grade 1.  Then resume protocol therapy  
Grade 4 
Discontinue protocol therapy 
 
6.6.11 Other immune-mediated AEs (eg, ocular, joint, myocardial, pericardial) – See 
Appendix 
 
Other immune-mediated AEs not addressed have been observed with these agents. Permanently 
discontinue nivolumab for clinically significant or severe immune-mediated adverse reactions.  
Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone IV or IV 
equivalent for severe immune-mediated adverse reactions. Administer corticosteroid eye drops to 
patients who develop uveitis, iritis, or episcleritis. 
 
ALL OTHER 
EVENTS 
Management/Next Dose for Nivolumab  
≤ Grade 1 
Continue protocol therapy at investigator discretion. 
Grade 2 
Consider corticosteroids as clinically indicated. Hold until ≤ grade 1 
OR baseline, then resume protocol therapy. 
Grade 3 
Discontinue protocol therapy 
Grade 4 
Discontinue protocol therapy 
Any patient started on corticosteroids initially who is subsequently determined not to require 
steroids treatment for an autoimmune adverse event may resume therapy at the discretion of the 
investigator. In such a case, steroids should be slowly tapered. 
 
 
Permitted and Prohibited concomitant medications and interventions 
All supportive therapy for optimal medical care will be given during the study period at the 


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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
discretion of the attending physician(s) within the parameters of the protocol and documented 
source documents as concomitant medication. 
6.7.1 Permitted Supportive/Ancillary Care and Concomitant Medications 
• Analgesics 
• Antibiotics 
• Anticonvulsants 
• Antiemetics 
• Anticoagulants 
• Antihistamines  
• Corticosteroids +/- mineralocorticoid component  
• Hydration 
• Immunosuppressive agents – other  
• Infliximab  
• Mycophenolate mofetil  
• Nutritional supplementation 
• Interventional use of growth factors is allowed if deemed necessary by the 
Investigator but only to treat grade 4 neutropenia or febrile neutropenia. 
Erythropoietin use is discouraged in accordance with ASCO guidelines.  
 
6.7.2 Prohibited therapies 
• Chronic systemic corticosteroids or other immunosuppressive agents for conditions 
other than for hypersensitivity or immune adverse effects associated with nivolumab 
as specified in the protocol. 
Patients in this study may use standard vaccines.  Where possible, routine vaccination 
for influenza, pneumococcal pneumonia should be given prior to the start of therapy 
but may be administered during treatment when clinically indicated. Vaccination 
should be given when there is enough separation to distinguish any vaccine reactions 
from drug toxicity.  NOTE: There is no experience using live attenuated vaccination 
during nivolumab therapy, so live vaccine should be used cautiously during 
treatment. 
Concomitant systemic or local anti-cancer medications or treatments are prohibited. 
• Erythropoietin is discouraged in accordance with FDA guidelines.  
• Treatment with other anticancer or experimental drugs is not permitted for patients 
treated on this protocol.  
• All palliative care necessary for optimal care of the patient should be provided. 
Palliative radiation is not allowed on study. If a patient requires palliative radiation 
they should be removed from the study. 


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Protocol- BrUOG 379 
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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
• Any live / attenuated vaccine (eg varicella, zoster, yellow fever, rotavirus, oral polio 
and measles, mumps, rubella (MMR)) during treatment and until 100 days post last 
dose. 
 
7 
Drug Supply ONC201 
7.1.1 Formulation, packaging and storage 
The study drug ONC201 is provided as 125 mg free base (approximately 150 mg of 
dihydrochloride), that may include microcrystalline cellulose, sodium starch glycolate, and/or 
magnesium stearate as excipients, filled into hydroxypropyl methylcellulose (HPMC) capsule 
shells.  
 
The ONC201 drug product capsules are intended for oral administration. The product is stored in 
a multi-dose container. The capsules are packaged in high-density polyethylene (HDPE) white 
opaque bottles, closed with an induction seal and capped with a white ribbed SecuRx® 
polypropylene (PPE) cap. The capsules are to be stored in the original closed container at room 
temperature (15 to 30°C). 
 
As of February 2019, ONC201 is produced with 10 capsules per bottle. This may vary in the future, 
however the number of capsules will be documented on the product label, per package. 
 
The study drug bottle label bears the following information:  
 
 
 
ONC201 Capsules, 125mg 
For Oral Use Only 
Caution: New Drug--Limited by Federal (or United States) law to investigational use. 
 
Storage: Preserve in original tightly closed containers at room temperature (15 to 30°C) 
 
Manufacturer: Oncoceutics, Inc. 
 
Batch # xxx-xxx-xxxx-xx             
Mfg date: XX-XXXX 
                             
                            Number of capsules: 
Figure 18: Investigational drug label 
 


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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
7.1.2 Drug accountability 
Upon receipt at the investigative site, study drug product must be stored at room temperature in 
the original packaging. The drug should be protected from light and excessive humidity in a 
monitored, locked, secure area with limited access. Storage area temperature conditions must be 
monitored and recorded daily.  
 
All temperature excursions will be reported to the Oncoceutics for assessment and authorization 
for continued use. BrUOG is required to be cc’d on this communication (BrUOG@brown.edu).  
Oncoceutics contact: Rohinton.tarapore@oncoceutics.com 
 
Study site staff must instruct patients on how to store and administer oral study drug agents that 
are dispensed for at-home administration, except in cycle 1.  
 
Accountability for study drug product is the responsibility of the investigator. The study site must 
maintain accurate records demonstrating dates and amount of study treatment received, to whom 
dispensed (patient-by-patient accounting), and accounts of any study treatment accidentally or 
deliberately destroyed. A written explanation must be provided for any discrepancies.  
 
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form.  (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.) 
 
Patients are to be instructed on proper accountability of the take-home study drugs and will be 
instructed to return any unused drug in the original packaging along with their completed diary 
cards at the appropriate clinic visits.  
 
The investigator must destroy or return all unused drug product provided, once approved to do so 
by BrUOG, who will obtain confirmation from Oncoceutics. 
7.1.3 Destruction and Return 
 
At the end of the study, unused supplies of ONC201 will be destroyed according to institutional 
policies once BrUOG confirms and approves destruction. BrUOG will obtain approval to destroy 
from Oncoceutics. Destruction will be documented in the Drug Accountability Record Form and 
the form will be routed to BrUOG. Each participating hospital and pharmacy must submit, up 
front and throughout the trial, the most up to date drug destruction policy, to BrUOG.  
 
Drug that is used (partially used vial for examples), can be destroyed in real-time as per the 
pharmacy destruction policy and do not need to be tracked on the accountability log.  
 
Expired drug: Contact BrUOG to provide the number of expired vials/bottles and the current 


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Protocol- BrUOG 379 
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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
accountability logs. BrUOG will obtain approval to destroy drug and will communicate approval 
the pharmacy. BrUOG will then require submission of the drug accountability log, documenting 
the drug destruction of expired material. 
7.1.4 Administration 
All patients will ingest capsules in front of research clinical staff during cycle 1. The capsules are 
not to be chewed or broken but need to be swallowed whole. ONC201 should be taken with a glass 
of water on an empty stomach, with no food for 2 hours prior to dosing or 2 hours following dosing 
The capsules should be taken at approximately the same day each week, at the same time on that 
day. 
 
 
7.1.5 Drug ordering 
Initial: 
• Following submission and approval of the required regulatory documents, BrUOG will share 
all approval documented with Oncoceutics and once confirmed by Oncoceutics and BrUOG, 
and post the SIV, BrUOG will activate the participating hospital, which will allow for initial 
drug request.    
 
All drug orders: 
• There is no drug order form for this trial, the drug request must be sent to the following email 
addresses, with the following information. Please allow 7-10 days for delivery. 
o Name of the PI, BrUOG 379, number of active patients, number of capsules dispensed 
per week, and delivery address. 
• It is required that the pharmacist confirm receipt of the requested drug shipment to the email 
addresses as well.  
• The drug request email must be printed and saved in the BrUOG 379 pharmacy study binder, 
along with the shipment/packaging slip and confirmation of receipt email. 
• All drug orders must be emailed to: 
o rohinton.tarapore@oncoceutics.com 
o  cc to BrUOG@brown.edu 
 
 
ONC201 Dose Modifications for phase II (see section 6.5) 
For treatment-emergent AEs, the dose-frequency of ONC201 will generally be held until 
resolution or lowered. However, preclinical studies suggest that adverse events can be mitigated 
by dose fractionation to lower Cmax. Thus grade 3 AEs (second occurrence) may be reduced or 
eliminated on subsequent cycle by dose fractionation. Six-hour separation of fractionated doses is 
selected based on the anticipated half-life of ONC201 in man and may be adjusted based on clinical 
data. In situations where this occurs during cycle 1, site personnel will be instructed in regards to 
pharmacokinetic blood draws, which will be modified.  


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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
The protocol intends to dose patients with the full intended dose at one time, given the preclinical 
safety data and pharmacodynamic data which supports such dosing. However, preclinical data 
suggests that dose fractionation could potentially mitigate treatment-emergent adverse events, 
which may be Cmax driven. Therefore, if a pattern of adverse events emerge during the conduct of 
the study and a mitigation strategy is felt to be warranted, the patient dose will be fractionated. 
Should this occur, a note-to-file will support the change in dosing and the protocol will reflect the 
updated dosing if an amendment is published. The total dose will be split into two doses and 
administered 6 hours apart from each other. The smaller amount of capsules will be given first, 
followed by the larger amount of capsules 6 hours later (e.g.: 625 mg dose level will be given as 
250 mg in the AM, followed by 375 mg 6 hours later). This strategy may be employed on an 
individual patient, if dose-modification due to a treatment-related adverse event does not 
adequately mitigate the AE after a dose delay or dose reduction, as detailed in Section 5.5 (Table 
4). 
 
Concomitant Medications ONC201 
7.3.1 Drug Interactions 
No formal metabolic or drug-drug interactions with ONC201 or any metabolites have been 
performed.  These studies will be performed later in the development of this agent.  A literature 
search revealed that ONC201 was inactive in a CYP450 screen. Strong inducers and inhibitors of 
the cytochrome P450 system should be used with caution.  
 
Nivolumab Drug Supply: 
 
7.4.1 PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with Nivolumab administered in this 
study can be found in Section 6.5 
 
7.4.2 Description 
 
Nivolumab is an anti-PD-1Mab with a molecular weight of 146,221 daltons. Nivolumab targets the 
programmed death–1 (PD-1, cluster of differentiation 279 [CD279]) cell surface membrane 
receptor. PD-1 is a negative regulatory receptor expressed by activated T and B lymphocytes. 
Binding of PD-1 to its ligands, programmed death–ligand 1 (PD-L1) and 2 (PD-L2), results in the 
down-regulation of lymphocyte activation. Nivolumab inhibits the binding of PD-1 to PD-L1 and 
PD-L2.  Inhibition of the interaction between PD-1 and its ligands promotes immune responses 
and antigen-specific T-cell responses to both foreign antigens as well as self-antigens. 
 
Nivolumab Injection is a clear to opalescent, colorless to pale yellow liquid; light (few particulates 


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Protocol- BrUOG 379 
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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
may be present. The drug product is a sterile, non-pyrogenic, single-use, isotonic aqueous solution 
formulated in sodium citrate, sodium chloride, mannitol, diethylenetriamine pentacetic acid 
(pentetic acid) and polysorbate 80 (Tween® 80), pH 6.0. 
7.4.3 Form 
Nivolumab Injection is a clear to opalescent, colorless to pale yellow liquid; light (few) 
particulates may be present. The drug product is a sterile, non-pyrogenic, single-use, isotonic 
aqueous solution formulated in sodium citrate, sodium chloride, mannitol, diethylenetriamine 
pentacetic acid (pentetic acid) and polysorbate 80 (Tween® 80), pH 6.0. 
 
Nivolumab is supplied by Bristol-Myers Squibb as 100 mg vials (10 mg/mL) with a 0.7 mL overfill.  
It is supplied in 10 mL type I flint glass vials, with butyl rubber stoppers and aluminum seals.  
7.4.4 Storage and Stability 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) vials of nivolumab injection must be stored at 
2ºC to 8ºC (36ºF to 46ºF) and protected from light and freezing. 
 
Undiluted Nivolumab Injection and Diluted Nivolumab Injection in the IV Container 
 
The administration of nivolumab infusion must be completed within 24 hours of preparation. If 
not used immediately, the infusion solution may be stored under refrigeration conditions (2°C to 
8°C, 36°F to 46°F) for up to 24 hours, and a maximum of 8 hours of the total 24 hours can be at 
room temperature (20ºC to 25ºC, 68ºF to 77ºF) and room light. The maximum of 8 hours under 
room temperature and room light conditions includes the product administration period. 
 
Shelf life 
Unopened vial 2 years. 
 
After opening: 
From a microbiological point of view, once opened, the medicinal product should be infused or 
diluted and infused immediately. 
 
After preparation of infusion 
From a microbiological point of view, the product should be used immediately. 
 
If not used immediately, chemical and physical in-use stability of OPDIVO has been 
demonstrated for 24 hours at 2ºC to 8ºC protected from light and a maximum of 8 hours at 20°C-
25°C and room light (this 8-hour period of the total 24 hours should be inclusive of the product 
administration 
7.4.5 Compatibility 
No incompatibilities between Nivolumab injection and polyvinyl chloride (PVC), non-PVC/non-
DEHP (di[2-ethylhexyl]phthalate) IV components, or glass bottles have been observed. 


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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
7.4.6 Handling 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.  
7.4.7 Availability 
Nivolumab will be provided by Bristol-Myers Squibb. 
7.4.8 Preparation 
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. 
 
Note: 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 study drug as an IV push or bolus injection 
Add the appropriate volume of 0.9% Sodium Chloride Injection solution or 5% Dextrose 
Injection solution. It is acceptable to add nivolumab solution from the vials into an appropriate 
pre-filled bag of diluent.  
 
Note: It is not recommended that so-called “channel” or pneumatic tube systems are used 
to transport prepared infusions of nivolumab. 
 
Attach the IV bag containing the nivolumab solution to the infusion set and filter. 
At the end of the infusion period, flush the line with a sufficient quantity of approved diluents. 
 
Please refer to the current Investigator Brochure. Due to parameters surrounding the use time of 
nivolumab, the time of preparation should be noted in the Pharmacy Source documents 
[accountability logs] or in study files as required for investigator sponsored research [FDA and 
GCP]. 
 
After nivolumab (BMS-936558-01) has been prepared for administration, the total storage time 
(combination of refrigeration and room temperature) is not to exceed 24 hours. Please refer to the 
Investigator Brochure for the details regarding storage, 
handling, and preparation of nivolumab. 
7.4.9 Nivolumab Administration 
Nivolumab is to be administered as an approximate 30-minute IV infusion, using a volumetric 


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Protocol- BrUOG 379 
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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
pump with a 0.2-micron to 1.2-micron pore size, low-protein binding polyethersulfone 
membrane in-line filter at 240 mg. It is not to be 
administered as an IV push or bolus injection. At the end of the infusion, flush the line with a 
sufficient quantity of normal saline. 
 
Nivolumab will be given every two weeks at a dose of 240 mg  
If an acute infusion reaction is noted, then acetaminophen/paracetamol 325 to 1000 mg PO 
and/or diphenhydramine 50 mg PO may be administered prior to nivolumab infusion. 
Corticosteroids (up to 25 mg of SoluCortef of equivalent) may also be used. 
 
The administration of undiluted and diluted solutions of Nivolumab must be completed within 24 
hours of preparation.  If not used immediately, the infusion solution may be stored up to 24 hours 
in a refrigerator at 2°-8°C (36°-46°F) and a maximum of 8 hours of the total 24 hours can be at 
room temperature (20°25°C, 68°-77°F) and room light.  The maximum 8-hour period under 
room temperature and room light conditions includes the product administration period. 
 
The single-use dosage form contains no antibacterial preservative or bacteriostatic agent.  
Therefore, it is advised that the product be discarded 8 hours after initial entry. 
7.4.10 Nivolumab Ordering 
It is possible that sites may have more than one clinical study on the same drug ongoing at the 
same time. It is imperative that only drug product designated for this protocol be used for this 
study 
 
If concerns regarding the quality or appearance of the investigational product arise, do not 
dispense the investigational product, and contact BMS immediately.  
 
Please allow for 5-7 business days for the shipment of drug. 
 
Initial Orders  
• Following submission and approval of the required regulatory documents, BrUOG will 
activate each site, which will allow a supply of nivolumab (when applicable) to be ordered by 
the investigational pharmacist via the BrUOG 379 (CA209-79E) drug order form.  
• It is required that the box “request for initial drug supply” be checked, the investigator address 
be confirmed as correct (if pre-populated) or populated (if blank), and that the # of vials being 
requested be documented on the form.  
• Once complete, email the form to the email addresses on the drug order form: 
distribution.allentown@thermofisher.com and Cc bruog@brown.edu. 
• Nivolumab:  
o Nivolumab will be supplied in 100 mg vials. 
o The initial order should be limited to 20 vials. Allow 5 business days for shipment of 
drug from BMS receipt of the Drug Request Form. Drug is protocol specific, but not 


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Protocol- BrUOG 379 
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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
patient specific. All drug product will be shipped by courier in a temperature-controlled 
container. It is possible that sites may have more than one nivolumab clinical study 
ongoing at the same time. It is imperative that only drug product designated for this 
protocol number be used for this study. 
• When drug is received, it is required that an email be sent to bruog@brown.edu to alert BrUOG 
the order was received.  
• Take note that drug should be transferred to +2°C/+8°C storage immediately upon receipt 
• Pharmacy supplies not provided by BMS:  Empty IV bags/containers, approved diluents, In-
line filters and infusion tubing 
 
Re-Supply 
• Drug re-supply request should be requested using the BrUOG 379 (CA209-79E) drug order 
form and allowing for 5-7 business days for drug shipment.  Deliveries will be made Tuesday 
through Friday. 
• When assessing need for resupply, institutions should keep in mind the number of vials used 
per treatment dose. Drug is not patient-specific. Be sure to check with your pharmacy regarding 
existing investigational stock to assure optimal use of drug on hand. 
• It is required that the box “request for resupply” be checked, the investigator address be 
confirmed as correct (if pre-populated) or populated (if blank), and that the # of vials being 
requested be documented on the form.  
• Once complete, email the form to the email addresses on the drug order form: 
distribution.allentown@thermofisher.com and Cc bruog@brown.edu. 
• When drug is received, it is required that an email be sent to bruog@brown.edu to alert BrUOG 
the order was received.  
 
Drug Excursions 
• Drug excursions should be reported immediately to BMS on the form provided with the 
study-specific drug order form. Please cc bruog@brown.edu on all drug excursion emails 
 
Questions on drug expiration, delayed shipments etc: 
• Send an email to Rashmi.gadkari@bms.com, and cc’ bruog@brown.edu 
• For questions on drug destruction please refer to 7.1.11 as this needs to be communicated 
directly with BrUOG only 
7.4.11 Accountability 
The investigator, or a responsible party designated by the investigator, will maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form.   
7.4.12 Destruction and Return 
At the end of the study, unused supplies of nivolumab will be destroyed according to institutional 
policies once BrUOG confirms and approves destruction. BrUOG will obtain approval to destroy 


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Protocol- BrUOG 379 
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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
from BMS. Destruction will be documented in the Drug Accountability Record Form and the 
form will be routed to BrUOG. Each participating hospital and pharmacy must submit, up front 
and throughout the trial, the most up to date drug destruction policy, to BrUOG.  
 
Drug that is used (partially used vial for examples), can be destroyed in real-time as per the 
pharmacy destruction policy and do not need to be tracked on the accountability log.  
 
Expired drug: Contact BrUOG to provide the number of expired vials and the current 
accountability logs. BrUOG will obtain approval to destroy drug and will communicate approval 
the pharmacy. BrUOG will then require submission of the drug accountability log, documenting 
the drug destruction of expired material. 
8 
STUDY PROCEDURES 
On days when ONC201 and nivolumab are administered on the same day, ONC201 should be 
administered within 30 minutes after completion of nivolumab  
 
The day an assessment (PE, Lab, scan etc) is performed is considered day 0 for counting. For 
example, labs done on a Friday can be used for dosing Monday as this is within 3 days. 
 
Baseline evaluations are to be conducted within 28 days prior to 
start of protocol therapy, unless otherwise specified 
below.  Scans must be done <28 days prior to registration. 
 
Baseline labs are required within 14 days of registration. HCG is 7 
days day 1 (of within 7 days of day -7 run-in for phase Ib). 
TSH within 28 days registration. 
Hepatitis required within 4 weeks registration 
Pre- 
Study to be sent to BrUOG with results prior 
to registration 
Informed consent(within 30 days of day 1) *pts are to be re-
consented if ICF will be outside 30 day window 
X 
Archival tissue 
X 
Baseline biopsy (At least 3-6 cores to Dr. El Deiry’s laboratory post 
consent and prior to ONC201)12,13 
X 
Demographics 
X 
Medical history8 
X 
Concurrent meds 8, 17 
X 
Physical exam8 
X 
Vital signs1,8 
X 
Height8 
X 


Page 69 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
Weight8 
X 
Performance status8 
X 
CBC w/diff, plts 4,8 
X 
Serum chemistry5,8 
X 
Hepatitis panel HBsAg, HCV Ab, if positive HCV Ab then order 
HCV RNA testing 8 
X 
TSH and coagulation 6,8 
X 
B-HCG 7, 8 
X 
PK plasma 9 (Phase IB patients only) 
X 
Blood sample for PD10 
X 
CfDNA11 
X 
Adverse event evaluation 2, 8 
X 
EKG 
X (within 8 weeks first dose) 
Tumor measurements 
X 
CT Chest, Abdomen. and Pelvis (MRI of the abdomen/pelvis may 
substitute for CT of the abdomen/pelvis)3 
X 
Brain MRI for patients with treated brain mets, scan must have been 
done post completion of treatment for brain mets3 
X 
Bone scan or bone X-Ray or PET scan for patients with bone 
metastases3 
X 
 
During treatment: 
The maximum duration of treatment will be 12 months unless it is determined that a patient would 
derive benefit from continued therapy beyond 12 months, as determined by the investigator. Follow-
up for all patients will be approximately 6 months.  
 
The study is expected to be completed over an approximate 3.5-year period 
Exam 
Day 
-7 
Cycle 1 8 
Pt to be seen 
as noted in 
table below 
Cycle 2 Pt to 
be seen as 
noted in table 
below 
Cycles 3-on, 
assessments Pt to 
be seen as noted 
in table below 
Off 
study 14 
(post 
complet
ion of 
entire 
cycle) + 
7 days 
30 day 
(+ 1 
week) 
and 100 
days (+ 
1 week) 
Follow-
up15 
Physical & HP (H&P 
due day 1, EOT and 30 
X 
Days 1, 
within 3 days 
X within 3 
days of 
X within 3 days 
of dosing day 1 
X 
X 
 


Page 70 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
day) 
D15 (pre-
nivo) 
dosing day 1 
Vitals 1, 8 
X 
Days 1, 
within 3 days 
D15 (pre-
nivo) 
X within 3 
days of 
dosing day 1 
and day 15 
X within 3 days 
of dosing day 1 
and day 15 
X 
X 
 
Conmeds 17 
X 
Days 1, 
within 3 days 
D 15 (pre-
nivo) 
X within 3 
days of 
dosing day 1 
within 3 days 
of dosing day 
1 and day 15 
X within 3 days 
of dosing day 1 
within 3 days of 
dosing day 1 and 
day 15 
X 
X 
 
PS 
X 
Days 1, 
within 3 days 
D 15 (pre-
nivo) 
X within 3 
days of 
dosing day 1 
X within 3 days 
of dosing day 1 
X 
X 
 
AE assessment 
X 
Days 1, 
within 3 days 
D 15 (pre-
nivo) 
X within 3 
days of 
dosing day 1 
within 3 days 
of dosing day 
1 and 15 
X within 3 days 
of dosing day 1 
within 3 days of 
dosing day 1 and 
15 
X 
X 
 
DLT assessment 
X 
Days 1, 
within 3 days 
D 15 (pre-
nivo) 
X (DLT 
assessment 
completed 
pre-cycle 2 
day 1) 
 
 
 
 
EKG 16 
 
as clinically 
indicated 
as clinically 
indicated 
as clinically 
indicated 
as 
clinicall
y 
indicate
d 
 
 
 
 
 
 
 
 
CT C/A/P3 
 
 
At week 8 
(+1 week)3 
Every 8 weeks 
(+1 week)3 
X 
unless 
one was 
complet
ed in 
prior 4 
weeks 
 
X3 
Brain MRI for patients 
with brain mets 3 
 
 
X 
X 
X 
unless 
one was 
complet
 
X3 


Page 71 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
ed in 
prior 4 
weeks 
Bone scan or bone X-
Ray for patients with 
bone metastases3 
 
 
X 
X 
X 
unless 
one was 
complet
ed in 
prior 4 
weeks 
 
X3 
CBC w/diff, plts 4,8 
 
8Weekly 
within 24 
hours of 
dosing each 
day 
X within 3 
days of 
dosing day 1 
and day 15 
X within 3 days 
of dosing day 1 
and day 15 
X 
 
 
Serum chemistry5,8 
 
8Weekly 
within 24 
hours of 
dosing each 
day 
X within 3 
days of 
dosing day 1 
and day 15 
X within 3 days 
of dosing day 1 
and day 15 
X 
 
 
TSH and coagulation 6,8  
8X D1 only 
X within 3 
days day 1 
only 
X within 3 days 
day 1 only 
X 
 
 
HCG 7, 8 
 
X  7,8 
X 
X 
 
 
 
PK plasma 9 (Phase IB 
patients only) 
X9 
X9 
See schedule 
for all 
requirements 
D1,2,3,7 
X9 
See schedule 
for all 
requirements 
D1,2,3,7 
X9 
 
 
 
Blood sample for PD10 
X10 
X10 
See schedule 
for all 
requirements 
D1,2,3,7 
X10 
See schedule 
for all 
requirements 
D1,2,3,7 
X10 
 
 
 
cfDNA11 
 
X prior to 
D15 dosing 
X 
X 
 
 
 
Tumor biopsy13 + 12 
 
 
Week 8 (+/- 7 
days) 
 
Biopsy 
at 
progress
ion if 
patient 
has not 
progress
ed13 
 
 
 
 
 
 
 
 
 
 


Page 72 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
Survival and disease 
status 
 
 
 
 
 
 
X15 
*ONC201 is to be taken by patient in front of research staff day -7, day 1, day 8, day 15, day 22 in cycle 1.  
1Height, weight, blood pressure, pulse, temperature and respiratory rate. Pulse oximetry should be performed as 
clinically indicated. 
2 Toxicity assessments must be obtained within 14 days prior to initiation of protocol treatment 
3Radiological tumor assessments will be performed at baseline within 28 days of registration (all imaging) and 
subsequently every 8 weeks (+1 week), until progression of disease (see information on patients remaining on study 
post PD). Patients with stable scans at the first restaging may have restaging scans performed every 8 weeks at the 
discretion of the investigator, including in the follow-up time-period. If patients come off study for progression, 
imaging will be stopped. CT C/A/P should be used for imaging, if an alternative imaging modality is used at 
baseline, the same imaging technique must be used throughout the study duration. Patients who continue treatment 
beyond initial PD, will require a repeat radiographic assessment within 8 weeks (±7 days) of initial PD to determine 
whether there has been a decrease in the tumor size or further progression, defined as an additional 10% increase in 
tumor burden from time of initial PD. Time to progression will be defined at the first time point of PD. Patients with 
brain or bone metastases at baseline, imaging post baseline, with brain MRI or bone scan, to occur as per 
institutional practice. When completed, site is required to be submit scans to BrUOG. 
4 Hematology – CBC with PLT differential (neutrophil including bands, lymphocyte, monocyte, eosinophil, 
basophil). 
5 Serum chemistry - K+, Na+, Ca++, Mg++, LDH, ALT, AST, total bilirubin, creatinine, amylase, alkaline 
phosphatase bicarbonate, phosphorus, glucose, BUN, albumin, and total protein. CEA, to be drawn monthly. 
6Coagulation - PT, PTT. With Coag labs, TSH will also be drawn Q monthly with pre-cycle labs 
7 Serum or urine pregnancy test (women of childbearing potential) required within 7 days prior to day -7, Also 
required every 4 weeks (+/- 1 week) while on-study. Cycle 1 day 1: required HCG for all women of child 
bearing potential within 24 hours (1 day) prior to dosing day 1 cycle 1 only and confirmation of negative HCG 
test required to be sent to BrUOG. Patients with a positive test are required to be taken off study prior to any 
dosing on study. 
8 If screening labs are performed greater than 14 days prior to Cycle 1 D-7, labs must be repeated on Cycle 1 D-7 
and must meet eligibility criteria. The patient may not start on study treatment until Cycle 1 D-7 labs meet eligibility 
criteria. If screening labs are performed within 14 days prior to Cycle 1 D-7, and meet eligibility criteria, labs do not 
need to be repeated on Cycle 1 D-7 unless the investigator believes they are likely to have changed significantly. 
History, AE & concomitant medication assessment, vitals, weight, height and performance status can be used from 
screening for cycle 1 D-7 if they were within the 14-day screening period (14 days from day 1). A physical exam 
within 7 days prior to cycle 1 D-7 can be utilized. 
9 PK plasma, (phase IB patients only):  
Blood draws taken at baseline (pretreatment- with screening labs).  
Then C1: Day 1 post ONC201 at 30 min+/- 15min, 2 hours +/-30 min, 4 hours +/- 30min, 6 hours +/- 30 min, 24 
hours +/- 1 hour, 48 hours +/- 1 hour, 7 days (). (this is day 8 pre-dosing ONC201). 
Then C2: Day 1 post ONC201 at 30 min+/- 15min, 2 hours +/-30 min, 4 hours +/- 30min, 6 hours +/- 30 min, 24 
hours +/- 1 hour, 48 hours +/- 1 hour, 7 days (-).(this is day 8 pre-dosing ONC201). 
Cycle 3-12: Pre-dosing 
Use one K2EDTA tube, 5mL sample: Tube should be gently inverted 8 times after draw and maintained at room 
temperature. Blood must be sent to research lab immediately after collected at the ambient temperature. 


Page 73 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
10 PD samples: all patients: Blood draws taken at baseline (pretreatment- with screening labs).  
Cycle 1: Day 1: 6 hours post ONC201 +/- 30 min, 2 days post, 3 days post, 7 days post (this is day 8 pre-dosing 
ONC201) 
Cycle 2: Pre-dosing day 1, 6 hours post ONC201 +/- 30 min, 2 days post, 3 days post, 7 days post (this is day 8, 
pre-dosing ONC201) 
Cycles 3-12: Pre-dosing day 1. Patients remaining on study post 12 cycles, will have samples drawn prior to 
dosing day 1 of each cycle.  
Use one red-top tube (no anti-coagulant), let sample clot, there is no processing.  Blood must be sent to 
research lab immediately after collection at ambient temperature. 
11 cfDNA: blood to be collected at baseline (pre-dosing ONC201, prior to day -7 cycle 1) and prior to ONC201 
and Nivolumab (twice a cycle with pre-Nivolumab labs) cycles 1-6. Cycles 7-on: CfDNA will be collected pre-
dosing each cycle day 1 only. CfDNA will not be collected once patient progresses. If patient remains on study 
post 12 cycles, cfDNA will only be drawn pre-dosing day 1 of each cycle:  Collect CfDNA whole blood 
sample in 1 K2EDTA tube. Post collection, invert sample 8-10 times and let site at room temperature. See 
section 11.1.3. 
12 Subjects providing informed consent will have tumor biopsy performed pre-treatment, at approximately 8 
weeks when the first tumor imaging assessment is performed, and at the time of progression. For those patients 
whose disease is progressing at the first post-treatment imaging assessment at 8 weeks they will only have 2 
biopsies.  
13 Tissue from a biopsy (at least 3-6 cores in 10% neutral buffered formalin) will be obtained by radiologic 
guidance and sent to the laboratory of Dr. El-Deiry. Only 2 biopsies will be required for patients who progress 
at the end of cycle 2.  
14 Off-study evaluation to occur post completion of entire cycle. Follow-up visits or other contact are required in 
order to identify SAEs during the first 100 days (+1 weeks) following the end of study treatment (Nivolumab, or 
ONC201), respectively. There will be a safety visit at 30 days (+1 week) and 100 days (+1 week) time points. SAEs 
need to be reported after 100 days if the SAE is thought to be related to study treatment. 30-day and 100-day safety 
evaluation time points required for all patients who receive at least one dose of drug on BrUOG 379, unless they 
withdraw consent. 
15 Survival and disease status will be collected for all patients who receive at least one dose of ONC201 once they 
come treatment (unless they withdraw consent), approximately every 3 months for (+/-1 month) 6 months  
16 EKG registration and as clinically indicated. Any findings from EKGs collected after initiation of study treatment 
will be captured as AEs if, in the opinion of the investigator, there has been a clinically significant change from 
baseline. 
17. Medications used by the patient and therapeutic procedures completed by the patient will be recorded in the CRF 
from screening through 100 days after the last dose of study drug or the start of subsequent antineoplastic therapy, 
whichever occurs first. 
9 
Criteria for Taking a Participant Off Protocol Therapy 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance.  
 
In the absence of treatment delays due to adverse event(s), treatment with nivolumab may 
continue as indicated in each cohort or until one of the following criteria applies: 
• 
Disease progression (see information on patients remaining on study post 
progression) 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 


Page 74 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
• 
Participant demonstrates non-compliance with treatment regimen and/or required 
study evaluations 
• 
Participant decides to withdraw from the protocol therapy 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
• 
Any required toxicity reason as noted in prior sections of the protocol requiring the 
patient stop treatment 
• 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the Investigator, presents a substantial clinical risk to the subject with 
continued nivolumab dosing 
• 
Oncoceutics decision to forgo further drug development of ONC201 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
10 Efficacy Evaluations 
Tumor assessment for solid tumors will include all known or suspected disease sites. Imaging may 
include chest, abdomen and pelvis CT or MRI scans (when applicable); brain CT or MRI scan for 
patients with known brain metastases or those with suspected brain metastases; bone scan and/or 
bone x-rays for patients with bone metastases, if applicable. CT (or MRI) of chest, abdomen and 
pelvis, will be used for response. 
 
Antitumor activity for patients with solid tumors will be assessed through radiological tumor 
assessments conducted at baseline, at the end of every other cycle (every 8 weeks), whenever 
disease progression is suspected (e.g., symptomatic deterioration), and at the time of withdrawal 
from the study (if not done in the previous 4 weeks). 
 
Assessment of response in these patients will be made using RECIST version 1.1. All patients’ 
files and radiologic images must be available for source verification. 
The same imaging technique used to characterize each identified and reported lesion at baseline 
will be employed in the following tumor assessments. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria. 
 
Treatment Beyond Disease Progression (also see information below on modified immune related 


Page 75 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
response criteria) 
Accumulating evidence indicated a minority of subjects treated with immunotherapy may derive clinical 
benefit despite initial evidence of progressive disease (PD). 
 
However, modification to these criteria will be employed to minimize the possibility that 
therapeutic agents that induce T cell infiltration into tumors as an early manifestation of anti-
tumor effect could be erroneously interpreted as disease progression on imaging and result in 
premature discontinuation of a therapeutically effective agent.   
 
Therefore, the protocol allows for patients to remain on study beyond initial progression if 
all of the following criteria are satisfied (and documented by treating MD and submitted to 
BrUOG): 
 
• No decrease in performance status 
• No requirement for immediate alternative treatment or urgent palliative treatment 
• Progression limited to an increase of 40% in the sum of diameters of target lesions 
• No more than 4 new lesions included in the sum. 
 
It is not required that patients be kept on study after initial progression.  
 
If the CT scan shows progression and the treating physician recommends continuing protocol 
treatment until a subsequent CT scan, this must be discussed with the patient and decisions to 
continue treatment beyond initial progression will be documented in the study records. 
 
For patients who continue treatment in the case of initial radiologic progression, a repeat 
CT scan will be obtained within 8 weeks (±7 days) of the initial detection of PD to determine 
whether there has been a decrease in the tumor size or further progression, defined as an 
additional 10% increase in tumor burden from time of initial PD. This includes an increase in the 
sum of diameters of all target lesions, increase in the sum of the diameters of new measurable 
lesions compared to the time of initial PD, and/or unequivocal progression in non-target lesions 
(compared to the time of initial PD).  
 
• Study treatment should be discontinued permanently upon documentation of 
further progression.  
If patient has not additional progression (10%) they can stay on treatment and continue 
on with study imaging as per the protocol time frames. However, if they subsequently 
progress by 10% at any time after, they must come off study. 
• If SD is documented, patients will be allowed to continue on study treatment. However, if 
they subsequently progress by 10% at any time after, they must come off study. 
For patients who experience a PR or CR (compared to baseline CT), they will continue 
treatment. They will be recorded as a delayed response  
 


Page 76 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
Definitions 
 
Evaluable for Target Disease response.  Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response.  These 
participants will have their response classified according to the definitions stated below.  
(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Participants who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions.  
 
Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by 
chest x-ray or ≥10 mm with CT scan (preferred), MRI, or calipers by clinical exam.  All 
tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  NOTE: bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast 
disease, abdominal masses (not followed by CT or MRI), and cystic lesions are all 
considered non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same participant, these are preferred for selection as 
target lesions. 


Page 77 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease.  
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow up.  
 
Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam.  
 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (inclusive of cervical masses and palpable lymph nodes) and ≥10 mm in 
diameter as assessed using calipers.    
Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT thickness is 5mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size of a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 


Page 78 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
 
(a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
(b)  No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly progression occurring at that site 
(if so, the date of PD will be the date of the initial abnormal FDG-PET scan).  If the positive 
FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not 
progressing on the basis of the anatomic images, this is not PD. 
(c)  FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or scarring.  
The use of FDG-PET in this circumstance should be prospectively described in the protocol 
and supported by disease-specific medical literature for the indication.  However, it must be 
acknowledged that both approaches may lead to false positive CR due to limitations of FDG-
PET and biopsy resolution/sensitivity. 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
PET-CT. the low dose or attenuation correction CT portion of a combined PET-CT is not 
always of optimal diagnostic CT quality for use with RECIST measurements and will not 
be used on this trial.  
 


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Protocol- BrUOG 379 
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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
Response Criteria 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 


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Protocol- BrUOG 379 
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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
Evaluation of New Lesions 
 
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up 
evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the lesion 
was discovered. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Participants with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 


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Protocol- BrUOG 379 
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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
For Participants with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
Modified immune-related response criteria (irRC), derived from RECIST 1.1 
This irRC classification is based on the recent learning from clinical studies with cancer 
immunotherapies that even if some new lesions appear at the beginning of a treatment or if the total 
tumor burden does not increase substantially, tumor regressions or stabilizations might still occur later. 
The irRC were created using bidimensional measurements (as previously widely used in the World 
Health Oganization criteria). For this trial, the concepts of the irRC are combined with RECIST 1.1 to 
come up with the modified irRC. 
For modified irRC, only target and measurable lesions are taken into account. In contrast to the RECIST 
1.1 criteria, the modified irRC criteria (a) require confirmation of both progression and response by 
imaging at 8 weeks after initial imaging and (b) do not necessarily score the appearance of new lesions 
as progressive disease if the sum of lesion diameters of target lesions (minimum of 10 mm per lesion, 
maximum of 5 tar et lesions, maximum of 2 per organ) and measurable new lesions does not increase 
by ≥ 20%. 
The same method of assessment and the same technique should be used to characterize each identified 
and reported target lesion(s) at baseline, during the trial, and at the end of trial visit. All measurements 
should be recorded in metric notation. The modified irRC based on RECIST 1.1 are displayed below. 
 
Modified immune-related response criteria are defined as follows:  
New measurable lesions: Incorporated into tumor burden. 
New non-measurable lesions: Do not define progression but precludes (irCR). 
Overall irCR: Complete disappearance of all lesions (whether measurable or not) and no new lesions. All 
measurable lymph nodes also must have a reduction in short axis to 10 mm. 
 
Overall irPR: Sum of the longest diameters of target and new measurable lesions decreases ≥ 30%. 
 
Overall irSD: Sum of the longest diameters of target and new measurable lesions neither irCR, irPR, 


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Protocol- BrUOG 379 
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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
(compared to baseline) or irPD (compared to nadir). 
 
Overall irPD:    Sum of the longest diameters of target and new measurable lesion       
      
increases ≥ 20% (compared to nadir). It is recommended that overall irPD be confirmed by a follow-up 
CT at least 4- 1 2  from the date first documented. 
 
Overall responses derived from changes in index, non-index, and new lesions are summarized in the table 
below. 
 
Overall Responses Derived from Changes in Index, Non-Index, and New Lesions 
Measurable Response 
Non-Measurable Response 
Overall Response Using 
Modified irRC 
Index and New, 
Measurable Lesions 
1
Non-Index Lesions 
New, Non- 
Measurable Lesions 
Decrease 100% 
Absent 
Absent 
irCR2 
Decrease 100% 
Stable 
Any 
irPR2 
Decrease 100% 
Unequivocal progression 
Any 
irPR2 
Decrease ≥ 30% 
Absent / Stable 
Any 
irPR2 
Decrease ≥ 30% 
Unequivocal progression 
Any 
irPR2 
Decrease < 30% to 
increase < 20% 
Absent / Stable 
Any 
irSD 
Decrease < 30% to 
increase < 20% 
Unequivocal progression 
Any 
irSD 
Increase ≥ 20% 
Any 
Any 
irPD 
1 Decreases assessed relative to baseline 
2 Assuming that the response (irCR and irPR) and progression (irPD) are confirmed by a second, 
consecutive assessment at least 4 weeks apart (normally it should be done 8 weeks apart). 
 
Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Participants without events reported are censored at the last 
disease evaluation). 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation.  
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
Progression-Free Survival 
 
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive. 
 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease 
evaluation. 
 
Time to Progression: Time to Progression (TTP) is defined as the time from 
randomization (or registration) to progression, or censored at date of last disease 
evaluation for those without progression reported. 
 
 
11 BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 Pharmacokinetic Evaluations 
During phase IB, plasma samples will need to be prepared from blood collected in K2EDTA tubes 
at baseline (pre-cycle 1 day 1), day 1: 30 minutes, 2, 4, 6, 24, 48, and 168 hours following the first 
two cycles of ONC201 and pre-dose on day 1 of subsequent cycles (through cycle 12 only). See 
schedule of evaluations for windows on each draw. 
 
Pharmacokinetic samples will be collected and stored in the laboratory of Dr. Wafik El Deiry and 
processed at a later time.  
 
Collect PK samples in one K2EDTA 5mL tube. Gently invert the tube 8 times after draw and 
maintain at room temperature.  
 
One K2EDTA tube (5mL) will be collected per time point. Each tube will be labeled as follows: 
BrUOG 379 
Patient initials  


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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
Patient study number 
PK sample 
Time point 
Time 24-hour clock 
 
As part of understanding the pharmacokinetics of the study drug, samples may be used for 
metabolite identification and/or evaluation of the bio-analytical method. These data will be used 
for exploratory purposes and will not be included in the clinical report. 
 
Prior to transporting samples, an email is to be sent from a member of the Lifespan Oncology 
Clinical Research Office to a member of Dr. El-Deiry’s lab (Email: lanlan_zhou@brown.edu) at 
least 24 hours prior to the collection of the sample(s). The email is to reference the patient initials 
and BrUOG 379 patient number, time point and samples. The lab will be informed that the sample 
will be transported post collection on <insert date>. This email is required to be de-identified and 
submitted to BrUOG with cycle data. 
 
Blood must be sent to the research lab immediately after collection at ambient temperature. Please 
call Lanlan Zhou at 267-259-7571 when samples are available.  
 
Lab address:  
70 Ship Street 
Room 537 
Providence, RI 02912 
11.1.1  Background 
Molecular markers involved in the molecular mechanism of ONC201 will be assessed on available 
tumor tissue and serum specimens as described below. 
11.1.2 Biomarkers in Blood: PD samples 
In addition to pharmacokinetics, this study will preserve samples at the laboratory of Dr. El-Deiry 
to conduct future correlative assays to measure biomarkers of therapeutic response to ONC201 
including molecular markers involved in the mechanism of action of ONC201. For each patient, 1 
tube of 5 mL of blood will be collected in red-top tubes (no anti-coagulants). 
 
During phase IB and II, blood samples for PD analyses will need to be collected at baseline (pre-
cycle 1 day 1), day 1: 6 hours, 2, 3, and 7 days after ONC201 treatment for cycles 1 and 2, and at 
pre-dose on day 1 for cycles 3 and beyond. Caspase-cleaved cytokeratin 18 (cCK18) will be 
measured as a biomarker of epithelial cell apoptosis and prolactin will be measured as a surrogate 
biomarker of DRD2 antagonism (Diapharma; #P10011). The 7-day collection is the same as pre-
dose after the first dose on the weekly ONC201 schedule (this aligns with day 8). See schedule of 
evaluations for windows on draws. Patients who remain on study post 12 cycles, PD samples will 
be drawn pre-dosing day 1 each cycle.  


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
Each sample will be drawn in one red-top with no anti-coagulant. The sample should clot, there is 
no processing to be done prior to the transport of the sample to the laboratory.  
 
One red-top tube with no anti-coagulant, will be collected per time point. Each tube will be labeled 
as follows: 
BrUOG 379 
Patient initials  
Patient study number 
PD sample 
Time point 
Time 24-hour clock 
 
Analysis of circulating tumor cells for enumeration and molecular analysis is also permitted.  
 
Prior to transporting samples, an email is to be sent from a member of the Lifespan Oncology 
Clinical Research Office to a member of Dr. El-Deiry’s lab (Email: lanlan_zhou@brown.edu) at 
least 24 hours prior to the collection of the sample(s). The email is to reference the patient initials 
and BrUOG 379 patient number, time point and samples. The lab will be informed that the sample 
will be transported post collection on <insert date>. This email is required to be de-identified and 
submitted to BrUOG with cycle data. 
 
Blood must be sent to the research lab immediately after collection at ambient temperature. Please 
call Lanlan Zhou at 267-259-7571 when samples are available.  
 
Lab address:  
70 Ship Street 
Room 537 
Providence, RI 02912 
11.1.3 CfDNA:  
 
Blood samples need to be collected for CfDNA analysis at baseline (pre-cycle 1 day 1), then 
every two weeks while on study cycles 1-6, pre-ONC201 and on same days as Nivolumab dosing 
(prior to dosing day 1 and day 15). In cycles 7-12, CfDNA will be drawn pre-dosing day 1 each 
cycle only. CfDNA will be drawn until progression. If a patient remains on study post 12 cycles, 
sample to be drawn prior to dosing day 1 each cycle only (cycles 13+). 
 
Each tube will be labeled as follows: 
BrUOG 379 
Patient initials  
Patient study number 


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Protocol- BrUOG 379 
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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
CfDNA sample 
Time point 
Time 24-hour clock 
 
Prior to transporting samples, an email is to be sent from a member of the Lifespan Oncology 
Clinical Research Office to a member of Dr. El-Deiry’s lab (Email: lanlan_zhou@brown.edu) at 
least 24 hours prior to the collection of the sample(s). The email is to reference the patient initials 
and BrUOG 379 patient number, time point and samples. The lab will be informed that the sample 
will be transported post collection on <insert date>. This email is required to be de-identified and 
submitted to BrUOG with cycle data. 
 
CfDNA samples: Whole blood to be collected in one K2EDTA tube each time point. Post 
collection, site personnel is required to invert sample 8-10 times and then let sit at room 
temperature until sent to laboratory. Blood must be sent to the research lab immediately after 
collection at ambient temperature. Please call Lanlan Zhou at 267-259-7571 when samples are 
available.  
 
Lab address:  
70 Ship Street 
Room 537 
Providence, RI 02912 
11.1.4 Biomarkers in Tumor Biopsy 
Archival Tissue: 
 
Research Biopsies: patients will undergo up to 3 biopsies on study.  
 
1) Prior to dosing: Required post consent and pre-ONC201 run-in dose 
2) At the beginning of cycle 3 (approximately 2 months) to align with imaging 
3) If patient was found to not progress at 2 months (1st scan), then 3rd biopsy would be 
completed at time of progression (if patient progresses during follow-up time period). This 
biopsy is optional.  
 
Tumor biopsies will be taken (pre-treatment and at the first imaging assessment post-treatment at 
8 weeks of the combinatorial regimen, and again at the time of progression).  
 
Tumor biopsies will be performed using 18G core biopsy needles (or as per standard radiologic 
procedures) and limited to 1–2 passes for each sample to reduce risk of hemorrhage and fine needle 
aspirations using 23G needles (or as per standard radiologic procedures) with immediate bedside 
cytopathological confirmation of presence of tumor cells.  
 
Based on some preclinical studies, the 48 post-treatment time point is adequate to measure 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
induction of ATF4 & CHOP, as well as DR5 & TRAIL induction. Preclinical studies with ONC201 
have implicated many proteins such as ATF4, CHOP, DR5 and TRAIL as drivers of the anti-tumor 
activity of ONC201. Changes in the expression of these markers will be assessed by 
immunohistochemistry at baseline and post-treatment. In addition, changes in key apoptotic 
proteins such as caspases and PARP will be carried out. Thus, we will correlate clinical outcomes 
with tumor & blood biomarkers including cancer stem cells, signaling intermediates and inhibitors, 
NK cells, TRAIL, granzyme, perforin and M30. NK cells in blood will be assessed in the phase Ib 
portion at similar time points as PK studies and then later in phase II. 
 
Tissue biopsies will be subjected to immunohistochemistry for CHOP (Proteintech; # 5204-1-AP), 
DR5 (Novus; NB100-56618), CD56 (BioLegend, Catalog X), Granzyme B (Abcam; Catalog X) 
and TUNEL (Novus; #NBP2-31164) as per the manufacturer’s instructions on slides prepared 
from formalin-fixed paraffin-imbedded tissue. NGS and RNA-seq will be performed on pre- and 
post-treatment biopsies looking for markers of sensitivity as well as mechanisms of resistance. A 
major goal is to understand the differences between responders and non-responders. Researchers 
will analyze T-cell and NK cell content of the tumor biopsies. PD1 and PD-L1 testing will also be 
performed. 
 
For tissue from research only biopsy: 
The research staff is to contact Dr. El Deiry’s laboratory (to submit de-identified email chain 
with data to BrUOG) at least 24 hours prior to collection of a research only biopsy.  Dr. El-
Deiry’s laboratory will be contacted by a member of the research team once the biopsy has been 
completed to retrieve the biopsy specimen (Email: lanlan_zhou@brown.edu).   Once the biopsy 
is complete, the Cancer Center research staff will be notified for pick-up of material. The tissue 
must be labeled with study number (BrUOG 379), patient initials, patient study number and time 
point.  
 
Each tissue biopsy is to include 3-6 cores and be stored in 10% neutral buffered formalin. 
 
Tissue to be sent to the research lab once collected. Please call Lanlan Zhou at 267-259-7571 when 
tissue is available.  
 
Lab address:  
70 Ship Street 
Room 537 
Providence, RI 02912 
 
12 ADVERSE EVENT REPORTING:  LIST AND REPORTING REQUIREMENTS  
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs and the characteristics of an observed AE will 
determine whether the event requires expedited reporting in addition to routine reporting. 
 


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CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 Expected Toxicities 
 
Adverse Event List(s) for Nivolumab 
 
Categorization of AEs Potentially Associated with Nivolumab 
 
In order to characterize AEs of special clinical interest that are potentially associated with the use 
of nivolumab, the Sponsor identified select AEs based on the following 4 guiding principles: 
• AEs that may differ in type, frequency, or severity from AEs caused by non-
immunotherapies 
• AEs that may require immunosuppression (e.g., corticosteroids) as part of their 
management 
• AEs whose early recognition and management may mitigate severe toxicity 
• AEs for which multiple event terms may be used to describe a single type of AE, thereby 
necessitating the pooling of terms for full characterization 
 
Based on these guiding principles and taking into account the types of AEs already observed 
across studies of nivolumab monotherapy, endocrinopathies, diarrhea/colitis, hepatitis, 
pneumonitis, nephritis, and rash are currently considered to be select AEs. Multiple event terms 
that may describe each of these are grouped into endocrine, GI, hepatic, pulmonary, renal, and 
skin select AE categories, respectively. The list of AEs belonging to select AE categories may 
evolve as more safety information becomes available in the nivolumab program. 
 
Hypersensitivity/infusion reactions were also analyzed along with the select AE categories 
because multiple AE terms may be used to describe these events, and therefore, pooling of terms 
provides a more complete characterization of the events. Hypersensitivity/infusion reactions do 
not, otherwise, meet criteria to be considered select AEs. 
Serious Adverse Events Reported from Clinical Trials with Nivolumab Monotherapy 
As of June 2017, the following serious AEs have been reported in clinical studies in which 
nivolumab was given as monotherapy. The frequency of ADRs is defined using the following 
convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 
1/100); rare (≥ 1/10,000 to < 1/1,000); and very rare (< 1/10,000). For further information, 
including SAEs that are rarely associated, please reference the IB. 
 
The following common SAE is associated: pneumonitis, diarrhea 
 
The following uncommon SAEs by system organ class are associated: 
• Endocrine: Adrenal insufficiency, Hypothyroidism 
• Gastrointestinal: Abdominal pain, Colitis, Diarrhea, Nausea, Pancreatitis, Vomiting 
• General and Administrative Site Conditions: Mucosal inflammation, Pyrexia 
• Hepatobiliary: Abnormal hepatic function 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
• Immune system: Hypersensitivity 
• Injury, Poisoning and Procedural Complications: Infusion-related reaction 
• Metabolism and Nutrition: Dehydration, Hyperglycemia 
• Neurologic: demyelinating polyneuropathy, myasthenic syndrome 
• Renal and Urinary: Acute renal failure, Tubulointerstitial nephritis 
• Respiratory, Thoracic and Mediastinal Disorders: Dyspnea, Hypoxia, Interstitial lung 
disease, Lung infiltration, Respiratory failure 
 
 
Nonserious Adverse Events Reported from Clinical Trials with Nivolumab Monotherapy 
 
As of June 2017, the following nonserious AEs have been reported in clinical studies in which 
nivolumab was given as monotherapy. The frequency of ADRs is defined using the following 
convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 
1/100); rare (≥ 1/10,000 to < 1/1,000); and very rare (< 1/10,000). 
 
The following very common nonserious AEs are associated: Fatigue, Diarrhea 
The following common nonserious AEs are associated: Arthralgia, Asthenia, Cough, Decreased 
appetite, Pyrexia, Rash, Nausea, Pruritus 
 
A complete list of adverse events observed with nivolumab are detailed in the Investigator’s 
Brochure (IB). 
 
 Expected list of toxicities ONC201:  
 
ONC201 is being evaluated in multiple on-going clinical trials. As of March 15, 2019, 150 patients 
have been treated with ONC201: 63 patients were male and 87 were female. The age ranged from 
2 to 85 years, with 40 (27%) of patients < 18 years old. Seventeen patients received ONC201 on a 
Q3W schedule, 133 patients received ONC201 on a Q1W schedule. Adults were administered a 
dose of 625 mg, while children (<18 years) were dosed from 125 mg to 625 mg depending on body 
weight.  
  
ONC201 has been well tolerated across the various Phase I clinical trials and administration 
schedules with dose levels ranging from 125 mg to 625 mg. Only 1 dose reduction (625mg to 
500mg) occurred in 1 patient with a Grade 3 neutropenia assessed by the PI as possibly related to 
ONC201. However, upon re-challenge neutropenia did not recur. 
  
Some patients who received ONC201 have experienced mild or moderate adverse events that were 
attributed as possibly related to ONC201: fatigue, abdominal pain, fever, nausea, vomiting, 
anorexia, weakness, elevated serum amylase, neutropenia, bone pain, generalized weakness, 
allergic reaction, and ataxia. 


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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
In summary, ONC201 is well tolerated when administered once every week or once every three 
weeks at doses ranging from 125 mg to 625 mg. 
 
Side effects seen in animals at exaggerated doses included the following: 
• Nausea 
• Salivation 
• Vomiting 
• Abnormal breathing 
• Twitching 
• Abnormal walking or standing 
• Death 
 
A complete list of adverse events observed with ONC201 are detailed in the Investigator’s 
Brochure (IB). 
 
 Adverse Event Characteristics 
This study will utilize the descriptions and grading scales found in the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 for grading all adverse events. 
All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy 
of the CTCAE version 5.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov).  
 
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and that does not necessarily have to 
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 Nivolumab or ONC 201, whether or not considered related to 
Nivolumabor ONC 201. This includes any newly occurring event or previous condition that has 
increased in severity or frequency since the administration of drug. 
 
During clinical trials, adverse events can be spontaneously reported or elicited during open-
ended questioning, examination, or evaluation of a subject. (In order to prevent reporting bias, 
subjects should not be questioned regarding the specific occurrence of one or more adverse 
events.) 
 
Adverse events (AEs) will be recorded in the case report form for the duration of the trial, 
regardless of whether or not the event(s) are considered related to trial medication.  
 
 Definitions 
An adverse event is any new, undesirable medical experience or change of an existing condition 
that occurs during or after treatment, whether or not considered product-related. 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
12.4.1 Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
Suspected adverse reaction: 
BrUOG, for the sponsor-investigator, is required to report in an IND safety report any suspected 
reaction to the study treatment that is both serious and unexpected.  
 
As per 21 CFR 312.32 (a), the FDA has defined a suspected adverse reaction as any adverse event 
where there is reasonable possibility that the drug may have caused the adverse event. A 
reasonable possibility means there is evidence suggesting a causal relationship between the drug 
and the adverse event.  
 
A suspected adverse reaction outlines the possibility of the causal relationship between the event 
and the drug, whereas an adverse reaction means the drug caused the event.  
 
12.4.2 Serious Adverse Events (SAE) Definition 
 
An adverse event occurring at any dose that results in any of the following outcomes (CFR 
312.32): 
• death 
• is life-threatening  
• inpatient hospitalization or prolongation of existing hospitalization excluding those for study 
drug administration, transfusion support, disease staging/re-staging procedures, concomitant 
radiotherapy, thoracentesis / paracentesis, or placement of an indwelling catheter, unless 
associated with other serious events. 
• persistent or significant disability or incapacity, 
• congenital anomaly / birth defect.  
 
The definition of serious adverse event (experience) also includes important medical event. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above.  These should 
also usually be considered serious.  Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do 
not result in hospitalization; or development of drug dependency or drug abuse. A new diagnosis 
of cancer during the course of treatment should be considered an important medical event. 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
Unexpected adverse event 
An adverse event that is not mentioned in the Investigator's Brochure or package insert or the 
specificity or severity of which is not consistent with the investigator's brochure or package 
insert. 
 
Life-threatening 
Any adverse drug experience that places the patient or subject, in the view of the investigator, at 
immediate risk of death from the reaction as it occurred.  It does not include a reaction that, had 
it occurred in a more severe form, might have caused death. 
 
 
 
12.4.3 Events requiring reporting as an Important Medical Event: 
 
 Potential drug induced liver injury (DILI) is also considered an important medical 
event.  
 
Potential drug induced liver injury is defined as:  
o ALT and/or AST elevation > 3 times upper limit of normal (ULN) 
AND 
o Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated 
serum alkaline phosphatase) 
AND 
o No other immediately apparent possible causes of AT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing 
chronic or acute liver disease, or the administration of other drug(s) known to be 
hepatotoxic. 
Wherever possible, timely confirmation of initial liver related laboratory abnormalities 
should occur prior to the reporting of a potential DILI event. All occurrences of potential 
DILIs, meeting the defined criteria, must be reported as SAEs. 
• Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the 
study drug is an SAE.  
• Although pregnancy, overdose, and cancer (a second primary, excluding non-melanoma 
skin cancer) are not always serious by regulatory definition, these events must be handled 
as SAEs. 
o Pregnancy: see section for information 
o 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. 
 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
NOTE: The following hospitalizations are not considered SAEs: 
 
− 
a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered “important medical event” or event life 
threatening)  
− 
elective surgery, planned prior to signing consent and which would have been 
documented to BrUOG at time of registration (otherwise it will be a SAE) 
− 
admissions as per protocol for a planned medical/surgical procedure per study 
− 
routine health assessment requiring admission for baseline/trending of health status 
(ie, routine colonoscopy)  
− 
medical/surgical admission for purpose other than remedying ill health state and was 
− 
planned prior to entry into the study. Appropriate documentation is required in these 
cases and which would have been documented to BrUOG at time of registration 
admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (ie, lack of housing, economic 
inadequacy, care-giver respite, family circumstances, administrative) 
 Monitoring of Adverse Events and Period of Observation 
Adverse events, both serious and non-serious, and deaths that occur during the patient’s study 
participation will be recorded in the source documents.   
 
 BRUOG ADVERSE EVENT REPORTING REQUIREMENTS  
Investigators are required by Federal Regulation to report adverse drug reactions. Questions 
regarding drugs as used in this study should be directed to the Brown University Oncology 
Research Group (BrUOG) Central Office, Phone: (401) 863-3000 Fax (401) 863-3820, which 
will in turn notify the Principal Investigator. 
 
All adverse events and special reporting situations, whether serious or non-serious, related or 
unrelated, will be reported from the time a signed and dated ICF is obtained until 100 days (+1 
week) after the last treatment (Nivolumab or ONC201, whichever is last), or until the subject 
withdraws consent from study participation (declines participation) or at the time patient 
becomes a screen failure, whichever occurs first. There will be a safety visit at 30 days (+1 
week) and 100 days (+1 week) time points. 
12.5.1 Pregnancies 
Pregnancies occurring while the subject is on study drug or within 100 days (+1 week) after the 
subject’s last treatment (Nivolumab or ONC201, whichever is last) are considered expedited 
reportable events.  If the subject is on active treatment, the treatment is to be discontinued 
immediately.  The pregnancy must be reported to the Brown University Oncology Research 
Group, by the site, immediately (within 24 hours of the site being made aware), via the site 
completed BMS pregnancy reporting Form and a 3500A MedWatch form (site to submit to 
BrUOG), and BrUOG will in turn report to BMS and Oncoceutics immediately (within 1 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
working day and once in receipt of the site submitted SAE forms). Pregnancies and suspected 
pregnancies (including a positive pregnancy test regardless of age or disease state) of a female 
subject occurring while the subject is on treatment (Nivolumab and/or ONC201), or within 100 
days (+1 week) of the subject’s last treatment (Nivolumab or ONC201, whichever is last), are 
considered immediately reportable events. Treatment is to be discontinued immediately. The 
pregnancy, suspected pregnancy, or positive pregnancy test must be reported to BMS Drug 
Safety and Oncoceutics immediately by facsimile, email, or other appropriate method (to be 
done by BrUOG), using the required reporting forms (Forms to be completed by site and sent to 
BrUOG). 
 
The Investigator will follow the subject until completion of the pregnancy, and must notify BMS 
and Oncoceutics (by informing BrUOG) of the outcome as specified below.  The Investigator 
will provide this information as a follow-up to the initial report. If the outcome of the pregnancy 
meets the criteria for immediate classification as a SAE (i.e., spontaneous abortion [any 
congenital anomaly detected in an aborted fetus is to be documented], stillbirth, neonatal death, 
or congenital anomaly), the Investigator should follow the procedures for reporting SAEs (i.e., 
report the event to BrUOG who will then report to BMS and Oncoceutics by facsimile or email 
within 1 working day of being made aware of the event via the sites formal submission of the 
SAE pregnancy forms). 
 
The patient should be referred to an obstetrician/gynecologist experienced in reproductive 
toxicity for further evaluation and counseling. 
 
All neonatal deaths that occur within 100 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 100 days that the Investigator suspects to 
be related to the in-utero exposure to the study drug should also be reported. In the case of a live 
“normal” birth, BMS and Oncoceutics should be advised as soon as the information is available 
(BrUOG will advise BMS once information is submitted to BrUOG). 
12.5.2 Serious Adverse Event Reporting Procedures  
All pregnancies or suspected pregnancies, including suspected fetal exposure or neonatal deaths 
must be reported to the Brown University Oncology Research Group immediately (within 24 
hours of being made aware of the event). BrUOG will report all pregnancies to BMS and 
Oncoceutics within 1 working day, and once being made aware of the event once in receipt of 
the site submitted required reports. All other SAEs are to be announced via email to BrUOG 
within 24 hours of being made aware of the event and the site has 5 business days (from being 
made aware of the event) to send the written MedWatch 3500A report to BrUOG, who will then 
report the SAE to BMS product safety and Oncoceutics within 1 working day of being in receipt 
of the completed and signed MedWatch report (submitted to BrUOG from the site).  Initial SAE 
information and all amendments or additions must be recorded on an SAE Form and faxed or 
emailed to BMS and Oncoceutics (to be done by BrUOG).  
 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
BMS Drug Safety and Oncoceutics Contact Information: (to be reported to by BrUOG) 
 
BMS SAE EMAIL ADDRESS: Worldwide.Safety@BMS.com 
Oncoceutics EMAIL ADDRESS:  
Pharmacovigilance@oncoceutics.com 
 
A copy of the fax transmission or email confirmation of the SAE report to BMS and Oncoceutics 
should be attached to the SAE and retained with the study records at BrUOG.  
 
The principal investigator (or his designee) has the obligation to report all serious adverse events 
to the Brown University Oncology Research Group’s (BrUOG) office who in return will report 
to the FDA, BMS, Oncoceutics and all sites participating in the trial.  All SAE reports will be 
forwarded to BMS Product Safety and Oncoceutics by BrUOG. All events must be reported by 
the investigator utilizing the Form FDA 3500A (MedWatch Form).  Sites must alert BrUOG to 
SAEs within 24 hours of being made aware of the event via phone or email, and the site will 
have 5 business days (from when site was made aware of the event) to submit formal signed 
report via the 3500A. BrUOG will then alert BMS and Oncoceutics within 1 business day of 
being in receipt of the signed MedWatch report. BrUOG will submit a SAE memo and 
MedWatch 3500A to the FDA within the reporting time frames. 
 
The initial report must be as complete as possible, including an assessment of the causal 
relationship between the event and the investigational product(s), if available.  Information not 
available at the time of the initial report (e.g., an end date for the adverse event or laboratory 
values received after the report) must be documented on a follow-up report.   
 
A final report to document discharge from hospital (or end of important medical event) is 
required.   
 
All deaths during treatment or within 100 days (+ 1 week) following completion of active 
protocol treatment (Nivolumab or ONC201, whichever is last) must be formally reported to 
BrUOG within 5 business days of being made aware of the event or as soon as the investigator is 
made aware of the event. If the death is thought to be related to the study treatment (Nivolumab 
and/or ONC201), deaths must be reported to BrUOG within 24 hours of the investigator being 
made aware of the event. 
 
All adverse events and special reporting situations, whether serious or non-serious, related or 
unrelated, will be reported from the time a signed and dated ICF is obtained until 100 days (+1 
week) after the last treatment (Nivolumab or ONC201, whichever is last), or until the subject 
withdraws consent from study participation (declines participation) or at the time patient 
becomes a screen failure, whichever occurs first. There will be a safety visit at 30 days (+1 
week) and 100 days (+1 week) time points. 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
Every adverse event, serious or non-serious, must be assessed by the investigator with regard to 
whether it is considered immune-mediated. 
 
Serious adverse events occurring more than 100 days (+1 week) after study discontinuation need 
only be reported if a relationship to the study treatment (Nivolumab and/or ONC201) is 
suspected.  
12.5.3 Types of Report: Guidelines for sites to report: 
Telephone report:  For SAE’s contact the BrUOG office within 24 hours of learning of a SAE. 
For SAE notification: (initial and follow-up) contact BrUOG Central Office (401) 863-3000 (or 
via email), with 24 hour noticed prior to submitting a SAE report. 
 
Written report: Send the signed MedWatch 3500A form (and BMS pregnancy reporting form 
for pregnancies if applicable) within 5 business days of being made aware of the event to the 
BrUOG Central Office by email. For Follow-up reports, please submit the signed MedWatch 
3500A when new information has become available and the event can be closed out.*Of note 
Oncoceutics will not receive BMS pregnancy form, just the Medwatch3500A* 
 
Brown University Oncology Research Group 
Phone: (401) 863-3000, Fax: (401) 863-3820 
Emails: BrUOG@brown.edu 
 
All deaths during treatment or within 100 days (+ 1 week)  following completion of active 
protocol treatment (Nivolumab or ONC201, whichever is last) must be reported within 5 
business days (from when site was made aware of the event) or as soon as the investigator is 
made aware of the event. If the death is thought to be related to the study treatment (Nivolumab 
and/or ONC201), deaths must be reported to BrUOG within 24 hours of the investigator 
being made aware of the event. SAEs post 100 days since last dose of drug (+1 week) that 
are thought to be possibly related to study treatment (Nivolumab or ONC201, whichever is 
last) must be reported to BrUOG within the 5-business day time frame noted above. 
 
MedWatch 3500A Reporting Guidelines: 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (section 5) of 
the MedWatch 3500A form: 
• Treatment regimen (dosing frequency, combination therapy): if related to treatment 
regimen add to section C suspect product, if not related to any, add to concomitant 
section noting Lot #  
• Protocol description (and number, if assigned) 
• Description of event, severity, treatment, and outcome, if known 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
• Action taken with Nivolumab and ONC201 as a result of the SAE and expectedness 
(based on IB and consent) 
• Supportive laboratory results and diagnostics 
• Investigator’s assessment of the relationship of the adverse event to each investigational 
product (Nivolumab) and suspect medication/treatment (ONC201) and if event(s) is/are 
immune mediated 
• Documentation if the event(s) are considered immune mediated 
• Site to be clear to outline which events are being reports as serious 
• Must be typed 
• **It is required that sites put the following numbers on the MedWatch form for 
tracking: 
o BrUOG 379 
o INSERT BMS tracking # CA209-79E 
 
A final report to document discharge from hospital (or resolution of important medical 
event) is required. 
 
All SAE reports (initial or follow-up), must be signed by the treating physician or PI of the trial. 
Any SAEs that are signed and submitted to BrUOG, but do not include required reporting 
information, will be queried for updating to ensure all required information is included. In such 
instances, SAEs will be updated by the reporting site and re-submitted to BrUOG. 
 
 
Follow-up information:   
For any follow-up SAE report, submit a new MedWatch 3500A report; do not resubmit the 
initial report with any additions. The follow-up report must be submitted to BrUOG with subject 
identifiers (subject number, initials, and date of birth), protocol description and number (BrUOG 
379 and tracking numbers(s) as noted above), suspect drug, a brief summary of previously 
reported SAE information, and any new information, including modification of prior events, 
causality, new serious events, discharge date, etc. 
A final report documenting discharge date from the hospital is required. 
The principal Investigator is required to notify his/her Institutional Review Board (IRB) of a 
serious adverse event according to institutional policy.   
 
 
BrUOG Responsibility Regarding Reporting:  
The sponsor-investigator by way of BrUOG, the sponsor representative and central coordinating 
office, is required to promptly review all information relevant to the safety of the drug (21 CFR 
312.32(b)).  
 
Safety Reporting for IND Holders 
In accordance with 21 CFR 212.32, Sponsor-Investigator of the study conducted under an IND 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
must comply with following safety-reporting requirements:  
 
The BrUOG Central Office will notify by fax all drug reaction reports to the FDA, the Principal 
Investigator, and the participating sites (who will in turn notify their local IRBs) as soon as 
possible but no later than 15 calendar days after initial receipt of the signed information, 
submitted to BrUOG by the site, as per regulatory requirements.  
 
BrUOG, for the sponsor-investigator, is required to report in an IND safety report any suspected 
reaction to the study treatment that is both serious and unexpected (21 CFR 312.32 (c)(1)(i)). It is 
required that events that are suspected, serious and unexpected, be reported to the FDA via an 
IND safety report. 
 
BrUOG will fax reports to the FDA for IND Safety Reports: to the CDER fax number. 
 
SAEs will be reported as an amendment to the IND (if applicable) within 15 days of sponsor 
notification. The FDA will all receive a simultaneous copy via facsimile of all adverse events 
filed with the FDA (which will be sent to the MedWatch fax line for IND exemption or to the 
division fax if there is an IND). A copy of the form will be kept by the BrUOG Central Office.    
• “IND safety report” for 15-day reports  
• “Follow-up IND safety report” for follow-up information  
• “7-day IND safety report” for unexpected fatal or life-threatening adverse reaction reports 
 
 
Fax: 1-800-FDA-0178 (1-800-332-0178) For IND exempt study or for IND study the SAE 
will be sent to Center Drug Evaluation Division fax line that has responsibility for review of 
IND 
Mail: For IND studies BrUOG will send the SAE as an amendment to the IND as well 
 
All SAEs that are serious and reasonably or probably related to the use of Nivolumab 
and/or ONC201 will be sent to: BMS and Oncoceutics 
 
BrUOG will alert BMS and Oncoceutics to an SAE within 1 business day of being in receipt of 
the complete signed site submitted documentation. 
 
All written IND Safety Reports submitted to the FDA by the Sponsor-Investigator must also be 
sent to BMS and Oncoceutics, as well as any pregnancy occurring in association with use of a 
BMS and Oncoceutics Product to (of note do not submit BMS pregnancy form to Oncoceutics):  
 
BrUOG will send to: BMS SAE Email Address: Worldwide.Safety@BMS.com 
BMS SAE Facsimile Number:  +1 609-818-3804 
Oncoceutics contact: Pharmacovigilance@oncoceutics.com 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
IND Annual Reports, for IND study only 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an annual 
report is provided to the FDA within 60-days of the IND anniversary date.  21 CRF 312.33 
provides the data elements that are to be submitted in the report.  The Annual Report should be 
filed in the study's Regulatory Binder, and a copy provided to BMS as a supporter of this study  
 
Adverse event updates/IND safety reports 
BMS shall notify the Brown University Oncology Research Group (BrUOG) via an IND Safety 
Report of the following information: 
• Any AE associated with the use of study drug in this study or in other studies that is both 
serious and unexpected. 
• Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 
 
BrUOG will then notify the sites who shall notify their IRB/EC promptly of these new serious 
and unexpected AE(s) or significant risks to subjects. 
 
13 
REGULATORY CONSIDERATIONS 
This research study is sponsored by the Principal Investigator, Dr. Khaldoun Almhanna, in 
collaboration with Brown University Oncology Research Group (BrUOG), which will serve as 
the central coordinating office for the study. This study is supported by BMS (the makers of 
Nivolumab) and Oncoceutics (the makers of ONC201). 
 
 
Protection of Human Subjects 
The Investigator must ensure that patients or their legally acceptable representatives are clearly 
and fully informed about the purpose, potential risks and other critical issues regarding clinical 
trials in which they volunteer to participate.  Preparation of the consent form is the responsibility 
of the Investigator and must include all elements required by CFR 21 Part 50.25 and the local 
IRB. 
 
 
Compliance with the Protocol and Protocol Revisions: 
The study must be conducted as described in this approved protocol.   
All revisions to the protocol must be created by Brown University Oncology Research Group, 
and approved by BMS and Oncoceutics.  The Investigator should not implement any deviation or 
change to the protocol without prior review and documented approval/favorable opinion from the 
IRB/IEC and BMS and Oncoceutics of an Amendment, except where necessary to eliminate an 
immediate hazard(s) to study patients. 
 
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to Brown University Oncology Research Group, BMS and Oncoceutics.  If the revision is an 
Administrative Letter, Investigators must inform their IRB(s)/IEC(s).  
 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
The Investigator must ensure that patients or their legally acceptable representatives are clearly 
and fully informed about the purpose, potential risks and other critical issues regarding clinical 
trials in which they volunteer to participate.  Preparation of the consent form is the responsibility 
of the Investigator and must include all elements required by CFR 21 Part 50.25 and the local 
IRB. 
 
After the study has been fully explained, written informed consent will be obtained from either the 
patient or his/her guardian or legal representative prior to study participation.  The method of 
obtaining and documenting the informed consent and the contents of the consent will comply with 
ICH-GCP and all applicable regulatory requirement(s). 
 
 
Protocol amendments or changes in study conduct:  
Any change or addition (excluding administrative) to this protocol requires a written protocol 
amendment that must be created the Brown University Oncology Research Group, BMS, 
Oncoceutics and the investigator before implementation. Amendments significantly affecting the 
safety of subjects, the scope of the investigation or the scientific quality of the study require 
additional approval by the IRB at each study center.  A copy of the written approval of the IRB 
must be provided to Brown University Oncology Research Group, Oncoceutics and BMS 
• Examples of amendments requiring such approval  
• Increases in drug dose or duration of exposure of subjects 
• Significant changes in the study design (e.g. addition or deletion of a control group) 
• Increases in the number of invasive procedures 
• Addition or deletions of a test procedure required for monitoring of safety. 
These requirements for approval should in no way prevent any immediate action from being 
taken by the investigator or by Brown University Oncology Research Group, Oncoceutics and 
BMS in the interests of preserving the safety of all patients included in the trial.  If an immediate 
change to the protocol is felt to be necessary by the investigator and is implemented for safety 
reasons Brown University Oncology Research Group, Oncoceutics and BMS must be notified 
and the IRB at the center must be informed immediately.  
14 DATA MONITORING / QUALITY ASSURANCE/ RECORD RETENTION 
 
Good Clinical Practice:  
The study will be conducted in accordance with the International Conference on Harmonisation 
(ICH) for Good Clinical Practice (GCP) and in the US Code of Federal Regulations.  The 
investigator will be thoroughly familiar with the appropriate use of the drug as described in the 
protocol and Investigator Brochures.  Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected.  Master files should 
be established at the beginning of the study, maintained for the duration of the study and retained 
according to the appropriate regulations.   


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
 
Patient Confidentiality:  
In order to maintain patient privacy, all data capture records, drug accountability records, study 
reports and communications will identify the patient by initials and the assigned patient number.  
The investigator will grant monitor(s) and auditor(s) from BMS, Oncoceutics or their designees 
and regulatory authority (ies) access to the patient’s original medical records for verification of 
data gathered on the data capture records and to audit the data collection process.  The patient’s 
confidentiality will be maintained and will not be made publicly available to the extent permitted 
by the applicable laws and regulations. 
 
 
Protocol Compliance:   
The investigator will conduct the study in compliance with the protocol given approval/favorable 
opinion by the IRB/IEC and the appropriate regulatory authority(ies).  Changes to the protocol 
will require approval from BMS, Oncoceutics and written IRB/IEC approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to patients.  The IRB/IEC may provide, if applicable regulatory authority (ies) permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval /favorable opinion of the IRB/IEC.  The investigator will submit all protocol 
modifications to BMS, Oncoceutics and the regulatory authority (ies) in accordance with the 
governing regulations. Any departures from the protocol must be fully documented in the source 
documents.   
 
 
On-site Audits:  
Regulatory authorities, the IRB and/or BMS and/or Oncoceutics clinical quality assurance group 
may request access to all source documents, data capture records, and other study documentation 
for on-site audit or inspection.  Direct access to these documents must be guaranteed by the 
investigator, who must provide support at all times for these activities. 
 
 
Drug Accountability:  
Accountability for the drug at all study sites is the responsibility of the principal investigator.  
The investigator will ensure that the drug is used only in accordance with this protocol.  Drug 
accountability records indicating the drug’s delivery date to the site (if applicable), inventory at 
the site (if applicable), use by each patient, and return to BMS and Oncoceutics for disposal of 
the drug (if applicable and if approved by BMS and Oncoceutics for their respective drugs) will 
be maintained by the clinical site.  Accountability records will include dates, quantities, lot 
numbers, expiration dates (if applicable), and patient numbers.   
 
All material containing Nivolumab and ONC201 will be treated and disposed of as hazardous 
waste in accordance with governing regulations. 
 
 
Premature Closure of the Study:  
This study may be prematurely terminated, if in the opinion of the investigator, Oncoceutics or 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
BMS, there is sufficient reasonable cause.  Written notification documenting the reason for study 
termination will be provided to the investigator, Oncoceutics or BMS by the terminating party.   
 
Circumstances that may warrant termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to patients 
• Failure to enter patients at an acceptable rate 
• Insufficient adherence to protocol requirements 
• Insufficient complete and/or evaluable data 
• Plans to modify, suspend or discontinue the development of the drug 
• Should the study be closed prematurely, all study materials must be returned to BMS and 
Oncoceutics (unless another method if approved by the company (ies) 
 
 
Record Retention:  
The investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s).   
 
The Brown University Oncology Research Group, as coordinator of this study, is responsible for 
ensuring proper conduct of the study with regard to protocol adherence and the validity of the 
data recorded on the case report forms. The Principal Investigator (Khaldoun Almhanna, M.D.) 
and Brown University Oncology Research Group will monitor this study. The case report forms 
will be monitored against the submitted documents for accuracy, completeness, adherence to the 
protocol and regulatory compliance.  
 
U.S. FDA regulations (21CFR312.62[c] require all records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including CRFs, consents 
forms, laboratory test results and medication inventory records, must be retained by the Principal 
Investigator for 2 years after marketing application approval. If no application is filed, these 
records must be kept 2 years after the investigation is discontinued and the FDA and the 
applicable local health authorities are notified. BMS will notify the Principal Investigator if an 
application is filed.  
 
15 
DATA SAFETY AND MONITORING BOARDS 
All trials initiated by the Brown University Oncology Research Group (BrUOG) are subject to 
oversight by the Data Safety Monitoring Board (DSMB).  This board meets two times per year 
with any additional meetings scheduled when needed.  The responsibilities are as follows: 
• Familiarize themselves with the research protocol (s)  
• The DSMB reviews trial performance information such as accrual information.   
• Review interim analyses of outcome data and cumulative toxicity data summaries to 
determine whether the trial should continue as originally designed, should be changed, or 
should be terminated based on these data.   


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
• The DSMB also determines whether and to whom outcome results should be released 
prior to the reporting of study results. 
• All adverse events are reviewed by the committee, with assurances that these have been 
in fact sent for review to all pertinent IRBs. 
• Review of reports of related studies to determine whether the monitored study needs to be 
changed or terminated. 
• Review major proposed modifications to the study prior to their implementation (e.g., 
termination, dropping an arm based on toxicity results or other reported trial outcomes, 
increasing target sample size). 
• Following each DSMB meeting, provide the study leadership with written information 
concerning findings for the trial as a whole related to cumulative toxicities observed and 
any relevant recommendations related to continuing, changing, or terminating the trial.  
 
The study leadership will provide information on cumulative toxicities and relevant 
recommendations to the local principal investigators to be shared with their IRB’s. 
16 
DATA ANALYSIS/STATISTICAL METHODS 
 
Sample Size Determination for Phase I 
No formal sample size determination is possible for Phase I of this trial due to the inherent nature 
of Phase I de-escalation trials. If no DLTs are observed in the first 3 patients entered at the initial 
ONC 201 dose level (625mg weekly) then 3 additional patients will be entered on the phase IB 
portions to further assess safety and pharmacokinetics. The protocol includes 2 additional de-
escalated levels that may be used dependent on toxicity.    
 
Safety Analysis 
The primary population for the assessment of the MTD is defined as all patients experiencing a 
DLT during DLT observation window (run-in dose day -7, cycle 1 to assessment pre-dosing cycle 
2) following the first administration of the combination of ONC201 and nivolumab.  
 
Patients receiving less than 80% of the ONC201 planned dose during the first cycle will not be 
evaluable for the assessment of the MTD provided that the dose reduction is not related to any-
grade drug toxicity (if it is related to a toxicity- see DLT definition). 
 
DLTs will be presented by dose level. 
 
DLT definition: 
 
Hematologic: 
• Grade 4 neutropenia that persists for >7 consecutive days 
• Febrile neutropenia (defined as neutropenia ≥ Grade 3 and a body temperature 38.5°C) 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
• Grade ≥ 3 neutropenic infection 
• Grade 4 thrombocytopenia (platelets <25,000 cells/mm3) or Grade ≥ 3 thrombocytopenia 
with bleeding 
 
Nonhematologic: 
• Any other treatment related, clinically significant Grade ≥ 3 toxicity not classified under 
CTCAE blood or bone marrow with the exception of grade 3 nausea, vomiting, or 
diarrhea in patients who have received optimal treatment with antiemetics or anti-
diarrheals and who do not downgrade to a grade 1 within 72 hours; Grade 4 (life 
threatening) diarrhea or vomiting will be considered DLTs, irrespective of the duration of 
the event. alopecia is not a DLT 
• Delay of > 2 weeks secondary to a treatment related AE that is deemed possibly or 
definitely related to either drug  
• Failure to receive at least 80% of the planned dose on ONC201 due to treatment related 
AEs (ONC201) in cycle 1 (5 doses ONC201 with run-in).  
 
Although toxicities may be observed at any point during treatment, only those occurring during 
the defined DLT observation window of treatment that are considered DLTs will guide dose de-
escalation decisions, expansion of a dose level, or evaluation of intermediate dose levels. 
16.2.1 Early Stopping Rule for Safety for Phase II study 
Formal early stopping rules will not be utilized. Safety in this trial is governed by the DLT rules 
and oversight provided by the BrUOG DSMB. It is anticipated that severe toxicity will not exceed 
30%.  
 
In the phase II cohort an additional 28 patients will be accrued so that a total of 34 patients will be 
treated at the RP2D (including 6 patients treated at the RP2D on the phase IB portion of the trial).  
 
Accrual will be suspended for excess toxicity if over 9 of the initial 12 Phase II patients experience 
an event that was defined as a DLT in the phase I portion. The chance of early study suspension 
(i.e., ≤ 17 subjects accrued) is 50% if the true toxicity is 50% and 4.0% if it is 30%. Similarly, 
accrual will be suspended if, at any point among the 34 patients, 15 or more subjects are observed 
with an event that was defined as a DLT in the phase I portion. Suspension will occur, either early 
or finally, with probability 82% if true toxicity is 50% and 7.8% if it is 30%.  
 
A patient experiencing a toxicity defined as a DLT, post cycle 2 (phase I) or in the phase II 
portion, is required to have treatment (both drugs) held, once the toxicity reduces to a grade 1 or 
less, dose reduce (ONC201) and resume treatment, even though it will no longer be defined as a 
DLT. 
 
Efficacy Analysis for Phase II 
All patients who have received a minimum of 1 cycle of study treatment, had baseline assessments 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
and at least one on-study tumor assessment will be considered evaluable for response.  
Response rate is defined as the proportion of patients with a Complete (CR) or Partial Response 
(PR) relative to the total number of evaluable patients. Responses will be defined according to the 
RECIST version 1.1 guidelines for solid. 
The best overall response is the best response recorded from the start of treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started) or the withdrawal from the study. Stable disease will be 
considered the best response when observed at least after two months from baseline. Tumor 
responses will be analyzed in a descriptive manner. The number and percentage of objective 
response (CR+PR) will be tabulated. Response rate may be summarized with the corresponding 
95% exact confidence interval. 
Progression free survival will be defined as the number of days between the first treatment with 
protocol specified therapy and death or progression, whichever comes first.  Individuals who are 
alive and progression free at last contact will be censored at that time. 
Overall survival (OS) will be defined as the number of days between the first treatment with 
protocol specified therapy and death.  Individuals who are alive at last contact will be censored at 
that time. 
Progression free survival and overall survival time distributions in the Phase II study population 
will be summarized using the methods of Kaplan and Meier. 
 
Primary Analysis for Phase II 
Following completion of the Phase I trial, we will conduct a single-arm, double endpoint Phase II 
study to evaluate the efficacy of the promising treatment combination.  In Phase II, we will 
evaluate the co-primary outcomes of response and Progression Free Survival (PFS), testing the 
composite null hypothesis that Pr, the chance of response, is at most 5% AND the chance of PFS 
at 3 months, Ps, is at most 50%. The alternative for which power is computed is that the Pr is at 
least 20% OR Ps is at least 71% (this corresponds to median PFS of 6 months, assuming an 
exponential model). Our double end-point design (Sill et al., 2012) evaluates an initial cohort of 
17 patients. If 1 of 17 respond or 4/17 are Progression Free (PF) at 3 months then recruitment will 
continue to 34 patients. The null is rejected if there are at least 5/34 responses or at least 22/34 
patients PF at 3 mo. Statistics under independence of response and PFS at 3 months (i.e., Prs = 
p(response AND PFS at 3 months) = Pr*Ps), as well as the most extreme forms of dependence, 
(Prs = min(Pr,Ps) or Prs = max(0, Pr+Ps-1)), were computed. Power: The design provides at least 
80% power and at most 7.9% type I error. The chance of early stopping under the null is at least 
52% and at most 10.7% under any alternative.  
 
Pharmacokinetic Analysis 
All patients who complete at least one day of PK blood sampling will be included in the PK 
analyses. Plasma concentration/time data of ONC201 obtained at the designated times will be 
summarized descriptively and presented graphically by dose and day of assessment. The 
concentration/time data of ONC201 will be analyzed using non-compartmental methods to obtain 
PK parameters in individual patients. These PK parameters include the maximum plasma 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
concentration (Cmax), time to maximum plasma concentration (Tmax), area under the plasma 
concentration versus time curve to 24 hours (AUC24hr) and area under the plasma concentration 
versus time curve to the time of the last measurable concentration (AUClast). If data permit, area 
under the plasma concentration versus time curve to infinity (AUCinf), terminal elimination half-
life (t1/2), oral plasma clearance (CL/F) and apparent volume of distribution (Vd/F) will be also 
estimated.  
Individual values and descriptive statistics of these PK parameters will be provided by dose and 
day of assessment in tabular form.  
To determine any interactions between ONC201 and nivolumab, plasma concentrations of both 
drugs will be monitored closely. Changes in PK parameters, such as Tmax, Cmax, λz, t½, AUClast, 
AUCinf, Cmin and, CL/F, of ONC201 will be compared between single agent ONC201 (run-in 
component) and ONC201+ nivolumab. Similarly, PK parameters of nivoumab will be compared 
to historical control (Gaudreault J, Cancer Chemother Pharmacol). 
17 
REFERENCES 
Abdulghani, J., and El-Deiry, W. S. (2010). TRAIL receptor signaling and therapeutics. Expert 
Opinion on Therapeutic Targets 14, 1091-1108. 
Allen, J. E., and El-Deiry, W. S. (2010). Circulating Tumor Cells and Colorectal Cancer. Current 
Colorectal Cancer Reports 6, 212-220 
Allen, J. E., and El-Deiry, W. S. (2011). Oxaliplatin Uses JNK to Restore TRAIL Sensitivity in 
Cancer Cells Through Bcl-xL Inactivation. Gastroenterology 141, 430-434. 
Allen, J. E., Krigsfeld, G., Mayes, P. A., Patel, L., Dicker, D. T., Patel, A. S., Dolloff, N. G., 
Messaris, E., Scata, K. A., Wang, W., et al. (2013). Dual inactivation of Akt and ERK by TIC10 
signals Foxo3a nuclear translocation, TRAIL gene induction and potent anti-tumor effects. Science 
Translational Medicine. 
Allen, J. E., Crowder R, El-Deiry WS. (2015). First-In-Class Small Molecule ONC201 Induces 
DR5 and Cell Death in Tumor but not Normal Cells to Provide a Wide Therapeutic Index as an 
Anti-Cancer Agent. PLoS One Nov 18;10(11):e:0143082. 
Ashkenazi, A., Pai, R. C., Fong, S., Leung, S., Lawrence, D. A., Marsters, S. A., Blacki.e., C., 
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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
Eisenhauer, E. A., Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R., Dancey, J., 
Arbuck, S., Gwyther, S., Mooney, M., et al. (2009). New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer 45, 228-247. 
Greco, F. A., Bonomi, P., Crawford, J., Kelly, K., Oh, Y., Halpern, W., Lo, L., Gallant, G., and 
Klein, J. (2008). Phase 2 study of mapatumumab, a fully human agonistic monoclonal antibody 
which targets and activates the TRAIL receptor-1, in patients with advanced non-small cell lung 
cancer. Lung Cancer 61,82-90. 
Herbst, R. S., Eckhardt, S. G., Kurzrock, R., Ebbinghaus, S., O'Dwyer, P. J., Gordon, M. S., 
Novotny, W., Goldwasser, M. A., Tohnya, T. M., Lum, B. L., et al. (2006). Phase I Dose-
Escalation Study of Recombinant Human Apo2L/TRAIL, a Dual Proapoptotic Receptor Agonist, 
in Patients With Advanced Cancer. Journal of Clinical Oncology 28, 2839-2846. 
Herbst, R. S., Eckhardt, S. G., Kurzrock, R., Ebbinghaus, S., O'Dwyer, P. J., Gordon, M. S., 
Novotny, W., Goldwasser, M. A., Tohnya, T. M., Lum, B. L., et al. (2010). Phase I Dose-
Escalation Study of Recombinant Human Apo2L/TRAIL, a Dual Proapoptotic Receptor Agonist, 
in Patients With Advanced Cancer. Journal of Clinical Oncology 28, 2839-2846. 
Jin, Z., and El-Deiry, W. S. (2005). Overview of cell death signaling pathways. Cancer Biology & 
Therapy 4, 139-163. 
Kagawa, S., He, C., Gu, J., Koch, P., Rha, S.-J., Roth, J. A., Curley, S. A., Stephens, L. C., and 
Fang, B. (2001). Antitumor Activity and Bystander Effects of the Tumor Necrosis Factor-related 
Apoptosis- inducing Ligand (TRAIL) Gene. Cancer Research 61, 3330-3338. 
Leong, S., Cohen, R. B., Gustafson, D. L., Langer, C. J., Camidge, D. R., Padavic, K., Gore, L., 
Smith, M., Chow, L. Q., von Mehren, M., et al. (2009). Mapatumumab, an Antibody Targeting 
TRAIL-R1, in Combination With Paclitaxel and Carboplatin in Patients With Advanced Solid 
Malignancies: Results of a Phase I and Pharmacokinetic Study. J Clin Oncol 27, 4413-4421. 
Modur, V., Nagarajan, R., Evers, B. M., and Milbrandt, J. (2002). FOXO Proteins Regulate Tumor 
Necrosis Factor-related Apoptosis Inducing Ligand Expression. Journal of Biological Chemistry 
277, 47928-47937. 
Mom, C. H., Verweij, J., Oldenhuis, C. N. A. M., Gietema, J. A., Fox, N. L., Miceli, R. e., Eskens, 
F. A. L. M., Loos, W. J., de Vries, E. G. E., and Sleijfer, S. (2009). Mapatumumab, a Fully Human 
Agonistic Monoclonal Antibody That Targets TRAIL-R1, in Combination with Gemcitabine and 
Cisplatin: a Phase I Study. Clinical Cancer Research 15, 5584-5590. 
Ozoren, N., and El-Deiry, W. S. (2003). Cell surface Death Receptor signaling in normal and 
cancer cells. Seminars in Cancer Biology 13, 135-147. 
Plummer, R., Attard, G., Pacey, S., Li, L., Razak, A., Perrett, R., Barrett, M., Judson, I., Kaye, S., 
Fox, N. L., et al. (2007). Phase 1 and Pharmacokinetic Study of Lexatumumab in Patients with 
Advanced Cancers. Clinical Cancer Research 13, 6187-6194. 
Senderowicz, A. M. (2010). Information Needed to Conduct First-in-Human Oncology Trials in 
the United States: A View from a Former FDA Medical Reviewer. Clinical Cancer Research 16, 
1719-1725. 
Sill M.W., Rubinstein L., Litwin S., Yothers G.. A method for utilizing co-primary efficacy 
outcome measures to screen regimens for activity in two-stage Phase II clinical trials. Clin Trials. 
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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
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89(15): p. 1138-47. 
Stein M, Mehnert, Mayer TM, Moss RA, Silk AW et al. First-in-human Clinical Trial of Oral 
ONC201 in Patients with Refractory Solid Tumors. Clin Cancer Res. 2017 Aug 1;23(15):4163-
4169. doi: 10.1158/1078-0432. 
Tolcher, A. W., Mita, M., Meropol, N. J., von Mehren, M., Patnaik, A., Padavic, K., Hill, M., 
Mays, T., McCoy, T., Fox, N. L., et al. (2007). Phase I Pharmacokinetic and Biologic Correlative 
Study of Mapatumumab, a Fully Human Monoclonal Antibody With Agonist Activity to Tumor 
Necrosis Factor Related Apoptosis-Inducing Ligand Receptor-1. J Clin Oncol 25, 1390-1396. 
Trarbach, T., Moehler, M., Heinemann, V., Kohne, C. H., Przyborek, M., Schulz, C., Sneller, V., 
Gallant, G., and Kanzler, S. Phase II trial of mapatumumab, a fully human agonistic monoclonal 
antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-
1 (TRAIL-R1), in patients with refractory colorectal cancer. Br J Cancer 102, 506-512. 
Vogelstein, B., and Kinzler, K. W. (2004). Cancer genes and the pathways they control. Nat Med 
10, 789-799. 
Wang, S., and El-Deiry, W. S. (2003). TRAIL and apoptosis induction by TNF-family death 
receptors. Oncogene 22, 8628-8633. 
Wagner J, Kline CL, Zhou L, Campbell KS, MacFarlane AW, Olszanski AJ, Cai KQ, Hensley 
HH, Ross EA, Ralff MD, El-Deiry WS .et al. Dose intensification of TRAIL-inducing ONC201 
inhibits metastasis and promotes intratumoral NK cell recruitment. J Clin Invest. 
2018;128(6):2325-2338 
Yang, J.-Y., Zong, C. S., Xia, W., Yamaguchi, H., Ding, Q., Xi.e., X., Lang, J.-Y., Lai, C.-C., 
Chang, C.- J., Huang, W.-C., et al. (2008a). ERK promotes tumorigenesis by inhibiting FOXO3a 
via MDM2- mediated degradation. Nat Cell Biol 10, 138-148. 
Yang, W., Dolloff, N. G., and El-Deiry, W. S. (2008b). ERK and MDM2 prey on FOXO3a. Nat 
Cell Biol 10, 125-126. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
 
 
 
 
 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
APPENDIX A Eligibility CHECKLIST 
 
BrUOG 379: Phase Ib/II investigator-initiated, single arm study of ONC201 plus 
Nivolumab in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) patients 
 
Inclusion criteria: 
______(y/n) Patients must have a histologically/cytologically-confirmed MSS primary colorectal 
adenocarcinoma tumor, with confirmation of being microsatellite stable. 
______(y/n) Radiographic or clinical evidence of metastatic disease that has progressed after at least 2 prior 
regimens. Prior bevacizumab, cetuximab, trifluridine and tipiracil, or regorafenib is allowed, prior FOLFIRI 
and FOLFOX treatment is required. (Treatment with a FOLFIRINOX regimen will count as 2 regimens). 
Prior treatment not required to be have been administered in the metastatic setting. 
______(y/n) Patients must have measurable disease by RECIST criteria 
______(y/n) All patients must have a tumor(s) located in an area that that can be biopsied as confirmed by 
treating physician 
______(y/n) All patients must submit representative tissue from their malignancy if it is confirmed there 
is enough tissue from prior surgery or most recent biopsy. This can consist of archival tumor samples or 
tissue collected at biopsy to prove recurrence. In both cases, samples should consist of a formalin-fixed 
paraffin embedded (FFPE) tumor tissue block or at least 20 unstained slides (charged) of 4 uM thickness 
sent to the lab address in section 11.1.4. Tissue located outside of Lifespan Cancer Institute hospitals must 
be confirmed as requested prior to enrollment.  
______(y/n) All previous therapies for cancer, including radiotherapy, major surgery and investigational 
therapies must be discontinued for ≥ 14 days before the first dose of ONC201 (D-7 run in). 
______(y/n) All clinically significant adverse events related to any prior therapy must have resolved to 
Grade ≤ 1 Common Terminology Criteria for Adverse Events (CTCAE v5.0), except alopecia or parameters 
defined in this eligibility list. 
______(y/n) Age ≥ 18 years. 
______(y/n) ECOG performance status ≤ 2. 
______(y/n) Adequate organ and marrow function as defined below: 
a. Absolute neutrophil count ≥1,000/mm3 without growth factor use ≤ 7 days prior to 
treatment (this is Day -7) ______(y/n) 
b. Platelets ≥75,000/mm3 without platelet transfusion ≤ 7 days prior to treatment (this is 
Day -7) ______(y/n) 
c. Hemoglobin >8.0 mg/dL without red blood cell transfusion ≤ 7 days prior to treatment 
(this is Day -7) ______(y/n) 
d. Total serum bilirubin <1.5 X upper limit of normal (ULN) ______(y/n) 
e. AST (SGOT)/ALT (SGPT) 
≤2 X ULN; ≤ 5 X ULN if liver dysfunction is felt to be 
secondary to tumor burden within 14 days prior to treatment (this is Day -7) ______(y/n)  
f.  Serum creatinine ≤ 1.5 X ULN (OR creatinine clearance ≥ 60 mL/min/1.73 m2) within 
14 days prior to treatment (this is Day -7) ______(y/n) 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
g. Serum or urine pregnancy test (for females of childbearing potential) negative ≤7 days of 
treatment (this is Day -7) ______(y/n) 
______(y/n) Ability to understand and the willingness to sign a written informed consent document and 
comply with the study scheduled visits, treatment plans, laboratory tests and other procedures.  
______(y/n) Female patients of child-bearing potential must be practicing an effective form of 
contraception from the time of informed consent and for the duration of the study treatment through 5 
months after the last dose of drug (ONC201 or Nivolumab, whichever is administered last). The decision 
of effective contraception will be based on the judgment of the principal investigator or a designated 
associate. 
______(y/n) Male patients who are with women of child-bearing potential must be surgically sterile 
(provide date of surgery) or must agree to use effective contraception from the time of informed consent 
and for the duration of  the study treatment through 7 months after the last dose of drug (ONC201 or 
Nivolumab, whichever is administered last). The decision of effective contraception will be based on 
the judgment of the principal investigator or a designated associate. 
______(y/n) Patients must agree to the required tumor biopsies to enroll in the trial. Pre-treatment biopsies 
can occur any time post consent and prior to run-in ONC201 dose, a second biopsy will be required at the 
end of cycle 2 to assess response biomarkers, a final biopsy is included at the time of progression to assess 
for resistance mechanisms. Only 2 biopsies will be required for patients who initially progress at time of 
2nd biopsy. 
Exclusion 
______(y/n) Patients with symptomatic brain metastases are excluded. Patients with asymptomatic and 
treated CNS metastases may participate in this trial. The patient must have completed any prior treatment 
for CNS metastases > 28 days prior to registration, including radiotherapy or surgery. Steroids for the 
treatment of brain metastasis are not permitted. 
______(y/n) Patients with prior treatment with ONC201 or who have had prior therapy with nivolumab or 
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 immune check point pathways will be excluded 
______(y/n) Active inflammatory gastrointestinal disease such as severe chronic diarrhea (unless related to 
underlying malignancy), gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to 
study registration. Gastroesophageal reflux disease under controlled treatment with proton pump inhibitors 
is allowed. 
______(y/n) Pregnant or breast feeding. 
______(y/n) Current active treatment in another clinical study (treatment trial) within 14 days of D-7. 
______(y/n) Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection 
requiring IV antibiotics, hepatitis, active rheumatologic or collagen vascular disease, symptomatic 
congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements.  
 
NOTE: Participants with active or a history of Hepatitis B or C infection as follows: 
______(y/n) Active hepatitis B (positive hepatitis B surface antigen [HBsAg] or hepatitis C virus 
(HCV) (positive HCV RNA) are not eligible to participate.  


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
______(y/n) HBV carriers or those participants requiring antiviral therapy are not eligible to 
participate. 
______(y/n) Participants positive for HCV antibody are eligible only if PCR is negative for HCV 
RNA. If PCR is positive, they are not eligible to participate. 
______(y/n) Past HBV infection or resolved HBV infection are may be eligible on this trial 
provided the following criteria are met prior to randomization: Positive for hepatitis B core 
antibody (HBcAb), the absence of hepatitis B surface antigen (HBsAg), and no detectable HBV 
DNA in serum.  
______(y/n) Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS)-related illness. (testing is not required for eligibility). 
______(y/n) Any of the following in the previous 3 months: myocardial infarction, severe/unstable angina, 
coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, 
transient ischemic attack or symptomatic pulmonary embolism as defined by treating physician.  
______(y/n) Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that 
may increase the risk associated with study participation or study drug administration, or may interfere with 
the interpretation of study results, or in the judgment of the investigator would make the patient 
inappropriate for entry into the study. 
______(y/n) Participants with an active, known or suspected autoimmune disease. Participants with type I 
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, 
psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence 
of an external trigger are permitted to enroll. 
______(y/n) Participants with a condition requiring systemic treatment with either corticosteroids (> 10 
mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of day 1 of 
treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone 
equivalent, are permitted in the absence of active autoimmune disease 
______(y/n) Patients with a history of other invasive malignancies, with the exception of non-melanoma 
skin cancer are excluded if there is any evidence of other malignancy being present within the last three 
years (2 years for invasive breast cancer). However, patients with a malignancy that is non-likely to require 
treatment, as per the treating physician, in the next 2 years, such as a completely resected, early stage breast 
cancer, or other malignancies treated with curative intent are eligible. Patients are also excluded if their 
previous cancer treatment contraindicates this protocol therapy. 
______(y/n) Prior treatment with immunotherapy for any cancer, including immune checkpoint inhibitors 
or anti-CTLA4 agents 
______(y/n) Participants who have received a live / attenuated vaccine within 30 days of first treatment. 
 
 
 
 
 
 
 
 
 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
 
 
 
Signed informed consent: The patient must be aware of the neoplastic nature of his/her disease and must 
willingly consent after being informed of the procedure to be followed, the experimental nature of the 
therapy, alternatives, potential benefits, side effects, risks, and discomforts. 
 
The support documentation, per the requirements under the study parameters section of this study, as well 
as the consent form and this checklist, must be faxed to the BrUOG Central Office at the time of 
registration.  Please check if “Enclosed”, state reason when “Not Enclosed,” or check if "Not Applicable."  
 
1) Eligibility Form  
 
Enclosed __Not Enclosed   
___ Not Applicable  __ 
2) Heme/Onc initial note 
Enclosed __Not Enclosed   
___ Not Applicable  __ 
3) Pathology Report(s)         
Enclosed __Not Enclosed   
___ Not Applicable  __ 
4) MRI/CT Report(s)   
Enclosed __Not Enclosed   
___ Not Applicable  __ 
5) Lab Source Document        Enclosed __Not Enclosed   
___ Not Applicable  __ 
6) ICF signature page 
 
7) Other documentation 
 
It is required that each item from schedule of evaluations be submitted to BrUOG along with confirmation 
via source to match each inclusion and confirm each exclusion criteria. 
 
Most recent IRB approval date (whether this be the initial, latest amendment or CR):  
 
  
 
Date of research biopsy pre-treatment:__________________________________ 
Date of day -7 treatment:_____________________________________________ 
Date of treatment day 1:______________________________________________ 
Hospital where patient will be treated with Oncologist:    
 
 
 
Name of treating physician: ___________________________________________ 
Your signature:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
 
 
 
 
Appendix B 
Agreement to Participate in a Research Study and Authorization for Use and Disclosure of 
Information 
 
 
Phase Ib/II investigator-initiated, single arm study of ONC201 plus Nivolumab in 
microsatellite stable (MSS) metastatic colorectal cancer (mCRC) patients 
 
You are being asked to take part in a research study.  All research studies carried out at 
<INSERT HOSPTIAL NAME> are covered by rules of the Federal government as well as rules 
of the State and <INSERT HOSPTIAL NAME>.  Under these rules, the researcher will first 
explain the study, and then he or she will ask you to participate.  You will be asked to sign this 
agreement that states that the study has been explained, that your questions have been answered, 
and that you agree to participate. 
 
The researcher will explain the purpose of the study. He or she will explain how the study will be 
carried out and what you will be expected to do.  The researcher will also explain the possible 
risks and possible benefits of being in the study.  You should ask the researcher any questions 
you have about any of these things before you decide whether you wish to take part in the study.  
This process is called informed consent. 
 
This form also explains the research study.  Please read the form and talk to the researcher about 
any questions you may have.  Then, if you decide to be in the study, please sign and date this 
form in front of the person who explained the study to you. You will be given a copy of this form 
to keep. 
 
Nature and Purpose 
Your doctors are participating in this research study sponsored by the Principal Investigator, Dr. 
Khaldoun Almhanna, in collaboration with the Brown University Oncology Research Group 
(BrUOG), which will serve as the central coordinating office for the study.  
 
You are invited to take part in a clinical trial, a type of research study, because you have 
advanced colon cancer. You previously received standard chemotherapy but your cancer has 
spread and become worse. The purpose of this research study is to test how safe and how well an 
investigational drug known as ONC201 works in combination with the immunotherapy drug 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
nivolumab in treating advanced colon cancer.   
 
“Investigational” means that the FDA (the U.S. Food and Drug Administration) has not approved 
ONC201 as a treatment for colon cancer or any other cancer. ONC201 is a newly discovered 
compound that may stop cancer cells from growing, however this is not yet known. This drug 
has been shown in laboratory experiments to use a new mechanism (way) that creates a response 
to kill cancer cells but not normal cells.  
 
Nivolumab is a drug that helps stimulate your immune system to fight certain cancers. It is FDA 
approved to treat some forms of cancer such as lung cancer, kidney cancer, a form of skin cancer 
called melanoma and a rare form of colon cancer called “microsatellite unstable colon cancer”. 
However, nivolumab does not show activity against your form of colon cancer (microsatellite 
stable colon cancer) and is not FDA approved for your form of colon cancer. In the laboratory, 
Researchers are testing if ONC201 may help nivolumab be more effective in stimulating the 
immune system to treat cancer.  
 
Bristol-Myers Squibb, a pharmaceutical company that makes the drug Nivolumab, is financially 
supporting this research study by providing the study drug nivolumab and funding for the study. 
Upon completion of the trial, Bristol-Myers Squibb Company will not continue to supply study 
drug to subjects/investigators.  Your doctor is responsible to ensure that you receive appropriate 
standard of care or other appropriate treatment to treat your condition. 
 
ONC201 is being supplied by the pharmaceutical company Oncoceutics, Inc.  
 
Dr. Wafik El-Deiry is a person involved in this medical research study who owns a patent on the new 
drug being studied. Research studies like the one you are thinking about joining are done to 
determine whether the new drug is safe and effective. If the research in question shows that the new 
drug is safe and effective, Dr. El-Deiry may benefit financially from the success of this drug.  
How Many People will take part in the Study?  
It is expected that approximately 34 people will take part in this research study.  
 
Explanation of Procedures   
 
What will happen if I take part in this research study?  
If the exams, tests and procedures show that you can be in the study, and you choose to take part, 
then you will need the following tests, while on the study.  They are part of regular cancer care.  
 
• A medical history, which includes questions about your health, current medications, and 
any allergies. 
• Safety evaluations, which collects information on how you are feeling  
• Performance status, which evaluates how you are able to carry on with your usual 


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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
activities.  
• An assessment of your tumor by CT (Computerized Tomography) scan 
• Complete Blood Count (CBC) and serum chemistry blood tests to determine your 
general health status and screen for certain diseases 
• Pharmacokinetic (PK) blood samples. This looks at the movement and metabolism of 
the drug into and throughout the body. Each blood sample will be approximately 2 
teaspoons. 
• Pharmacodynamic (PD) blood samples. This looks at the effect of the drug on the 
body. Each blood sample will be approximately 2 teaspoons. 
• cfDNA blood samples. This looks at the DNA fragments in the blood plasma. Each 
blood sample will be approximately 2 teaspoons. 
• Pregnancy test (blood), if you are a female of child-bearing potential. 
• Electrocardiogram (ECG), which measures the electrical activity of your heart 
• Tumor Biopsy: A sample of your tumor from your initial diagnosis or the most recent 
biopsy procedure will be requested by your study doctor. Additionally, a biopsy will also 
be performed  prior to starting treatment and post consent. A biopsy will be repeated 
approximately 2 months after you begin treatment on this study.  
 
While on study: 
 
Tumor Biopsy: A sample of your tumor will be biopsied prior to starting treatment and post 
consent. A biopsy will be repeated approximately 2 months after you begin treatment on this 
study. If at the time of the 2-month biopsy, your cancer progressed (worsened), no further 
biopsies will be taken.  If your cancer is stable, there will be a third and optional biopsy 
performed if/when your cancer progresses during treatment or in follow up.  Researchers at 
Rhode Island Hospital, Brown University, and collaborating laboratories will examine your 
tumor tissue to see how the study treatment may affect your cancer. If you choose to sign this 
consent form and participate in this trial, your doctors will also request a portion of your tumor 
tissue for storage for use in future research. 
 
This is the first study testing the combination of ONC201 and nivolumab.  
 
Phase Ib: 
In the first part of the study (phase IB portion of the study), patients will be treated in groups of 
3-6 patients to determine the best safe dose of the combination of ONC201 and nivolumab. The 
initial 3-6 patients will receive the recommended dosages of ONC201 (5 capsules) and 
nivolumab when each drug is administered alone. Patients will receive one dose of ONC201 
alone and then will begin treatment approximately one week later with both ONC201 and 
Nivolumab. One treatment cycle will be 4 weeks. You will be given Nivolumab once every 2 
weeks into your vein (by intravenous infusion). ONC201 will be given orally once a week using 
capsules.  


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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
If the side effects are too severe, the dosages will be lowered for the next 3-6 patients on the 
Phase IB portion until a safe dose is found.  
 
Phase II: 
Once the safe combined dose is found, in the phase II portion of the study, 28 patients be treated, 
using the dose found in the phase IB portion of the study.  
 
Patients will receive one dose of ONC201 alone and then will begin treatment approximately one 
week later with both ONC201 and Nivolumab. One treatment cycle will be 4 weeks. You will be 
given Nivolumab once every 2 weeks into your vein (by intravenous infusion). ONC201 will be 
given orally once a week using capsules.  
 
Both phases: 
You will be told what part of the study you are participating in. If severe effects are severe, both 
drugs may be permanently stopped.   
 
Treatment is for up to 12 months unless it is determined by your treatment team there may be 
benefit for you to continue treatment beyond 12 months. 
 
It is possible that your CT scan may show an increase in the size of your cancer but your doctor 
thinks you may still benefit from treatment and that your doctor may suggest you continue on 
treatment until you have a follow-up CT scan. This will be discussed with you.  
 
Once you come off treatment there will be a safety visit that will occur approximately 30 days 
and then again approximately 100 days after your last treatment. At this visit, your doctor will 
collect information on how you are feeling and any side effects you may be experiencing.  
 
All patients who receive treatment will be followed for approximately 6 months after treatment 
completion, to collect information on disease status and survival. 
 
 Pre-medications: You may be pre-medicated with drugs to reduce the chance of having a 
reaction to the study treatment. If you tolerate the study treatment without a reaction, then pre-
medications may be changed by your doctor. If you do have a reaction to the drugs your doctor 
may start or change pre-medications to reduce the chance of you having another reaction. 
 
Study Visits: You will be seen in the oncology clinic approximately every 14 days (prior to each 
treatment with nivolumab).  
  
This visit will involve the following: 
Clinical Exams: During this visit you will have a physical exam including vital signs and you 
will be asked questions about your general health and  


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
This visit will involve the following: 
• Clinical Exams:  During this visit you will have a physical exam and you will be asked 
questions about your general health and specific questions about any problems that you 
might be having and any medications you may be taking. 
• Performance status, which evaluates how you are able to carry on with your usual 
activities.  
• Blood tests (approximately 3 tablespoons) to determine your general health status and 
screen for certain diseases 
• Pharmacokinetic (PK) blood samples. This looks at the movement and metabolism of 
the drug into and throughout the body. Each blood sample will be approximately 2 
teaspoons. 
o For patients on the Phase IB part of the study additional research blood tests 
for pharmacokinetics (metabolism of ONC201) will be drawn as follows: 
Cycles 1 & 2: Pretreatment, then 30 minutes, 2 hours, 4 hours, 6 hours, 24 hours, 
48 hours, and 168 hours (7days) after the second treatment of ONC201. Day 7 to 
align with pre-dosing week 2. Cycles 3-12: Pre-treatment 
 
• Pharmacodynamic (PD) blood samples. This looks at the effect of the drug on the 
body. Each blood sample will be approximately 2 teaspoons. 
o All patients on this study (Phase IB and Phase II parts of this study) will have 
research blood tests for pharmacodynamics (effect of ONC201 on the body) 
as follows: cycles 1 and 2: Pre-treatment, then at 6 hours, 2 days, 3 days, 7 days, 
after ONC201. Day 7 to align with pre-dosing week 2. In cycles 3-12: Pre-
treatment. In patients who remain on study longer than 12 cycles, a sample will 
also be drawn pre-dosing day 1 of each cycle.  
• CfDNA blood samples. This looks at the DNA fragments in the blood plasma. All 
patients will have blood samples drawn every 2 weeks in cycles 1-6. The first sample will 
be taken prior to ONC201, therefore in cycle 1 there will be 3 samples taken. Each blood 
sample will be approximately 2 teaspoons. In cycles 7-on and in patients who remain on 
study longer than 12 cycles, a sample will be drawn pre-dosing day 1 of each cycle only. 
Review of your medicines 
• Safety evaluations, which collects information on how you are feeling and any side 
effects you may be experiencing 
 
Additional Testing:  
• CT Scan: A CT scan will be performed approximately every 2 months to assess your 
tumor response to treatment. 
 
Throughout the study a total of approximately 125 tablespoons of blood will be taken.  As 
described above, this amount will be taken over the course of the trial, not all at once.  The 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
amount may be less depending on what phase of the study you are on and how many cycles 
of treatment you complete. 
 
Can I stop being in the study?  
Yes. You can decide to stop at any time.  Tell your doctor if you are thinking about stopping or 
decide to stop.  He or she will tell you how to stop safely.   
 
It is important to tell your doctor if you are thinking about stopping so any risks from the 
discontinuation of treatment can be evaluated. Another reason to tell your doctor that you are 
thinking about stopping is to discuss what follow-up care and testing could be most helpful for 
you.  
 
Your doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest; if you do not follow the study rules; or if the study is stopped.  
 
Costs for participating in this study  
Some of the services you will receive are being performed only because you are participating in 
this research study.  Examples of these ‘research only’ services include  
 
• The drugs Nivolumab and ONC201. These drugs will be will be provided by BMS and 
Oncoceutics, respectively, the makers of the drugs, at no charge and will not be billed to 
you or your health insurance company.  
• The costs of the research biopsies (biopsy performed prior to beginning treatment, 8 
weeks after starting treatment, and at tumor progression).  
• Research blood tests (pharmacokinetics and pharmacodynamics and cfDNA)  
• Analysis of all tissue and blood research samples collected and drawn 
• EKG’s 
 
Other services you will receive during this research study are considered "routine clinical 
services" that you would have received even if you were not in the research study. 
 
These include all study doctor visits, standard blood tests, the administration costs of the drugs 
Nivolumab and ONC210, drugs used to reduce side effects, doctor visits, all blood tests not 
outlined above, the biopsy performed prior to beginning treatment, pregnancy tests, CT scans, 
MRIs, and PET scans. Therefore, all of the services listed in this paragraph will be billed to your 
health insurance company, but you will be responsible for paying any deductibles, co-payments, 
or co-insurance that are a normal part of your health insurance plan. If you do not have health 
insurance or your insurance does not cover these services, you will be responsible for those 
costs. 
 
Contact Information: If you have any questions regarding this study, you may contact your 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
site’s Principal Investigator, <INSERT NAME AND CONTACT> 
 
Discomforts and Risks 
There are risks to taking part in any research study. One risk is that you may get a study drug that 
does not help treat your disease or that makes your condition or disease worse.  Another risk is 
that there may be side effects.   
 
All cancer treatments can have side effects, which can range from mild and reversible to severe, 
long lasting and possibly life-threatening.  There is a great deal of variability among side effects 
of different cancer treatments and between individuals.  In a research study, all of the risks or 
side effects may not be known before you start the study. You need to tell your doctor or a 
member of the study team immediately if you experience any side effects.  
 
Everyone in the research study will be watched carefully for side effects.  You will be monitored 
during the administration of study drugs to keep track of your blood counts and organ function, 
particularly your kidney and liver function.  If you experience side effects, they may go away 
after you stop taking the study drug.  Some side effects can be mild; but others can be long 
lasting and may never go away.  Some may be life-threatening or fatal.  
 
Since the effect of the study drug(s) taken with other medications may not be known, it is 
important that you tell the research doctor about all prescription and non-prescription drugs, 
herbal preparations and nutritional supplements that you are taking or planning to take. There 
may also be some foods that you should avoid while on this research study and your research 
doctor will review this information with you. 
 
During the research study, you will be notified of newly discovered side effects or significant 
findings, which may affect your health or willingness to participate.  You may be asked to sign a 
new consent form that shows that you have been informed of new information relating to this 
research study. 
Taking part in this study may lead to time away from work. 
 
The side effects of nivolumab and ONC201 are described below. There are also some side 
effects which may not yet be known. It is not known if the side effects of the combination 
(Nivolumab and ONC201) may be worse or the same as single agent (one drug only) use.  
Many side effects might go away soon after you stop taking the ONC201. In some cases, side 
effects can be serious, long lasting, or may never go away. There is also a risk of death. Several 
clinical studies involving ONC201 are currently ongoing with more than 200 people who have 
received ONC201. Due to the ongoing status of these clinical programs, the safety information is 
incomplete. 
Risk of Study Drug  


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
At this time, greater than 350 patients have been treated with ONC201. 
As of August 31, 2020, some patients receiving ONC201 have reported side effects as described 
below.  Although most were mild or moderate, some may be serious:  
 
Frequent (In 100 people receiving ONC201 21 or greater may have >21%) adverse events 
(side effects) that were attributed as possibly related to ONC201 include: 
• Fatigue 
• Nausea 
• Headache 
• Vomiting 
Occasional (In 100 people receiving ONC201 4 to 20 may have (4-20%)) adverse events (side 
effects) that were attributed as possibly related to ONC201 include: 
• Gait disturbance 
• Decrease in the number of a type of white blood cell (lymphocytes) 
• Insomnia 
• High blood sugar 
• Weakness on one side of the body 
• Anemia (low count of red blood cells) 
 
Rare (In 100 people receiving ONC201, 3 or fewer may have (<3%) adverse events (side 
effects) that were attributed as possibly related to ONC201 include: 
• Decreased number of a type of white blood cell (neutrophil/granulocyte) 
• Abdominal pain 
• Small bowel obstruction 
• Death 
• Damage to multiple organs (kidneys, liver, lungs, others)  
• Encephalopathy 
• Pneumonia 
• Bleeding 
• Blood infection 
• Change in thinking patterns 
• Abnormal body movement 
• Rash 
• Bleeding in the brain or lungs 
• Blood clot in the lung 
• Tumor Lysis syndrome, a disease caused by cancer cells dying 
• Stroke 
• Trouble breathing 
 
Sometimes people have allergic reactions to drugs. If you have a very bad allergic reaction, 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
you could die. Some things that happen during an allergic reaction that could be a sign or 
symptom of a life-threatening allergic reaction (anaphylaxis) are: 
• A rash 
• Sneezing  
• Itchy, runny or blocked nose (allergic rhinitis) 
• Itchy, red, watering eyes (conjunctivitis) 
• Chest tightness, shortness of breath and a cough 
• Swollen lips, tongue, eyes or face or other areas 
• A fast pulse 
• Sweating 
• A feeling of dread 
• Swelling around the eyes and mouth 
• Swelling of the throat 
• Wheezing 
• Having a hard time breathing 
• A sudden drop in blood pressure (making you feel dizzy or lightheaded) 
• Inability to breathe without assistance 
 
You should get medical help and contact the study doctor or study staff if you have any of 
these or any other side effects during the study. You should talk to your study doctor about any 
side effects or changes in your health that you have while taking part in the research study, 
whether or not you think they are related to the study drug. Adverse reactions may occur 
following dosing with ONC201. You will be monitored for adverse events.  
At least one patient with advanced cancer who received ONC201 has experienced tumor lysis 
syndrome, when a large number of cancer cells die quickly and release their content into the 
blood, which can cause changes in laboratory levels, leading to kidney injury, heart damage, 
muscle weakness, and rarely seizures. 
Some patients with advanced cancer who received ONC201 have died within 30 days of 
receiving the study drug. High doses of ONC201 in animals have caused death. 
 
 
Nivolumab: 
Nivolumab is an agent involved in the inhibition of “immune checkpoints,” and may result in 
severe and possibly fatal immune-mediated side effects probably due to activation and growth of 
immune cells (T-cells).  Immune-mediated side effects have been reported in patients receiving 
Nivolumab.  In clinical trials, most side effects were reversible and managed by stopping 
Nivolumab temporarily, administration of corticosteroids and supportive care. While rare, 
immune mediated side effects may also occur after stopping Nivolumab. These are considered 
late onset immune mediated toxicities, which may begin even months after stopping treatment. 
Your doctor will closely monitor you after you stop treatment and provide supportive care as 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
necessary. There are also some side effects which may not yet be known. There is a small 
risk of death 
 
Frequent - Greater than 10% chance this will happen 
• Diarrhea 
• Nausea 
• Fatigue 
• Rash 
• Itchiness  
 
Occasional – Between 1 and 10% chance this will happen  
• Thyroid gland abnormalities. May cause fatigue, weight gain, fluid retention, sensitivity 
to cold & mental apathy. Can be serious or life threatening.  
• Elevated blood sugar  
• Bowel inflammation. This could result in severe diarrhea and may require hospitalization 
for treatment. Severe and prolonged diarrhea can be life-threatening.  
• Inflammation or ulceration of the mouth and lining of the digestive tract  
• Vomiting  
• Abdominal pain  
• Constipation  
• Dry mouth  
• Fevers  
• Swelling of the face, body, arms, or legs (edema).  
• Abnormally high levels of enzymes produced by the liver meaning your liver is not 
functioning properly. Although this is usually mild and reversible, this can be serious or 
life threatening. 
• Reaction to the drug infusion, including flushing, shortness of breath, dizziness, chest 
pain, or other symptoms.  
• Infections  
• Blood abnormalities, including low blood phosphate, magnesium, potassium, or sodium 
levels. These may require repletion or correction of abnormal blood test values.  
• Blood test abnormalities, including increase in lipase or amylase, which may reflect 
inflammation of the pancreas.  
• Decreased appetite  
• Joint or muscle pain or stiffness  
• Tingling, burning, or numbness in hands and feet  
• Headache  
• Dizziness  
• Kidney failure which is when both of your kidneys fail and your body holds fluid which 
can be serious or life threatening. Your blood pressure rises and harmful wastes build up 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
in your body. When this happens, you may need to be hospitalized or else be placed in 
dialysis.  
• Shortness of breath  
• Cough  
• Loss of color (pigment) from areas of skin  
• Skin reactions, including hives, redness, and dry skin. Rarely, a skin reaction may be 
severe and result in extensive skin blistering (Stevens Johnson syndrome). This can be a 
life-threatening event.  
• Hair thinning or loss  
• Elevated blood pressure  
• Inflammation of the lungs which can cause shortness of breath and difficulty breathing. If 
severe, this can be life threatening. 
• Muscle or joint pain 
 
Rare – Less than 1% chance this will happen  
• Changes in heart rhythm, resulting in a fast or irregular heartbeat. Certain types of 
irregular heartbeats can be serious or life-threatening.  
• Adrenal gland abnormalities, which may cause you to feel weak.  
• Pituitary gland abnormalities, which may cause headaches, change in eyesight, increased 
thirst, and increased frequency passing urine.  
• Diabetes. This is an elevated blood sugar that can occur when your body is not able to 
regulate blood sugar levels normally. Elevated blood sugar levels may be life-threatening 
and may require hospitalization for treatment.  
• Inflammation of the eyes. This may result in decreased or blurry vision.  
• Inflammation of the pancreas. This could become severe and cause nausea and vomiting, 
fever and rapid heart rate. This could require hospitalization and may be life threatening.  
• Inflammation of the airways. This can result in cough or shortness of breath.  
• Swollen lymph nodes  
• Autoimmune disorders, including Guillain-Barre syndrome, which can be associated with 
progressive muscle weakness or paralysis.  
• Inflammation or loss of the lining of the brain and spinal cord, which may cause 
neurological damage including confusion, hallucinations, difficulty walking or using 
arms  
• Myasthenia gravis, when the body’s immune system attacks muscle nerve cell receptors 
causing weakness in the muscles. This can be severe or life-threatening.  
• Abnormal brain function due to brain inflammation (encephalitis), which can be 
potentially life-threatening or fatal.  
• Inflammation of the blood vessels, which could cause possible bleeding and/or bruising. 
• Cardiac issues, including the risk of heart inflammation, or myocarditis 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
Lung Inflammation (pneumonitis):  It is possible that nivolumab may cause inflammation of 
the tissues of the lung.  This adverse effect has been reported infrequently in patients treated with 
nivolumab.  While many patients with x-ray or CT abnormalities have not developed any 
symptoms, some patients have developed mild to severe symptoms and in rare cases, death has 
occurred as a result of their lung inflammation.  Signs and symptoms of lung inflammation may 
include difficulty breathing, pain or discomfort while breathing, chest pain, cough, shortness of 
breath, increased rate of breathing, fever, low blood oxygen levels, or fatigue.   
   
Your study doctor and nurse will watch you closely for changes in your ability to breathe and for 
other signs or symptoms that might show you are developing this type of lung inflammation and 
will perform regular tests including physical exams, measurement of oxygen levels through non-
invasive testing (i.e., pulse oximeter), blood tests, chest x-rays and/or CT scans. 
 
Please inform your study doctor or nurse AT ONCE if you experience any of the following: 
• Any new or increased shortness of breath; 
• Any new or increased chest pain; 
• Any new or increased pain/difficulty while breathing; 
• Any new or increased cough or any significant change in your type of cough; for example 
any new or increased mucous or blood in your cough;   
• Any change in the amount of oxygen you require; 
• Any fever, fatigue, or other symptoms that occur at the same time as any changes to your 
breathing or other lung symptoms.  
 
If you start to develop symptoms, your study doctor will ask you to return to the clinic for 
additional tests, which could include a physical exam, measurement of oxygen levels, blood 
tests, chest x-rays, and/or CT scans. You will be monitored very closely for changes in your 
overall lung symptoms, monitoring may require hospitalization. You may require specific 
treatment in order to control pneumonitis. You may also be seen by a special doctor called a 
pulmonologist, who has special training to be an expert in how your lungs work. 
 
Prolonged treatment with medicines that suppress inflammation, sometimes needed to manage 
the side effects of nivolumab treatment, may lower your body’s ability to fight off certain 
infections (i.e., opportunistic infections). These infections may require treatment with antibiotic 
or antifungal medications and may be fatal. 
 
Reproductive Risks From nivolumab and ONC201 
Nivolumab and ONC201 may decrease sperm count. This is usually temporary but can be 
permanent, which would result in sterility (not being able to father a baby).  
 
Because the drugs in this study can affect an unborn baby, you should not become pregnant 


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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
while on this study. 
 
Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of 
contraception from time of consent and for the duration of study treatment through 5 months after 
the last dose of study treatment (ONC201 or Nivolumab, whichever is last) The decision of 
effective contraception will be based on the judgment of the principal investigator or a designated 
associate. 
 
Males who are sexually active with WOCBP must agree to follow instructions for method(s) of 
contraception from time of consent and for the duration of study treatment through 7 months after 
the last dose of study treatment (ONC201 or Nivolumab, whichever is last). The decision of 
effective contraception will be based on the judgment of the principal investigator or a designated 
associate. 
 
Ask your study doctor for more information regarding preventing pregnancy during the study 
treatments. 
 
You should not nurse your baby while on this study. If you are premenopausal, your periods are 
likely to stop temporarily and may stop permanently due to the study treatments, which may lead 
to symptoms of menopause, such as hot flashes, and the inability to become pregnant, which may 
be permanent. If you are concerned about this, ask your study doctor about options for 
preserving your reproductive choices, which may include referral to a specialist in this field.   
 
By signing this document, you are acknowledging that you understand and agree to the 
information presented in this Reproductive Risk section. 
 
Antiemetics (anti-nausea medications): Various medications used to prevent nausea and 
vomiting may cause drowsiness, dry mouth, diarrhea, constipation, headache, restlessness, 
agitation, anxiety, dizziness, involuntary tremors, skin rash, and possible allergic reaction. 
You will receive pre-medication to reduce the risk of infusion/injection reactions on your 
treatment days. Overall, the pre-medications you will be given are well tolerated. 
 
Venipuncture (inserting a needle into a vein to obtain blood or give medication): May cause 
inflammation, pain, bruising, bleeding, or infection. 
 
When you receive chemotherapy by vein, there is a slight risk that some of the drug may leak out 
around the needle at the injection site. A skin burn may result. Most skin burns are treatable and 
heal well. 
 
In order to monitor the side effects, your physician will examine you frequently and obtain 
laboratory tests (blood tests, chest x-rays, or CT scans as needed) to determine the effects of your 
treatment and alter the drug dosages if necessary. 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
Risk of CT imaging: CT imaging uses x-rays. The radiation dose associated with this procedure 
is estimated to be a small fraction of the annual permissible dose to an x-ray technologist. There 
is no significant risk from this amount of radiation. 
There may be other side effects that have not been reported. If you have any unusual symptoms, 
you should report them immediately to your doctor or nurse. 
 
Risk of Biopsy:  May cause bruises, bleeding, pain, or infection. 
 
Benefits 
While it is possible that the combination of ONC201 and nivolumab may be active against your 
cancer, and the side effects of this combination are not too severe, this is not yet known. We do 
not know if taking part in this study will help you. This study may help researchers learn 
information that could help people in the future. 
 
Alternative Therapies 
 
Taking part in this research study is voluntary. Instead of being in this research 
study, you have other options which may include the following: 
 
• Receive standard treatment. Your doctor will discuss with you specific standard treatment 
options. 
• Take part in another research study if there is one available. 
• Receive no therapy specific to your cancer. 
• Comfort care, also called palliative care. This type of care may help to reduce pain, 
tiredness, appetite problems and other problems caused by the cancer. It does not treat the 
cancer directly, but instead tries to treat the symptoms. 
 
Please talk to the research doctor about your options before you decide whether 
you will take part in this research study. 
 
Refusal/Withdrawal 
It is up to you whether you want to be in the study.  You are not required to enroll or participate.  
If you decide to participate, you can always change your mind and quit at any time.  If you 
decide not to be in the study, or if you quit later, you will still be able to get the health care 
services you normally get.  If you join, but later on the researcher or your doctor feels being in 
the study is no longer good for you, they may choose to take you out of the study before it is 
over.  If new information becomes available that might change your mind about whether you 
want to stay in the study the researcher will share this information with you as soon as possible. 
If you make the decision to withdraw from this study (stop taking study medication) for any 
reason, tell your doctor immediately. You will be asked to sign a form indicating whether you 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
give your permission for your doctor and the research staff to continue to collect and submit 
follow-up information on your health status from your physicians and medical record. After 
signing the form, you still have the right to change your mind, at any time, regarding follow-up 
after withdrawal. 
 
Medical Treatment/Payment in Case of Injury 
A research injury is any physical or mental injury or illness caused by being in the study. If you 
are injured by a medical treatment or procedure you would have received even if you were not in 
the study that is not a research injury. To help avoid research injury and added medical expenses, 
it is very important to follow all study directions carefully. If you do experience a research 
injury, <INSERT HOSPITAL NAME> or the study doctor can arrange medical treatment for 
you. Such treatment will be paid for as described below.  
 
Medical treatment will be available if you suffer a research related injury; however, you and/or 
your health insurance company will be charged for this treatment. The study will not pay for this 
medical treatment. Neither Dr. Khaldoun Almhanna nor BrUOG, the coordinating center, have 
money set aside to reimburse you for medical bills from treatment of a research related injury or 
otherwise compensate you in the event of a study-related injury.  
 
If you have insurance and have a research injury that is not covered by the study, it is possible 
that some or all of the cost of treating you could be billed to your insurer. If your health 
insurance will not cover such costs, it is possible you would have to pay out of pocket. In some 
cases, <INSERT HOSPITAL NAME> might be able to help you pay if you qualify for free care 
under <INSERT HOSPITAL NAME> policy. However, <INSERT HOSPITAL NAME> has no 
policy to cover payment for such things as lost wages, expenses other than medical care, or pain 
and suffering. 
 
Rights and Complaints 
Signing this form does not take away any of your lawful rights. If you have any complaints about 
this study, or would like more facts about the rules for research studies, or the rights of people 
who take part in research studies you may contact <INSERT CONTACT NAME OF IRB> 
 
Confidentiality 
 
 
Your research records will be treated as private health care records and will be protected 
according to <INSERT HOSPITAL NAME> privacy practices and policies that are based on 
state and federal law. In particular, federal law requires us to get your permission to use or 
disclose (release your information to someone outside of <INSERT HOSPITAL NAME>) your 
health information for research purposes. If you sign this form you agree to be in this research 
study and you permit the use and disclosure of your health information for the purpose of 
conducting the research, providing treatment, collecting payment and running the business of the 
hospital. This permission has no expiration date. You may withdraw from the study at any time. 
However, if you do not want the researchers to use or disclose any further information in this 


Pa ge 1 2 9  of 1 4 5  
 
Pr ot oc ol - Br U O G 3 7 9  
C O N FI D E N TI A L  
Dates: 1 1/ 0 4/ 2 0 1 8, 1 1/ 1 1/ 1 8, 1 1/ 1 6/ 1 8, 1 1/ 2 4/ 1 8, 1 1/ 3 0/ 1 8, 1 2/ 2/ 1 8, 1 2/ 6/ 1 8, 1 2/ 7/ 1 8, 1 2/ 1 0/ 1 8, 1/ 8/ 1 9 B M S 
re vie w, 1/ 9/ 1 9, 1/ 1 3/ 1 9, 1/ 1 5/ 1 9, 1/ 1 6/ 1 9, 1/ 1 7/ 1 9, 1/ 2 0/ 1 9, 1/ 2 2/ 1 9, 2/ 4/ 1 9, 2/ 1 9/ 1 9, 3/ 1 9/ 1 9, A M # 1 7/ 2 2/ 1 9, B M S 
re vie w 8/ 2 3/ 1 9, A M # 2 3/ 3/ 2 0, B M S a p pr o ve d 4/ 1/ 2 0, O nc oce utics a p pr o ve d 4/ 2 4/ 2 0, A M # 3 1 0/ 2 6/ 2 0 2 0, B M S 
a p pr o ve d 1/ 5/ 2 1, O nc oce utics a p pr o ve d 3/ 3 0/ 2 1  
 
st u d y y o u m ust ca ncel per missi o n i n writi n g a n d ma y d o s o at a n y ti me. If y o u ca ncel y o ur 
per missi o n, y o u will st o p ta ki n g part i n t he st u d y a n d n o ne w i nf or mati o n will be c ollecte d a b o ut 
y o u. H o w e ver, if y o u ca n cel y o ur per missi o n, it will n ot a p pl y t o acti o ns alrea d y ta ke n or 
i nf or mati o n alrea d y c ollecte d a b o ut y o u b y t he h os pital or t he researc h ers b ef ore y o u ca n cele d 
y o ur p er missi o n.  
Ge ner all y, t he e ntire r esearc h r ec or d a n d a n y me di cal re c or ds hel d b y t he h os pital ma y be us e d 
a n d release d f or res ear c h p ur p oses. T he f oll o wi n g pe o ple or b usi nesses/c o m pa nies mi g ht use, 
releas e, or r ecei v e s uc h i nf or mati o n:  
 T he researc h er a n d t h eir s u p p ort staff;  
 T he st u d y s p o ns or:  
 
 D oct ors, n urses, la b or at ories a n d ot hers w h o pr o vi de ser vices t o y o u i n c o n necti o n wit h t his 
st u d y;  
 T he c o m pa n y or secti o n of t he U. S. g o v er n me nt t hat is pa yi n g f or t h e st u d y a n d ot h ers t he y 
hire t o o versee, a d mi nister, or c o n d u ct t he res earc h;  
 T he U nite d States F o o d a n d Dr u g A d mi nistrati o n, t he De part me nt of Healt h a n d H u ma n 
Ser vices, t he Office of I ns pect or Ge n eral, a n d t he Office of Ci vil Ri g hts;  
 Pe o ple w h o v ol u nteer t o be patie nt a d v ocates or researc h v ol u nteer pr otect ors;  
 Me m bers of t he h os pital's a d mi nistra ti ve staff res p o nsi ble f or re vie wi n g, a p pr o vi n g a n d 
a d mi nisteri n g cli nical tri als a n d ot her healt hcare or researc h acti vities.  
 
  
 
T h ere are ti mes w h e n t he la w mi g ht re q uire or p er mit <I N S E R T H O S PI T A L N A M E >  t o rel ease 
y o ur h ealt h i nf or mati o n wit h o ut y o ur per missi o n. F or e x a m ple, <I N S E R T S T A T E > la w re q uires 
researc hers a n d healt h care w or k ers t o re p ort a b us e or ne glect of c hil dre n t o t he De part me nt of 
C hil dre n, Y o ut h a n d Fa milies ( D C Y F) a n d t o re p ort a b use or ne gl ect of p e o ple a ge 6 0 a n d ol d er 
t o t he De part me nt of El d erl y Aff airs. 
All resear c hers a n d healt h care pr o vi ders are re q uire d t o pr otect t he pri vac y of y o ur healt h care 
i nf or mati o n. Ot her pe o pl e a n d b usi nesses/ or ga nizati o ns t hat are n ot healt h care pr o vi ders are n ot 
re q uire d b y la w t o d o t hat s o it is p ossi ble t he y mi g ht re-rel ease y o ur i nf or mati o n.  
Y o u ha ve t he ri g ht t o r ef use t o si g n t his f or m a n d n ot partici pate i n t he res earc h. Y o ur ref usal 
w o ul d ha ve n o effect o n y o ur tr eat me nt, c h ar ges bille d t o y o u, or be n efits at a n y <I N S E R T 
H O S PI T A L N A M E > h ealt h care site. If y o u d o n ot si g n, y o u will n ot be a ble t o e nr oll i n t he 
researc h st u d y a n d will n ot recei ve treat me nt as a st u d y partici p a nt.  
  
  
q uit t he st u d y after si g ni n g t his f or m ( as descri be d i n Secti o n 6) n o ne w i nf or mati o n will be 
c ollecte d a b o ut y o u u nless y o u ga v e us per missi o n t o d o s o. H o we ver, t he h os pital or t he 
researc hers ma y c o nti n ue t o use i nf or mati o n t hat was c ollecte d b ef ore y o u q uit t he st u d y t o 
c o m plete a nal ysis a n d r e p orts of t his researc h. 
A d diti o nall y, a des cri pti o n of t his cli nical trial will be a vaila ble o n 


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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
http://www.ClinicalTrials.gov, as required by U.S. law. This Web site will not include 
information that can identify you. At most, the Web site will include a summary of the results. 
You can search this Web site at any time.  
If after you have signed this form you have any questions relating to your rights, please contact 
<INSERT IRB CONATACT INFORMATION> 
 
 
about your privacy rights see the <INSERT HOSPITAL NAME> which has or will be given to 
you. 
Research authorization for use and disclosure of information.   
The purpose of this section of the document is to provide you with some more information about 
how the information learned about you during the study will be used and shared. 
We understand that your medical information is very personal and we will work hard to keep it 
private. If you sign this form you consent to participate in this research study and are giving us 
permission to use and share your personal health information in the ways described in this form.   
Understandings and notifications 
 
The main purpose of permitting the use and release of your information is to allow the research 
project to be conducted and to ensure that the information relating to that research is available to 
all parties who may need it for research purposes.  Your information may also be used as 
necessary for your research-related treatment, to collect payment for your research-related 
treatment (when applicable), and to run the business operations of the hospital. 
 
All health care providers are required to protect the privacy of your information.  However, most 
persons or entities (i.e., businesses, organizations) that are not health care providers are not 
bound by law to protect the privacy of your information.  You understand that if the person or 
entity that receives your information is not a health care provider bound to protect your privacy, 
such person or entity might re-release your health information.  
 
 
You have the right to refuse to sign this form.  If you do not sign this form, none of your health 
care outside the study, or the payment for your health care, or your health care benefits will be 
affected.  However, if you do not sign this form, you will not be able to enroll in the research 
study described in this form, and you will not receive treatment as a study participant.  
If you sign this consent form, you may withdraw from the study at any time.  However, if you do 
not want the researchers to use or disclose any further information in this study you must cancel 
permission in writing and may do so at any time. If you cancel your permission, you will stop 
taking part in the study and no new information will be collected about you.  However, if you 
cancel your permission, it will not apply to actions already taken or information already collected 
about you by the hospital or the researchers before you canceled your permission.  This 
information or action may be needed to complete analysis and reports of this research. This 
permission will never expire unless you cancel it.  To cancel this permission, please write to Dr. 
Khaldoun Almhanna, MD c/o the Medical Oncology Clinical Research Office at Rhode Island 
Hospital, 593 Eddy Street, APC Building Rm. 131, Providence, RI 02903. 


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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
If after you have signed this form you have any questions relating to your rights, please contact 
<INSERT IRB CONTACT> 
Uses and releases covered by this authorization (permission) 
Who will release, receive, and/or use your information?  This form will allow the following 
person(s), class(es) of persons, and/or organization(s)* to release, use, and receive the 
information listed below in connection with this Study, or as required by law: 
 
Every research site for this study, including this hospital, and including each site's 
research staff and medical staff 
 
Health care providers who provide services to you in connection with this study 
 
Laboratories and other individuals and organizations that analyze your health information 
in connection with this study, in accordance with the study’s protocol 
 
The following research sponsors and the people and companies that they use to oversee, 
administer, or conduct the research:  
The study sponsor: Dr. Khaldoun Almhanna and The Brown University Oncology Research 
Group (the group coordinating this trial) and its representatives, Bristol Myers Squibb (the 
makers of Nivolumab and financial supporter of this trial) and Oncoceutics, Inc (the makers of 
ONC201), Pathology and laboratory departments of Rhode Island Hospital and Brown 
University, , and other laboratories and collaborators as contracted to perform the applicable 
testing or assess collected samples 
 
The United States Food and Drug Administration, the Department of Health and Human 
Services, the Office of Inspector General, and the Office of Civil Rights 
 
The members and staff of the Institutional Review Board(s) or Ethics Committee(s) that 
approves this study 
 
Principal Investigator and other Investigators 
 
Study Coordinator 
 
Additional members of the Research Team 
 
The Patient Advocate or Research Volunteer Protector: _____________________ 
 
Members of the hospital's administrative staff responsible for administering clinical trials 
and other research activities 
 
Contract Research Organization (A contract research organization is an independent 
organization that agrees to oversee and make possible, various aspects of the clinical research 
process for the research sponsor.) 
 
Data and Safety Monitoring Boards and others that monitor the conduct of the Study, for 
example a Clinical Events Committee 
 
The members and staff of the hospitals affiliated Privacy Board (if such a board is used) 
 
Others: 
 
 
 
 
_____________________________ 
* If, during the course of the research, one of the companies or institutions listed above merges 
with or is purchased by another company or institution, this permission to use or release 
protected health information in the research will extend to the new company or institution.  
 
 The entire research record and any medical records held by the hospital may be used and 


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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
released.   
 The following information: _____________________________________________ 
 
 
GINA STATEMENT  
This study involves ‘genetic testing’ as defined by the Genetic Information Nondiscrimination 
Act of 2008 (GINA). GINA generally makes it illegal for health insurance companies, group 
health plans, and most employers to discriminate against you based on your genetic 
information.  There are some limitations to GINA’s protections (it does not apply to all insurers 
or employers, nor does it apply to all genetic information, such as information related to a 
genetic disease that you already have).  In addition to GINA’s protections regarding the ultimate 
use to which your genetic information is put, <INSERT HOSPITAL NAME>’s privacy policies 
generally protect the privacy of such information and restrict its release outside of <INSERT 
HOSPITAL NAME>, unless you specifically authorize its disclosure or unless disclosure 
without your authorization is permitted under applicable privacy laws.  
 
Participation in Specimen Banking  
You are agreeing to participate in this research study by signing this form (the “Main Study”) 
tissue samples will be collected from you, which will be referred to here as your ‘Specimen.’  In 
addition to being analyzed as part of the Main Study, your Specimen may be useful for future 
research purposes.  By signing this consent form, you give permission for your Specimen to be 
stored in a specimen bank indefinitely, until it is no longer usable. The Specimen may also be 
used to create a cell line, which would also be stored for an indefinite period of time. Along with 
the specimens, portions of your personal health information collected as part of the Main Study 
will also be stored.  Your Specimen and personal health information may be stored and analyzed 
at Lifespan; or, they may be shared with researchers at other institutions or companies that may 
store them and use them for their own research.  It is very unlikely that any future research 
performed using your Specimen would benefit you directly.  However, the research may provide 
important medical knowledge that in the future could help other patients with your medical 
condition or other medical problems.     
 
At this time, we do not know what future research studies may be done using your Specimen.  
Such research studies may include genetic tests that would analyze your DNA, RNA or other 
gene products, like proteins and metabolites.  These genetic tests may be done by Lifespan, or 
they may be done by other researchers with whom your Specimen and data have been shared.  
Because any genetic testing of your Specimen would be for research purposes, the results would 
have no clear implications for your health or medical condition, or that of your family members.  
Any testing results would not be made available to you or to any insurance company, your 
employer, your family, or any physician who treats you in the future.       
 
There is a very remote possibility that your Specimen and some associated data may become part 
of a process or product that ultimately has commercial value.  For instance, the Specimen could 


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review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
be used to establish a cell line (a group of cells that are able to reproduce, sometimes 
indefinitely) that could be patented and licensed.  There are no plans to provide financial 
compensation to you should this occur. 
 
If you decide at some time in the future that you no longer wish your stored Specimen to be used 
in future studies, you have the right to request that the Specimen be withdrawn from the 
specimen bank.  However, withdrawal cannot be guaranteed and may be impossible.  For 
example, it is possible that the Specimen might no longer be identifiable as belonging to you, or 
it may have been used up, or it may already have been shared with other institutions or 
companies for their own research.  To request withdrawal of your Specimen, please write to: Dr. 
Khaldoun Almhanna, MD 593 Eddy Street APC1 Providence, RI 02903. 
 
 
 
 


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Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
SIGNATURE 
I have read this informed consent and authorization form.  ALL OF MY QUESTIONS HAVE 
BEEN ANSWERED, AND I WANT TO TAKE PART IN THIS RESEARCH STUDY. 
By signing below, I give my permission to participate in this research study and for the described 
uses and releases of information.  I also confirm that I have been now or previously given a copy 
of the <INSERT HOSPITAL NAME> Privacy Notice 
 
 
 
The Researcher is required to provide a copy of this consent to you.  
 
_________________________________________ ________          ____________ 
Signature of study volunteer/authorized representative* Date         and    Time when signed 
 
 
 
I was present during the consent PROCESS AND signing of this agreement by the study 
volunteer or authorized representative 
 
__________________________________________ 
 
______________ 
Signature of witness (required if consent  
 
 
Date 
is presented orally or at the request of the IRB)  
 
 
 
 
 
 
 
 
__________________________________________ 
 
______________ 
Signature of Translator 
 
 
 
 
 
Date 
 
___________________________________________ ________          __________ 
Signature of researcher or designate  
 
 
Date         and    Time when signed 
 
* If signed by agent other than study volunteer, please explain below. 
______________________________________________________________________________ 
This informed consent document expires on ______________.   
DO NOT sign this document after this expiration date 


Page 135 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
Appendix C: Performance Status 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
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. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 


Page 136 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
APPENDIX D I-O AE ALGORITHMS 
 
 


Page 137 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 


Page 138 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 


Page 139 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 


Page 140 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
 


Page 141 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 


Page 142 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
 
 


Page 143 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
 


Page 144 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
Appendix E: FDA MedWatch Reporting Checklist for site to submit with report 
 
Patient #: ______ Initials: _____ 
☐ Initial SAE Report   ☐ Follow-up #1 SAE Report    ☐ Follow-up #2 SAE Report 
 
☐ Report must be typed 
☐ Mfr Report #: enter the BMS Protocol # CA209-79E 
 
☐ Section A Include protocol # (and patient number, if assigned) (i.e. Br379 initials #) 
 
Section B Description of event:  
☐ Include description of event (i.e. this is an initial SAE report to document pt X presented to 
the hospital on XX-XX-XXXX for X, X, X) 
 
☐ Include protocol description (i.e. pt X began treatment on BrUOG 379 on X) 
 
☐ Include treatment regimen (dosing frequency, combination therapy) (i.e. patient received last 
dose of X on XX-XX-XX) 
 
☐ Clearly outline which events are being reported as serious and non-serious (i.e. serious events 
are grade 3 fatigue and grade 3 nausea, non-serious events at time of hospitalization include 
grade 1 fever and grade 1 vomiting) 
 
☐ Investigator’s assessment of the relationship of the serious adverse event to each 
investigational product (Nivolumab) and suspect medication (ONC201) (i.e. fatigue is not related 
to Nivolumab, related to disease) 
 
☐ Include documentation if the event(s) is/are immune mediated  
 
☐ Include treatment of event (i.e. patient received IV antibiotics and fluids for treatment of 
serious event X) 
 
☐ Outcome of event, if known (i.e. grade 3 serious fatigue resolved upon discharge or grade 3 
serious fatigue downgraded to non-serious grade 2 upon discharge) 
 
☐ Action taken with Nivolumab and ONC201 as a result of the SAE and expectedness (based on 
the IB and consent) if it is unknown at the time of submission, please indicate “at this time, 
treating MD is uncertain when study treatment with Nivolumab and ONC201 will resume” 
 
☐ Create unscheduled event in REDCap and upload all supportive documents 


Page 145 of 145 
 
Protocol- BrUOG 379 
CONFIDENTIAL 
Dates: 11/04/2018, 11/11/18, 11/16/18, 11/24/18, 11/30/18, 12/2/18, 12/6/18, 12/7/18, 12/10/18, 1/8/19 BMS 
review, 1/9/19, 1/13/19, 1/15/19, 1/16/19, 1/17/19, 1/20/19, 1/22/19, 2/4/19, 2/19/19, 3/19/19, AM#1 7/22/19, BMS 
review 8/23/19, AM#2 3/3/20, BMS approved 4/1/20, Oncoceutics approved 4/24/20, AM#3 10/26/2020, BMS 
approved 1/5/21, Oncoceutics approved 3/30/21 
 
 
☐ A final report to document discharge from hospital (or resolution of important medical event) 
if patient still admitted at the time of report, this must be submitted as a follow-up 
 
☐ Section C Suspect Products(s) site to complete if the initial reporter suspected the product 
was associated with the SAE. If the product was not suspected to be associated with the SAE, 
only C2 conmed section should be completed (lot # and expiration date must be included if 
applicable).