Clinical trial NCT03442569
Conditions: Colon Cancer
Sponsor: UNC Lineberger Comprehensive Cancer Center
Start date: 2018-03-09; Completion date: 2024-12-02
Enrollment: 56 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To investigate the combination of nivolumab and ipilimumab with panitumumab in subjects with unresectable, refractory, KRAS/NRAS/BRAF wild-type, microsatellite stable (MSS) metastatic colorectal cancer.

Detailed description:
The investigators will conduct a single-arm, open-label Phase II clinical trial investigating the combination of nivolumab and ipilimumab with panitumumab in subjects with unresectable, refractory, KRAS/NRAS/BRAF wild-type, microsatellite stable (MSS) metastatic colorectal cancer (mCRC). There will be an initial safety lead-in cohort to ensure the combination is well-tolerated. The primary objective of this study is to estimate the overall response rate in these subjects at 12 weeks . Secondary objectives include the following: estimating the overall response rate in these subjects at 12 weeks by immune-related RECIST criteria (irRECIST), estimating the best response rate by both RECIST 1.1 and irRECIST criteria, estimating progression-free survival (PFS) and duration of response using both RECIST 1.1 and irRECIST criteria, estimating overall survival (OS), and characterizing the safety issues associated with this regimen. Exploratory objectives involve investigating various biomarkers and peripheral blood and tumor assays.

Arms: arm 1: Nivolumab and ipilimumab with panitumumab
Interventions: intervention 1: Panitumumab intervention 2: Nivolumab intervention 3: Ipilimumab
Intervention descriptions: intervention 1: 6 mg/kg via IV every 2 weeks in combination with nivolumab and ipilimumab intervention 2: 240 mg via IV every 2 weeks in combination with panitumumab and ipilimumab intervention 3: 1 mg/kg via IV every 6 weeks in combination with nivolumab and panitumumab

Protocol documents:
Prot_SAP_000.pdf: 
LINEBERGER COMPREHENSIVE CANCER CENTER 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT #    2   
LCCC  1632:  Phase II multicenter trial of panitumumab, nivolumab, and ipilimumab for 
KRAS/NRAS/BRAF wild-type MSS refractory metastatic colorectal adenocarcinoma 
 
AMENDMENT INCORPORATES (check all that apply): 
  X  Editorial, administrative changes 
___ Scientific changes (IRB approval) 
  X   Therapy changes (IRB approval) 
_X_ Eligibility Changes (IRB approval) 
 
AMENDMENT RATIONALE AND SUMMARY: 
The purpose of this protocol amendment is to provide an administrative change to the risks of 
nivolumab and ipilimumab to include hemolytic anemia as a possible adverse event, provide 
additional guidance on managing immune-related adverse events, clarification on panitumumab 
dosing, update drug information for nivolumab and ipilimumab based on the new investigator 
brochure, provide clarification on the treatment visit window related to nivolumab dosing, to 
update multicenter language, and to change the Principal Investigator to Dr. Autumn McRee. 
Due to changes in the investigator brochure related to risk language, the related eligibility criteria 
were updated. Changes in therapy administration for nivolumab and ipilimumab were also 
updated based on the information in the new Investigator’s Brochure. 
 
Editorial/Administrative Change 
1. The Principal Investigator was changed to Dr. Autumn McRee. 
2. Section 4.3.1 and 4.3.2: Clarification on administration of doses of panitumumab over 
1000 mg 
3. Section 4.4.2, footnote f: Modified to clarify toxicity management guidance 
4. Section 4.4.2.1: Added footnote to clarify toxicity management guidance 
5. Section 4.4.2.3: Added a section (4.4.2.3.1) to provide guidance on cycle counting 
relative to treatment delays. 
6. Section 4.4.2.4: Adding paragraph related to dosing management. Removed paragraph 
with repeated information related to toxicity management.  
7. Section 4.4.2.5: Added ipilimumab to Discontinuation Criteria. Added paragraph on 
resuming dosing. 
8. Sections 5.2.2, 5.2.4, and 5.2.6: Updated nivolumab packaging, administration and 
stability information based on the new IB. 
9. Sections 5.3.2, 5.3.4: Updated ipilimumab packaging and administration information 
based on the new IB 
10. Section 5.3.4: Updated Section reference. 
11. Sections 5.2.8 and 5.3.8: Hemolytic anemia was added as a risk for nivolumab and 
ipilimumab.  
12. Section 6.1, Footnote 2: Added clarification related to the treatment window and the 
minimum 12-day time span between nivolumab treatments. 
13. Title page and Sections 7.3 and 9.4-9.6: Updated multicenter language was added.  


LINEBERGER COMPREHENSIVE CANCER CENTER 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
  
2 
 
14. Section 7.3.3: In the pregnancy subpart, revised the timing of contraceptive use after 
therapy to be consistent with updated drug information. 
15. Section 11.2: Added information related to additional guidance for managing immune-
related adverse events.  
16. Light mechanical editing throughout 
 
Therapy 
1. Section 4.3.1: Updated administration information for ipilimumab based on the new 
Investigator’s Brochure. 
2. Section 4.3.1 and 4.3.2 Tables: Updated administration information for nivolumab based 
on the new Investigator’s Brochure. 
 
Eligibility 
1. Criteria in 3.1.11, 3.1.12 and 3.2.8 were updated based off updated drug information. 
 
THE ATTACHED VERSION DATED October 01, 2020 INCORPORATES THE ABOVE 
REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 
 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
  
 
 
 
 
PROTOCOL AMENDMENT #    1   
LCCC  1632:  Phase II multicenter trial of panitumumab, nivolumab, and ipilimumab for 
KRAS/NRAS/BRAF wild-type MSS refractory metastatic colorectal adenocarcinoma 
 
AMENDMENT INCORPORATES (check all that apply): 
  X  Editorial, administrative changes 
___ Scientific changes (IRB approval) 
  X  Therapy changes (IRB approval) 
___ Eligibility Changes (IRB approval) 
 
AMENDMENT RATIONALE AND SUMMARY: 
The protocol was revised to clarify the dose delay and dose modification procedures, to 
remove duplicate information, add stool specimen collection, and to revise the registration, data 
management, and single subject/subject exception sections.  
In reference to the dose delay and dose modification updates, adverse reaction terms were 
inadvertently removed from the “Toxicities and Dosing Delays/Dose Modifications” section and 
have been added back: Infusion-related reactions; Dermatologic reaction; Pulmonary 
Fibrosis/ILD, Colitis, Pneumonitis, Hypophysitis, Type 1 Diabetes Mellitus, Nephritis and Renal 
Dysfunction, Rash, Encephalitis, Other. Also included with the updates are the following adverse 
reaction terms and their corresponding severity and dose modification action: Adrenal 
Insufficiency, Myocarditis, Infusion Related Reaction, and Uveitis, eye pain, blurred vision.  
Additionally, Baseline Liver Function Tests were inadvertently removed from the “Nivolumab 
and/or Ipilimumab Dose Modifications/Delays for Liver Toxicity” table and have been added 
back: AST or ALT normal, AST or ALT 1.1 to ≤ 2.5 X ULN (Grade 1), Total Bilirubin normal, 
and Total Bilirubin 1.1 to ≤ 1.5 X ULN (Grade 1).  
The registration, data management, and single subject/subject exception procedures were 
updated to align with current Lineberger Comprehensive Cancer Center procedures. In addition, 
pregnancy reporting requirements for female partners of male subjects was added.  
Lastly, stool specimen collection was added to identify gut microbial composition at 
baseline and at first restaging.  
 
Editorial and Therapy Changes: 
1. For section 1.6, a paragraph regarding stool specimen collection and rationale for 
addition of a stool specimen was added to this section. 
2. For section 2.3, exploratory objective 2.3.5 was added which states “To collect stool 
specimens to assay gut microbial composition at baseline and longitudinally.” 
3. For inclusion criterion 3.1.4, “OR CLIA-certified sequencing methodology such as 
Foundation One” was added as an additional method for Microsatellite stable detection. 
4. For section 4.1.1, the sample size was adjusted for accuracy. 
5. For section 4.3.1 and 4.3.2, an infusion window of +/- 15 minutes was added for the 
panitumumab, nivolumab and ipilimumab infusions.  


LINEBERGER COMPREHENSIVE CANCER CENTER 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
  
 
 
6. For section 4.4.1, the following adverse reaction criteria pertaining to the dosing 
delays/dose modifications criteria for panitumumab were inadvertently omitted from the  
 
 
table and have been added: Infusion-related reactions; Dermatologic reaction; Pulmonary 
Fibrosis/ILD.   
7. For section 4.4.2, “+/- Ipilimumab” was added to the section header.  
8. For section 4.4.2, the following adverse reaction terms and the corresponding severity 
and dose modification were added to the table: Adrenal insufficiency; Myocarditis; 
Infusion Related Reaction; Uveitis, eye pain, blurred vision. Additionally, the following 
adverse reaction terms were inadvertently omitted and have been added to the table: 
Colitis; Pneumonitis; Hypophysitis; Type 1 Diabetes Mellitus; Nephritis and Renal 
Dysfunction; Rash; Encephalitis; Other.  
9. For section 4.4.2, footnotes b, c, d, e and f were added to the table. 
10. For section 4.4.2.1, “and/or Ipilimumab” was added.  
11. For section 4.4.2.1, the following terms were inadvertently omitted and have been added 
to the table under column heading “Baseline Liver Function Test (NCI-CTCAEv4.03 
grade)”: AST or ALT normal; AST or ALT 1.1 to ≤ 2.5 X ULN (Grade 1); Total 
Bilirubin normal; Total Bilirubin 1.1 to ≤ 1.5 X ULN (Grade 1). 
12. For section 4.4.2.2, dose delay criteria for ipilimumab was added to this section and 
duplicate criteria was removed as this criteria has been incorporated into sections 4.4.2 
and 4.4.2.1. 
13. For section 4.4.2.3, “+/- Ipilimumab” was added to the section header. 
14. For section 4.4.2.4, section header revised to include immune related events for 
ipilimumab. 
15. Section 4.4.3 and subsections 4.4.3.1, 4.4.3.2 were deleted as this was a duplication of   
information.  
16. For section 4.5, prophylaxis for acneiform skin rash related to panitumumab therapy was 
clarified. 
17. For section 6.1, stool specimen collection was added to the pre-study and D1 Cycle 3-N 
columns.  Additionally, footnote #13 was added indicating the stool specimen should be 
collected +/- 7 days from C3D1. 
18. For section 6.1, footnote #1 was clarified to indicate that other evaluations except for 
pregnancy test must be performed within 3 weeks prior to Cycle 1 Day 1 (C1D1) of 
treatment, rather than 2 weeks. 
19. For section 6.2, it was clarified that the pre-study assessments are to be conducted 
within 3 weeks rather than 2 weeks. 
20. For section 6.1, prophylaxis for panitumumab-associated rash was clarified in footnote 
#9. 
21. For section 6.2, stool specimen collection was added as pre-study assessment.  
22. For section 6.3.5, stool specimen collection was added as a D1 of Cycle 3-N assessment. 
23. For section 6.5, information regarding the specimen collection was added to correlative 
studies. 
24. For section 7.3.3, wording was added to clarify that if a female partner of a male subject 
becomes pregnant, the study personnel at the site must be informed immediately and the 
pregnancy followed per protocol. 


LINEBERGER COMPREHENSIVE CANCER CENTER 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
  
 
 
25. For section 9.3, subject registration procedures were updated to reflect current Lineberger 
Comprehensive Cancer Center procedures. 
26. For section 9.4, data monitoring procedures were updated to reflect current Lineberger  
 
Comprehensive Cancer Center procedures. 
27. For section 9.5.2, wording was revised to indicate that eligibility single subject 
exceptions are not permitted for Lineberger Comprehensive Cancer Center Investigator 
Initiated Trials.  
 
THE ATTACHED VERSION DATED JULY 30, 2018 INCORPORATES THE ABOVE 
REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 
 
 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
  
 
 
LCCC  1632: Phase II multicenter trial of panitumumab, nivolumab, and ipilimumab for 
KRAS/NRAS/BRAF wild-type MSS refractory metastatic colorectal adenocarcinoma 
 
 
Principal Investigator 
Autumn McRee, MD  
Associate Professor  
University of North Carolina at Chapel Hill 
Lineberger Comprehensive Cancer Center 170 
Manning Rd, CB# 7305 
919-966-5902 (PHONE) 
919-966-6735 (FAX) 
autumn_mcree@med.unc.edu 
 
 
Biostatistician 
Dominic T. Moore 
dominic_t_moore@unc.edu 
Phone: 919-966-8647 
Fax: 919-966-4244 
 
Clinical Protocol Office 
Lineberger Comprehensive Cancer Center 
The University of North Carolina at Chapel Hill 
450 West Drive, 3rd  Floor, CB# 7295 
Chapel Hill, NC 27599-7295 
 
Multicenter Project Manager: 
Phone: 919-966-7359 
Fax: 919-966-4300 
 
Sponsor:  Lineberger Comprehensive Cancer Center 
 
Funding Source: Amgen, Inc. 
Version date: October 01, 2020 
 
IND # 136740 


LINEBERGER COMPREHENSIVE CANCER CENTER 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
  
 
 
LCCC  1632: Phase II multicenter trial of panitumumab, nivolumab, and ipilimumab for 
KRAS/NRAS/BRAF wild-type MSS refractory metastatic colorectal adenocarcinoma 
 
 
Principal Investigator Autumn McRee, MD 
Associate Professor  
University of North Carolina at Chapel Hill 
Lineberger Comprehensive Cancer Center 170 
Manning Rd, CB# 7305 
919-966-5902 (PHONE) 
919-966-6735 (FAX) 
autumn_mcree@med.unc.edu 
 
 
 
 
 
 
 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
Principal Investigator (PI) Name:  
 
 
PI Signature:   
 
 
Date:  
 
 
Version date: October, 01, 2020 


LINEBERGER COMPREHENSIVE CANCER CENTER 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
  
i 
 
LIST OF ABBREVIATIONS 
 
ACTH 
Adrenocorticotropic hormone 
ADCC 
Antibody dependent cellular cytotoxicity 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BID 
Bis in die (twice daily) 
BUN 
Blood urea nitrogen 
BRAF 
Murine sarcoma viral oncogene homolog B 
CBC 
Complete blood count 
CEA 
Carcinoembryonic antigen 
CIN 
Chromosome instability 
CR 
Complete response 
CRC 
Colorectal cancer 
CRP 
C-reactive protein 
CT 
Computer tomography 
CTLA-4 
Cytotoxic T lymphocyte antigen-4 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid 
DSMC 
Data safety monitoring committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EGFR 
Epidermal growth factor receptor 
GSEA 
Gene set enrichment analysis 
g/dL 
Grams per deciliter 
HIPAA 
Health Insurance Portability and Accountability Act 
β-HCG 
Beta-Human Chorionic Gonadotropin 
HBs-Ag 
Hepatitis B surface antigen 
HBc 
Hepatitis B core 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
IB 
Investigator’s brochure 
IDS 
Investigational drug service 
Ig 
Immunoglobulin 
IgE 
Immunoglobulin E 
IgG2 
Immunoglobulin G2 
IHC 
Immunohistochemistry 
ULN 
Upper limit of normal 
irRECIST 
Immune-related response evaluation criteria in solid tumors 
IV 
Intravenous 
J-STEPP 
Japanese skin toxicity evaluation protocol with panitumumab 
Kg 
Kilograms 
Kras 
Kirsten rat sarcoma (viral oncogene) 
LCCC 
Lineberger Comprehensive Cancer Center 
LDH 
Lactate dehydrogenase 
Mabs 
Monoclonal antibodies 
MAPK 
Mitogen activated protein kinase 
mCRC 
Metastatic colorectal cancer 
Mg 
Milligrams 
Mo 
Months 
MSI-H 
Microsatellite instability - high 
MSS 
Microsatellite stable 


LINEBERGER COMPREHENSIVE CANCER CENTER 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
  
ii 
 
 
MRI 
Magnetic resonance Imaging 
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria for 
Adverse Events 
NF-B 
Nuclear factor kappa light-chain enhancer of activated B cells 
NK 
Natural killer 
N-ras 
Neuroblastoma sarcoma viral oncogene homolog 
ORR 
Overall response rate 
OS 
Overall survival 
PABA 
Para-aminobenzoic acid 
PBMC 
Peripheral blood mononuclear cells 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PD-1 
Programmed cell death-1 
PET 
Positron Emission Tomography 
PFS 
Progression free survival 
PFT 
Pulmonary function test 
Pgp 
P-glycoprotein 
PHI 
Personal health information 
PK 
Pharmacokinetic(s) 
PO 
Per os (by mouth) 
PR 
Partial response 
PRC 
Protocol review committee 
QD 
Quaque die (once daily) 
Q2wks 
Every 2 weeks 
RAS 
Rat sarcoma (viral oncogene) 
RBC 
Red blood cell 
RECIST 
Response evaluation criteria in solid tumors 
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
s.c. 
subcutaneous 
sCR 
Stringent complete response 
SD 
Stable disease 
SPF 
Sun protection factor 
SLM 
Study laboratory manual 
STEPP 
Skin toxicity evaluation protocol with panitumumab 
SUSAR 
Serious unexpected adverse reaction 
TPF 
Tissue Procurement Facility 
TRAIL 
Tumor necrosis factor related apoptosis inducing ligand 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
UNC 
University of North Carolina 
USP / USPI 
United States Pharmacopeia / US Product Insert 
UV 
Ultraviolet 
VEGFR 
Vascular endothelial growth factor receptor 
VGPR 
Very good partial response 
WOCBP 
Women of childbearing potential 
WT 
Wild-type 


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
iii 
 
 
 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .............................................................................................. i 
1.0 
BACKGROUND AND RATIONALE ................................................................... 1 
1.1 
Study Synopsis ....................................................................................................... 1 
1.2 
Colorectal Cancer Background .............................................................................. 1 
1.3 
Panitumumab in CRC ............................................................................................. 3 
1.4 
Ipilimumab and Nivolumab in CRC ...................................................................... 3 
1.5 
Rationale for LCCC1632 ....................................................................................... 4 
1.6 
Correlative Studies ................................................................................................. 6 
2.0 
STUDY OBJECTIVES ............................................................................................ 6 
2.1 
Primary Objective .................................................................................................. 6 
2.2 
Secondary Objectives ............................................................................................. 7 
2.3 
Exploratory Objectives ........................................................................................... 7 
2.4 
Endpoints ................................................................................................................ 8 
3.0 
SUBJECT ELIGIBILITY ....................................................................................... 9 
3.1 
Inclusion Criteria .................................................................................................... 9 
3.2 
Exclusion Criteria ................................................................................................. 11 
4.0 
TREATMENT PLAN ............................................................................................ 12 
4.1 
Schema ................................................................................................................. 12 
4.2 
Dose Limiting Toxicities for Safety Lead-in ....................................................... 14 
4.3 
Treatment Dosage and Administration ................................................................. 15 
4.4 
Toxicities and Dosing Delays/Dose Modifications .............................................. 16 


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
iv 
 
 
4.5 
Concomitant Medications/Treatments ................................................................. 23 
4.6 
Duration of Therapy ............................................................................................. 26 
4.7 
Duration of Follow Up ......................................................................................... 27 
4.8 
Removal of Subjects from Protocol Therapy ....................................................... 27 
4.9 
Study Withdrawal ................................................................................................. 27 
5.0 
DRUG INFORMATION ....................................................................................... 28 
5.1 
Panitumumab (Vectibix®) ................................................................................... 28 
5.2 
Nivolumab (Opdivo®) ......................................................................................... 29 
5.3 
Ipilimumab (Yervoy®) ......................................................................................... 32 
5.4 
Return and Retention of Study Drug .................................................................... 33 
6.0 
EVALUATIONS AND ASSESSMENTS ............................................................. 34 
6.1 
Time and Events Table ......................................................................................... 34 
6.3 
Treatment Assessments ........................................................................................ 39 
6.4 
Post-Treatment/Follow-up Assessments .............................................................. 41 
6.5 
Correlative Studies Procedures ............................................................................ 42 
6.6 
Assessment of Safety ........................................................................................... 43 
6.7 
Assessment of Efficacy ........................................................................................ 43 
7.0 
ADVERSE EVENTS ............................................................................................. 47 
7.1 
Definitions ............................................................................................................ 47 
7.2 
Documentation of non-serious AEs or SARs ....................................................... 49 
7.3 
SAEs or Serious SARs ......................................................................................... 49 
7.4 
Data and Safety Monitoring Plan ......................................................................... 55 
8.0 
STATISTICAL CONSIDERATIONS ................................................................. 56 
8.1 
Study Design/Study Endpoints ............................................................................. 56 


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
v 
 
 
8.2 
Sample Size and Accrual ...................................................................................... 56 
8.3 
Toxicity Monitoring ............................................................................................. 57 
8.4 
Data Analysis Plans .............................................................................................. 57 
9.0 
STUDY MANAGEMENT ..................................................................................... 58 
9.1 
Institutional Review Board (IRB) Approval and Consent ................................... 58 
9.2 
Required Documentation ...................................................................................... 58 
9.3 
Registration Procedures ........................................................................................ 59 
9.4 
Data Management and Monitoring/Auditing ....................................................... 59 
9.5 
Adherence to the Protocol .................................................................................... 59 
9.6 
Amendments to the Protocol ................................................................................ 62 
9.7 
Record Retention .................................................................................................. 62 
9.8 
Obligations of Investigators ................................................................................. 62 
11.0 
APPENDICES ........................................................................................................ 69 
11.1 
ECOG Performance Status ................................................................................... 69 
11.2 
Treatment Algorithms for Nivolumab Therapy ................................................... 70 
11.3 
Cockcroft-Gault Formula ..................................................................................... 76 
 


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
1 
 
 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Study Synopsis 
We will conduct a single-arm, open-label Phase II clinical trial investigating the 
combination of nivolumab and ipilimumab with panitumumab in subjects with 
unresectable, refractory, KRAS/NRAS/BRAF wild-type, microsatellite stable 
(MSS) metastatic colorectal cancer (mCRC). There will be an initial safety lead-in 
cohort to ensure the combination is well-tolerated. The primary objective of this 
study is to estimate the overall response rate (CR + PR) in these subjects at 12 
weeks by RECIST 1.1 criteria and also by irRECIST criteria. Secondary 
objectives include the following: estimating the overall response rate (CR + PR) 
in these subjects at 12 weeks by irRECIST criteria, estimating the best response 
rate by both RECIST 1.1 and irRECIST criteria, estimating PFS and duration of 
response using both RECIST 1.1 and irRECIST criteria, estimating OS, and 
characterizing the safety issues associated with this regimen. Exploratory 
objectives involve investigating various biomarkers and peripheral blood and 
tumor assays. 
 
This treatment regimen will be of clinical interest if the objective response rate 
increases from the standard of care response rate of 22% with panitumumab alone 
to approximately 35% with combination therapy (adding nivolumab and 
ipilumumab to panitumumab). 
 
1.2 
Colorectal Cancer Background 
CRC is the second most common cause of cancer mortality in the United States, 
causing an estimated 49,190 deaths in 2016. Mortality is primarily driven by the 
20% of CRC subjects with metastatic disease, who suffer 5-year overall survival 
of only 12.9% 1.  Subjects with mCRC, have experienced improvements in 
median overall survival (OS), from 14.2 months for those diagnosed in 1990-1997 
to over 29 months for those diagnosed after 20042. Much of these improvements 
are attributable to development of novel therapies. Previously, only 
fluoropyrimidines were standard options for subjects with CRC, but starting in the 
mid-2000s, increasing numbers of subjects were treated with novel chemotherapy 
agents such as irinotecan, oxaliplatin, and novel biologic drugs such as 
bevacizumab and the monoclonal antibodies targeting the epidermal growth factor 
receptor (EGFR); subsequent widespread use of these agents has contributed to 
improvements in survival. Nevertheless, barring surgical resection of 
oligometastatic disease, inevitably metastatic cancers develop resistance to 
therapies, thus resulting in clinical progression and ultimately death. There is a 
great unmet need to better understand biologic mechanisms of resistance to 
available therapies and use this knowledge to guide future therapy choices for 
individual subjects with CRC. 
 
While efforts have been extensive to identify molecular markers to guide 
evidence-based therapy for subjects with CRC, the impact of these efforts thus far 


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
2 
 
 
on the standard of care for CRC has been limited. Microsatellite instability high 
(MSI-H) is a molecular fingerprint of a deficient mismatch repair system that is 
evident in approximately 15% of CRC that has been recognized since the 1990s3. 
The MSI-H phenotype is a unique subset characterized by less aggressive 
behavior and a favorable prognosis compared to microsatellite stable (MSS) CRC, 
at least among subjects with stage II disease4. The prognostic value of MSI-H 
should be evaluated in all stage II CRC subjects regarding chemotherapy as some 
subjects can be spared adjuvant chemotherapy. Evidence for supporting the 
preferential efficacy of irinotecan in MSI-H tumors is continuing to emerge but 
remains inconclusive based on disparate results from clinical trials3,5,6. 
 
Currently, available biomarkers for CRC are limited to identifying subjects for 
whom certain treatment is not suited, rather than identifying those who may 
benefit from treatment7. KRAS and NRAS mutation status provide a basis for 
subject selection regarding benefit from EGFR targeting antibodies8 as subjects 
with KRAS or NRAS mutations, which are detected in approximately 40% of 
CRCs, do not derive benefit from these treatments. There are no prognostic or 
predictive molecular markers for bevacizumab-based therapy which is directed 
against the vascular endothelial growth factor receptor (VEGF-R) pathway; 
moreover, due to the heterogeneous nature of CRC, a number of subjects receive 
little benefit or no benefit from these targeted agents7. Although unique subtypes 
within CRC have been identified as shown in Table 1 below based on a consensus 
molecular subtyping strategy devised and recently reported by the Colorectal 
Cancer Subtyping Consortium, 9,10 critical questions remain regarding the 
pathogenesis and biology of these tumors, and unfortunately, optimal biomarkers 
for evidence-based therapeutic approaches remain elusive. Key areas of unmet 
need include optimizing use of EGFR antibodies for RAS/RAF wild-type disease 
and improving treatment for subjects with RAS and RAF mutations where no 
proven targeted therapy exists. 
 
Table 1. Proposed taxonomy of CRC reflecting significant biological differences 
in gene expression-based molecular subtypes (adapted from Nat Med 2015 
21(11):1350-1356.) 
CRC 
Molecular 
subtypes 
CMS1 
MSI 
Immune 
CMS2 
Canonical 
CMS3 
Metabolic 
CMS4 
Mesenchymal 
Incidence 
14% 
37% 
13% 
23% 
Hypermutation 
MSI, 
Braf mutation 
Immune 
activation 
MSS, CIN 
WNT/MYC pathway 
activation, TP53 mutation, 
EGFR 
amplification/overexpression 
Low CIN 
Moderate 
WNT/MYC 
pathway 
activation, 
KRAS, 
PIK3CA and 
IGFBP2 
mutation 
CIN/MSI 
heterogeneous, 
Mesenchymal/TGF- 
beta activation, and 
NOTCH3/VEGFR2 
overexpression 
Prognosis 
Worse survival 
After relapse 
Worse relapse-free 
and overall survival 


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
3 
 
 
CIN = chromosomal instability; MSI= microsatellite instability; MSS = 
microsatellite stable 
 
1.3 
Panitumumab in CRC 
Panitumumab is indicated for treatment of subjects with KRAS wild-type mCRC 
as monotherapy after disease progression after prior treatment with 
fluoropyrimidine, oxaliplatin, and irinotecan containing chemotherapy regimens. 
Panitumumab is a fully human IgG2 antibody that binds the EGFR. The EGFR 
and proteins involved in its downstream signal transduction play important roles 
in oncogenesis and tumor progression in CRC. EGFR is a transmembrane 
receptor tyrosine kinase that homodimerizes upon ligand binding to activate 
downstream intracellular signal transduction cascades, notably including the 
mitogen activated protein kinase (MAPK) pathway via RAS, RAF, and MEK, to 
ultimately promote cell proliferation and survival.11 There are three human RAS 
genes that encode homologous proteins, HRAS, NRAS, and KRAS.12 Mutations in 
codons 12 and 13 of KRAS are found in 37-43% of colorectal cancer subjects,13,14 
and contribute to oncogenesis by driving cell proliferation in a growth factor- 
independent fashion.14 Panitumumab, administered at 6 mg/kg IV every 2 weeks, 
significantly improves progression-free survival (PFS) compared to best 
supportive care when administered to subjects with chemo-refractory mCRC 
whose tumors are wild-type in KRAS codons 12 and 13 (hazard ratio 0.45, 95% CI 
0.34 to 0.59). After additional studies demonstrated that benefit with anti-EGFR 
therapy was limited to subjects whose tumors are wild-type in exons 2, 3, and 4 of 
KRAS and NRAS, consensus guidelines now recommend that only subjects who 
are wild-type on extended RAS testing receive anti-EGFR therapy15. Additional 
studies have suggested that wild-type BRAF is also required for optimal response 
to anti-EGFR therapy16. Thus, while panitumumab is effective for subjects with 
extended RAS and BRAF wild-type mCRC, the duration of benefit is limited, and 
so improving on panitumumab monotherapy with novel combination therapies is 
needed to extend the duration of benefit. 
 
1.4 
Ipilimumab and Nivolumab in CRC 
Therapy with checkpoint inhibitor immunotherapies, such as inhibitory antibodies 
against cytotoxic T lymphocyte antigen-4 (CTLA-4) or programmed cell death-1 
(PD-1) receptors on T cells, relieves tumor immune evasion and allows cytotoxic 
antitumor immune attack. These therapies have been found to yield durable 
disease response in several malignancies, including melanoma and non-small-cell 
lung carcinoma, and are undergoing investigation in a variety of other 
malignancies. However, efficacy of immune checkpoint inhibitor monotherapy in 
CRC has been limited, with cases of prolonged disease response initially found 
only in the rare subjects with MSI-H disease 11,17-20. Subsequently, in subjects 
with MSI-H mCRC, nivolumab monotherapy yielded 31% response rate21, and 
nivolumab + ipilimumab yielded 33% response rate 20. Since only 11% of mCRC 
subjects are MSI-H,22 this indicates that immune checkpoint inhibitor 
monotherapy is ineffective in the majority of subjects, who have MSS mCRC. 


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
4 
 
 
Indeed, in early clinical trials of nivolumab monotherapy or nivolumab + 
ipilimumab in subjects with MSS mCRC, there was only 1/20 objective 
responses 20. Thus, investigating combinations of immune checkpoint therapy 
with additional agents to further activate the immune system’s antitumor response 
is necessary in order to improve outcomes in the majority of subjects with mCRC 
who have MSS disease. 
 
1.5 
Rationale for LCCC1632 
Monoclonal antibodies (Mabs) targeting the EGFR are commonly used as 
standard of care in the 40-50% of MSS mCRC subjects with tumors that are wild- 
type in KRAS and NRAS.14 Cetuximab is a chimeric mouse/human IgG1 Mab 
against EGFR, while panitumumab is a fully human IgG2 anti-EGFR Mab. 
Although inhibition of downstream signaling transduction from EGFR is an 
important mechanism of efficacy of these antibody therapies,23 the ineffectiveness 
of small molecule EGFR inhibitors in this setting implies that additional 
mechanisms may explain Mab efficacy. Indeed, Mabs are known to interface with 
the immune system to trigger antibody-dependent cellular cytotoxicity (ADCC) or 
facilitate activation of the adaptive immune system. Though the general 
consensus is that IgG2 Mabs like panitumumab do not trigger classical natural 
killer (NK) cell-mediated ADCC,24 panitumumab does recruit myeloid lineage 
cells, like neutrophils and monocytes, to perform ADCC and impair tumor 
growth.25 This observation and others noted below support the hypothesis that 
anti-EGFR Mab efficacy is also linked to immune modulation. 
 
In addition, immune activation does appear to play an important role in the 
efficacy of anti-EGFR Mabs in preclinical models. Novel murine xenograft 
models with reconstituted immune cells demonstrate that cetuximab requires both 
innate and adaptive immunity to cause tumor regression, including causing 
proliferation of tumor antigen-specific CD8+ T cells in draining lymph nodes.26 
Furthermore, peripheral blood mononuclear cells (PBMCs) derived from subjects 
in clinical trials of chemotherapy with cetuximab revealed increases of activated 
Th1 cytotoxic T-cells, central memory cells, and NK cells.27 Similarly, head and 
neck cancer subjects treated with cetuximab had a significant increase in 
circulating CD8+ T-cells specific to EGFR epitopes.28 The combination of 
cetuximab with cytotoxic chemotherapy increased dendritic cell activation and 
phagocytosis29  and increased ADCC.30  However, cetuximab conversely was 
found to also activate immunosuppressive M2 macrophages, causing upregulation 
of PD-L1 and contributing further to immune evasion.31 Indeed, our preliminary 
data based on gene set enrichment analysis (GSEA) of gene expression 
microarrays from 68 CRC subjects treated with cetuximab indicates that 
cetuximab-resistant subjects tend to have an increase in monocyte/macrophage 
signatures, and also have a signature reflecting PD1-ligated T-cells as compared 
to control T cells 32 This suggests that while cetuximab can induce ADCC and 
requires activation of cytotoxic T cells, there is also an immunosuppressive effect 
triggered by cetuximab that may ultimately limit its activity. Translational studies 
in subjects treated with panitumumab show similar immunologic effects. Notably, 


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
5 
 
 
response to panitumumab in a phase II clinical trial was predicted by a high level 
of CD8+ tumor infiltrating lymphocytes and tumor FOXP3 expression.33,34 
Furthermore, first-line treatment with panitumumab and chemotherapy yielded 
increases in  all lymphocyte subsets, total dendritic cells, and dendritic cell 
subsets, suggesting an impact on in vivo T-cell mediated responses.35 Thus, we 
hypothesize that the immunosuppressive effect of anti-EGFR Mabs combined 
with chemotherapy may be overcome and the pro-adaptive immune response may 
be potentiated by co-administration with immune checkpoint inhibitors. 
 
In studies of immune checkpoint inhibitors in melanoma36, non-small cell lung 
cancer37, and MSI-H CRC,20 the combination of ipilimumab and nivolumab has 
yielded greater response rates and PFS than nivolumab alone. Additionally, 
CTLA4+ regulatory cells may impair cytotoxicity associated with anti-EGFR 
antibodies in head and neck cancers.38 Thus, administration of the anti-CTLA-4 
antibody ipilimumab may facilitate suppression of the inhibitory regulatory T 
cells and help activate an immune response driven by enhanced antigen 
presentation via effective therapy with panitumumab, while anti-PD-1 antibody 
nivolumab may allow this nascent T cell response to be more effectively 
unleashed. Given the otherwise poor efficacy of immune checkpoint therapy in 
MSS mCRC, we propose adding the combination of CTLA-4 inhibition and PD-1 
inhibition, through administration of ipilimumab and nivolumab, to treatment 
with panitumumab. 
 
Though panitumumab and cetuximab have clinically shown comparable 
efficacy,39-44 cetuximab has a greater incidence of infusion-related reactions than 
panitumumab (13% vs 3%), including grade 3-4 reactions (2% vs <0.5%). These 
hypersensitivity and anaphylactic reactions triggered by cetuximab infusion are 
particularly relevant in broad swaths of the Southeastern U.S., as grade 3-4 
reactions during the first infusion of cetuximab reach rates as high as 22% in this 
region.45 These infusion-related reactions are possibly related to geographically 
prevalent IgE antibodies that target an oligosaccharide present on cetuximab but 
not panitumumab.46 There is no cross-reactivity with panitumumab,47 and 
consequently panitumumab is used as the standard of care anti-EGFR mAb rather 
than cetuximab in the Southeastern U.S due to its superior safety profile and 
equivalent efficacy. Given the limited safety data currently available for the 
combination of cetuximab with immune checkpoint inhibitors in a geographic 
region with high rates of grade 3-4 immunologically-mediated hypersensitivity 
reactions to cetuximab, and the unclear effects of immunotherapy on these 
anaphylactic reactions, we favor pursuing a clinical trial of nivolumab + 
ipilimumab combined with panitumumab. 
 
Thus, we propose a single-arm, open-label, multicenter Phase II clinical trial 
investigating the combination of nivolumab and ipilimumab with panitumumab in 
subjects with unresectable refractory KRAS/NRAS/BRAF wild-type MSS mCRC. 
There will be an initial safety lead-in cohort to ensure the combination is well 
tolerated. 


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
6 
 
 
1.6 
Correlative Studies 
We will collect peripheral blood samples serially to facilitate analyses such as 
mutation analysis of circulating free tumor DNA and quantitation of circulating 
cytokines and EGFR ligands including epiregulin and amphiregulin. There is a 
growing body of evidence that one mechanism of resistance to anti-EGFR Mab 
therapy is the emergence of mutations or amplification in key components of the 
MAPK signaling pathways, including in EGFR, KRAS, and NRAS. 48-51 In 
addition, we have retrospective data indicating that treatment with anti-EGFR 
Mabs is associated with differential levels of cytokines and growth factors, 
including epiregulin and TRAIL. 52 These different resistance mechanisms, 
especially circulating TRAIL levels, are likely to have consequences on immune 
activation and response, and the association of each of these markers with RR, 
PFS, and OS will be determined. 
 
We will also plan to perform peripheral blood immune monitoring, such as 
assessment of ADCC and T cell activity, and can consider sequencing peripheral 
blood mononuclear cells for FcγRIIa and FcγRIIIa polymorphisms. There have 
been conflicting studies regarding the prognostic utility of FcγRIIa or FcγRIIIa 
polymorphisms and anti-EGFR Mab efficacy,25,53-59 though the largest study to 
date showed no significant association in KRAS wild-type subjects with mCRC.60 
Since these factors may affect immune activation, sequencing for polymorphisms 
in FCGR2A and FCGR3A may be informative. Additionally, isolation of T cells 
and NK cells from subject-derived PBMCs to perform ex vivo ADCC assays and 
interferon γ release assays would provide important data on the activation of 
adaptive and innate immune cells. 
 
Additionally, we will include optional serial tumor biopsies to identify potential 
biomarkers for immune checkpoint inhibitors and anti-EGFR antibodies. These 
could include integrated genomic analysis with multiplex next generation DNA 
and RNA sequencing for baseline mutation analysis, and gene expression 
analyses. This approach can also facilitate sequencing of low-diversity B cell and 
T cell receptors, both at baseline and serially in subjects who opt to undergo serial 
biopsies, which may aid in discovery of future potential targets for intervention. 
 
Finally, we will collect stool specimens to identify gut microbial composition at 
baseline and at first restaging. Several studies have shown significant associations 
between gut microbial dysbiosis and lack of efficacy of immune checkpoint 
inhibitors, and we will perform exploratory studies to determine the association 
between baseline gut microbiome and efficacy of therapy. 
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To evaluate the clinical efficacy of panitumumab/nivolumab/ipilimumab or 
panitumumab/nivolumab therapy in subjects with unresectable refractory 
KRAS/NRAS/BRAF wild-type MSS mCRC, by determining overall response rate 
(ORR) at 12 weeks by RECIST 1.1 criteria. 


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PI: Autumn McRee, MD 
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UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
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2.2 
Secondary Objectives 
 
2.2.1 
To determine the best overall response associated with 
panitumumab/nivolumab/ipilimumab or panitumumab/nivolumab therapy in 
subjects with unresectable refractory KRAS/NRAS/BRAF wild-type MSS 
metastatic colorectal adenocarcinoma based on both RECIST1.1 and irRECIST 
criteria. 
 
2.2.2 
To determine the overall response rate (ORR) associated with 
panitumumab/nivolumab/ipilimumab or panitumumab/nivolumab therapy in 
subjects with unresectable refractory KRAS/NRAS/BRAF wild-type MSS 
metastatic colorectal adenocarcinoma at 12 weeks by irRECIST criteria. 
 
2.2.3 
To determine PFS associated with panitumumab/nivolumab/ipilimumab or 
panitumumab/nivolumab therapy in subjects with unresectable refractory 
KRAS/NRAS/BRAF wild-type MSS metastatic colorectal adenocarcinoma based 
on both RECIST 1.1 and irRECIST criteria. 
 
2.2.4 
To determine OS of subjects with unresectable refractory KRAS/NRAS/BRAF 
wild-type MSS metastatic colorectal adenocarcinoma treated with 
panitumumab/nivolumab/ipilimumab or panitumumab/nivolumab therapy. 
 
2.2.5 
To determine the duration of response of subjects with unresectable refractory 
KRAS/NRAS/BRAF wild-type MSS metastatic colorectal adenocarcinoma treated 
with panitumumab/nivolumab/ipilimumab or panitumumab/nivolumab therapy 
based on both RECIST1.1 and irRECIST criteria 
 
2.2.6 
To evaluate the toxicity of panitumumab/nivolumab/ipilimumab in subjects with 
unresectable refractory KRAS/NRAS/BRAF wild-type MSS mCRC, by 
determining the number of treatment-emergent grade 3 and 4 toxicities as defined 
by National Cancer Institute - Common Terminology Criteria for Adverse Events 
(NCI CTCAE v4.03). 
 
2.3 
Exploratory Objectives 
 
2.3.1 
 
 


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PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.4 
Endpoints 
 
2.4.1 
Primary Endpoint 
ORR is defined as the percentage of subjects with unresectable refractory 
KRAS/NRAS/BRAF wild-type MSS mCRC who achieve a complete response or a 
partial response (CR+PR) by 12 weeks to panitumumab/nivolumab/ipilimumab or 
panitumumab/nivolumab therapy per RECIST 1.1 criteria. 
 
2.4.2 
Secondary Endpoints 
 
2.4.2.1 
The best overall responses for both RECIST 1.1 and irRECIST are defined as the 
best response achieved across all time points prior to progression (for example, a 
subject who has SD at first assessment, PR at second assessment, and PD on last 
assessment has a best overall response of PR). Please Note: In the case of SD, 
measurements must have met the SD criteria at least once after study entry at a 
minimum interval of 12 weeks from initiation of treatment. 
 
2.4.2.2 
The immune-related response rate is defined as the percentage of subjects with 
unresectable refractory KRAS/NRAS/BRAF wild-type MSS mCRC who achieve 
a CR+PR by 12 weeks to panitumumab/nivolumab/ipilimumab or 
panitumumab/nivolumab therapy per irRECIST criteria. (See section 6.7.5.1) 
 
2.4.2.3 
Assessment of immune-related PFS is defined as starting from the first day of 
treatment or Day 1 (D1) until the event of disease progression as defined by 
irRECIST, or death from any cause in subjects with unresectable refractory 
KRAS/NRAS/BRAF wild-type MSS mCRC (See section 6.7.5.1). Any subject 
that has not had a documented event at the time of analysis will be censored. 
Assessment of PFS (as defined by RECIST 1.1) is defined from D1 of treatment 
until the event of disease progression occurs or death from any cause in subjects 
with unresectable refractory KRAS/NRAS/BRAF wild-type MSS mCRC. Any 


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
9 
 
 
subject that has not had a documented event at the time of analysis will be 
censored. 
 
2.4.2.4 
OS is defined as the time from D1 of treatment until death from any cause. Any 
subject that has not died by the analysis date will be censored. 
 
2.4.2.5 
The duration of response as defined by RECIST 1.1 will be defined as the time 
elapsed from first scan documenting partial response or complete response until 
the event of disease progression occurs. Any subject that has not had a 
documented progression at the time of analysis will be censored. The duration 
of response as defined by irRECIST will be defined as the time elapsed from 
first scan documenting partial response or complete response until the event of 
disease progression occurs. Any subject that has not had a documented 
progression at the time of analysis will be censored. 
 
2.4.2.6 
Treatment-related adverse events will be assessed per NCI-CTCAE v4.03. 
 
3.0 
SUBJECT ELIGIBILITY 
3.1 
Inclusion Criteria 
Subjects must meet all of the inclusion criteria as listed below to participate in this 
study. 
3.1.1 
Histologically or cytologically confirmed colorectal adenocarcinoma, with 
unresectable metastatic or locally advanced disease documented on diagnostic 
imaging studies. 
 
3.1.2 
Previously received 1-2 prior lines of therapy. Subjects who relapse within 6 
months of adjuvant chemotherapy comprised of oxaliplatin and a 
fluoropyrimidine will have their adjuvant therapy count as one prior line of 
therapy. 
 
3.1.3 
Confirmed wild-type in KRAS and NRAS codons 12, 13, 59, 61, 117, and 146; 
and BRAF codon 600, by standard of care testing of tumor specimen. Tissue used 
for testing may have been collected from primary or metastatic site. 
 
3.1.4 
Microsatellite stable as detected by PCR-based assay OR CLIA-certified 
sequencing methodology such as Foundation One; OR mismatch repair 
proficient as detected by immunohistochemistry showing intact nuclear staining 
of MLH1, MSH2, MSH6, and PMS2. 
 
3.1.5 
Radiographically measurable disease present per RECIST 1.1 


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PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
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3.1.6 
Age ≥ 18 years at the time of consent. 
 
3.1.7 
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 
 
3.1.8 
Blood counts performed within 3 weeks prior to starting study therapy must have 
absolute neutrophil count ≥ 1,500/mm3, platelets ≥ 100,000/mm3, and hemoglobin 
≥ 9 g/dL. 
 
*Note: Hematology and other lab parameters that are ≤ grade 2 BUT still meet 
criteria for study entry are allowed. Furthermore, changes in laboratory 
parameters during the study should not be considered adverse events unless they 
meet criteria for dose modification(s) of study medication outlined by the protocol 
and/or worsen from baseline during therapy. 
3.1.9 
Liver function tests performed within 3 weeks prior to starting study therapy must 
have total bilirubin ≤ 1.5 x upper limit of normal (ULN), alanine aminotransferase 
and aspartate aminotransferase ≤ 3 x ULN, and albumin ≥ 2.5 g/dL. 
 
3.1.10 Serum creatinine performed within 3 weeks prior to starting study therapy must 
be ≤ 1.5 x ULN, or have calculated creatinine clearance (using Cockcroft-Gault 
formula provided in Appendix 11.3) of ≥ 50 mL/minute. 
 
3.1.11 Females of childbearing potential must have a negative serum pregnancy test 
within 24 hours prior to receiving the first dose of study medication. Females of 
childbearing potential must agree to use 2 methods of effective contraception or 
abstain from heterosexual sex throughout the treatment period and for 5 months 
after the last dose of study treatment. Females of childbearing potential are 
women who have not been surgically sterilized (have undergone a hysterectomy, 
bilateral tubal ligation, or bilateral oophorectomy) or have not been free of 
menses for >1 year. 
 
3.1.12 Male subjects with female partners must have had a prior vasectomy or agree to 
use an adequate method of contraception (i.e., double barrier method: condom 
plus spermicidal agent) starting with the first dose of study therapy through 6  
months after the last dose of study treatment. 
 
3.1.13 Written informed consent and HIPAA authorization for release of personal health 
information. NOTE: HIPAA authorization may be included in the informed 
consent or obtained separately. 
 
3.1.14 An adequate amount of archival tumor tissue must be available at baseline to be 
eligible for enrollment in the study. If archival tissue is not available or is 
inadequate, then the subject must consent to undergo a mandatory biopsy at 
baseline in order to participate in the study. 


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
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3.2 
Exclusion Criteria 
 
3.2.1 
Past treatment with an antibody targeting EGFR including cetuximab or 
panitumumab. 
 
3.2.2 
Past treatment with an antibody targeting immune checkpoints including CTLA-4, 
PD-1, PD-L1, PD-L2, or CD137. 
 
3.2.3 
Known untreated brain metastasis or brain metastasis treated within 3 months 
prior to enrollment in this trial. 
 
3.2.4 
Has evidence of interstitial lung disease or active, non-infectious pneumonitis. 
 
3.2.5 
Has a known additional malignancy that is active and/or progressive requiring 
treatment; exceptions include basal cell or squamous cell skin cancer, in situ 
cervical or bladder cancer, or other cancer for which the subject has been disease- 
free for at least five years. 
 
3.2.6 
Treatment within 21 days of the first dose of study drug with any other 
chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or 
investigational treatment for the treatment of malignancy, or failure to recover 
from adverse effects of prior therapies administered over 4 weeks prior to Study 
Day 1. All toxicities from prior therapies must be ≤ Grade 1 (or ≤ Grade 2 for 
alopecia or peripheral neuropathy). Prior systemic treatment in the adjuvant 
setting is allowed. See note above under inclusion 3.1.8 
 
3.2.7 
Any serious and/or unstable pre-existing medical disorder (aside from malignancy 
exception above), psychiatric disorder, or other conditions that could interfere 
with subject’s safety, obtaining informed consent, or compliance to the study 
procedures. 
 
3.2.8 
Pregnant or planning to become pregnant within 6 months after the end of 
treatment. (NOTE: breast feeding and storage of breast milk is not allowed 
while mother is being treated, and for up to 5 months after stopping nivolumab, 
2 months after stopping panitumumab and/or ipilumumab.   
 
3.2.9 
History of organ allograft or other history of immunodeficiency, or is receiving 
systemic steroid therapy or any other form of immunosuppressive therapy within 
7 days before the first dose of investigational treatment. 
 
3.2.10 Inability or unwillingness to comply with study and/or follow-up requirements. 
 
3.2.11 Any major surgery, extensive radiotherapy, chemotherapy with clinically 
significant delayed toxicity, biologic therapy, or immunotherapy within 21 days 


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
12 
 
 
prior to randomization and/or daily or weekly chemotherapy without the potential 
for delayed toxicity within 14 days prior to randomization. 
 
3.2.12 Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to study drug. 
 
3.2.13 Known Human Immunodeficiency Virus (HIV), Hepatitis B virus (HBV), or 
Hepatitis C virus (HCV) infection. Subjects with laboratory evidence of cleared 
HBV and HCV infection will be permitted. 
 
3.2.14 Active autoimmune disease requiring systemic treatment in the past 3 months (for 
example with disease modifying agents, corticosteroids, or immunosuppressive 
drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment. Subjects with vitiligo or resolved childhood 
asthma/atopy would be an exception to this rule. Subjects that require intermittent 
use of bronchodilators, local steroid injections, or inhaled or topical steroids 
would not be excluded from the study. Subjects with hypothyroidism stable on 
hormone replacement or Sjogren's syndrome will not be excluded from the study. 
 
3.2.15 Active infection requiring intravenous systemic therapy. 
 
 
4.0 
TREATMENT PLAN 
4.1 
Schema 
 


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
13 
 
 
4.1.1 Rationale for Doses Selected 
We plan to perform a single-arm, open-label, multicenter Phase II clinical trial of 
nivolumab 240 mg IV q2wk), ipilimumab (1 mg/kg IV q6wk), and panitumumab 
(6 mg/kg IV q2wk), after a safety lead-in cohort of a total of 6 subjects has 
completed 12 weeks of combination therapy at the proposed starting doses. The 
starting doses and schedule were carefully selected after consideration of existing 
clinical studies and preclinical data. The efficacy of ipilimumab monotherapy is 
dose-dependent, but the rate and severity of immune-related adverse events is also 
dose-dependent 61. The FDA-approved dose of combination ipilimumab and 
nivolumab in management of metastatic melanoma is ipilimumab 3 mg/kg IV 
q3wk for four doses combined with nivolumab 1 mg/kg IV q3wk; followed by 
nivolumab monotherapy 240 mg flat dose IV q2wk. Notably, studies of 
combination ipilimumab and nivolumab have started both antibodies 
concurrently, with the rationale that preclinical models showed that the 
combination is synergistic only when administered concurrently rather than 
sequentially62, and so we plan to administer the investigational drugs concurrently 
as well. Subsequent clinical trials have investigated combinations of ipilimumab 
and nivolumab that would attenuate the frequency and severity of immune-related 
adverse events without mitigating efficacy. The efficacy and toxicity profiles of 
more infrequent dosing of ipilimumab combined with nivolumab were studied in 
a phase I study in subjects with chemotherapy-naïve recurrent stage IIIB or IV 
NSCLC, CheckMate 012. In this study, treatment with ipilimumab 1 mg/kg q6wk 
combined with nivolumab 3 mg/kg q2wk was much better tolerated than 
treatment with ipilimumab 1 mg/kg q3wk combined with nivolumab 3 mg/kg 
q3wk. Additional dosing combination regimens tested revealed inferior efficacy 
when nivolumab dosing was decreased to 1 mg/kg. Treatment with ipilimumab 1 
mg/kg q6wk combined with nivolumab 3 mg/kg q2wk resulted in a 33% rate of 
grade 3-4 treatment-related AEs, but only 13% rate of treatment-related AEs 
leading to study drug discontinuation63 (compared to 19% grade 3-4 treatment- 
related AEs and 10% treatment-related AEs leading to discontinuation in 
nivolumab 3 mg/kg IV q2wk arm).29 The FDA has determined that based on 
population pharmacokinetics models, there is a negligible difference in overall 
exposure between nivolumab 240 mg IV q2wk and 3 mg/kg IV q2wk. 
Consequently, we plan the ipilimumab and nivolumab dosing within safety cohort 
1 to be ipilimumab 1 mg/kg IV q6wk plus nivolumab 240 mg IV q2wk. The dose 
of panitumumab selected within dose level 1 is the FDA-approved monotherapy 
dose. 
 
If DLTs occur in no more than one subject in the first 6 subjects treated during the 
12 week assessment period in the first safety cohort, then the trial would continue 
enrolling subjects to the remainder of the first stage of the  phase II portion to 
complete enrollment to 32 subjects to assess efficacy of panitumumab, ipilimumab 
and nivolumab (3-drug combination). This would then be followed by interim 
analysis to determine whether the second stage would merit enrollment. If the 3-
drug combination is not well tolerated, then 6 additional subjects will be enrolled 
into safety cohort 2 and receive panitumumab and nivolumab (2-drug 
combination).  If no more than one subject experiences a DLT in safety cohort 2, 
then the trial will continue enrolling subjects into the phase II portion and the 2-


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
14 
 
 
drug combination of panitumumab and nivolumab will be evaluated for efficacy. 
Subjects may continue combination treatment as long as they are benefitting from 
therapy until disease progression, unacceptable toxicity or withdrawal for other 
reasons as deemed necessary by the investigator. 
 
DLT definitions applicable to the safety assessment run-in are defined in section 
4.2. Subjects will undergo disease evaluation every 6 weeks for the first year, and 
will continue on this disease assessment schedule if they are at least stable but 
have less than a CR. If subjects continue on study after one year with a CR, then 
disease evaluations may occur every 12 weeks from that point forward. 
 
4.2 
Dose Limiting Toxicities for Safety Lead-in 
The safety lead-in DLT assessment period is defined as the first 12 weeks (84 
days) of ipilimumab/nivolumab/panitumumab therapy. An event will be 
considered a DLT if it occurs within the first 84 days of combination therapy and 
meets one of the following criteria. 
 
 
Grade 4 neutropenia lasting ≥ 5 days 
 
Febrile neutropenia 
 
Grade 4 thrombocytopenia 
 
Grade 4 anemia 
 
Grade 2 drug-related uveitis that does not respond to topical therapy and 
does not improve to Grade 1 severity within 6 weeks OR requires systemic 
treatment 
 
Grade 3 drug-related uveitis 
 
Grade 3-4 pneumonitis 
 
Grade 3-4 bronchospasm 
 
Grade 3-4 diarrhea 
 
Grade 3-4 colitis 
 
Grade 3-4 neurologic adverse event 
 
Grade 3-4 adrenal insufficiency 
 
Grade 3-4 hypersensitivity reaction 
 
Grade 3-4 infusion reaction of any duration 
 
Grade 3 non-skin, drug-related non-hematologic toxicity per NCI-CTCAE 
criteria 4.03 lasting over 7 days 
 
Grade 4 non-hematologic toxicity per NCI-CTCAE criteria 4.03 
(excluding alopecia, isolated electrolyte disturbances that responds to 
correction within 72 hours of onset, isolated amylase or lipase 
abnormalities that are not associated with symptoms or clinical signs of 
pancreatitis and decrease to < Grade 4 within 1 week of onset) 


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
15 
 
 
4.3 
Treatment Dosage and Administration 
Dosing should be based on the subject’s baseline weight on day 1 of cycle 1, as 
measured according to institutional standards; doses will be adjusted for subjects 
who experience a ≥10% change in weight during the study. 
 
4.3.1 
Safety Cohort 1 Schedule (3-drug combination) 
 
REGIMEN DESCRIPTION –Safety Cohort 1 ) 
Agent 
Premedications; 
Precautions 
Dose/Frequency 
Route 
Schedule 
Cycle 
Length 
Panitumumab 
See Section 4.5 
and 4.5.1 
6mg/kg 
every 2 weeks 
IV (specific 
details 
below) 
 
D1, D15, 
D29 of 
each cycle 
For doses ≤ 1000 mg IV over 60 
(± 15) 
minutes 
For doses >1000 mg, IV over 90 
(± 15) 
minutes  
Ipilimumab 
See Section 4.5.3 
1 mg/kg 
every 6 weeks 
IV over 30 (± 
15) minutes 
D1 of 
each cycle 
Nivolumab 
See sections 4.5.2 
and 4.5.3 
240 mg 
every 2 weeks 
IV over 30 (± 
15) minutes 
D1, D15, 
D29 of 
each cycle 
 
4.3.2 
Safety Cohort-2 Schedule (2-drug combination) 
 
REGIMEN DESCRIPTION – Safety Cohort 2 
Agent 
Premedications; 
Precautions 
Dose/Frequency 
Route 
Schedule 
Cycle 
Length 
Panitumumab 
See Section 4.5 
and 4.5.1 
6mg/kg 
every 2 weeks 
IV(specific 
details 
below) 
 
D1, D15, 
D29 of 
each cycle 
For doses ≤1000 mg, IV over 60 
(±15) 
minutes  
For doses >1000 mg, IV over 90 
(± 15) 
minutes 
Nivolumab 
See section 4.5.2 240 mg 
every 2 weeks 
IV over 30 (± 
15) minutes 
D1, D15, 
D29 of 
each cycle 
 
If the 3-drug combination is not tolerated in Cohort 1, then ipilimumab will be omitted 
and panitumumab in combination with nivolumab will be evaluated for safety. If no 
more than 1 subject out of 6 experiences DLTs after 12 weeks on therapy, then 
additional subjects will be enrolled to evaluate the safety and efficacy of panitumumab 
and nivolumab (2-drug combination). If neither the 3-drug or 2-drug combination is 
well-tolerated, the dosing approach for these agents will be reconsidered. 


LCCC 1632 
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UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
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4.4 
Toxicities and Dosing Delays/Dose Modifications 
 
4.4.1 
Panitumumab Dosing Delays/Dose Modifications 
 
Toxicity grades per NCI-CTCAE Criteria v 4.03 
Adverse Reaction 
Severity 
Dose Modification 
Infusion-related reactions 
Grade 1 or 2 
Reduce infusion rate by 50% 
Grade 3 or 4 
 Terminate the infusion 
 Depending on the severity and /or 
persistence of the reaction, permanently 
discontinue panitumumab 
Dermatologic reaction 
Grade 3 – 1st occurrence 
Withhold 1 or 2 doses of Panitumumab, if 
reaction improves to < grade 3, reinitiate at 
original dose 
Grade 3 – 2nd occurrence 
Withhold 1 or 2 doses of Panitumumab, if 
reaction improves to < grade 3, reinitiate at 
80% of the original dose 
Grade 3 – 3rd occurrence 
Withhold 2 doses of panitumumab, if 
reaction improves to < grade 3, reinitiate at 
80% of the original dose 
Grade 3 - 4th occurrence 
Permanently discontinue panitumumab 
Grade 3 reaction that not 
recover after withholding 
1 or 2 doses  OR 
Grade 4 
Permanently discontinue panitumumab 
Pulmonary Fibrosis/ILD 
Acute onset of 
pulmonary symptoms 
Interrupt panitumumab until resolution 
ILD confirmed 
Permanently discontinue panitumumab 
Ocular toxicities 
Acute or ulcerative 
keratitis 
Interrupt panitumumab or permanently 
discontinue panitumumab for acute or 
worsening keratitis 
Warnings 
Electrolyte 
depletion/Monitoring 
Monitor subjects for hypomagnesemia and hypocalcemia prior to 
initiating panitumumab and periodically during panitumumab 
treatment, and for up to 8 weeks after the completion of therapy. 
Replete magnesium with oral or IV supplements as indicated. 


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UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
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4.4.2 
Nivolumab +/- Ipilimumab Dosing Delays/Dose Modifications 
 
Toxicity grades per NCI-CTCAE Criteria v 4.03 
Adverse Reaction 
Severity 
Dose Modification 
Adrenal Insufficiencyf 
Grade 2 adrenal insufficiency 
Withhold dosea 
Grade 3-4 adrenal insufficiency 
Permanently discontinuee 
Myocarditis 
Grade 3-4 myocarditis 
Permanently discontinue 
Infusion Related Reaction 
Grade 1-2 infusion related reaction 
See section 4.5.2 for guidance 
Grade 3-4 infusion related reaction or 
anaphylaxis 
Permanently discontinue 
Uveitis, eye pain, blurred 
vision 
Grade 2 that does not respond to topical 
therapy and does not improve to grade 1 
severity within re-treatment period OR 
requires systemic treatment 
Permanently discontinue 
Grade 3-4 uveitis or eye pain or blurred 
vision 
Permanently discontinue 
Colitisf 
Grade 2 diarrhea or colitis 
Withhold dosea 
Grade 3 diarrhea or colitis 
Withhold dosea 
Grade 4 diarrhea or colitis 
Permanently discontinue 
Pneumonitisf 
Grade 2 pneumonitis 
Withhold dosea 
Grade 3 or 4 pneumonitis 
Permanently discontinue 
Hypophysitisf 
Grade 2hypophysitis 
Withhold dosea 
Grade 3-4 hypophysitis 
Permanently discontinuee 
Type 1 Diabetes Mellitusf 
Grade 3 hyperglycemia 
Withhold dosea 
Grade 4 hyperglycemia 
Permanently discontinuee 
Nephritis and Renal 
Dysfunctionf 
Serum creatinine more than 1.5 and 
up to 6X ULN 
Withhold dosea 
Serum creatinine more than 6X ULN 
Permanently discontinue 
Rashf 
Grade 3 rash 
Withhold dosea 
Grade 4 rash 
Permanently discontinue 
Encephalitisf 
New-onset moderate or severe 
neurologic signs or symptoms 
Withhold dosea 
Immune-mediated encephalitis 
Permanently discontinue 
Hepatitis 
See section  4.4.2.1 for guidance 
Otherf 
 Other Grade 3 adverse reaction b  
First occurrence 
Recurrence of same Grade 3 adverse 
reaction 
Withhold dosea 
Permanently discontinue 
Life-threatening or Grade 4 adverse 
reactiond 
Permanently discontinue 
Requirement for 10 mg per day or 
greater prednisone or equivalent for 
more than 12 weeks 
Permanently discontinue 
Persistent Grade 2 or 3 adverse reactions 
lasting 12 weeks or longerc 
Permanently discontinue 
a) Resume treatment when adverse reaction returns to Grade 0 or 1. If toxicity persists > 6 weeks, 
permanently discontinue nivolumab +/- ipilimumab. May discuss with Medical Monitor. 
 
b) Except for grade 3 lymphopenia, leukopenia, isolated laboratory abnormalities without clinical 
significance, or amylase or lipase abnormality that is not associated with symptoms or clinical 


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UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
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manifestations of pancreatitis.  
 
c) Except for grade 2 fatigue, some subjects with baseline grade 1 LFT abnormalities who have grade 2 
elevation of AST/ALT/bilirubin as described in 4.4.2.3, or subjects with grade 2-3 endocrine toxicities 
not described elsewhere in the table that are adequately treated with physiologic hormone replacement 
(e.g. hypothyroidism) 
 
d) Except for grade 4 lymphopenia, leukopenia, isolated electrolyte abnormalities without clinical 
significance that are corrected with supplementation/appropriate management within 72 hours of onset, or 
amylase or lipase abnormality that is not associated with symptoms or clinical manifestations of 
pancreatitis and decreases to <grade 4 within 1 week of onset.  
 
e) Selected subjects with transient episodes of grade 3-4 endocrine toxicities who are adequately treated and 
stabilized on physiologic hormone replacement or other supportive medications with improvement to 
grade 1-2 may not require discontinuation after discussion with and approval from the Medical Monitor. 
 
f) For additional management, including monitoring and use of corticosteroids or additional 
immunosuppressant therapies, recommend using guidelines for management of immunotherapy related 
toxicities, primarily the NCCN Management of Immunotherapy-Related Toxicities Version 1.2020. 
Section 11.2 has algorithms for possible management of selected toxicities, but management does not 
have to follow direction of Section 11.2.


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
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4.4.2.1 
Nivolumab and/or Ipilimumab Dose Modifications/Delays for Liver Toxicity 
Recognizing that mCRC is often associated with the presence of liver 
metastases at baseline, the following criteria will be used for dose 
modifications/delays of nivolumab and/or ipilimumab for liver toxicity. 
 
Baseline Liver Function Test 
(NCI-CTCAEv4.03 grade) 
Adverse Reaction Severity 
Dose Modification * 
AST or ALT normal 
AST or ALT ≥ 3 X ULN to ≤ 5 
X ULN 
Withhold dosea 
AST or ALT > 5 X ULN 
Permanently discontinue 
AST or ALT 1.1 to ≤ 2.5 X ULN 
(Grade 1) 
AST or ALT ≥ 5 X ULN to ≤ 8 X 
ULN 
Withhold dosea 
AST or ALT > 8 X ULN 
Permanently discontinue 
Total Bilirubin normal 
> 1.5 to ≤ 3 X ULN 
Withhold dosea 
> 3 X ULN 
Permanently discontinue 
Total Bilirubin 1.1 to ≤ 1.5 X ULN 
(Grade 1) 
≥ 3 to 5 X ULN 
Withhold dosea 
> 5 X ULN 
Permanently discontinue 
a) Resume treatment when adverse reaction returns to Grade 0 or 1. If toxicity persists > 6 
weeks, permanently discontinue nivolumab +/- ipilimumab 
* 
For additional management, including monitoring and use of corticosteroids or additional 
immunosuppressant therapies, recommend using guidelines for management of 
immunotherapy related toxicities, primarily the NCCN Management of Immunotherapy-
Related Toxicities Version 1.2020. Section 11.2 has algorithms for possible management 
of selected toxicities, but management does not have to follow direction of Section 11.2. 
 
 
4.4.2.2 
Dose Delay Criteria for Nivolumab +/- Ipilimumab 
Because of the potential for clinically meaningful nivolumab-related AEs requiring 
early recognition and prompt intervention, management algorithms have been 
developed for suspected AEs of selected categories [see current Investigator 
Brochure and Appendix 11.2].  Hepatotoxicity guidelines are provided in the section 
above. 
 
Dose delay criteria apply for all drug-related adverse events related to nivolumab 
and/or ipilimumab (regardless of whether or not the event is attributed to nivolumab, 
ipilimumab, or both). If both nivolumab and ipilimumab are being administered, both 
must be delayed until treatment can resume. 
 
Nivolumab +/- ipilimumab administration should be delayed per the criteria in 4.4.2 
and 4.4.2.1.  
 
 
Additionally, nivolumab +/- ipilimumab should be held in the event of any AE, 
laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication. 


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UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
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Subjects who require delay of nivolumab +/- ipilimumab should be re-evaluated 
weekly or more frequently if clinically indicated and resume nivolumab +/- 
ipilimumab dosing when re-treatment criteria are met. 
 
4.4.2.3 
Criteria to Resume Nivolumab +/- Ipilimumab Treatment 
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to 
Grade ≤1 or baseline value, with the following exceptions: 
• 
Subjects may resume treatment in the presence of Grade 2 fatigue 
• 
Subjects who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity 
• 
Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose 
delays for reasons other than a 2-grade shift in AST/ALT or total bilirubin may 
resume treatment in the presence of Grade 2 AST/ALT OR total bilirubin 
• 
Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to 
baseline before treatment is resumed. Subjects with persistent Grade 1 
pneumonitis after completion of a steroid taper over at least 1 month may be 
eligible for retreatment if investigator allows. 
• 
Subjects with drug-related endocrinopathies adequately controlled with only 
physiologic hormone replacement may resume treatment if the investigator allows 
it, but this should be documented clearly in the electronic case report form 
(eCRF). 
 
4.4.2.3.1 
Guidance on Cycle Counting after Treatment Delay 
If the criteria to resume treatment are met, and treatment was delayed for up to one week (≤ 7 
days), make up the missed treatment visit. If treatment was delayed for 8-42 days, skip the 
missed treatment(s) and resume treatment at the next relevant cycle/day treatment visit, unless 
the subject is ≥ 42 days from the last dose of ipilimumab, in which case resume treatment at day 
1 of the next treatment cycle. 
 
If treatment is delayed or interrupted for > 6 weeks due to toxicity, adverse effect, or medical 
comorbidity, the subject must be permanently discontinued from study therapy, except as 
specified in the discontinuation section 4.4.2.5. 
 
4.4.2.4 
Management Algorithms for Immune-related Events for Nivolumab +/- 
Ipilimumab 
Guidelines for the management of immune-related events can be found in the current 
Nivolumab Investigator Brochure AND in the approved USPI in the US. 
 
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and 
duration than AEs caused by other therapeutic classes. Nivolumab is considered an 
I-O agent in this protocol. Early recognition and management of AEs associated with 
immuno-oncology agents may mitigate severe toxicity. Management algorithms have 
been developed to assist investigators in assessing and managing the following groups of 
AEs: 
 
For mandatory guidance on dosing of nivolumab and/or ipilimumab with 
specified immune related adverse events, please refer to section 4.4.2 and 


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PI: Autumn McRee, MD 
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UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
21 
 
 
section 4.4.2.1. For additional management, including monitoring and use of 
corticosteroids or additional immunosuppressant therapies, recommend using 
guidelines for management of immunotherapy related toxicities, primarily the 
NCCN Management of Immunotherapy-Related Toxicities Version 1.2020. 
Section 11.2 has algorithms for possible further management of selected 
toxicities, but management does not have to follow direction of Section 11.2. 
Instead, these algorithms are only an additional resource to complement other 
guidelines and the Investigator’s medical judgment. 
 
4.4.2.5 
Discontinuation Criteria for Nivolumab and/or ipilimumab 
Treatment with nivolumab and ipilimumab should be permanently discontinued 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 
• 
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the 
following exceptions for drug-related laboratory abnormalities, uveitis, 
pneumonitis, bronchospasm, hypersensitivity reactions, and infusion reactions, 
and endocrinopathies: 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity 
reaction, or infusion reaction of any duration requires discontinuation 
o Grade 3 drug-related endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation 
o Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except those noted below 
• 
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding 
requires discontinuation 
• 
Any drug-related liver function test (LFT) abnormality that meets the following 
criteria requires discontinuation: 
o If baseline AST or ALT is within normal limits, AST or ALT > 5 x ULN 
o If baseline AST or ALT is Grade 1, AST or ALT > 8 x ULN 


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PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
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o If baseline total bilirubin is within normal limits, total bilirubin > 3x ULN 
o If baseline total bilirubin is Grade 1, total bilirubin > 5 x ULN 
 
• 
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
following events which do not require discontinuation: 
o Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4 
within 1 week of onset. 
o 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 
o Grade 4 lymphopenia or leucopenia 
o Grade 4 drug-related endocrinopathy adverse events, such as adrenal 
insufficiency, ACTH deficiency, hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose- 
controlling agents, respectively, may not require discontinuation after 
discussion with and approval from the Investigator 
• 
Any dosing interruption lasting > 6 weeks with the following exceptions: 
o Dosing delays or interruptions to allow for prolonged steroid tapers to manage 
drug-related adverse events are allowed. Prior to re-initiating treatment in a 
subject with a dosing interruption lasting > 6 weeks, the Investigator must be 
consulted. Tumor assessments should continue as per protocol even if dosing 
is interrupted or delayed 
o Dosing interruptions or delays lasting > 6 weeks that occur for non-drug- 
related reasons may be allowed if approved by the Investigator. Prior to re- 
initiating treatment in a subject with a dosing interruption lasting > 6 weeks, 
the Investigator must be consulted. Tumor assessments should continue as per 
protocol even if dosing is interrupted 
• 
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 and ipilimumab dosing 
 
Additionally, after any immune related adverse event that does not meet the mandatory 
discontinuation requirement, the treating investigator should carefully consider the safety of 
resuming nivolumab and/or ipilimumab.  In select cases, like for colitis, it would be appropriate to 
discontinue ipilimumab but continue nivolumab. This should be discussed with the medical monitor, 
and decisions should use guidelines for rechallenge after immune-related adverse events, such as 
found in the NCCN Management of Immunotherapy-Related Toxicities Version 1.2020.


LCCC 1632 
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CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
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4.5 
Concomitant Medications/Treatments 
Subjects on the trial are allowed to receive all supportive care therapy needed to 
alleviate symptoms related to CRC or other medical problems at the investigator’s 
discretion. No treatments should be withheld due to a subject’s participation in 
this study. Prophylaxis for infusion-related reactions should be employed per 
institutional guidelines. 
 
Infusion-related reactions (including anaphylaxis) may occur during the infusion 
of nivolumab. Infusion-related reactions are also associated with panitumumab 
treatment, but no prophylaxis measures are suggested. The infusion of nivolumab 
(and panitumumab) should be administered at a site properly equipped and staffed 
to manage anaphylaxis should it occur. Monitor subjects during infusion. If 
anaphylaxis occurs immediately and permanently discontinue administration of 
the study medication and administer appropriate medical therapy per institutional 
standards. If a mild or moderate infusion-related reaction occurs, the infusion 
should be interrupted, or the rate of infusion slowed, and appropriate medical 
management instituted. Subjects who experienced a prior infusion-related reaction 
to nivolumab should be pre-medicated for subsequent infusions per institutional 
standards. Premedication may include acetaminophen, an antihistamine and a 
corticosteroid. 
 
Brief (up to 7 days) and episodic use of systemic corticosteroids for other general 
conditions (e.g. pre-medication for radiographic imaging due to IV contrast 
allergy, COPD exacerbation, poison ivy, etc.) is allowed. 
 
4.5.1 
Prophylaxis for acneiform skin rash related to panitumumab therapy 
Subjects receiving panitumumab should receive prophylactic management for 
EGFR-I associated skin toxicity in accordance with the strategies employed in the 
STEPP and J-STEPP randomized clinical trials. Subjects should be educated 
thoroughly on avoiding sun exposure as able. If sun avoidance is not possible, 
subjects should be advised to wear a hat with brim and to cover extremities with 
non-restrictive UV protectant clothing. 
 
All subjects should be prescribed prophylactic oral tetracycline antibiotic 
(Doxycycline 100mg PO BID or Minocycline 100mg PO Daily). 
 
Additionally, the following measures are suggested for rash 
prophylaxis/management: 
 
1. 
Skin moisturizer applied to face, hands, feet, neck, back and chest both in the 
morning on rising and evening (bedtime) 
2. 
Sunscreen (PABA Free, UVA and UVB protectant, SPF 25 or higher) 
applied to potentially sun-exposed areas before going outdoors. 
3. 
Topical steroids (0.5% Hydrocortisone Cream) applied to face, hands, feet, 
neck, back and chest both in the morning on rising and evening (bedtime) 


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
24 
 
 
Prophylactic management with the above regimen was continued for 8 weeks in 
the STEPP and J-STEPP studies (or until the development to intolerance to a 
component of the prophylactic regimen). Treatment with the above regimen can 
be continued for the duration of panitumumab-containing therapy at the discretion 
of the treating physician. 
 
While skin toxicity management is employed pre-emptively per the J-STEPP 
regimen described above, emergent skin toxicity may still occur. Additional 
measures for the alleviation of emergent skin toxicity grade 2 or higher will be at 
the discretion of the treating physician. Treatment strategies/agents selected may 
include higher-potency topical steroids, oral steroids, and additional topical or 
systemic antibiotics. Grade 3 rash is considered to be at the panitumumab 
treatment threshold, and panitumumab dose reduction or delay are implemented 
also at the discretion of the treating physician. Dermatology consultation is 
recommended for subjects being considered for dose reduction or cessation due to 
skin toxicity. Referral to dermatologist should also be recommended for grade 3 
or 4 toxicity, skin toxicity that is difficult to manage employing the measures 
above or does not improve within 1-2 weeks, and any skin toxicity that is severely 
symptomatic or has an uncharacteristic appearance or distribution. 
 
4.5.2 
Treatment of Therapy-Related Infusion Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, it is 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. 
Panitumumab caused grade 3-4 infusion reactions in <0.5% of subjects44. 
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 CTCAEv4.03 
guidelines. 
 
Treatment recommendations are provided below and may be modified based on 
local treatment standards and guidelines as appropriate: 
 
For Grade 1 symptoms during panitumumab infusion: (Mild reaction; 
infusion interruption not indicated; intervention not indicated). Remain at bedside 
and monitor subject until recovery from symptoms. The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and 325 to 1000 mg acetaminophen at least 30 minutes before 
additional therapeutic antibody administrations. Decrease the infusion rate of 
panitumumab to 50% of the original infusion rate. 
 
For Grade 1 symptoms during nivolumab infusion: (Mild reaction; infusion 
interruption not indicated; intervention not indicated). Remain at bedside and 


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
25 
 
 
monitor subject until recovery from symptoms. The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and 325 to 1000 mg acetaminophen at least 30 minutes before 
additional nivolumab administrations. 
 
For Grade 2 symptoms during panitumumab infusion: (Moderate reaction 
requires therapy or infusion interruption but responds promptly to symptomatic 
treatment [eg, antihistamines, non-steroidal anti- inflammatory drugs, narcotics, 
corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated 
for 24 hours). 
 
Stop the panitumumab infusion, begin an IV infusion of normal saline, and treat 
the subject with diphenhydramine 50 mg IV (or equivalent) and 325 to 1000 mg 
acetaminophen; 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. Monitor subject closely. If 
symptoms recur, then no further panitumumab 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 electronic case report form (eCRF). The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and 325 to 1000 mg acetaminophen should be administered at 
least 30 minutes before additional NVB administrations. If necessary, 
corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or 
equivalent) may be used. 
 
For Grade 2 symptoms during nivolumab infusion: (Moderate reaction 
requires therapy or infusion interruption but responds promptly to symptomatic 
treatment [eg, antihistamines, non-steroidal anti- inflammatory drugs, narcotics, 
corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated 
for 24 hours). 
 
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the 
subject with diphenhydramine 50 mg IV (or equivalent) and 325 to 1000 mg 
acetaminophen; 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 electronic case report form (eCRF). 
The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and 325 to 1000 mg (acetaminophen) 


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
26 
 
 
should be administered at least 30 minutes before additional NVB 
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 of panitumumab or nivolumab: (Severe 
reaction, Grade 3: prolonged [ie, not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion]; recurrence of symptoms 
following initial improvement; hospitalization indicated for other clinical sequelae 
[eg, renal impairment, pulmonary infiltrates]). Grade 4: (life threatening; pressor 
or ventilatory support indicated). 
 
Immediately discontinue infusion of the therapeutic antibody. 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. The offending 
therapeutic antibody will be permanently discontinued. Investigators should 
follow their institutional guidelines for the treatment of anaphylaxis. Remain at 
bedside and monitor subject until recovery from symptoms. 
 
In the case of late-occurring hypersensitivity symptoms (eg, appearance of a 
localized or generalized pruritus within 1 week after treatment), symptomatic 
treatment may be given (eg, oral antihistamine, or corticosteroids). 
 
4.5.3 
Special warnings and precautions 
 Nivolumab and ipilimumab are associated with immune-related AEs. 
Subjects should be monitored continuously (at least up to 5 months after the 
last dose) as an AE with nivolumab/ipilimumab may occur at any time during 
or after discontinuation of therapy. 
 
 For suspected immune-related reactions, adequate evaluation should be 
performed to confirm etiology or exclude other causes. Based on the 
severity of the adverse reaction, nivolumab/ipilimumab should be withheld 
and corticosteroids administered. If immunosuppression with corticosteroids 
is used to treat an AE, a taper of at least 1-month duration should be 
initiated upon improvement. Rapid tapering may lead to worsening of the 
AE. Non-corticosteroid immunosuppressive therapy should be added if 
there is worsening or no improvement despite corticosteroid use. 
 
4.6 
Duration of Therapy 
Subjects should continue protocol therapy as described until: 
• 
Disease progression (Note: treatment should continue until progression is 
confirmed by repeat scan approximately 6 weeks later to rule out 
pseudoprogression based on investigator discretion) 
• 
Inter-current illness prevents further administration of treatment 
• 
Unacceptable adverse event(s) 


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UNIVERSITY OF NORTH CAROLINA 
October 01,, 
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• 
Subject decides to withdraw from the study, OR 
• 
General or specific changes in the subject’s condition render the subjects 
unacceptable for further treatment in the judgment of the investigator. 
 
4.7 
Duration of Follow Up 
Subjects will be followed for up to 3 years after removal from study treatment for 
determination of OS. Subjects removed from study treatment for unacceptable 
AEs will be followed for resolution or stabilization of the adverse event(s). All 
subjects (including those withdrawn for AEs) should be followed after removal 
from study treatment as stipulated in the protocol. 
 
4.8 
Removal of Subjects from Protocol Therapy 
Subjects will be removed from protocol therapy and the PI notified when any of 
the criteria listed in section 4.6 apply. The reason for discontinuation of protocol 
therapy will be documented on the eCRF. 
 
In case a subject decides to prematurely discontinue protocol therapy (“refuses 
treatment”), the subject should be asked if she or he may still be contacted for 
further scheduled study assessments. The outcome of that discussion should be 
documented in both the medical records and in the eCRF. 
 
Excessive subject withdrawals from protocol therapy or from the study can render 
the study un-interpretable; therefore, unnecessary withdrawal of subjects should 
be avoided. 
 
4.9 
Study Withdrawal 
If a subject decides to withdraw from the study (and not just from protocol 
therapy) an effort should be made to complete and report study assessments as 
thoroughly as possible. At the time of withdrawal, the investigator should attempt 
to establish as completely as possible the reason for the study withdrawal. 
 
The subject should be asked if they are willing to allow for the abstraction 
of relevant information from their medical record in order to meet the long 
term follow up (e.g., survival) objectives outlined in the protocol. 
 
A complete final evaluation at the time of the subject’s study withdrawal 
should be obtained with an explanation of why the subject is withdrawing 
from the study. 
 
If the subject is noncompliant and does not return for an end of study 
follow up assessment, this should be documented in the eCRF. 
 
If the reason for removal of a subject from the study is an adverse event, 
the principal specific event will be recorded on the eCRF. 


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
28 
 
 
Excessive subject withdrawals from protocol therapy or from the study can render 
the study un-interpretable; therefore, unnecessary withdrawal of subjects should 
be avoided. 
 
5.0 
DRUG INFORMATION 
5.1 
Panitumumab (Vectibix®) 
For additional information, refer to the Panitumumab Investigator’s Brochure (IB) 
and the prescribing information for Vectibix® (panitumumab) available at the 
link provided: http://pi.amgen.com/united_states/vectibix/vectibix_pi.pdf 
 
5.1.1 
Description, Packaging and Labeling 
Panitumumab is supplied as a sterile, colorless, preservative-free solution 
containing 20 mg/mL panitumumab in a single-use vial. Panitumumab is a sterile, 
colorless, pH 5.6 to 6.0 liquid for intravenous (IV) infusion, which may contain a 
small amount of visible translucent-to-white, amorphous, proteinaceous, 
panitumumab particulates. 
 
Panitumumab is provided in 12 units/kit and 6 units/kit. Each single-use 10 mL 
vial contains 200 mg of panitumumab, 58 mg sodium chloride, 68 mg sodium 
acetate, and Water for Injection, USP. Each single-use 20 mL vial contains 400 
mg of panitumumab, 117 mg sodium chloride, 136 mg sodium acetate, and Water 
for Injection, USP.  Panitumumab kit description is as follows: 
 
 (200mg) Panitumumab, 20 mg/ml, 10 ml vial, 12 units/kit 
 
 (400mg) Panitumumab, 20mg/ml,  20ml vial,  6 units/kit 
5.1.2 
Storage and Handling 
Store vials in the original carton under refrigeration at 20 to 80C (360 to 460F) until 
time of use. Protect from direct sunlight. DO NOT FREEZE. Since panitumumab 
does not contain preservatives, any unused portion remaining in the vial must be 
discarded. 
 
5.1.3 
Dose, Schedule and Administration 
See section 4.3 
 
5.1.4 
Preparation 
See the panitumumab prescribing information for preparation instructions. 
 
5.1.5 
Stability 
The diluted infusion of panitumumab should be used within 6 hours of 
preparation if stored at room temperature, or within 24 hours of dilution if stored 
at 20 to 80C (360 to 460F).  DO NOT FREEZE. 


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
29 
 
 
5.1.6 
Return and Retention of Panitumumab 
Unused vials will be handled per instructions from Amgen, Inc. Partially used 
and completely used vials will be destroyed per institutional guidelines. 
 
5.1.7 
Adverse Events Associated with Panitumumab 
The most common adverse events (≥20%) with panitumumab monotherapy are 
skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. 
The adverse events listed below have been reported in subjects receiving 
panitumumab. See section 4.4.1 for further instruction on the management 
adverse events associated with panitumumab therapy. 
 Dermatologic and soft tissue toxicity 
 Increased tumor progression, increased mortality, or lack of benefit in RAS- 
and KRAS-mutant mCRC 
 Electrolyte depletion 
 Infusion reactions 
 Acute renal failure in combination with chemotherapy 
 Pulmonary fibrosis/interstitial lung disease 
 Photosensitivity 
 Ocular toxicities 
 Increased mortality and toxicity with panitumumab in combination with 
bevacizumab and chemotherapy 
 
5.2 
Nivolumab (Opdivo®) 
See the Nivolumab Investigator’s Brochure (IB) and the prescribing information 
for Opdivo® (Nivolumab) at http://packageinserts.bms.com/pi/pi_opdivo.pdf for 
more detailed information. 
 
5.2.1 
Description 
Nivolumab (BMS 936558-01*) injection drug product is a sterile, non-pyrogenic, 
single-use, isotonic aqueous solution formulated at 100mg/10 mL. The vials 
supplied contain 100 mg.  Nivolumab is a sterile, preservative-free, non- 
pyrogenic clear to opalescent, colorless to pale-yellow liquid that may contain 
light (few) particles for IV administration. Nivolumab will be supplied by Bristol- 
Myers Squibb (BMS) at no charge to study subjects. 
 
*Nivolumab may be labeled as BMS936558-01 solution for injection. 
 
5.2.2 
Packaging and Labeling 
Primary Packaging (Volume)/Label type: Carton of 5  
Secondary Packaging (Qty)/Label type: 10-cc Type 1 flint glass vials stoppered 
with butyl stoppers and sealed with aluminum seals. 
 
5.2.3 
Storage and Handling 
Store nivolumab under refrigeration at 20C to 80C (360F-460F) in the original 
package until time of use. Protect from light and freezing. Do not shake the vial. 


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
30 
 
 
 
If stored in a glass front refrigerator, vials should be stored in the carton. 
Recommended safety measures for preparation and handling of nivolumab 
include laboratory coats and gloves. 
 
For additional details on prepared drug storage and use time of nivolumab under 
room temperature/light and refrigeration, please refer to the BMS-936558 
(nivolumab) Investigator Brochure section for “Recommended Storage and Use 
Conditions”. 
 
The investigator should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as per product 
information and the Investigator Brochure and per local regulations. It is the 
responsibility of the investigator to ensure that investigational product is only 
dispensed to study subjects. The investigational product must be dispensed only 
from official study sites by authorized personnel according to local regulations. If 
concerns regarding the quality or appearance of the study drug arise, the study 
drug should not be dispensed and contact BMS immediately. 
 
5.2.4 
Dose, Schedule and Administration 
See section 4.3 
 
Nivolumab will be given every two weeks at a dose of 240 mg, to be administered 
as a 30-minute IV infusion. 
 
Subjects may be dosed no less than 12 days from the previous dose of drug. There 
are no premedications recommended for nivolumab on the first cycle. 
 
The dosing calculations should be based on the actual body weight at baseline. If 
the subject’s weight on the day of dosing differs by > 10% from the weight used 
to calculate the original dose, the dose must be recalculated. All doses should be 
rounded to the nearest milligram. There will be no dose modifications allowed. 
 
Subjects should be carefully monitored for infusion reactions during nivolumab 
administration. If an acute infusion reaction is noted, subjects should be managed 
according to institutional guidelines (See section 4.5.2). 
 
Doses of nivolumab may be interrupted, delayed, or discontinued depending on 
how well the subject tolerates the treatment. 
 
5.2.5 
Preparation 
See the nivolumab prescribing information for preparation instructions. 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) is to be administered as an IV 
infusion through a 0.2-micron to 1.2-micron pore size, low-protein binding 
polyether sulfone membrane in-line filter at the protocol-specified dose. It is not 
to be administered as an IV push or bolus injection. Nivolumab injection can be 


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
31 
 
 
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. 
 
5.2.6 
Stability 
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 nivolumab 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 period). 
 
5.2.7 
Return and Retention of Nivolumab 
Unused vials will be handled per instructions from BMS. Partially used and 
completely used vials will be destroyed per institutional guidelines. 
 
5.2.8 
Adverse Events Associated with Nivolumab 
The adverse events listed below have been reported in subjects receiving NVB. 
See section 4.4 for further instruction on the management of adverse events 
associated with nivolumab therapy. 
 Immune-mediated pneumonitis: Defined as requiring use of 
corticosteroids and no clear alternate etiology, including fatal cases have 
occurred with nivolumab treatment.
 Immune-mediated colitis: Defined as requiring use of corticosteroids and 
no clear alternate etiology, including fatal cases have occurred with 
nivolumab treatment.
 Immune-mediated hepatitis: Defined as requiring use of corticosteroids 
and no clear alternate etiology have occurred with nivolumab treatment.
 Immune-mediated endocrinopathies: Hypophysitis, adrenal insufficiency, 
hypo- and hyper-thyroidism, and type I diabetes mellitus have occurred 
with nivolumab treatment.
 Immune-mediated nephritis and renal dysfunction: Defined as renal 
dysfunction or ≥Grade 2 increased creatinine, requirement for 
corticosteroids, and no clear alternate etiology, can occur with nivolumab 
treatment.
 Immune-mediated rash: Severe rash (including rare cases of fatal toxic 
epidermal necrolysis) can occur with nivolumab treatment.
 Immune-mediated encephalitis: Withhold nivolumab in subjects with new- 
onset moderate to severe neurologic signs or symptoms.
 Other immune-mediated adverse reactions: Monitor for as described 
in section 4.4.2
 Infusion reactions: Severe infusion reactions have been reported in <1.0% 
of subjects in clinical trials of nivolumab. See section 4.5.2 for 
information on the management of nivolumab-related infusion reactions.
 Other events may occur. One event that has been observed is hemolytic 
anemia


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
32 
 
 
5.3 
Ipilimumab (Yervoy®) 
See the Ipilimumab Investigator’s Brochure (IB) and the prescribing information 
for Yervoy® (Ipilimumab) at http://packageinserts.bms.com/pi/pi_yervoy.pdf 
for more detailed information. 
 
5.3.1 
Description 
Ipilimumab is a sterile, preservative-free, clear to slightly opalescent, colorless to 
pale yellow solution of IV infusion, which may contain a small amount of visible 
translucent-to-white, amorphous ipilimumab particulates. It is suppled in single- 
use vials of 50 mg/10mL and 200 mg/40 mL. 
 
5.3.2 
Packaging and Labeling 
Primary Packaging (Volume)/Label type: Carton of 6 (50 mg/10 mL) or 4 vials 
(200 mg/40 mL) 
 
5.3.3 
Storage and Handling 
Store ipilimumab under refrigeration at 20C to 80C (360F-460F) in the original 
package until time of use. Protect from light. Do not freeze. 
 
Store the diluted solution for no more than 24 hours under refrigeration 20 to 80C 
(360 to 460F) or at room temperature 200 to 250C (680 to 770F). 
5.3.4 
Dose, Schedule and Administration 
See section 5.3.4 
 
The recommended dose of ipilimumab for metastatic melanoma is 3mg/kg 
administered over 90 minutes every 3 weeks for a maximum of 4 doses. The 
recommended dose for adjuvant treatment of melanoma is 10 mg/kg administered 
over 90 minutes every 3 weeks for 4 doses followed by 10mg/kg every 12 weeks 
for up to 3 years. 
 
In this trial, ipilimumab will be given at a dose of 1mg/kg administered over 30 
minutes every 6 weeks if DL1 is tolerated as outlined in the study schema and 
described in section 4.3. 
 
5.3.5 
Preparation 
See the ipilimumab prescribing information for preparation instructions. Do not 
shake the product. Inspect for particulate matter or discoloration prior to 
administration. Discard vial if solution is cloudy, there is pronounced 
discoloration (solution may have pale yellow color) or there is foreign particulate 
matter other than translucent-to-white, amorphous particles. 
 
5.3.6 
Stability 
Store the diluted solution for no more than 24 hours under refrigeration 20 to 80C 
(360 to 460F) or at room temperature 200 to 250C (680 to 770F). 


LCCC 1632 
PI: Autumn McRee, MD 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01,, 
2020 
33 
 
 
5.3.7 
Return and Retention of Ipilimumab 
Unused vials will be handled per instructions from BMS. Partially used and 
completely used vials will be destroyed per institutional guidelines. 
 
5.3.8 
Adverse Events Associated with Ipilimumab 
The adverse events noted here have been reported in subjects receiving 
ipilimumab. See section 4.4.3 for further instruction on the management of 
adverse events associated with ipilumumab in combination with nivolumab 
therapy. 
 Common adverse events occurring in ≥ 5% of subjects on ipilimumab are 
fatigue, diarrhea, pruritus, rash, and colitis.
 Additional common adverse reactions at the 10mg/kg dose (≥ 5%) include 
nausea, vomiting, headache, weight loss, pyrexia, decreased appetite, and 
insomnia.
 Other events may occur. One event that has been observed is hemolytic 
anemia
 
5.4 
Return and Retention of Study Drug 
The investigator is responsible for keeping accurate records of the clinical 
supplies received from the study, the amount dispensed to the subjects and the 
amount remaining at the conclusion of the trial. 
 
Upon completion or termination of the study, all unused and/or partially used and 
completely used vials of investigational product will be destroyed per UNC IDS 
drug destruction policy for drug received by UNC. All unused drug will be 
handled per instructions provided by the manufacturer. In general, it is the 
Investigator’s responsibility to arrange for disposal of all empty containers, 
provided that procedures for proper disposal have been established according to 
applicable federal, state, local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. 


 
LCCC 1632 
CONFIDENTIAL 
PI: Autumn McRee, MD 
UNIVERSITY OF NORTH CAROLINA 
 
 
6.0 
EVALUATIONS AND ASSESSMENTS 
6.1 
Time and Events Table 
Assessment 
Pre- 
Study1 
D12 
Cycle 1 
D152 
Cycle 1 
D292 
Cycle 1 
D12 
Cycle 2 
D152 
Cycle 2 
D292 
Cycle 2 
D12 
Cycle 
3-N 
D152 
Cycle 
3-N 
D292 
Cycle 
3-N 
End of 
Treat 
ment3 
30-day 
Follow 
up3 
100- 
day 
Follow 
up3 
Long 
term 
Follow 
up3 
Informed Consent 
X 
History4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tumor measurement5 
X 
X5 
Pregnancy test6 
X 
X6 
X6 
X6 
X6 
X6 
Hematology7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistries7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TSH, Free T3/T48 
X 
X 
X 
X 
ACTH/Amylase/Lipase8 
X 
X 
X 
X 
CEA8 
X 
X 
X 
X 
Toxicity Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Meds9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ipilimumab IV  (if DL1 safe)10 
X 
X 
X 
Nivolumab IV10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Panitumumab IV10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Request archival or Perform 
mandatory biopsy 
X11 
Blood sample12 
X 
X 
X 
X 
Stool specimen 
X 
 
 
X13 
 
On treatment Tumor biopsy 
(Optional; goal n=15) 
X 
X14 
Survival analysis 
X 
X 
 
 
36 


LCCC 1632 
PI: Autumn McRee, 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01, 2020 
37 
 
 
1. Radiological assessments and physical exam may be performed within 4 weeks prior to 
day 1 of treatment.  Other evaluations except for pregnancy test must be performed 
within 3 weeks prior to Cycle 1 Day 1 (C1D1) of treatment. Serum or urine β-HCG must 
be performed within 24 hours prior to first dose of study medication for women of 
child-bearing potential. Other screening labs performed within 72 hours prior to Cycle 1 
Day 1 do not need to be repeated on C1D1. 
 
2. Treatment cycles are to be repeated every 42 days until progression. A window of +/- 3 
days applies to all study visits unless otherwise specified. While the treatment window 
is +/- 3 days, a minimum of 12 days must pass before the next dose of nivolumab. 
 
3. The end of treatment visit should only occur when subjects permanently stop study 
treatment. Subjects who have an ongoing ≥grade 2 or serious AE (SAE) at this visit will 
continue to be followed until the event is resolved or deemed irreversible by the 
investigator.   The 30-day (+/- 7 days) follow up visit after stopping study treatment 
should be performed to check for ongoing toxicity. Subsequently, subjects should be 
contacted by telephone at approximately 100 days (+/- 7 days) after discontinuing study 
treatment for the emergence of SAEs (including checking for pregnancy) and to ensure 
contraceptive guidelines are followed as stipulated in inclusion criteria 3.1.11 and 3.1.12. 
Subsequent long-term follow-up for survival, defined as every 90 days thereafter (+/- 15 
days) for up to 3 years or until death (whichever is first) may be conducted via telephone 
or chart review and/or clinic visit. Long term survival follow up will be limited to history 
of any subsequent cancer treatments, an assessment of any SAEs (including checking for 
pregnancy) considered to be possibly or probably related to study treatment until 
resolution, and survival status. 
 
4. Complete history at baseline only, thereafter focused history on symptoms/toxicity; 
physical exam to include height (baseline only), examination of the skin, weight, and 
vital signs. Note that starting with cycle 7, only include assessment by physician on days 
15 and 29 if clinical signs and symptoms warrant MD consult 
 
5. Tumor imaging should remain consistent throughout study and should include those 
thought by investigator to best capture status of disease. Disease assessments should 
include contrasted computed tomography (CT) of the chest and either contrasted CT of 
abdomen and pelvis or MRI of abdomen and pelvis. Repeat tumor imaging every 12 
weeks (+/- 1 week). 
 
6. Urine or serum β-HCG must be performed within 24 hours prior to first dose of study 
medication for women of child-bearing potential. The test result must be confirmed as 
negative prior to dosing with study medication. A serum or urine pregnancy test must be 
repeated every 6 weeks while receiving study medications and repeated approximately 30 
days after discontinuing the study medications. 
 
7. Hematology: CBC with differential including Hgb, and platelet count. Serum chemistries 
will include a complete metabolic panel (ie, BUN, creatinine, sodium (Na), potassium 
(K), Chloride (Cl), Bicarbonate (CO2), glucose, calcium (Ca), albumin, total protein, total 
bilirubin, ALT, AST, and alkaline phosphatase) + magnesium (Mg) and phosphorus. 
 
8. Thyroid function test: TSH and free T3/T4 should be assessed prior to initiating study 
treatment and performed every 6 weeks +/- 3 days during study treatment and at the end 
of treatment. ACTH, amylase and lipase should be measured at baseline (pre-study) and 


LCCC 1632 
PI: Autumn McRee, 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01, 2020 
38 
 
 
then on D1 of each cycle. CEA should be measured pre-study and then on D1 of each 
cycle. 
 
9. Please note all subjects should receive prophylaxis for panitumumab-associated rash with 
a tetracycline antibiotic (like doxycycline or minocycline) and continue for at least the 
duration of the first cycle of study combination treatment (i.e., 6 weeks), as described in 
section 4.5.1 
 
10. Ipilimumab dosing will be halted and will not be given if the triple combination is 
determined to be unsafe during the safety run-in period (Cohort 1). If this is the case then 
subjects will be dosed with panitumumab and nivolumab in (Cohort 2) as described in 
section 4.3.2 
 
11. Fixed paraffin-embedded blocks or slides from the original diagnostic specimen or from a 
metastatic or recurrent site must be requested for subjects at baseline. Subjects with 
inadequate archival specimens must undergo a mandatory biopsy prior to initiating study 
medications. 
 
12. Blood samples will be collected for correlative studies on D1 of each cycle prior to 
dosing, and at the end of treatment visit. 
 
13. Stool specimen should be collected +/- 7 days from C3D1. 
 
14. We will collect fresh on-treatment biopsies (optional) in consenting patients for 
correlative studies in up to 15 patients. The on-treatment biopsy will be performed during 
cycle 1 on or between days 28 and 35. 
 
6.2 
Pre-Study Assessments 
Pre-study evaluations are to be conducted within 3 weeks prior to start of protocol 
therapy.  Scans for tumor evaluation must be done within 4 weeks prior to the 
start of therapy.  Pre-study assessments include: 
 
Complete medical history and physical examination (including height and weight) 
ECOG Performance Status (see appendix 11.1) 
Laboratory evaluations: 
 Hematology: CBC with differential 
 Complete Metabolic Panel (plus Mg and Phosphorus) 
 TSH/Free T3/Free T4 
 ACTH/Amylase/Lipase 
 CEA 
 Serum or urine pregnancy test in women of childbearing potential (Note: 
pregnancy test to be done within 24 hours of day 1 of treatment) 
Concomitant medication(s): All concomitant medications will be recorded. 
Tumor evaluation: Contrasted computed tomography (CT) of the chest, and either 
contrasted CT of abdomen and pelvis or MRI of abdomen and pelvis. 
Tissue (archival and/or fresh biopsy): Obtain archival tissue from diagnostic 
regimen for correlative studies if available. If insufficient tissue available, subject 
must agree to mandatory pretreatment biopsy to participate in the clinical trial. 
Stool Specimen: Collect pre-treatment stool specimen from patients as described in 


LCCC 1632 
PI: Autumn McRee, 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01, 2020 
39 
 
 
Laboratory manual. 
Toxicity evaluation: Use NCI CTCAEv4.03 for notation of any baseline toxicity 
 
6.3 
Treatment Assessments 
 
6.3.1 D1 of Cycle 1 
Focused history and physical examination (including weight) 
ECOG  Performance  Status  (see  appendix  11.1) 
Laboratory evaluations: 
 Hematology: CBC with differential 
 Complete Metabolic Panel (plus Mg and Phosphorus) 
 Blood sample for correlatives 
 Serum or urine pregnancy test in women of childbearing potential (Note: 
pregnancy test to be done within 24 hours of day 1 of treatment) 
Concomitant medication(s): All concomitant medications will be recorded. 
Toxicity evaluation: Use NCI CTCAEv4.03 for notation of any baseline toxicity 
Administer Study Medications according to Safety Cohort 1 or 2 schedule as 
depicted in sections 0 and 4.3.2, respectively. 
 
6.3.2 D15 of Cycles 1 and 2 
Focused history and physical examination (including weight) 
ECOG  Performance  Status  (see  appendix  11.1) 
Laboratory evaluations: 
 Hematology: CBC with differential 
 Complete   Metabolic   Panel   (plus   Mg   and   Phosphorus) 
Concomitant medication(s): All concomitant medications will be recorded. 
Toxicity evaluation: Use NCI CTCAEv4.03 for notation of any baseline toxicity 
Administer Study Medications according to Safety Cohort 1 or 2schedule as 
depicted in sections 0 and 4.3.2, respectively 
 
6.3.3 D29 of Cycles 1 and 2 
Focused history and physical examination (including weight) 
ECOG  Performance  Status  (see  appendix  11.1) 
Laboratory evaluations: 
 Hematology: CBC with differential 
 Complete Metabolic Panel (plus Mg and Phosphorus) 
 Tumor biopsy (optional): Applies to cycle 1 days 28-35 only 
Concomitant medication(s): All concomitant medications will be recorded. 
Toxicity evaluation: Use NCI CTCAEv4.03 for notation of any baseline toxicity 
Administer Study Medications according to Safety Cohort 1 or 2 schedule as 
depicted in sections 4.3.1 and 4.3.2, respectively 


LCCC 1632 
PI: Autumn McRee, 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01, 2020 
40 
 
 
6.3.4 D1 of Cycle 2 
Focused history and physical examination (including weight) 
ECOG  Performance  Status  (see  appendix  11.1) 
Laboratory evaluations: 
 Hematology: CBC with differential 
 Complete Metabolic Panel (plus Mg and Phosphorus) 
 TSH/Free T3/Free T4 
 ACTH/Amylase/Lipase 
 CEA 
 Serum or urine pregnancy test in women of childbearing potential (within 
24 hours of dosing with study medications 
 Blood sample for correlative studies 
Concomitant medication(s): All concomitant medications will be recorded. 
Toxicity evaluation: Use NCI CTCAEv4.03 for notation of any baseline toxicity 
Administer Study Medications according to Safety Cohort 1 or 2 schedule as 
depicted in sections 0 and 4.3.2, respectively 
 
6.3.5 D1 of Cycle 3-N 
Focused history and physical examination (including weight) / 
ECOG  Performance  Status  (see  appendix  11.1)  
Laboratory evaluations: 
 Hematology: CBC with differential 
 Complete Metabolic Panel (plus Mg and Phosphorus) 
 TSH/Free T3/Free T4 
 ACTH/Amylase/Lipase 
 CEA 
 Serum or urine pregnancy test in women of childbearing potential (within 
24 hours of dosing with study medications 
 Blood sample for correlative studies 
Concomitant medication(s): All concomitant medications will be recorded. 
Tumor evaluation: Contrasted computed tomography (CT) of the chest, and 
either contrasted CT of abdomen and pelvis or MRI of abdomen and pelvis on 
cycles 3, 5, 7, etc. Note: Repeat tumor imaging every 12 weeks (+/- 1 week). 
Stool Specimen: Collect stool specimen from patients as described in Laboratory 
manual +/- 7 days from Day 1 of Cycle 3 only. 
Toxicity evaluation: Use NCI CTCAEv4.03 for notation of any baseline toxicity 
Administer Study Medications according to Safety Cohort 1 or 2 schedule as 
depicted in sections 4.3.10 and 4.3.2, respectively 
 
6.3.6 D15 of Cycles 3-N 
Focused history and physical examination (including a weight) / Note: after 6 
cycles completed, only include assessment by physician if clinical signs and 
symptoms warrant MD consult 
ECOG Performance Status (see appendix 11.1) 
Laboratory evaluations: 
 Hematology: CBC with differential 
 Complete Metabolic Panel (plus Mg and Phosphorus) 


LCCC 1632 
PI: Autumn McRee, 
CONFIDENTIAL 
UNIVERSITY OF NORTH CAROLINA 
October 01, 2020 
41 
 
 
Concomitant medication(s): All concomitant medications will be recorded. 
Toxicity evaluation: Use NCI CTCAEv4.03 for notation of any baseline toxicity 
Administer Study Medications according to Safety Cohort 1 or 2 schedule as 
depicted in sections 4.3.1 and 4.3.2, respectively 
 
6.3.7 D29 of Cycles 3-N 
Focused history and physical examination (including a weight) / Note: after 6 
cycles completed, only include assessment by physician if clinical signs and 
symptoms warrant MD consult 
ECOG Performance Status (see appendix 11.1) 
Laboratory evaluations: 
 Hematology: CBC with differential 
 Complete   Metabolic   Panel   (plus   Mg   and   Phosphorus) 
Concomitant medication(s): All concomitant medications will be recorded. 
Toxicity evaluation: Use NCI CTCAEv4.03 for notation of any baseline toxicity 
Administer Study Medications according to Safety Cohort 1 or 2 schedule as 
depicted in sections 4.3.1 0and 4.3.2, respectively 
 
6.4 
Post-Treatment/Follow-up Assessments 
6.4.1 End of treatment 
Focused history and physical examination (including weight) 
ECOG  Performance  Status  (see  appendix  11.1) 
Laboratory evaluations: 
 Hematology: CBC with differential 
 Complete Metabolic Panel (plus Mg and Phosphorus) 
 TSH/Free T3/Free T4 
 ACTH/Amylase/Lipase 
 CEA 
 Serum or urine pregnancy test in women of childbearing potential 
 Blood sample for correlative studies 
Concomitant medication(s): All concomitant medications will be recorded. 
Toxicity evaluation: Use NCI CTCAEv4.03 for notation of any baseline toxicity. 
Note: Subjects who experienced a grade 3 or 4 event or SAE during the treatment 
phase will be contacted every 2 weeks until the event is resolved or deemed 
irreversible by the investigator. 
 
6.4.2 30-day follow up 
Focused history and physical examination (including weight) 
Laboratory evaluations: 
 Serum or urine pregnancy test in women of childbearing potential 
Concomitant medications 
Toxicity evaluation: Use NCI CTCAEv4.03 for notation of any baseline toxicity. 
Note: Subjects who experienced a grade 3 or 4 event or SAE during the treatment 
phase will be contacted every 2 weeks until the event is resolved or deemed 
irreversible by the investigator. 


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6.4.3 100-day follow up 
Survival and Toxicity evaluation: Use NCI CTCAEv4.03 for notation of any 
baseline toxicity. Note: Subjects who experienced a grade 3 or 4 event or SAE 
during the treatment phase will be contacted every 2 weeks until the event is 
resolved or deemed irreversible by the investigator. 
 
6.4.4 Long-term follow up 
Subsequent long-term follow-up visits should occur per standard of care, defined 
as every 90 days thereafter (+/- 15 days) for up to 3 years or until death 
(whichever is first) and may be conducted via telephone, medical record check, 
and/or via clinic visit. These visits will be limited to history of any subsequent 
cancer treatments, an assessment of any SAE’s considered to be possibly or 
probably related to study treatment until resolution, and survival status. 
 
6.5 
Correlative Studies Procedures 
Blood samples will be collected for correlative studies on D1 of each cycle and at 
the end of treatment visit. Collection details will be provided in the study 
laboratory manual. 
 
Stool specimens will be collected during screening and on approximately Cycle 3 
Day 1 (see 6.1 for details on timing of collection). Collection details will be 
provided in the study laboratory manual. 
 
Handling of Biospecimens Collected for Correlative Research 
Biospecimens collected for this study will be stored in the Lineberger 
Comprehensive Cancer Center (LCCC) Tissue Procurement Facility (TPF), or if 
needed, in a secure off-site storage facility. All biospecimen samples will be 
obtained in accordance with procedures outlined in the LCCC 1632 Study 
Laboratory Manual and stored in containers with controlled access. Each sample 
will be assigned a unique code number and no identifiable personal health 
information (PHI) will be on the specimen label. Information about the subject’s 
disease will be linked to the specimens stored in the repository database. TPF- 
associated research staff, LCCC Bioinformatics staff who support the TPF 
database and the LCCC Data Warehouse, and researchers with IRB-approval for 
access to PHI for each subject in this study will be able to link specimens to 
relevant medical information. Some results from laboratory analyses that occurred 
during the subject’s participation in the clinical study may also be included. This 
information may be important for understanding how the subject’s cancer 
developed and responded to treatment. 
 
All the planned correlative research studies will be performed by laboratories 
affiliated with UNC-Chapel Hill (for additional details please consult the 
laboratory manual). 
 
Storage Time: 
The biospecimen will be used first and foremost for research purposes 
outlined within the confines of this protocol. Samples will be 
discarded/destroyed after relevant data are collected for this study, 


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unless consent was obtained from the subject to use tissue for other 
research purposes (e.g., TPF consent form was signed by the subject).  
In this circumstance, there is no time limit on how long biospecimens 
may be stored. 
o  The investigator must agree to abide by policies and procedures of the 
TPF facility and sign a letter of research agreement for ethical and 
appropriate conduct of their research that utilizes specimens obtained from 
the TPF facility (e.g., Use of leftover specimens will require a protocol 
outlining the research plan for biospecimen use). 
 
Compliance Statement 
Biospecimen collection for this study will be conducted in full accordance to all 
applicable University of North Carolina (UNC) Research Policies and Procedures 
and all applicable Federal and state laws and regulations including 45 CFR 46, 
and the Health Insurance Portability and Accountability Act (HIPAA) Privacy 
Rule. Any episode of noncompliance will be documented. 
 
The investigators will perform the study in accordance with this protocol, will 
obtain consent and assent (unless a waiver is granted), and will report unexpected 
problems in accordance with The UNC IRB Policies and Procedures and all 
federal requirements. Collection, recording, and reporting of data will be accurate 
and will ensure the privacy, health, and welfare of research subjects during and 
after the study. 
 
6.6 
Assessment of Safety 
Any subject who receives at least one dose of study therapy on this protocol will 
be evaluable for toxicity. Each subject will be assessed periodically for the 
development of any toxicity according to the Time and Events table. Toxicity 
will be assessed according to the NCI CTCAEv4.03. 
 
6.7 
Assessment of Efficacy 
Efficacy will be assessed per RECIST 1.1 Criteria in the next section and by 
irRECIST as described in Section 6.7.5.1. 
 
6.7.1 Assessment of Disease-Tumor Measurement Based on RECIST 1.1 
See the international criteria proposed by the Response Evaluation Criteria in 
Solid Tumors (RECIST) Committee, version 1.1 (Eur J Cancer 45;2009:228-247) 
for additional details on RECIST1.1. 
 
Measurable disease will be defined as the presence of at least one measurable 
lesion that can be accurately measured in at least one dimension with the longest 
diameter a minimum size of: 
 >10mm by CT scan (CT scan slice thickness no greater than 5 mm) 
 10mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non- 
measurable). 
 20 mm by chest x-ray. 


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For malignant lymph nodes to be considered pathologically enlarged and 
measurable, a lymph node must be ≥15mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5mm). At 
baseline and in follow-up, only the short axis will be measured and followed. 
 
All other lesions, including small lesions (longest diameter <10mm or 
pathological lymph nodes with ≥10 to <15 mm short axis) as well as truly non- 
measurable lesions, will be considered non-measurable. Lesions considered truly 
non-measurable include: leptomeningeal disease; ascites; pleural/pericardial 
effusion; inflammatory breast disease; lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is 
not measurable by reproducible imaging techniques. 
 
All measurements should be recorded in metric notation, using calipers if 
clinically assessed. All baseline evaluations should be performed as close as 
possible to the treatment start 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 should always be done rather than clinical 
examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam. Clinical lesions will only be considered measurable 
when they are superficial and ≥10 mm diameter as assessed using calipers (e.g. 
skin nodules). For the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesions is recommended. 
 
6.7.2 Baseline Documentation of Target and Non-Target Lesions 
All measurable lesions up to a maximum of 5 lesions total (and a maximum of 
two lesions per organ) representative of all involved organs should be identified 
as target lesions and will be recorded and measured at baseline. 
 
Target lesions should be selected on the basis of their size (lesions with the longer 
diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements. 
 
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, only the short axis is 
added into the sum. The baseline sum diameters will be used as reference to 
further characterize the objective tumor response of the measurable dimension of 
the disease. 
 
All other lesions (or sites of disease) including pathological lymph nodes should 
be identified as non-target lesions and should also be recorded at baseline. 
Measurements are not required, and these lesions should be followed as 
“present” or “absent”, or in rare cases “unequivocal progression”. 


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6.7.3 Evaluation of Target Lesions using RECIST 1.1 Criteria 
NOTE: In addition to the information below, also see section 4.3.2 in the 
international criteria proposed by the Response Evaluation Criteria in Solid 
Tumors (RECIST) Committee, version 1.1 (Eur J Cancer 45;2009:228-247) for 
special notes on the assessment of target lesions. 
 
Complete response (CR)−Disappearance of all target lesions. Any pathological 
lymph node (LN) (whether target or non-target) must have decreased in short axis 
to <10mm. 
 
Partial response (PR)−At least a 30% decrease in the sum of the LD of the target 
lesions taking as reference the baseline sum LD. 
 
Progressive Disease (PD)−At least a 20% increase in the sum of the LD of the 
target lesions taking as reference the smallest sum LD recorded since the 
treatment started including baseline 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 5mm.  The appearance of one or more new lesions also constitutes PD. 
 
Stable disease (SD)−Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as references the smallest sum LD since the 
treatment started. 
 
6.7.4 Evaluation of Non-Target Lesions using RECIST 1.1 Criteria 
Complete response (CR)−Disappearance of all non-target lesions and 
normalization of tumor marker levels. All LN must be non-pathological in size 
(<10mm short axis). 
 
Non-complete response (non-CR)/non-progression (non-PD)−Persistence of one 
or more non-target lesion(s) or/and 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. 
 
NOTE: Any progressive disease as defined by RECIST1.1 in subjects that are 
asymptomatic without signs or symptoms of impending visceral crisis SHOULD 
be confirmed by repeat scan to rule out "tumor flare" (pseudoprogression) related 
to immune response. In these subjects and per MD discretion, study therapy 
should be continued in these subjects until the repeat scan is performed 
approximately 4 weeks but no more than 6 weeks later. If PD is confirmed, 
subjects will be withdrawn from study. If tumor flare confirmed, subjects may 
continue therapy as per protocol. Subjects that have clear progressive disease as 
defined by RECIST 1.1 should be withdrawn from treatment and a repeat scan is 
not necessary. 


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6.7.4.1 Evaluation of Best Overall Response - The best overall responses for both 
RECIST 1.1 and irRECIST are defined as the best response achieved across all 
time points prior to progression (for example, a subject who has SD at first 
assessment, PR at second assessment, and PD on last assessment has a best overall 
response of PR). Please Note: In the case of SD, measurements must have met the 
SD criteria at least once after study entry at a minimum interval of 12 weeks from 
initiation of treatment. 
 
The best overall response will be defined according to the following table: 
 
Overall 
Response First 
Time Point 
Overall Response 
Subsequent Time 
Point 
BEST Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR1 
CR 
SD 
SD provided minimum criteria for SD duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
CR 
NE2 
SD provided minimum criteria for SD duration met, otherwise, 
NE2 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
PR 
NE2 
SD provided minimum criteria for SD duration met, otherwise, 
NE2 
NE 
NE2 
NE2 
1 If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the subject had PR, not CR at the 
first time point.  Under these circumstances, the original CR should be changed to PR and the best response is PR. 
2  NE=inevaluable 
 
6.7.5 Other Efficacy Parameters (Immune Response Criteria) 
 
6.7.5.1 Evaluation of Response by irRECIST 
Secondary objectives of this study involve assessment of ORR and PFS based in 
immune response criteria as outlined below (see Guidelines for the evaluation of 
immune therapy activity in solid tumors: immune-related response criteria. 
Wolchok JD et al. Clin Cancer Res 2009;15(23):7412-20, Nishino et al. Clin 
Cancer Res 19(14):3936-43, and Bohnsack O. et al., Adaptation of the immune 
related response criteria: irRECIST. Annals of Oncology (2014) 25 (suppl_4): 
iv361-iv372. 10.1093/annonc/mdu342, 2014). 
 
irRECIST criteria are based on irRC criteria (Wolchok et al) adapted for 
unidimensional measurement as outlined by Nishino et al. The adaptation 
described by Bohnsack et al. further aligns irRECIST to allow for assessment of 


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UNIVERSITY OF NORTH CAROLINA 
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baseline non-target lesions and new non-measurable lesions and discusses the 
impact of those lesions on the overall tumor response assessment. The adaptation 
by Bohnsack et al. allows for evaluation of subjects with non-target disease only 
and subjects in the adjuvant setting (not applicable for this study in subjects with 
metastatic disease). 
 
Overall response using the irRECIST is based on tumor burden as follows: 
 
irCR 
Complete disappearance of all lesions (whether measurable or 
not, and no new lesions) Lymph nodes must decrease to < 10 
mm in short axis. Confirmation of response is not mandatory. 
irPR 
Decrease in tumor burden ≥30% in TMTB relative to baseline 
confirmed by a consecutive assessment at least 4 weeks after 
first documentation, non-target lesions are irNN, and no 
equivocal progression of new non-measurable lesions. 
irSD 
Not meeting criteria for irCR, irPR, in absence of irPD 
irPD 
Increase in tumor burden ≥20% increase and minimum 5 mm 
absolute increase in TMTB compared to nadir, or irPD for non- 
target or new non-measurable lesions confirmed by a repeat, 
consecutive assessment no less than 4 weeks from the date first 
documented 
irNN 
No target disease was identified at baseline and at follow-up the 
subject fails to meet criteria for irCR or irPD. 
irNN = irNon-CR/Non-PD 
TMTB = Total measureable tumor burden 
 
7.0 
ADVERSE EVENTS 
7.1 
Definitions 
 
7.1.1 Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence (e.g., an abnormal 
laboratory finding, symptom, or disease temporally associated with the use of a 
drug) in a subject or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not related to the 
medicinal product. 


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Hospitalization for elective surgery or routine clinical procedures that are not the 
result of an AE (e.g., surgical insertion of central line) need not be considered 
AEs and should not be recorded as an AE. Disease progression should not be 
recorded as an AE unless it is attributable by the investigator to the study therapy. 
 
7.1.2 Suspected Adverse Reaction (SAR) 
A suspected adverse reaction (SAR) is any AE for which there is a reasonable 
possibility that the drug is the cause. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the drug and the AE. A 
suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
 
Causality assessment to a study drug is a medical judgment made in consideration 
of the following factors: temporal relationship of the AE to study drug exposure, 
known mechanism of action or side effect profile of study treatment, other recent 
or concomitant drug exposures, normal clinical course of the disease under 
investigation, and any other underlying or concurrent medical conditions. Other 
factors to consider in considering drug as the cause of the AE: 
 Single occurrence of an uncommon event known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson 
Syndrome) 
 One or more occurrences of an event not commonly associated with drug 
exposure, but otherwise uncommon in the population (e.g., tendon 
rupture); often more than once occurrence from one or multiple studies 
would be needed before the sponsor could determine that there is 
reasonable possibility that the drug caused the event. 
 An aggregate analysis of specific events observed in a clinical trial that 
indicates the events occur more frequently in the drug treatment group 
than in a concurrent or historical control group 
 
7.1.3 Unexpected AE or SAR 
An AE or SAR is considered unexpected if the specificity or severity of it is not 
consistent with the applicable product information (e.g., Investigator’s Brochure 
(IB) for an unapproved investigational product or package insert/summary of 
product characteristics for an approved product). Unexpected also refers to AEs 
or SARs that are mentioned in the IB as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug but are not 
specifically mentioned as occurring with the particular drug under investigation. 
 
7.1.4 Serious AE or SAR 
An AE or SAR is considered serious if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 
 Death; 
 Is life-threatening (places the subject at immediate risk of death from 
the event as it occurred); 


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 Requires in subject hospitalization (>24 hours) or prolongation of 
existing hospitalization;* 
 Results in congenital anomaly/birth defect; 
 Results in a persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions; 
 Important medical events that may not result in death, be life- 
threatening, or require hospitalization may be considered a serious 
adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the subject or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed 
in the definition. For reporting purposes, also consider the occurrences 
of pregnancy as an event which must be reported as an important 
medical event. 
 Potential drug induced liver injury (DILI) is also considered an 
important medical event. 
 Suspected transmission of an infectious agent (eg, pathogenic or 
nonpathogenic) via the study drug is an SAE. 
 Although pregnancy, overdose, and cancer are not always serious by 
regulatory definition, these events must be handled as SAEs. 
 
*Hospitalization for anticipated or protocol specified procedures such as 
administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered 
serious adverse events. 
 
Pregnancy that occurs during the study must also be reported as an SAE. 
 
7.2 
Documentation of non-serious AEs or SARs 
For non-serious AEs or SARs, documentation must begin from day 1 of study 
treatment and continue through the 100-day follow-up period after treatment is 
discontinued. 
 
Collected information should be recorded in the electronic Case Report Forms 
(eCRF) for that subject. Please include a description of the event, its severity 
or toxicity grade, onset and resolved dates (if applicable), and the relationship 
to the study drug. Documentation should occur at least monthly. 
 
7.3 
SAEs or Serious SARs 
 
7.3.1 Timing 
After informed consent but prior to initiation of study medications, only SAEs 
caused by a protocol-mandated intervention will be collected (e.g. SAEs related to 
invasive procedures such as biopsies, medication washout). 


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For any other experience or condition that meets the definition of an SAE or a 
serious SAR, recording of the event must begin from day 1 of study treatment and 
continue through the 100-day follow-up period after treatment is discontinued. 
 
7.3.2 Documentation and Notification 
SAEs or Serious SARs must be recorded in the SAE console within Oncore™ for 
that subject within 24 hours of learning of its occurrence. Additionally, the 
Regulatory Associate and Medical Monitor must also be notified via email of all 
SAEs within 24 hours of learning of its occurrence. 
 
7.3.3 Reporting 
IRB Reporting Requirements: 
UNC: 
 The UNC-IRB will be notified of all SAEs that qualify as an 
Unanticipated Problem as per the UNC IRB Policies using the IRB’s web- 
based reporting system within 7 days of the Investigator becoming aware 
of the problem. These events must be reported to the sponsor within 24 
hours of learning of the occurrence. 
 
Affiliate sites: 
 For affiliate sites using a local IRB of record, please submit adverse events 
per local IRB policy. 
 For affiliate sites relying on the UNC-IRB, an aggregated list of all SAEs 
will be submitted to the UNC IRB annually at the time of study renewal 
according to the UNC IRB policies and procedures. In addition, any SAEs 
that qualify as an Unanticipated Problem will be entered into Oncore by 
the affiliate site and reported to the UNC IRB by the Multicenter 
Regulatory Associate using the IRB’s web-based reporting system within 
7 days of the Investigator becoming aware of the problem. 
Pregnancy 
Pregnancies and suspected pregnancies (including a positive pregnancy test 
regardless of age or disease state) of a female subject or a female partner of a 
male subject occurring while the subject is on study, or within the period 
stipulated for continued contraceptive use for WOCBP (5 months) and sexually 
active men (6 months) after the subject’s last dose of study medication should be 
recorded as SAEs. The female subject is to be discontinued immediately from the 
study for a pregnancy event. 
 
For Affiliate sites, the pregnancy, suspected pregnancy, or positive pregnancy test 
must be reported to the Multicenter Project Manager immediately (within 24 
hours) at CPOMultiCenter@med.unc.edu (primary route of submission) or 
facsimile (919) 966-4300 (back-up)). The Multicenter Project Manager will then 
report the event to the Funding Source (see requirements below). The female 
subject or the female partner of a male subject should be referred to an 
obstetrician-gynecologist, preferably one experienced in reproductive toxicity for 
further evaluation and counseling. 


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The Investigator will follow the female subject or female partner of a male subject until 
completion of the pregnancy, and must document the outcome of the pregnancy (either 
normal or abnormal outcome) and report the condition of the fetus or newborn to the 
Multicenter Project Manager. If the outcome of the pregnancy was abnormal (e.g., 
spontaneous or therapeutic abortion), the Investigator should report the abnormal outcome 
as an AE. If the abnormal outcome meets any of the serious criteria, it must be reported as 
an SAE. 
 
Note if the female subject or female partner of a male subject has received nivolumab, the 
investigator must immediately notify Worldwide Safety @BMS of this event via the 
Pregnancy Surveillance Form in accordance with SAE reporting procedures. The 
nivolumab IB notes that non-clinical safety findings of adverse pregnancy outcomes and 
infant losses in the absence of maternal toxicity have been reported. Findings in monkeys 
suggest a potential risk to human pregnancy if there is continued treatment with 
nivolumab during pregnancy. 
 
Laboratory Test Abnormalities 
The following laboratory abnormalities should be documented and reported appropriately: 
 any laboratory test result that is clinically significant or meets the definition 
of an SAE 
 any laboratory abnormality that required the subject to have study drug discontinued or 
interrupted 
 any laboratory abnormality that required the subject to receive specific corrective 
therapy. 
 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as an SAE. 
 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x rays, and any other potential safety assessments, whether or not 
these procedures are required by the protocol, should also be recorded as a nonserious or 
serious AE, as appropriate, and reported accordingly. 
 
Funding Source Amgen Reporting Requirements: 
Safety Data 
Timeframe for Submission to Amgen 
Suspected Unexpected 
Serious Adverse Reaction 
Sent to Amgen at time of regulatory submission 
Serious Adverse Events (SAEs) 
Not required, unless contractually specified per 
study 
Adverse Events not meeting 
serious criteria 
Not required, unless contractually specified per 
study 
Events of Interest 
Not required, unless contractually specified per 
study 
Pregnancy/Lactation 
Within 10 calendar days of Sponsor awareness 
Event listing for reconciliation 
As specified per contract 


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*Specific requirements are to be outlined in the Research Agreement 
 
To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1- 
800-772-6436) or Food and Drug Administration (FDA) at 1-800-FDA-1088 
or www.fda.gov/medwatch. 
 
For all studies – aggregate reports*: 
Safety Data 
Timeframe for submission to Amgen 
Annual Safety Report 
(eg, EU Clinical Trial Directive [CTD] 
Annual Safety Report, and US IND 
Annual Report) 
Annually 
Other Aggregate Analyses 
(any report containing safety data 
generated during the course of a study) 
At time of ISS sponsor submission to 
any body governing research conduct 
(eg, RA, IRB, etc) 
Final (End of Study Report, 
including: 
 Unblinding data for blinded studies 
 Reports of unauthorized use of a 
marketed product 
At time of ISS sponsor submission to 
any body governing research conduct 
(eg, RA, IRB, etc) but not later than 1 
calendar year of study completion 
*Specific requirements are to be outlined in the Research Agreement 
 
 
Bristol-Myers Squibb (BMS) Reporting Requirements 
For studies conducted under an Investigator IND in the US, any event that is both 
serious and unexpected must be reported to FDA as soon as possible and no later 
than 7 days (for a death or life-threatening event) or 15 days (for all other SAEs) 
after the investigator’s or institution’s initial receipt of the information. BMS will 
be provided with a simultaneous copy of all adverse events filed with the FDA. 
 
Wordwide.safety@bms.com 
 
MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 


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All SAEs should simultaneously be faxed or e-mailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
FDA Expedited Reporting requirements for studies conducted under an IND: 
A sponsor (in this case the LCCC) must report any suspected adverse reaction that 
is both serious and unexpected to the FDA. The sponsor must report an adverse 
event as a suspected adverse reaction only if there is evidence to suggest a causal 
relationship between the drug and the adverse event, such as: 
 A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (e.g., angioedema, hepatic injury, Stevens- 
Johnson Syndrome); 
 One or more occurrences of an event that is not commonly associated with 
drug exposure, but is otherwise uncommon in the population exposed to 
the drug (e.g. tendon rupture); 
 An aggregate analysis of specific events observed in a clinical trial (such 
as known consequences of underlying disease or condition under 
investigation or other events that commonly occur in the study population 
independent of drug therapy) that indicates those events occur more 
frequently in the drug treatment group than in a concurrent or historical 
control group. 
 
The sponsor must submit each IND safety report on FDA Form 3500A. Each 
notification to FDA must bear prominent identification of its contents, i.e., “IND 
Safety Report,” and must be transmitted to the review division that has the 
responsibility for review of the IND. In each IND safety report, the sponsor must 
identify all IND safety reports previously submitted to FDA concerning a similar 
suspected adverse reaction, and must analyze the significance of the suspected 
adverse reaction in light of previous, similar reports or any other relevant 
information. 
 
Timing 
FDA must be notified of potential serious risks within 15 calendar days after the 
sponsor determines the event requires reporting. FDA must be notified of 
unexpected fatal or life-threatening suspected adverse reactions as soon as possible 
but in no case later than 7 calendar days after the sponsor’s initial receipt of the 
information. The sponsor must be notified by the investigator within 24 hours of 
the event. For Multicenter trials, Lineberger is the sponsor, therefore, the 
Multicenter Project Manager must be notified of the SAE within 24 hours of the 
event. If the results of a sponsor’s investigation show that an adverse event not 
initially determined to be reportable is reportable, the sponsor must report such 
suspected adverse reaction in an IND safety report as soon as possible, but in no 
case later than 15 calendar days after the determination is made. 
 
Follow-up 


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The sponsor must promptly investigate all safety information it receives. Relevant 
follow-up information to an IND safety report must be submitted as soon as the 
information is available and as such the Multicenter Project Manager should be 
updated within 24 hours of the information being available via a follow-up 
MedWatch Form 3500A. 
 
Notification of Investigators 
The sponsor must notify all participating investigators (i.e., all investigators to 
whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks, from clinical trials or any 
other source, as soon as possible, but in no case later than 15 calendar days after 
the sponsor determines that the information qualifies for reporting. 
 
Process 
If the sponsor deems that an event is both a serious SAR AND unexpected, it must 
also (in addition to Oncore) be recorded on the MedWatch Form 3500A. 
Unexpected adverse events or adverse reaction refers to an event or reaction that is 
not listed in the investigator’s brochure/IND or is not listed at the specificity or 
severity that has been observed; or if an investigator’s brochure is not required or 
available, is not consistent with the risk information described in the general 
investigation plan or elsewhere in the current IND application. 
 
The MedWatch 3500A form and supporting documents defining the event and 
causality should be sent to the electronic mailbox (CPOMultiCenter@med.unc.edu; 
primary route of submission) (or facsimile (919) 966-4300 (back-up)) of the 
Multicenter Project Manager along with supporting documentation defining the 
event and causality. The Multicenter Project Manager will then send the report to 
the Funding Source. The MedWatch 3500a form can be accessed at: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm. 
 
(Please be sure and access form 3500a, and not form 3500). 
 
Once the UNC Principal Investigator determines an event is a serious SAR AND 
unexpected, the MedWatch 3500A form will be submitted to the FDA. If the event 
is serious, unexpected and considered to be possibly-, probably- or definitely-related 
to the study treatment, the Multicenter Project Manager will inform the Regulatory 
Associate at UNC and IND Specialist. The MedWatch form will be submitted 
according to LCCC SOP for safety reporting for a multi-site study. 
 
All IND safety reports must be submitted on Form 3500A and be accompanied by 
Form 1571. The FDA must be notified or any unexpected or life-threatening 
suspected adverse reactions as soon as possible, but no later than 7 calendar days of 
learning of the event. 


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The Multicenter Project Manager will also be responsible for informing each 
Affiliate site of all serious and unexpected SARs reported to the FDA via fax as 
soon as possible. 
 
Additional Reporting Requirements 
The following additional items must be reported via IND safety report: 
 Findings from other studies. The sponsor must report any findings from 
epidemiological studies, pooled analysis of multiple studies, or clinical 
studies, whether or not conducted under an IND, and whether or not 
conducted by the sponsor, that suggest a significant risk to humans 
exposed to the drug. 
 Findings from animal or in vitro testing. The sponsor must report any 
findings from animal or in vitro testing, whether or not conducted by the 
sponsor, that suggest a significant risk in humans exposed to the drug, 
such as reports of mutagenicity, teratogenicity, or carcinogenicity, or 
reports of significant organ toxicity t or near the expected human 
exposure. 
 Increased rate of occurrence of serious suspected adverse reactions. 
 
Additional Guidance 
Please refer to 21CFR312.32 and “Guidance for Industry and Investigators: 
Safety Reporting Requirements for INDs and BA/BE Studies” for additional 
information and reporting requirements. All IND Safety Reports will be submitted 
in accordance with these regulations/guidances. 
 
7.4 
Data and Safety Monitoring Plan 
The Principal Investigator will provide continuous monitoring of subject safety in 
this trial with periodic reporting to the Data and Safety Monitoring Committee 
(DSMC). 
 
Meetings/teleconferences will be held at a frequency dependent on study accrual, 
and in consultation with the study Biostatistician. These meetings will include the 
investigators as well as protocol nurses, clinical research associates, regulatory 
associates, data managers, biostatisticians, and any other relevant personnel the 
principal investigators may deem appropriate.  At these meetings, the research 
team will discuss all issues relevant to study progress, including enrollment, 
safety, regulatory, data collection, etc. 
 
The team will produce summaries or minutes of these meetings. These summaries 
will be available for inspection when requested by any of the regulatory bodies 
charged with the safety of human subjects and the integrity of data including, but 
not limited to, the oversight (Office of Human Research Ethics (OHRE) 
Biomedical IRB, the Oncology Protocol Review Committee (PRC) or the North 
Carolina TraCS Institute Data and Safety Monitoring Board (DSMB). 


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The UNC LCCC Data and Safety Monitoring Committee (DSMC) will review the 
study on a regular (quarterly to annually) basis, with the frequency of review 
based on risk and complexity as determined by the UNC Protocol Review 
Committee. The UNC PI will be responsible for submitting the following 
information for review: 1) safety and accrual data including the number of 
subjects treated; 2) significant developments reported in the literature that may 
affect the safety of participants or the ethics of the study; 3) preliminary response 
data; and 4) summaries of team meetings that have occurred since the last report. 
Findings of the DSMC review will be disseminated by memo to the UNC PI, 
PRC, and the UNC IRB and DSMB. 
 
8.0 
STATISTICAL CONSIDERATIONS 
8.1 
Study Design/Study Endpoints 
 
This study will be a prospective, single arm, multicenter, open-label phase II 
clinical trial investigating the combination of nivolumab and ipilimumab with 
panitumumab in subjects with unresectable, refractory, KRAS/NRAS/BRAF wild- 
type, microsatellite stable metastatic colorectal cancer. The primary objective of 
this study is to estimate the ORR (CR + PR) in these subjects at 12 weeks by 
RECIST 1.1 criteria. Secondary objectives include the following: estimating the 
ORR (CR + PR) at 12 weeks by irRECIST criteria, estimating the best response 
rate by both RECIST 1.1 and irRECIST criteria, estimating PFS and duration of 
response using both RECIST 1.1 and irRECIST criteria, estimating OS, and 
characterizing the safety issues associated with this regimen. Exploratory 
objectives involve investigating various biomarkers and peripheral blood and 
tumor assays. 
 
8.2 
Sample Size and Accrual 
Power and sample size considerations for this study are based on the primary 
objective. The historical overall response rate (CR+PR) of KRAS wild-type 
mCRC to panitumumab is approximately 22%. The proposed treatment regimen 
is expected to increase the response rate to a clinically relevant rate of at least 
35%. A Simon two-stage minimax design will be used, with an alpha=0.10, and 
power of 80%, to evaluate the efficacy of this treatment regimen. The null and 
alternative hypothesis overall response rates (CR + PR) are 22% and 35%, 
respectively. In the first stage, 32 evaluable subjects will be enrolled and treated. 
If 6 or less of these 32 first stage subjects are ‘responders’ (i.e., either a CR or a 
PR), the trial will be suspended and study investigators will consult with the study 
funding sources (BMS and Amgen) and with the DSMC about whether or not to 
continue accruing subjects to the study. However, if 7 subjects or more are found 
to be responders, another 24 evaluable subjects will be accrued for a total of at 
least 56 evaluable subjects. If a total of 17 (or more) responders are observed 


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among the total of 56 evaluable subjects, then this treatment regimen would be 
considered of clinical interest and therefore would justify further development. 
 
We expect to accrue subjects at a rate of approximately 4 subjects per month. At 
this rate, we expect total accrual to this study to take approximately 30 months, 
allowing for up to 6 month assessment period for response between the first and 
second stages. 
 
8.3 
Toxicity Monitoring 
Toxicity will be assessed using NCI CTCAE version 4.03. Subjects will be monitored 
for excessive toxicity over the duration of the study. A toxicity rate due to the study 
regimen greater than 35% would be considered unacceptable.  Toxicity events that 
will be monitored will be those that call for discontinuation of therapy, as defined in 
Section 4.4. 
 
Pocock-type boundaries will be utilized as described in Ivanova, A., et al. Biometrics. 
2005; 61(2):540-5. If a toxicity boundary is reached, accrual for the study will be 
suspended and the Data Safety and Monitoring Committee (DSMC) will be alerted. 
The DSMC (in consultation with the Principal Investigator and the drug company) 
will evaluate the toxicity events to help determine whether or not to terminate the 
study. 
 
Accrual to the trial is to be suspended if the number of protocol defined toxic 
events is equal to or larger than boundary in the table below. 
 
Number of Subjects 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 
Boundary 
- - - - 5 6 
6 7 7 8 9 9 10 10 11 11 12 12 13 13 
Number of Subjects 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 
Boundary 
13 14 14 15 15 16 16 17 17 18 18 19 19 19 20 20 21 21 22 22 
Number of Subjects 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 
Boundary 
22 23 23 24 24 25 25 26 26 26 27 27 28 28 28 29 29 30 30 31 
Number of Subjects 61 62 63 64 65 66 
Boundary 
31 31 32 32 33 33 
 
8.4 
Data Analysis Plans 
 
ORRs and best response rates will be determined using both the RECIST 1.1 and 
irRECIST criteria will be reported along with their corresponding 95% confidence 
intervals. Wilson’s method will be used to calculate confidence intervals for these 
rates (reported as percentages). PFS and the duration of response estimates using 
both the RECIST 1.1 and irRECIST criteria will be calculated using the Kaplan- 
Meier (or product-limit) method. OS will also be calculated using the Kaplan- 
Meier (or product-limit) method. These time to event estimated functions will be 
plotted, and median time to estimates will be reported along with their 95% 


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confidence intervals. The confidence intervals for these time to event functions 
will be calculated using the standard and well known “loglog” method. If 
appropriate, 6, 12, and 24 month estimates for the time to event functions will 
also be reported. 
 
The primary analysis will apply to the total number of evaluable subjects. 
Toxicity and safety information will be reported in a descriptive manner in the 
form of frequency tables. Toxicity will be defined through the number and 
frequency of treatment-emergent grade 3 and 4 toxicities as defined by National 
Cancer Institute - Common Terminology Criteria for Adverse Events (NCI 
CTCAE v4.03). Hypothesis generating exploratory analyses will be performed 
when appropriate sample size considerations allow. The definitions of the 
outcomes (or endpoints) of interest can be found in section 2.4. 
 
9.0 
STUDY MANAGEMENT 
9.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations. The IRB should approve the 
consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration 
of Helsinki. 
 
Before recruitment and enrollment onto this study, the subject will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the subject and the investigator is assured that 
the subject understands the implications of participating in the study, the subject 
will be asked to give consent to participate in the study by signing an 
IRB-approved consent form. 
 
Prior to a subject’s participation in the trial, the written informed consent form 
should be signed and personally dated by the subject and by the person who 
conducted the informed consent discussion. 
 
9.2 
Required Documentation 
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Protocol Office (CPO) at the University of North 
Carolina. 
 
 A copy of the official IRB approval letter for the protocol and 
informed consent 


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 IRB membership list 
 CVs and medical licensure for the principal investigator and any sub- 
investigators who will be involved in the study. 
 Form FDA 1572 
 Financial disclosure 
 CAP and CLIA Laboratory certification numbers and institution lab 
normal values 
 Executed clinical research contract 
9.3 
Registration Procedures 
All subjects must be registered with the LCCC CPO Multicenter Office at the University 
of North Carolina before enrollment to study.  To register a subject call the Multicenter 
office at 919-966-7359 Monday-Friday 8:30 am – 5:00 pm EST.  Scan and email the 
Multicenter Project Manager (preferred) or fax (919-966-4300) the registration form, 
signed informed consents, signed eligibility form and all source documents to confirm 
eligibility. Eligibility may be confirmed by the UNC Study Coordinator for subjects 
treated at UNC. When sending registration request with eligibility documentation, 
please allow 24 hours for source to be reviewed. 
 
 
9.4 
Data Management and Monitoring/Auditing 
UNC LCCC will serve as the coordinating center for this trial. Data will be collected 
through a web based clinical research platform, OnCore®. Other study institutions will 
be given a password to directly enter their own data onto the web site via electronic 
case report forms (eCRFs). Multicenter personnel will coordinate and manage data for 
quality control assurance and integrity. 
 
All data will be collected and entered into OnCore® by Clinical Research Associates 
(CRAs) from UNC LCCC and participating institutions. The investigators at each site 
will allow monitors to review all source documents supporting data entered into 
OnCore®. The Multicenter Data Coordinator can be reached at 919-843-2742 or 1-877-
668-0683. 
 
All data will be monitored and source data will be verified on selected subjects.  Queries 
will be issued on an ongoing basis on all subjects. Participating sites should respond to 
data queries within 14 days of receipt. The LCCC compliance committee or their 
designee will audit trial sites every twelve months while still enrolling or subjects are still 
on treatment. Participating sites must send source and regulatory documents to LCCC 
upon request, for remote monitoring and/or audit review. 
 
9.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study subject requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol. 


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9.5.1 
Emergency Modifications 
UNC and Affiliate investigators may implement a deviation from, or a change of, the 
protocol to eliminate an immediate hazard(s) to trial subjects without prior UNC or 
their respective institution’s IRB/IEC approval/favorable opinion. 
 
For Institutions Relying on UNC’s IRB: 
For any such emergency modification implemented, a UNC IRB modification form 
must be completed by UNC Research Personnel within five (5) business days of 
making the change. 
 
For Institutions Relying on Their Own IRB: 
For Affiliate investigators relying on their own institution’s IRB, as soon as 
possible after the modification has been made, the implemented deviation or 
change and the reasons for it should be submitted to: 
 
 To UNC Principal Investigator for agreement 
 The Affiliate institution’s IRB for review and approval. (Once 
IRB’s response is received, this should be forwarded to the 
Multicenter Regulatory Associate). 
 
9.5.2 
Single Subject/Subject Exceptions 
Eligibility single subject exceptions are not permitted for Lineberger Comprehensive 
Cancer Center Investigator Initiated Trials under any circumstances. Other types of 
single subject exceptions may be allowed if proper regulatory review has been 
completed in accordance with Lineberger Comprehensive Cancer Center’s Single 
Subject Exceptions Policy. 
 
 
9.5.3 
Other Protocol Deviations/Violations 
According to UNC’s IRB, a protocol deviation is any unplanned variance from an IRB 
approved protocol that: 
 Is generally noted or recognized after it occurs 
 Has no substantive effect on the risks to research participants 
 Has no substantive effect on the scientific integrity of the research plan or 
the value of the data collected 
 Did not result from willful or knowing misconduct on the part of the 
investigator(s). 
 
An unplanned protocol variance is considered a violation if the variance meets any 
of the following criteria: 


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 Has harmed or increased the risk of harm to one or more research 
participants. 
 Has damaged the scientific integrity of the data collected for the study. 
 Results from willful or knowing misconduct on the part of the 
investigator(s). 
 Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies. 
If a deviation or violation occurs please follow the guidelines below: 
For Institutions Relying on UNC’s IRB: 
Protocol Deviations: UNC or Affiliate personnel will record the deviation in 
OnCore®, and report to any sponsor or data and safety monitoring committee in 
accordance with their policies. Deviations should be summarized and reported to 
the IRB at the time of continuing review. 
 
Protocol Violations: Violations should be reported by UNC personnel within one 
(1) week of the investigator becoming aware of the event using the same IRB 
online mechanism used to report Unanticipated Problems. 
 
For Institutions Relying on Their Own IRB: 
In addition to adhering to the policies regarding protocol compliance set forth by 
your institution’s IRB, the following is also required: 
 
Protocol Deviations: In the event a deviation from protocol procedures is 
identified, record the deviation in OnCore®. 
 
Protocol Violations: Any protocol violation that occurs must be reported to your 
IRB per institutional policies and reported to the Multicenter Project Manager 
within 5 days. UNC-CH will determine if the violation affects the safety of the 
subject and integrity of the data. Once your institution’s IRB response is received, 
please forward to the Multicenter Regulatory Associate. 
 
Unanticipated Problems: 
UNC 
Any events that meet the criteria for “Unanticipated Problems” as defined by 
UNC’s IRB must be reported by the Study Coordinator using the IRB’s web- 
based reporting system. 
 
Affiliate Sites: 
Any events that meet the criteria for “Unanticipated Problems (UPs)” as defined 
by UNC’s IRB must also be reported to the Multicenter Project Manager. The 
Multicenter Project Manager will report the event to the UNC IRB using the 
IRB’s web-based reporting system. Examples of such UPs include a lost or stolen 
laptop computer that contains sensitive study information. 


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9.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be 
originated and documented by the Principal Investigator at UNC. It should also 
be noted that when an amendment to the protocol substantially alters the study 
design or the potential risk to the subject, a revised consent form might be 
required. 
 
For Institutions Relying on UNC’s IRB: 
The written amendment, and if required the amended consent form, must be sent 
to UNC’s IRB for approval prior to implementation. 
 
For Institutions Relying on Their Own IRB: 
Investigators must submit the amendment to their institution’s IRB for approval. 
For multicenter studies, any multicenter site must submit their informed consent 
revisions to the Multicenter Regulatory Associate prior to submission to their 
IRB. 
 
9.7 
Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed subject consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study 
documentation pertaining to the conduct of a clinical trial must be retained by the 
study investigator. In the case of a study with a drug seeking regulatory approval 
and marketing, these documents shall be retained for at least two years after the 
last approval of marketing application in an International Conference on 
Harmonization (ICH) region. In all other cases, study documents should be kept 
on file until three years after the completion and final study report of this 
investigational study. 
 
9.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki. The Principal Investigator is responsible for personally 
overseeing the treatment of all study subjects. The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study 
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations 
and guidelines regarding clinical trials both during and after study completion. 


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The Principal Investigator at each institution or site will be responsible for 
assuring that all the required data will be collected and entered into the eCRFs. 
Periodically, monitoring visits will be conducted, and the Principal Investigator 
will provide access to his/her original records to permit verification of proper 
entry of data. At the completion of the study, all eCRFs will be reviewed by the 
Principal Investigator and will require his/her final signature to verify the 
accuracy of the data. 
 
 
 


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promoting type 2 macrophages by EGFR-targeting antibody cetuximab. Clin Cancer Res 
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Nabholtz JM, Abrial C, Mouret-Reynier MA, et al. Multicentric neoadjuvant 
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+ chemotherapy in advanced colorectal cancer subjects. J Clin Oncol; 2008. 
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Zhang W, Gordon M, Schultheis AM, et al. FCGR2A and FCGR3A 
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Oncology 2007;25:3712-8. 
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first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of 
an open-label, phase 1, multicohort study. Lancet Oncol 2017;18:31-41. 


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11.0 APPENDICES 
11.1 
ECOG Performance Status 
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
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). 
2 
In bed <50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., 
Davis, T.E., McFadden, E.T., Carbone, P.P. Toxicity and Response Criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative 
Oncology Group, Robert Comis M.D., Group Chair. 


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11.2 
Treatment Algorithms for Nivolumab Therapy 
 
Algorithms are presented for management of GI, renal, hepatic, pulmonary, endocrine, 
skin and neurological toxicities are provided. NCI-CTCAEv4.03 criteria apply as 
referenced in the protocol. The algorithms are potential suggested schemes for 
management of potential irAEs but should only serve as a complement to 
investigator judgment and additional guidelines for monitoring and management of 
immune related toxicities. Additionally, recommend management referring to NCCN 
Guidelines “Management of Immune Checkpoint Inhibitor-Related Toxicities.” In cases 
of discrepancy between the algorithms and additional guidelines, investigator judgment 
should be used, and highly encourage consultation with medical monitor.


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11.3 
Cockcroft-Gault Formula 
 
Males: 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age) 
. 
72 x serum creatinine (mg/dL) 
Females: 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age) 
 
x 0.85 
72 x serum creatinine (mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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