Clinical trial NCT03642067
Conditions: Microsatellite Stable (MSS) Colorectal Adenocarcinomas Colorectal Adenocarcinoma
Keywords: Relatlimab Nivolumab Immunotherapy Anti-PD-1 Anti-LAG-3 Antibody MSS PD-L1 Microsatellite stability Colorectal cancer Colon cancer Rectal cancer
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Start date: 2019-02-12; Completion date: 2024-09-18
Enrollment: 59 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and clinical activity of nivolumab and relatlimab in patients with metastatic or locally advanced microsatellite stable (MSS) colorectal cancer.

Detailed description:

Arms: arm 1: Participants were pre-screened for CPM score. The CPM score integrates the percent of PD-L1 expression at the tumor interface and the percent of acellular mucin in the tumor area (\[%PD-L1 + % acellular mucin\]/2) using each participant's primary tumor tissue. A CPM score cutoff of greater than or equal to 15% was used to determine CPM positivity.

Participants received 480mg Nivolumab and 160mg Relatlimab. arm 2: Participants were pre-screened for CPM score. The CPM score integrates the percent of PD-L1 expression at the tumor interface and the percent of acellular mucin in the tumor area (\[%PD-L1 + % acellular mucin\]/2) using each participant's primary tumor tissue. A CPM score cutoff of less than 15% was used to determine CPM negativity.

Participants received 480mg Nivolumab and 160mg Relatlimab. arm 3: Participants were not pre-screened for composite PD-L1/mucin (CPM) score.

Participants received 480mg Nivolumab and 960mg Relatlimab (dose reduced to 480mg or 160mg).
Interventions: intervention 1: Nivolumab intervention 2: Relatlimab
Intervention descriptions: intervention 1: Nivolumab was administered IV on day 1 of each 28 day cycle. intervention 2: Relatlimab was administered IV on day 1 of each 28 day cycle.

Protocol documents:
Prot_SAP_000.pdf: 
Cover Page for Protocol – J18119 
NCT Number: 
NCT03642067 
Official title of study 
A Phase 2 study Evaluating Response 
and Biomarkers in Patients with 
Microsatellite Stable (MSS) Advanced 
Colorectal Cancer treated with 
Nivolumab in Combination with 
Relatlimab 
Document Date: 
March 31, 2022 


J18119/Amendment 8 / Version 9.0 / March 31, 2022 
1
TITLE: A Phase 2 study Evaluating Response and Biomarkers in Patients with Microsatellite 
Stable (MSS) Advanced Colorectal Cancer treated with Nivolumab in Combination with 
Relatlimab 
 
Johns Hopkins Protocol #: J18119, IRB00173537 
 
BMS Protocol #: 
 
CA224-068 
 
Principle Investigator: 
Dung Le, M.D.  
 
Sidney Kimmel Comprehensive Cancer Center, 
 
 
 
 
Johns Hopkins University 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bristol-Myers Squibb Supplied Agents: 
Nivolumab (BMS-936558; anti-PD-1 mAb) 
 
 
 
 
 
 
Relatlimab (BMS-986016, anti-LAG-3 mAb) 
 
IND:  
 
 
IND 140419 
 
IND Sponsor:  
 
Dung Le, M.D. 
 
Date of Issue:  
 
Original/Version 1/August 6, 2018 
Original/Version 1.1/September 4, 2018  
Amendment 1/Version 2.0/October 29, 2018 
Amendment 2/Version 3.0/November 14, 2018 
Amendment 3/Version 4.0/February 5, 2019 
Amendment 4/Version 5.0/June 21, 2019 
Amendment 5/Version 6.0/June 16, 2020 
Amendment 6/Version 7.0/August 19, 2020 
Amendment 7/Version 8.0/ August 3, 2021 
Amendment 8/Version 9.0/March 31, 2022 
 


 
2
TABLE OF CONTENTS 
1. 
Objectives .......................................................................................................................... 4 
1.1. 
Primary Objective ............................................................................................................... 4 
1.2. 
Secondary Objective ........................................................................................................... 4 
1.3. 
Exploratory Objectives ....................................................................................................... 4 
1.4. 
Study Design ....................................................................................................................... 5 
2. 
Background ....................................................................................................................... 7 
2.1. 
Study Disease ...................................................................................................................... 7 
2.2. 
Dual Blockade of PD-1 and LAG-3 .................................................................................... 7 
2.3. 
Relatlimab Dose Selection .................................................................................................. 7 
2.4. 
Rationale ........................................................................................................................... 11 
3. 
Patient Selection .............................................................................................................. 14 
3.1. 
Eligibility Criteria ............................................................................................................. 14 
3.2. 
Exclusion Criteria ............................................................................................................. 16 
3.3. 
Inclusion of Women and Minorities ................................................................................. 18 
3.4. 
Composite PD-L1/Mucin (CPM) Score  ........................................................................... 18 
3.5. 
MSI Testing ...................................................................................................................... 20 
4. 
Treatment Plan ............................................................................................................... 20 
4.1. 
Agent Administration ....................................................................................................... 20 
4.2. 
General Concomitant Medication and Supportive Care Guidelines ................................. 21 
4.3. 
Prohibited and/or Restricted Treatments .......................................................................... 23 
4.4. 
Other Restrictions and Precautions ................................................................................... 23 
4.5. 
Permitted Therapy ............................................................................................................. 23 
4.6. 
Definition of an Overdose for this Protocol ...................................................................... 24 
4.7. 
Unacceptable Toxicity ...................................................................................................... 25 
4.8. 
WOCBP, Contraception, Use in Pregnancy, Use in Nursing ........................................... 25 
4.9. 
Duration of Therapy .......................................................................................................... 29 
4.10. 
Criteria for Removal from Treatment ............................................................................... 29 
4.11. 
End of Treatment (EOT) ................................................................................................... 32 
4.12. 
Duration of Follow Up ...................................................................................................... 32 
5. 
Dosing Delays/Dose Modifications ................................................................................. 33 
5.1. 
Dose Modifications ........................................................................................................... 33 
5.2. 
Dose Delays ...................................................................................................................... 33 
6. 
Adverse Events: List and Reporting Requirements .................................................... 35 
6.1. 
Definitions ........................................................................................................................ 35 
6.2. 
Relationship ...................................................................................................................... 37 
6.3. 
Expectedness ..................................................................................................................... 38 
6.4. 
Handling of Expedited Safety Reports ............................................................................. 38 
6.5. 
Reporting .......................................................................................................................... 38 
7. 
Pharmaceutical Information .......................................................................................... 42 
7.1. 
Agent Accountability ........................................................................................................ 42 
7.2. 
Mode of Action ................................................................................................................. 42 
7.3. 
Description ........................................................................................................................ 42 
7.4. 
Packaging and Labeling Information ................................................................................ 43 
7.5. 
Preparation ........................................................................................................................ 43 
7.6. 
Storage .............................................................................................................................. 44 
7.7. 
Stability ............................................................................................................................. 44 


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7.8. 
Route of Administration ................................................................................................... 44 
7.9. 
Subject Care Implications ................................................................................................. 45 
7.10. 
Returns and Reconciliation ............................................................................................... 46 
8. 
Correlative/Special Studies ............................................................................................ 47 
8.1. 
Tumor Tissue Studies ....................................................................................................... 47 
8.2. 
Whole Blood ..................................................................................................................... 47 
8.3. 
Peripheral Blood Mononuclear Cells (PBMCs)................................................................ 48 
8.4. 
Serum and Plasma Marker Studies ................................................................................... 48 
8.5. 
Diagnostic Tissue Samples ............................................................................................... 48 
8.6. 
Microbiome Studies .......................................................................................................... 48 
8.7. 
Genomic Analysis ............................................................................................................. 49 
9. 
Study Calendar ............................................................................................................... 50 
9.1. 
Cohorts A and B ............................................................................................................... 50 
9.2. 
Cohort C ............................................................................................................................ 53 
10. 
STUDY ENDPOINTS ..................................................................................................... 56 
10.1. 
Primary Endpoint .............................................................................................................. 56 
10.2. 
Secondary Endpoint .......................................................................................................... 56 
10.3. 
Exploratory Endpoints ...................................................................................................... 56 
11. 
Data Reporting/ Regulatory Requirements .................................................................. 57 
11.1. 
Data Collection and Processing ........................................................................................ 57 
11.2. 
Safety Meetings ................................................................................................................ 58 
11.3. 
Monitoring ........................................................................................................................ 58 
11.4. 
Study Documentation ....................................................................................................... 58 
12. 
Statistical Considerations ............................................................................................... 60 
12.1. 
Study Design/Endpoints ................................................................................................... 60 
12.2. 
Safety Analysis ................................................................................................................. 62 
13. 
References ........................................................................................................................ 63 
APPENDIX A: Performance Status Criteria ......................................................................................... 66 
APPENDIX B: Management Algorithms ............................................................................................... 67 
APPENDIX C: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors .......................................................................... 76 
APPENDIX D: Description of the iRECIST Process For Assessment of Disease Progression .......... 79 
APPENDIX E: SAE Reporting Form ..................................................................................................... 84 
 
 
 
 
 


 
4
1. 
OBJECTIVES 
 
1.1. 
Primary Objective 
 
Cohort A/B: To estimate the objective response rate (ORR) in patients with metastatic or locally 
advanced microsatellite stable (MSS) colorectal cancer that have a positive and negative composite 
PD-L1/Mucin (CPM) score treated with nivolumab and relatlimab. 
 
Cohort C: To estimate the objective response rate (ORR) in patients with metastatic or locally 
advanced microsatellite stable (MSS) colorectal cancer without prospective biomarker selection 
treated with nivolumab and relatlimab. 
 
1.2. 
Secondary Objective 
 
1.2.1. To assess safety and characterize toxicities of nivolumab in combination with 
relatlimab.  
 
1.3. 
Exploratory Objectives 
 
1.3.1. To assess the overall survival (OS), progression free survival (PFS), time to-
progression (TTP), disease control rate (DCR), best overall response (BOR), 
duration of response (DOR), duration of clinical benefit (DCB), and time to 
objective response (TTOR) of patients with metastatic or locally advanced 
microsatellite stable (MSS) colorectal cancer that have a positive and negative CPM 
score treated with nivolumab and relatlimab. 
 
1.3.2. To assess immune objective response rate (iORR) by immune-related RECIST 
criteria (iRECIST). 
 
1.3.3. To evaluate CPM score and determine the cut-off threshold as a predictive marker 
for I-O treatment in patients with MSS CRC. 
 
1.3.4. To collect pre- and on-treatment biopsies to explore the association of features of 
the tumor microenvironment with response to therapy, including assessment of T 
cell subset markers (CD4, CD8, FoxP3, Granzyme A/B, CD69), immune regulation 
(PD-L1, PD-L2, CTLA4, LAG-3, IDO1, TIM-3), and immune cell population 
markers (NK, DC, B cell, MDSC). 
 
1.3.5. To evaluate molecular determinants such as KRAS and BRAF status 
 
1.3.6. To evaluate molecular determinants of response using next generation sequencing 
and other sequencing techniques. 
 
 Characterize the tumor mutational landscape through exomic sequencing for 
mutation analysis and MANA prediction. 
 


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5
1.3.7. To assess tumor burden dynamics using standard protein biomarkers when 
available 
as 
well 
as 
circulating 
biomarkers 
(i.e. 
ctDNA). 
 
1.3.8. To collect peripheral blood lymphocytes to explore the association of lymphocyte 
activation markers with clinical response. 
 
1.3.9. To evaluate clonal T cell populations in the tumor and in the periphery through T 
cell receptor sequencing, and to functionally assess mutation associated 
neoantigen-specific T cells. 
 
1.3.10. To collect stool and oral wash (and/or buccal mucosal) samples at baseline and 
throughout treatment to explore the association of changes in the host microbiome 
and clinical outcome. 
 
 Microbial community analysis to correlate gut microbiome composition with 
response (OS, PFS and best overall response). 
 
 Whole metagenome functional profiling analysis via shotgun sequencing to 
correlate microbiome composition and microbial functions and pathways with 
response (OS, PFS and best overall response). 
 
1.4. 
Study Design 
 
This is an open-label, two stage, phase 2 study to evaluate the safety and clinical activity of 
nivolumab and relatlimab in patients with metastatic or locally advanced microsatellite stable 
(MSS) colorectal cancer that have a positive and negative composite PD-L1/Mucin (CPM) score. 
The primary endpoint is objective response rate (ORR) assessed using RECIST 1.1.   
 
The trial will enroll two cohorts of MSS mCRC patients receiving 480mg nivolumab/160mg 
relatlimab: patients with MSS colorectal adenocarcinomas who have a positive CPM score (Cohort 
A); and patients with MSS colorectal adenocarcinomas who have a negative CPM score (Cohort 
B). The cutoff threshold > 15% of CPM will be used to determine CPM positivity. An additional 
cohort of MSS mCRC patients without biomarker selection will be enrolled to receive either 
480mg nivolumab/960mg relatlimab or 480mg nivolumab/480mg relatlimab (Cohort C). As of 
Amendment 6, enrollment will begin to Cohort C. Enrollment to Cohorts A and B will resume 
once enrollment to Cohort C is complete.  
 
As of Amendment 7, newly enrolled patients in Cohort C will receive 480mg nivolumab/480mg 
relatlimab Q4W. Patients previously treated in Cohort C at 960mg relatlimab will either be dose 
reduced to relatlimab 160mg, 480mg, or continue to receive relatlimab 960mg if they are past the 
8 week safety window at the discretion of the Principal Investigator.  
 
 
. Patients receiving 
relatlimab 480mg or 960mg will have an increase in the frequency of safety monitoring per Section 
9. 
  


 
6
 
Each cohort will enroll up to 32 evaluable patients. The primary endpoint is objective response 
rate (ORR) per RECIST 1.1, and the three cohorts will be analyzed separately for the primary 
analysis of rate of ORR. For each cohort, the treatment will be considered inactive and of no 
interest for further evaluation if the ORR is 5% or less and considered active if the ORR is 20% or 
greater. This design allows for the simultaneous evaluation of the efficacy of the treatment and 
CPM as a predictive marker.   
  
Simon two-stage minimax design is planned for each cohort.  Initially, 18 patients per cohort will 
be treated in Stage 1. Patients will be considered evaluable if they receive at least one dose of study 
drug. If there is at least 1 response in the initial 18 patients in a cohort, then an additional 14 
patients will be enrolled in Stage 2 for a total of 32 (18 + 14 = 32) patients in that cohort. If a total 
of 4 or more responses are observed in Stages 1 and 2 combined, we conclude the regimen is 
promising and warrants further study. This design has 90% power to reject the null response rate 
of 5% in favor of 20% response rate, with one-sided type 1 error 0.1.   
 
We expect that the prevalence of a positive CPM score is 10-15% among MSS CRC patients. 
Therefore, we will need to pre-screen 220-320 MSS CRC patients in order to identify 32 marker 
positive MSS CRC patients. Assuming 95% of CRC patients are MSS, we will pre-screen a total 
of 235-340 CRC patients. 
 
The study will consist of a pre-screening period (for Cohorts A and B), a screening period (within 
28 days of the first dose), a treatment period, and a follow-up period. Subjects will receive 
treatment on 28 day cycles, and will come to clinic for dosing and/or assessments on Day 1 of each 
cycle and additional days for safety and immune monitoring follow up as per the study schedule 
in Section 9. No dose escalations or reductions of nivolumab or relatlimab are allowed. Complete 
information on study drug administration, schedule, and dosing can be found in Section 4.1. 
 
The study will include a safety run-in for the first six patients for Cohorts A and B only. If more 
than 1 of the first 6 patients experiences an unacceptable toxicity within the first cycle, then 
enrollment will be halted and the overall risk-benefit ratio of the study will be reconsidered. At 
any time thereafter, if more than 33% of patients are observed to experience unacceptable toxicity 
within the first cycle, enrollment will be halted and the safety of the combination will be re-
evaluated. Complete unacceptable toxicity criteria can be found in Section 4.7. 
 
Treatment may continue per investigator discretion, or until discontinuation due to toxicity, lack 
of clinical benefit as determined by the investigator, subject withdrawal, or termination of the study 
by the IND sponsor. Subjects may continue on treatment with radiographic disease progression if 
subject is clinically stable and investigator believes the treatment is providing benefit. Criteria for 
removal from treatment are found in Section 4.10.  
 
Tumor biopsies, PBMC, serum and plasma collection, microbiome samples, and computed 
tomography (CT) scans or magnetic resonance imaging (MRI), if CT is contraindicated, will be 
obtained at baseline and during treatment for clinical assessments and correlative analyses. Tumor 
assessments will be made using RECIST 1.1 and iRECIST. 
 


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7
Subjects will return to the study site 30 (+/- 7) days after the final administration of study treatment 
for an end of treatment (EOT) evaluation. Subjects will be considered in the treatment period until 
30 days after the last dose of study drug. After completion of treatment and EOT assessments, all 
subjects will continue to be followed per Section 4.12. 
 
Information on progression-free survival and overall survival may continue to be gathered for 
supplementary analyses after the completion of the primary analysis.  
 
2. 
BACKGROUND 
 
2.1. 
Study Disease 
 
As the third leading cause of cancer in both men and woman in the United States, it is estimated 
that 50,630 people will die from colorectal cancer (CRC) in 2018[1]. The majority of CRC cases 
are due to spontaneous genetic changes, which can include microsatellite instability (MSI), 
chromosomal instability (CIN), and the CpG island methylator phenotype (CIMP)[2]. 
Approximately 15 percent of all CRC (4% in metastatic CRC) are considered microsatellite 
instability (MSI-high), whereas 85 percent of all CRC cases are microsatellite stable (MSS) or 
MSI-low. The immune system has long been known to play a role in CRC, where intratumoral 
immune infiltration has been shown to correlate with improved prognosis[3-11]. While durable 
objective responses (OR) following T cell checkpoint inhibition in the treatment of refractory solid 
tumors[12-16] are a proof of principle that endogenous adaptive immune responses can be 
harnessed by immunotherapy[17-20],  no objective clinical responses with anti-PD-1 
(nivolumab)[21] or an anti-PD-L1 antibody (BMS936559/MDX-1105)[13] were observed in CRC 
patients with the rare exception in an MSI-H CRC patient[22].  
 
2.2. 
Dual Blockade of PD-1 and LAG-3 
 
Lymphocyte-activation gene 3 (LAG-3) is a cell surface molecule expressed on activated T cells, 
and has a negative regulatory effect on T cell function. While the mechanism by which it modulates 
T lymphocyte activity is incompletely understood, it has structural homology with CD4 and binds 
its primary ligand, MHC class II with higher affinity than CD4, thereby mediating a state of T cell 
exhaustion. Relatlimab (BMS-986016) is fully human monoclonal immunoglobulin (Ig) G4 
antibody that binds to a defined epitope on LAG-3 with high affinity and specificity and potently 
blocks the interaction of LAG-3 with MHC class II, resulting in a reversal of LAG-3-mediated T-
cell downregulation. 
 
In preclinical models and early clinical studies, anti-LAG-3 antibodies have demonstrated minimal 
anti-tumor activity as a single agent but synergistic activity when combined with anti-PD-1 
antibody. The combination of the PD-1 inhibitor nivolumab plus the LAG-3 inhibitor relatlimab 
is being tested in the ongoing phase 1/2a trial CA224020. As of April 2017, 268 subjects had been 
treated with relatlimab monotherapy (N=25) or combination with nivolumab (N=243), with 
acceptable safety profile observed at all doses tested. Of 48 evaluable patients in the PD-1/PD-L1 
experienced melanoma cohort, an ORR of 12.5% and DCR of 54% was observed [23].  
 
2.3. 
Relatlimab Dose Selection 


 
8
 
Nivolumab was recently approved for use at a dosing of 480 mg flat dosing every 4 weeks in 
multiple cancers, based on clinical data and population PK (PPK) simulations and exposure-
response analyses suggesting no significant impact on toxicity or efficacy. Similarly, a Q4 weekly 
dosing of relatlimab is highly desirable from an economic standpoint and for patient convenience. 
The justification for the flat dosing of relatlimab at 160 mg Q4 weekly is based on PPK simulation 
predicting similar exposure to that seen with Q2W dosing. The safety of relatlimab 160 mg Q4W 
in combination with nivolumab 480 mg Q4W is being evaluated in the ongoing Phase 1/2a study 
CA224020, and will be further evaluated in the present study. Please see the Relatlimab 
Investigator’s Brochure for more information regarding experience and safety of 
nivolumab/relatlimab 160/480 Q4W dose. 
 
2.3.1. Justification for 480 or 960 mg Q4W 
 
The target dose of relatlimab 480 mg Q4W dose is based on the consideration of clinical safety 
and target engagement will provide meaningful clinical activity. The relatlimab dose was selected 
after consideration of several factors including relatlimab PK, pharmacodynamics, population 
pharmacokinetic (PPK) model predicted exposure metrics, benefit/risk assessment of relatlimab 
and nivolumab co-administration, and extensive nivolumab monotherapy clinical experience. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety: 
 


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9
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 


 
10
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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11
 
 
 
 
 
 
 
Please see the Relatlimab Investigator’s Brochure for more information regarding experience and 
safety of relatlimab 480 mg Q4W dose. 
 
2.4. 
Rationale 
 
Mismatch repair (MMR) deficient tumors, also termed MSI-high, harbor hundreds to thousands of 
mutation-associated neoantigens (MANAs) that can be recognized and targeted by T cells. Several 
studies have revealed that anti-CTLA-4 or anti-PD-1 therapies can unleash and amplify preexisting 
MANA-specific tumor-infiltrating T cells in the tumor and peripheral blood[25, 26]. Data from a 
phase II trial by Le et al demonstrated that 90 percent of MSI-high patients (9/10) experienced 
either an objective response or disease stabilization, as compared to only 11 percent of MSS 
patients (2/18), with disease stabilization being the best response seen in MSS patients[27]. The 
updated overall response rate (ORR) was 53% in MSI-H CRC[28].  In a separate clinical trial, 
nivolumab resulted in a 31% response rate and the combination of nivolumab and ipilimumab led 
to a 55% ORR[29, 30]. One explanation that could account for why some MSI-high patients 
progress after checkpoint blockade and conversely, why some MSS patients exhibit disease control 
could potentially be found in the differences in tumor immune microenvironment (TiME). 
We recently established that the high density of somatic mutations found in MSI-high CRC tumors 
exhibit robust IFNγhiPD-1hiCD8+ T cell infiltration that is associated with myeloid expression of 
the PD-1 ligand, PD-L1, in response to IFNγ production in the TiME[31]. Upregulated expression 
of several T cell checkpoints, including LAG-3, CTLA-4, and PD-1, suggest that MSI-high CRC 
tumors trigger an endogenous anti-tumor immune response that is counter-regulated by the 
expression of a variety of immunoregulatory ligands[31]. 
 
 
 
 
 


 
12
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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13


 
14
 
This study aims to target immune checkpoints PD-1 and LAG-3 to synergistically improve T cell 
activation and proliferation by circumventing T cell exhaustion and regulation that promote 
immune evasion by tumors. This study will be an open label, phase II study to evaluate ORR in 
patients with metastatic or locally advanced MSS CRC that have a positive and negative CPM 
score treated with nivolumab and relatlimab. 
 
3. 
PATIENT SELECTION 
 
3.1. 
Eligibility Criteria 
 
3.1.1. Age ≥18 years. 
 
3.1.2. ECOG performance status of 0-1 (Appendix A). 
 
3.1.3. Patients with histologically proven metastatic or locally advanced microsatellite 
stable (MSS) colorectal adenocarcinoma. 
 
3.1.4. Cohort A: Primary lesion has a composite PD-L1/Mucin (CPM) score ≥ 15%. 
 
3.1.5. Cohort B: Primary lesion has a composite PD-L1/Mucin (CPM) score < 15%. 
 
3.1.6. Cohort C: Prior surgical resection of primary tumor. Prospective biomarker 
evaluation not required. 
 
3.1.7. Patients who have received at least one prior cancer chemotherapy regimen in the 
locally advanced/metastatic setting. Adjuvant therapy can only be counted if 
recurrence occurred within 6 months of completing systemic chemotherapy.  


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15
Radiosensitizing doses of chemotherapy are not considered systemic 
chemotherapy.  Patients should be considered for standard therapies. 
 
3.1.8. Presence of at least one lesion with measurable disease as defined by 10 mm in 
longest diameter for a soft tissue lesions or 15 mm in short axis for a lymph node 
by RECIST 1.1. 
 
3.1.9. Patients must have available archival tissue from the surgical resection of their 
primary tumor for CPM score determination. 
 
3.1.10. Patient’s acceptance to have a tumor biopsy of an accessible lesion at baseline and 
on treatment if the lesion can be biopsied with acceptable clinical risk (as judged 
by the investigator). 
 
3.1.11. Life expectancy of greater than 3 months. 
 
3.1.12. Patients must have normal organ and marrow function as defined below: 
- 
Leukocytes 
 
 
≥ 2,000/mm3 
- 
Absolute neutrophil count 
≥1,500/mm3 
- 
Platelets 
 
 
 
≥100,000/mm3 
- 
Hemoglobin 
 
 
≥8.5 g/dL 
- 
Total bilirubin 
 
 
≤ 1.5 x ULN except subjects with Gilbert’s  
Syndrome, who must have normal direct 
bilirubin 
- 
AST(SGOT) and ALT(SGPT) 
≤ 3.0 x ULN 
- 
Albumin  
 
 
≥ 2.8 g/dl 
- 
Lipase and amylase 
 
< 1.5 x ULN Subjects with values > 1.5  
ULN may enroll if there are neither clinical 
nor radiographic signs of a pancreatitis. 
- 
Creatinine  
 
 
≤ 1.5 x ULN or creatinine clearance (CrCl)  
≥ 40 mL/min (if using the Cockroft-Gault 
formula below): 
 
Female CrCl = (140 - age in years) x weight in kg x 0.85 
                              72 x serum creatinine in mg/dL 
 
    Male CrCl = (140 - age in years) x weight in kg x 1.00  
                     
 
 
 
 
72 x serum creatinine in mg/dL 
 
3.1.13. LVEF assessment with documented LVEF ≥ 50% by either TTE or MUGA (TTE 
preferred) within 6 months from first study drug administration. 
 
3.1.14. Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 3 
days prior to start of study drug. In a case of a positive HCG test, a vaginal 
ultrasound must be used to confirm a lack of pregnancy. WOCBP is defined in 


 
16
Section 4.8. WOCBP must agree to follow instructions for method(s) of 
contraception for the duration of treatment with study drugs plus an additional 165 
days (approximately 24 weeks) after the last dose of nivolumab and/or relatlimab. 
Should a woman become pregnant or suspect she is pregnant while she or her 
partner is participating in this study, she should inform her treating physician 
immediately. Men who are sexually active with WOCBP must agree to follow 
instructions for method(s) of contraception for the duration of treatment with study 
drugs plus an additional 225 days (approximately 33 weeks) after the last dose of 
study drug. 
 
3.1.15. Patient understands the study regimen, its requirements, risks and discomforts and 
is able and willing to sign the informed consent form in accordance with regulatory 
and institutional guidelines must be obtained before the performance of any 
protocol related procedures that are not part of normal patient care. Subjects must 
be competent to report AEs, understand the drug dosing schedule and use of 
medications to control AEs.  
 
3.2. 
Exclusion Criteria 
 
3.2.1. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least 
four weeks prior to the first dose of trial treatment and any neurologic symptoms 
have returned to baseline), have no evidence of new or enlarging brain metastases, 
and are not using steroids for at least 1 week prior to initiation of study treatment. 
This is not applicable to patients with primary brain tumors. 
 
3.2.2. Patient is expected to require any other form of systemic or localized antineoplastic 
therapy while on study. 
 
3.2.3. Patients with a history of prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CTLA4, or anti-Lag-3 antibodies. 
 
3.2.4. Any of the following procedures or medications: 
- 
Within 2 weeks prior to initiation of study treatment: 
o Systemic or topical corticosteroids at immunosuppressive doses (> 10 
mg/day of prednisone or equivalent). Inhaled or topical steroids, and adrenal 
replacement steroid doses ≤ 10 mg daily prednisone equivalent, are 
permitted in the absence of active autoimmune disease. 
o Palliative radiation or gamma knife radiosurgery. 
o Chemotherapy 
- 
Within 4 weeks prior to initiation of study treatment: 
o Any investigational cytotoxic drug. Exposure to any non-cytotoxic drug 
within 4 weeks or 5 half-lives (whichever is shorter) is prohibited. If 5 half-
lives is shorter than 4 weeks, agreement with IND Sponsor is mandatory. 
o Non-oncology vaccines containing live virus. 


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17
o Allergen hyposensitization therapy. 
o Growth factors, e.g. granulocyte-colony stimulating factor (G-CSF), 
granulocyte 
macrophage-colony 
stimulating 
factor 
(GM-CSF), 
erythropoietin 
o Major surgery 
 
3.2.5. History of severe hypersensitivity reaction to any monoclonal antibodies or related 
compounds or to any of their components (e.g., history of severe hypersensitivity 
reactions to drugs formulated with polysorbate 80).  
  
3.2.6. Uncontrolled intercurrent acute or chronic medical illness. 
 
3.2.7. Has an active known or suspected autoimmune disease. Subjects with type I 
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin 
disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, 
or conditions not expected to recur in the absence of an external trigger are 
permitted to enroll. 
 
3.2.8. Has a diagnosis of immunodeficiency.  
 
3.2.9. Prior tissue or organ allograft or allogeneic bone marrow transplantation. 
Exceptions can be approved by the IND Sponsor if loss of the graft is not a clinical 
concern. 
 
3.2.10. A known or underlying medical condition that, in the opinion of the Investigator, 
could make the administration of study drug hazardous to the subject or could 
adversely affect the ability of the subject to comply with or tolerate study. 
 
3.2.11. Patients with a history of interstitial lung disease. 
 
3.2.12. Requirement for daily supplemental oxygen. 
 
3.2.13. Uncontrolled or significant cardiovascular disease (i.e. cardiomyopathy, congestive 
heart failure with New York Heart Association (NYHA) functional classification 
III-IV, pericarditis, significant pericardial effusion, significant coronary stent 
occlusion), including, but not limited to any of the following:  
- 
Myocardial infarction (MI) or stroke/transient ischemic attack within the 6 
months prior to consent 
- 
Uncontrolled Angina within the 3 months prior to consent 
- 
Any history of clinically significant arrhythmias (such as ventricular 
tachycardia, ventricular fibrillation, or torsades de pointes) 
- 
QTc prolongation > 480 msec 
- 
Cardiovascular disease-related requirement for daily supplemental oxygen 
- 
History of two or more MIs OR two or more coronary revascularization 
procedures 
- 
Subjects with history of myocarditis, regardless of etiology. 


 
18
 
3.2.14. Troponin T (TnT) or I (TnI) >2 x ULN. Subjects with TnT or TnI levels between 
>1 to 2 x ULN will be permitted if repeat levels within 24 hours are ≤ 1 x ULN. If 
TnT or TnI levels are >1 to 2 x ULN within 24 hours, the subjects may undergo a 
cardiac evaluation and be considered for treatment, following a discussion with the 
IND Sponsor.  When repeat levels within 24 hours are not available, a repeat test 
should be conducted as soon as possible. If TnT or TnI repeat levels beyond 24 
hours are < 2 x ULN, the subject may undergo cardiac evaluation and be considered 
for treatment, following discussion with the IND Sponsor. 
 
3.2.15. Has a confirmed history of encephalitis, meningitis, or uncontrolled seizures in the 
year prior to informed consent. 
 
3.2.16. Positive blood screen for Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies) or known acquired immunodeficiency syndrome (AIDS). 
 
3.2.17. Any positive test for Hepatitis B or Hepatitis C virus indicating presence of virus, 
e.g. Hepatitis B surface antigen or Hepatitis C antibody positive (except if HCV- 
RNA negative).  
 
3.2.18. Has active infection requiring systemic antibacterial, antiviral, or antifungal 
therapy ≤ 7 days prior to initiation of study drug. 
 
3.2.19. Subjects unable to undergo venipuncture and/or tolerate venous access. 
 
3.2.20. Any other sound medical, psychiatric, and/or social reason as determined by the 
Investigator. 
 
3.2.21. Patient is, at the time of signing informed consent, a regular user (including 
“recreational use”) of any illicit drugs or had a recent history (within the last year) 
of substance abuse (including alcohol). 
 
3.2.22. Women who are pregnant or nursing. 
 
3.2.23. Women with a positive pregnancy test on enrollment or prior to investigational 
product administration. 
 
3.2.24. WOCBP and men with female partners (WOCBP) who are not willing to use 
contraception. 
 
3.3. 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
3.4. 
Composite PD-L1/Mucin (CPM) Score  
 


J18119/Amendment 8 / Version 9.0 / March 31, 2022 
19
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
20
 
3.5. 
MSI Testing 
 
Microsatellite instability (MSI), a form of genomic instability, occurs through the insertion or 
deletion of repeating nucleotides during DNA replication and failure of the mismatch repair system 
to correct errors in nucleotide repeat markers. All MSI testing will be performed in a CLIA-
certified laboratory for mismatch repair deficiency (MRD) or MSI using IHC, PCR, or next 
generation sequencing (NGS). MMRd or MSI status is determined by examining either 1) protein 
expression by IHC of 4 MMR enzymes (MLH1/MSH2/MSH6/PMS2) or 2) 3-5 tumor 
microsatellite loci using PCR-based assay, respectively. Tumors are classified as MSS when no 
allelic shifts among the 3-5 analyzed microsatellite markers are detected by PCR, or presence of 
all 4 mismatch repair protein expression is detected by IHC. Subjects that are MSS will be enrolled 
in this study. 
 
4. 
TREATMENT PLAN 
 
4.1. 
Agent Administration 
 
Treatment will be administered on an outpatient basis. Appropriate dosing delays are described in 
Section 5. No investigational or commercial agents or therapies other than those described below 
in Table 2 may be administered with the intent to treat the patient’s malignancy. 
 
Table 2: Regimen Description 
 
REGIMEN DESCRIPTION 
Agent 
Premedications; 
Precautions 
Administration 
Type 
Dose 
Route 
Schedule 
Cycle 
Length 
Cohort A/B: 
Nivolumab/ 
Relatlimab 
 
No prophylactic 
pre-medication 
will be given 
unless indicated 
by previous 
experience in an 
individual 
subject per 
Section 4.2 
Co-administration 
480mg/160mg 
 
 
IV 
infusion 
over 60  
(+/-15) 
min* 
Day 1 
 
28 
days 
 
Cohort C: 
Nivolumab/ 
Relatlimab  
 
Sequential**  
 
480mg/960mg 
or 
480mg/480mg 
*** 
 
Each drug 
infused IV 
over 30  
(+/-10) 
min* 
 
Co-administration 
480mg/160mg 
*** 
*Infusion times are approximate and may be adjusted based on subject tolerability. 
** Order of administration is nivolumab followed by relatlimab. Subjects should be observed for 
a minimum of 30 minutes between each infusion. 


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21
***Patients enrolling during or after Amendment 7 will receive nivolumab/relatlimab 
480mg/480mg. Patients who enrolled prior to Amendment 7 and are within 8 weeks of their first 
dose will be dose reduced to nivolumab/relatlimab 480mg/160mg or 480mg/480mg at the 
discretion of the Principal Investigator. Patients who are past 8 weeks from their first dose may 
continue 
to 
receive 
nivolumab/relatlimab 
480mg/960mg 
or 
be 
dose 
reduced 
to 
nivolumab/relatlimab 480mg/160mg or 480mg/480mg at the discretion of the Principal 
Investigator. 
 
Please see Section 5.2 for guidance regarding dosing delays. 
 
Antiemetic medications should not be routinely administered prior to dosing of drugs. See Section 
4.2.1 for subsequent premedication recommendations following an infusion reaction.  
 
4.2. 
General Concomitant Medication and Supportive Care Guidelines 
 
Nivolumab and relatlimab are fully human monoclonal immunoglobulin (Ig) G4 antibodies. 
Subjects should be closely monitored for potential AEs during antibody infusion and potential AEs 
throughout the study. 
 
4.2.1. Infusion Reactions 
 
Since nivolumab and relatlimab contain only human immunoglobulin protein sequences, 
they are unlikely to be immunogenic and induce an infusion or hypersensitivity reaction. 
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 
allergic-like reactions. All grade 3 or 4 infusion reactions should be reported within 24 
hours to the IND Sponsor, Regulatory Specialist, and BMS and reported as an SAE if 
criteria are met. Infusion reactions should be graded according to CTCAE (version 5.0) 
guidelines.  
 
Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines as appropriate: 
 
For grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not 
indicated): 
 
Remain at bedside and monitor subject until recovery from symptoms. The 
following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg at 
least 30 minutes before additional administrations. 
 
For grade 2 symptoms (moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [e.g., antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for 24 hours): 
 


 
22
Stop the infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen 325 to 1000 mg; 
remain at bedside and monitor subject until resolution of symptoms. Corticosteroid 
or bronchodilator therapy may also be administered as appropriate. If the infusion 
is interrupted, 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 study drug will be administered at that visit. 
Administer diphenhydramine 50 mg IV, and remain at bedside and monitor the 
subject until resolution of symptoms. The amount of study drug infused must be 
recorded on the case report form (CRF).  
 
The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg 
should be administered at least 30 minutes before study drug infusions. If 
necessary, corticosteroids (up to 25 mg of SoluCortef or equivalent) may be used.  
 
For grade 3 or grade 4 symptoms (severe reaction, grade 3: prolonged [i.e., not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical 
sequelae [e.g., renal impairment, pulmonary infiltrates]; grade 4: (life threatening; pressor 
or ventilator support indicated): 
 
Immediately discontinue infusion of study drug. 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. 
All study drugs will be permanently discontinued. Investigators should follow their 
institutional guidelines for the treatment of anaphylaxis. Remain at bedside and 
monitor subject until recovery from symptoms.  
 
In the case of late-occurring hypersensitivity symptoms (e.g., appearance of a 
localized or generalized pruritus within 1 week after treatment), symptomatic 
treatment may be given (e.g., oral antihistamine, or corticosteroids). 
 
4.2.2. Nivolumab and Relatlimab-Related Adverse Events 
 
Blocking PD-1 or LAG-3 function may permit the emergence of auto-reactive T cells and 
resultant clinical autoimmunity. Rash/pruritus, diarrhea/colitis, pneumonitis, hepatitis, and 
hypothyroidism were drug-related, presumptive autoimmune events noted in previous 
nivolumab studies.  
 
For the purposes of this study, a nivolumab- or relatlimab-related AE is defined as an AE 
of unknown etiology, associated with drug exposure and is consistent with an immune 


J18119/Amendment 8 / Version 9.0 / March 31, 2022 
23
phenomenon. Efforts should be made to rule out neoplastic, infectious, metabolic, toxin or 
other etiologic causes. Serological, immunological, and histological (biopsy) data should 
be used to support the diagnosis of an immune-mediated toxicity. Suspected nivolumab- 
or relatlimab-related AEs must be documented on an AE or SAE CRF. Identification and 
treatment of nivolumab- and relatlimab-related AEs can be found in Appendix B. 
Additional guidance can be found in the nivolumab and relatlimab Investigator’s 
Brochures (IB).  
 
Subjects who experience a grade 2 or higher nivolumab- or relatlimab-related AE should 
be discussed with the IND Sponsor immediately.  
 
4.3. 
Prohibited and/or Restricted Treatments 
 
The following medications are prohibited during the study: 
 
  Immunosuppressive agents unless they are utilized to treat an AE or as specified in 
Sections 4.2 and 4.5. 
 Concurrent administration of any anticancer therapies (investigational or approved) 
with the exception of subjects in the survival period of the study. 
 Use of growth factors unless prior discussion and agreement with the IND Sponsor. 
  Use of allergen hyposensitization therapy 
 
Palliative radiotherapy is permitted only under certain conditions as described in Section 4.5. 
 
4.4. 
Other Restrictions and Precautions 
Any vaccination containing attenuated or inactivated virus may be permitted if clinically indicated. 
However, this must be discussed and documented with the IND Sponsor prior to administration 
and may require a study drug washout period prior to and after administration of the vaccine. 
Inactivated influenza vaccination will be permitted on study without restriction.  
It is the local imaging facility’s responsibility to determine, based on subject attributes (e.g., 
allergy history, diabetic history and renal status), the appropriate imaging modality and contrast 
regimen for each subject. Imaging contraindications and contrast risks should be considered in this 
assessment. Subjects with renal insufficiency should be assessed as to whether or not they should 
receive contrast and if so, what type and dose of contrast is appropriate. Specific to MRI, subjects 
with severe renal insufficiency (i.e., estimated glomerular filtration rate (eGFR) < 30 
mL/min/1.73m2) are at increased risk of nephrogenic systemic fibrosis. MRI contrast should not 
be given to this subject population. In addition, subjects are excluded from MRI if they have 
tattoos, metallic implants, pacemakers, etc.  
The ultimate decision to perform MRI in an individual subject in this study rests with the site 
radiologist, the investigator and the standard set by the local IRB/Ethics Committee.  
4.5. 
Permitted Therapy 


 
24
Subjects are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Immunosuppressive agents and the use of 
systemic corticosteroids are permitted in the context of treating AEs, prophylaxis prior to a 
diagnostic procedure (e.g., contrast MRI/CT scans) or as specified in Section 4.2. A brief course 
of corticosteroids for prophylaxis (e.g., contrast dye allergy) is permitted.  
Subjects may continue to receive hormone replacement therapy (HRT).  
Palliative and supportive care for disease-related symptoms may be offered to all subjects on the 
trial.  
The potential for overlapping toxicities with radiotherapy and relatlimab  nivolumab is currently 
not known. Therefore, palliative radiotherapy is not recommended while receiving any of these 
drugs, alone or in combination. If palliative radiotherapy in short courses and for isolated fields is 
required to control symptoms, then drug administration should be withheld, if possible, for at least 
1 week before radiation and for at least 1 week after its completion. Subjects should be closely 
monitored for any potential toxicity during and after receiving radiotherapy. Prior to resuming 
study drug treatment, radiotherapy-related AEs should resolve to Grade 1 or baseline and subjects 
must meet relevant eligibility criteria as determined by the IND Sponsor. The IND Sponsor must 
be consulted prior to re-initiating treatment in a subject with a dosing interruption lasting > 6 weeks 
after the last dose.  
Details of palliative radiotherapy should be documented in the source records and electronic case 
report form (eCRF). Details in the source records should include: dates of treatment, anatomical 
site, dose administered and fractionation schedule, and AEs. Subjects receiving palliative radiation 
of target lesions will have the evaluation of ORR just prior to radiotherapy but such subjects will 
no longer be evaluable for determination of response subsequent to the date palliative radiation 
occurs.  
For subjects who need to undergo elective surgery (not tumor-related) during the study, it is 
recommended to hold study drug(s) for at least 2 weeks before and 2 weeks after surgery, or until 
the subject recovers from the procedure, whichever is longer. Prior to resuming study drug 
treatment, surgically-related AEs should resolve to Grade 1 or baseline and subjects must meet 
relevant eligibility criteria as determined by the IND Sponsor. The IND Sponsor must be consulted 
prior to re-initiating treatment in a subject with a dosing interruption lasting > 6 weeks after the 
last dose.  
4.6. 
Definition of an Overdose for this Protocol 
 
Overdose of nivolumab or relatlimab is defined as: 
 
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. Appropriate supportive treatment should be 
provided if clinically indicated. 
 


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25
All reports of overdose (with and without an AE) must be reported within 24 hours to the IND 
Sponsor, Regulatory Specialist, and Bristol-Myers Squibb (BMS) as an SAE per Section 6. 
4.7. Unacceptable Toxicity 
 
Unacceptable toxicities are defined as: 
 
1. Any treatment-related > grade 3 AEs.  Exceptions include: 
 
 Asymptomatic laboratory abnormalities 
 Grade 3 fatigue 
 Diarrhea, nausea, or vomiting that resolves to < grade 3 within 24 hours of intervention 
 Grade 3-4 hyperglycemia or grade 3 endocrinopathies where symptoms are controlled 
on hormone replacement therapy 
 
2. Treatment related blood bilirubin > 5 x ULN or concurrent blood bilirubin > 2 x ULN and 
AST or ALT > 3 x ULN 
 
3. Treatment related eye pain ≥ grade 2 or reduction of visual acuity that does not respond to 
topical therapy and does not improve to ≤ grade 1 severity within 2 weeks of starting 
therapy, or requires systemic therapy is an unacceptable toxicity. 
 
If more than 1 of the first 6 patients experiences an unacceptable toxicity within the first cycle, 
then enrollment will be halted, and the overall risk-benefit ratio of the study will be reconsidered. 
At any time thereafter, if more than 33% of patients are observed to experience unacceptable 
toxicity within the first cycle, then enrollment will be suspended until further review and 
consideration by the IND Sponsor. There will be no dose reductions for nivolumab or relatlimab. 
 
4.8. 
WOCBP, Contraception, Use in Pregnancy, Use in Nursing 
 
4.8.1. Definition of Women of Childbearing Potential 
 
WOCBP is defined as any female who has experienced menarche and who has not 
undergone surgical sterilization (hysterectomy or bilateral oophorectomy) and is not 
postmenopausal. Menopause is defined as 12 months of amenorrhea in a woman over age 
45 in the absence of other biological or physiological causes. In addition, females under 
the age of 55 years must have a documented serum follicle stimulating hormone (FSH) 
level > 40mIU/mL to confirm menopause.  
 
Females treated with hormone replacement therapy (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic 
FSH level. The duration of the washout period is a function of the type of HRT used. The 
duration of the washout period below are suggested guidelines and the investigators should 
use their judgment in checking serum FSH levels.  
 
 1 week minimum for vaginal hormonal products (e.g., rings, creams, gels)  


 
26
 4 weeks minimum for transdermal products  
 8 week minimum for oral products  
 
Other parenteral products may require washout periods as long as 6 months. If the serum 
FSH level is > 40 mlU/mL at any time during the washout period, the woman can 
considered postmenopausal. 
 
4.8.2. Contraception 
 
One of the highly effective methods of contraception listed below is required during study 
duration and until the end of relevant systemic exposure, defined as 24 weeks after the end 
of study treatment.* 
 
Highly Effective Contraceptive Methods That Are User Dependent  
Failure rate of <1% per year when used consistently and correctly.a  
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb  
 oral  
 intravaginal  
 transdermal  
 Progestogen-only hormonal contraception associated with inhibition of ovulationb  
 oral  
 injectable  
Highly Effective Methods That Are User Independent  
 Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b 
 Hormonal methods of contraception including oral contraceptive pills containing a 
combination of estrogen and progesterone, vaginal ring, injectables, implants and 
intrauterine hormone-releasing system (IUS)c 
 Intrauterine device (IUD)c 
 Bilateral tubal occlusion 
 Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used.  


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27
 Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant. 
 It is not necessary to use any other method of contraception when complete abstinence is 
elected.  
 WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 9.  
 Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence  
NOTES:  
a Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants 
participating in clinical studies.  
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the 
efficacy of the contraceptive method.  Hormonal contraception is permissible only when there is 
sufficient evidence that the IMP and other study medications will not alter hormonal exposures such 
that contraception would be ineffective or result in increased exposures that could be potentially 
hazardous.  In this case, alternative methods of contraception should be utilized.  
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of 
contraception in the absence of definitive drug interaction studies when hormone exposures from 
intrauterine devices do not alter contraception effectiveness 
 
Unacceptable Methods of Contraception* 
 Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously 
 Diaphragm with spermicide 
 Cervical cap with spermicide 
 Vaginal Sponge with spermicide 
 Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action 
 Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
 Withdrawal (coitus interruptus). 
 Spermicide only 
 Lactation amenorrhea method (LAM) 
 
* Local laws and regulations may require use of alternative and/or additional 
contraception methods. 


 
28
 
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH 
PARTNER(S) OF CHILD BEARING POTENTIAL. 
Male participants with female partners of childbearing potential are eligible to participate 
if they agree to the following during the treatment and until the end of relevant systemic 
exposure. 
 Inform any and all partner(s) of their participation in a clinical drug study and the need 
to comply with contraception instructions as directed by the investigator. 
 Male participants are required to use a condom for study duration and until end of 
relevant systemic exposure defined as 33 weeks after the end of study treatment. 
 Female partners of males participating in the study to consider use of effective methods 
of contraception until the end of relevant systemic exposure, defined as 7 months after 
the end of treatment in the male participant. 
 Male participants with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile vaginal intercourse or use a male condom during each episode of 
penile penetration during the treatment and until 33 weeks after the end of study 
treatment.  
 
Refrain from donating sperm for the duration of the study treatment and until 7 months 
after the end of study treatment. 
 
4.8.3. Use in Pregnancy 
 
The investigational agents used in this protocol may have adverse effects on a fetus; 
therefore, women with a positive pregnancy test at screening will not be eligible for 
enrollment.  If a subject inadvertently becomes pregnant while on treatment, the subject 
will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.   
 
Pregnancy in female subjects throughout the study or within 24 weeks of completing 
treatment as well as any pregnancy in partners of male subjects throughout the study or 
within 33 weeks of completing the study should be reported initially as a serious adverse 
event (see SAE reporting procedures in Section 6.5.1 and 6.5.4) by the investigator within 
24 hours of learning of its occurrence. Pregnancy information must be reported on the 
Pregnancy Form. 
 
Protocol required procedures for study discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated.  
 
Follow-up information regarding the course of the pregnancy, including any voluntary or 
spontaneous termination, perinatal and neonatal outcome and where applicable, offspring 
information must be reported on the Pregnancy Follow-up Form. Pregnancy outcomes 
must also be collected for the female partners of any males in this trial. Consent to report 


J18119/Amendment 8 / Version 9.0 / March 31, 2022 
29
information regarding these pregnancy outcomes should be obtained from the female 
partner.  
 
4.8.4. Use in Nursing Women 
 
Since many drugs are excreted in human milk, and because of the potential for serious 
adverse reactions in the nursing infant, subjects who are breast-feeding are not eligible for 
enrollment. 
 
4.9. 
Duration of Therapy 
 
Subjects who are clinically stable and meet dosing requirements (per Section 5.2) may continue 
to receive treatment per investigator discretion.  
 
4.10. Criteria for Removal from Treatment 
 
The reason for study removal and the date the subject was removed will be documented in the 
CRF. A subject must be discontinued from the trial for any of the following reasons: 
 
 The subject or legal representative (such as parent or legal guardian) withdraws 
consent. 
 
A subject must be discontinued from treatment (but may continue to be monitored in the post-
treatment follow-up portion of the trial) for any of the following reasons: 
 
 The subject or legal representative (such as a parent or legal guardian) withdraws 
consent for treatment, 
 Disease progression as defined in Section 4.10.1, 
 Intercurrent illness that prevents further administration of treatment, 
 Severe or life-threatening nivolumab- or relatlimab-related AE(s) (see Section 4.10.2), 
 Need for >2 dose delays due to the same related toxicity as per the dose delay guidelines 
(see Section 5.2) 
 If in the opinion of the Investigator, a change or temporal or permanent discontinuation 
of therapy would be in the best interest of the patient (The IND Sponsor should be 
included in this decision), 
 Noncompliance with trial treatment or procedure requirements, 
 Patient is lost to follow-up, 
 Patient becomes pregnant, or 
 Completed 24 months of treatment with nivolumab and relatlimab. Note: 24 months of 
study medication is calculated from the date of the first dose. 
 
4.10.1 Disease Progression 
 
Nivolumab and relatlimab are expected to trigger immune-mediated responses, which 
require activation of the immune system prior to the observation of clinical responses. Such 
immune activation may take weeks to months to be evident. Some subjects may have 


 
30
objective volume increase of tumor lesions or other disease parameters within weeks 
following the start of immunotherapy. Such subjects may not have had sufficient time to 
develop the required immune activation or, in some subjects, tumor volume or other disease 
parameter increases may represent infiltration of lymphocytes into the original tumor. In 
conventional studies, such tumor volume or relevant laboratory parameter increases during 
the first 2-4 months of the study would constitute disease progression and lead to 
discontinuation of imaging to detect response, thus disregarding the potential for 
subsequent immune-mediated clinical response. This phenomenon was observed in 
approximately 10% of subjects in the Phase 1 study of nivolumab and has also been 
reported for ipilimumab monotherapy[38]. 
 
Subjects will be permitted to continue with treatment beyond RECIST 1.1 defined PD as 
long as they meet the following criteria: 
 
No symptoms or signs, including worsening of laboratory values, indicating disease 
progression* 
 
Investigator-assessed clinical benefit, and 
 
Subject is tolerating study drug. 
 
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. The 
following criteria need to be taken into consideration: 
 
No decline in ECOG performance status. 
 
Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (e.g., cord compression) requiring urgent alternative medical intervention. 
 
*An exception to the above may be made for patients with PD who have only local 
symptoms that are amenable to radiation. 
 
All decisions to continue treatment beyond PD must be discussed with the IND Sponsor 
and documented in the study records. 
 
Tumor assessments will be made using RECIST 1.1 and iRECIST (Appendix C and D).  
 
4.10.2 Nivolumab- and Relatlimab-Related Adverse Events Requiring Permanent 
Discontinuation 
 
Permanent discontinuation of all study treatment should be considered for any of the 
following: 
1. Severe or life-threatening related AEs, including, but not limited to, any of the 
following (the IND Sponsor and BMS must be notified in the event of these AEs): 
 Any grade 2 treatment-related uveitis, 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 
 


J18119/Amendment 8 / Version 9.0 / March 31, 2022 
31
 Any grade 3 non-skin, drug-related AE lasting > 7 days or recurs, with the 
following exceptions: 
 
 Grade 3 treatment-related uveitis, pneumonitis, bronchospasm, neurologic 
toxicity, hypersensitivity reaction, or infusion reaction of any duration 
requires discontinuation 
 
 Grade 3 treatment-related endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation 
 
 Grade 3 treatment-related laboratory abnormalities do not require treatment 
discontinuation except: 
 
o Grade 3 treatment-related thrombocytopenia > 7 days OR that is 
associated with bleeding requires discontinuation 
 
o Any treatment-related liver function test (LFT) abnormality that 
meets the following criteria require discontinuation: 
 
ALT or AST > 8 x ULN, regardless of duration, or 
 
ALT or AST > 5 x and ≤ 8 x ULN, that fails to return to ≤ 
Grade 1 within 2 weeks despite medical intervention, or 
 
Total bilirubin > 5 × ULN, or 
 
Potential drug-induced liver injury (DILI) event (Section 
6.5.5) 
 
o Elevated troponin ≥ Grade 3 requires discontinuation (except Grade 
3 elevation without other signs of cardiac toxicity as determined by 
cardiac evaluation) 
 
 Any grade 4 treatment-related AE or laboratory abnormality, except for the 
following events which do not require discontinuation: 
 
 Grade 4 neutropenia ≤ 7 days 
 
 Grade 4 lymphopenia and leukopenia. 
 
 Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations. 
 
 Isolated grade 4 electrolyte imbalances/abnormalities that are not associated 
with clinical sequelae and are corrected with supplementation/appropriate 
management within 72 hours of their onset.  
 
 Grade 4 treatment-related endocrinopathy adverse events, such as adrenal 
insufficiency, ACTH deficiency, hyper- or hypothyroidism, or glucose 


 
32
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 IND Sponsor. 
 
 Any dosing interruption lasting > 6 weeks with the following exceptions: 
 
 Dosing 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 IND Sponsor must 
be consulted. Tumor assessments should continue as per protocol even if 
dosing is interrupted. Periodic study visits to assess safety and laboratory 
studies should also continue every 6 weeks or more frequently if clinically 
indicated during such dosing delays. 
 
 Dosing interruptions > 6 weeks that occur for non-drug-related reasons may 
be allowed if approved by the IND Sponsor. Prior to re-initiating treatment 
in a subject with a dosing interruption lasting > 6 weeks, the IND Sponsor 
must be consulted. Tumor assessments should continue as per protocol even 
if dosing is interrupted. Periodic study visits to assess safety and laboratory 
studies should also continue every 6 weeks or more frequently if clinically 
indicated during such dosing delays. 
 
 Any AE, laboratory abnormality, or intercurrent illness which, in the judgment 
of the Investigator, presents a substantial clinical risk to the subject with 
continued nivolumab or relatlimab dosing.  
 
In order to standardize the management of AEs for all subjects, treatment management 
algorithms are included in Appendix B. Additional AE treatment management algorithms 
included in the nivolumab and relatlimab IB might be considered for individual cases. 
 
4.11. End of Treatment (EOT) 
 
All subjects will return to the study site 30 days (± 7 days) after the last dose of study drug (or 
within 7 days prior to initiation of a new anti-cancer treatment, whichever comes first) for an EOT 
evaluation. Procedures and assessments performed at this visit and beyond should follow the 
respective guidelines described in Sections 4.12 and 9 as appropriate.  
 
4.12. Duration of Follow Up 
 
4.12.1 Safety Follow-up 
 
Subjects who discontinue treatment should be contacted by telephone or email at 100 days 
(+ 14 day reporting window) from their last dose of study drug or within 7 days before 
initiation of a new antineoplastic treatment (whichever comes first) to assess for treatment 


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33
related toxicities. In addition, all SAEs occurring during this time should be reported as 
well.  
 
Subjects who are discontinued from the study treatment due to an unacceptable drug-
related AE will be monitored for safety until the resolution of the AE to ≤ grade 1 or 
stabilization or until initiation of a new therapy for their cancer, whichever occurs first. 
 
4.12.2 Clinical Follow-up 
 
All enrolled subjects who discontinue treatment without disease progression will enter the 
clinical follow-up portion of the trial. Subjects will begin the clinical follow-up period after 
they complete the EOT visit. Clinical follow-up visits will occur every 12 weeks (± 2 
weeks) until: 1) start of a new antineoplastic therapy (information of the new cancer therapy 
will be collected), 2) disease progression, 3) death, 4) withdrawal of consent, or 5) study 
closure, whichever occurs first. Refer to Section 9 for the schedule of assessments that 
should be performed at each visit. After disease progression or start of a new antineoplastic 
therapy, subjects will enter the survival follow-up portion of the trial (Section 4.12.3).  
 
4.12.3 Survival Follow-up  
 
Subjects who discontinue treatment and have disease progression will enter the survival 
follow-up portion of the trial. Subjects should be contacted every 12 weeks (± 2 weeks) to 
monitor overall survival. Information of other cancer therapies after discontinuation from 
the study treatment will be collected as well.  
 
5. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
5.1. 
Dose Modifications 
 
Subjects will be monitored continuously for AEs while on study drug. Subjects will be instructed 
to notify their physician immediately for any and all AEs. Dose escalations or reductions of 
nivolumab or relatlimab will not be allowed.  
 
 
, patients who 
enrolled prior to Amendment 7 and are within 8 weeks of their first dose will be dose reduced to 
160mg or 480mg relatlimab at the discretion of the Principal Investigator. Patients who are past 8 
weeks from their first dose may continue to receive relatlimab 960mg or be dose reduced to 160mg 
or 480mg at the discretion of the Principal Investigator.  
 
5.2. 
Dose Delays 
 
In some cases, the natural history of select AEs associated with immunotherapy can differ from 
and be more severe than AEs caused by other therapeutic classes. Early recognition and 
management may mitigate severe toxicity. 
 


 
34
Guidance for Investigators is provided in the current relatlimab and nivolumab Investigator’s 
Brochures. Additionally, management algorithms have been developed to assist Investigators with 
select toxicities and can be found in Appendix B. Toxicities for which management algorithms 
have been developed include: 
 
 Pulmonary 
 Gastrointestinal 
 Hepatic 
 Endocrine 
 Dermatologic 
 Neurologic 
 Renal 
 Myocarditis 
 
Subjects who experience the following must have all study drugs held: 
 
 Select drug-related AEs and drug-related laboratory abnormalities: 
o Grade ≥ 1 pneumonitis 
o Increase from baseline of ≥ one grade (to at least grade 2) of AST, ALT, and/or 
total bilirubin 
o Grade ≥ 2 creatinine 
o Grade ≥ diarrhea or colitis 
o Grade ≥ 2 neurological AE 
o Grade 4 amylase and/or lipase abnormalities regardless of symptoms or clinical 
manifestations 
o Troponin >ULN requires a dose delay to allow for prompt cardiac evaluation 
 Between > 1 to 2 × ULN will be permitted if a repeat assessment remains 
≤ 2 × ULN and patient undergoes a cardiac evaluation  
 Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study drug. 
 
Subjects not meeting guidelines for permanent discontinuation will be permitted to resume 
therapy when the treatment-related AE(s) resolve to grade ≤1 or baseline value, with the 
following exceptions: 
 
 If the toxicity resolves to ≤ Grade 1 or baseline > 6 weeks after last dose, but the subject 
does not otherwise meet criteria for permanent discontinuation, and the Investigator 
believes that the subject is deriving clinical benefit, then the subject may be eligible to 
resume the study drugs following the approval of the IND Sponsor. 
 Subjects with grade 4 drug-related amylase and/or lipase increase that is not associated 
with symptoms or clinical manifestations of pancreatitis can be restarted on therapy 
once the levels have recovered to grade 3 or less. 
 Subjects may resume treatment in the presence of Grade 2 fatigue. 
 Subjects with baseline grade 1 AST, ALT or total bilirubin who require dose delays for 
reasons other than a drug-related hepatic event may resumed treatment in the presence 
of grade 2 AST, ALT or total bilirubin elevation. 


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35
 Subjects who require dose delays for drug-related elevations in AST, ALT, or total 
bilirubin may resume treatment when these values have returned to their baseline 
CTCAE grade or normal, provided the criteria for permanent discontinuation are not 
met. 
 Treatment-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment. 
 
Subjects eligible to resume study drug will resume study drug at the treatment visit following 
their last received study drug dose.  
 
The on treatment tumor assessments (i.e., CT/MRI, positron emission tomography [PET], etc.) 
will continue on an every 8-week schedule relative to the subject’s first dose regardless of any 
treatment delay incurred. Subjects who are required to permanently discontinue both study 
drugs are listed in Section 4.10. 
 
6. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
This study will use the descriptions and grading scales found in the revised CTCAE version 5.0 
for AE reporting.   
 
Information about all AEs, whether volunteered by the subject, discovered by investigator 
questioning, or detected through physical examination, laboratory test or other means, will be 
collected, recorded, and followed as appropriate.  
 
6.1. 
Definitions 
 
6.1.1 Adverse Event 
 
An AE is defined as any undesirable sign, symptom or medical condition occurring after 
starting the study drug (or therapy) even if the event is not considered to be related to the 
study. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs 
(e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., 
laboratory findings, electrocardiogram). Medical conditions/diseases present before 
starting the study treatment are only considered AEs if they worsen after starting the study 
treatment (any procedures specified in the protocol). New medical conditions / diseases 
occurring before starting the study treatment but after signing the informed consent form 
will not be recorded as AEs. Additionally, expected progression of the disease being 
studied will not be recorded as an adverse event.  
 
Laboratory abnormalities: Laboratory abnormalities present at the screening visit will 
be recorded as pre-treatment signs and symptoms. After study treatment administration, all 
grade 3 and 4 clinical laboratory results that represent an increase in severity from baseline 
will be reported as AEs. A grade 1 or 2 clinical laboratory abnormality should be reported 
as an AE only if it is considered clinically significant by the investigator (induce clinical 
signs or symptoms or require corrective therapy), meets the definition of an SAE, or 
requires the participant to have study drug discontinued or interrupted. It is expected that 


 
36
wherever possible, the clinical rather than laboratory term would be used by the reporting 
investigator (e.g., anemia versus low hemoglobin value). 
 
6.1.2 Serious Adverse Event 
 
A SAE is an undesirable sign, symptom or medical condition which:  
• 
Results in death  
• 
Is life threatening (defined as an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe)  
• 
Requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see note below for exceptions) for >24 hours 
• 
Results in persistent or significant disability/incapacity  
• 
Is a congenital anomaly/birth defect (note: reports of congenital anomalies/birth 
defects must also be reported on the Pregnancy Form)  
• 
Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention [e.g., medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.) Examples of such events include, but are 
not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) 
• 
Potential drug induced liver injury (DILI) is also considered an important medical 
event.  
• 
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) 
via the study drug is an SAE. 
• 
Is a new cancer (that is not a condition of the study) 
• 
Is associated with an overdose 
• 
Is a pregnancy or pregnancy outcome of spontaneous abortion, missed abortion, 
benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage, or stillbirth. 
 
Events not considered to be SAEs are hospitalizations for:  
• 
a visit to the emergency room or other hospital department <24 hours, that does not 
result in admission (unless considered an important medical or life-threatening 
event) 
• 
Admissions as per protocol for a planned medical/surgical procedure or to facilitate 
a procedure 
• 
Routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy)  
• 
Medical/surgical admission for purpose other than remedying ill health state and 
was planned prior to entry into the study. Appropriate documentation is required in 
these cases.  
• 
Admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (e.g., lack of housing, 


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37
economic inadequacy, care-giver respite, family circumstances, administrative). 
 
6.2. 
Relationship 
 
The relationship of an AE to the administration of the study drug is to be assessed by the 
investigator according to the following definitions:  
 
 No (unrelated, not related, no relation):  The time course between the administration of 
study drug and the occurrence or worsening of the adverse event rules out a causal 
relationship and another cause (concomitant drugs, therapies, complications, etc.) is 
suspected.  
 
 Yes (related): The time course between the administration of study drug and the 
occurrence or worsening of the adverse event is consistent with a causal relationship 
and no other cause (concomitant drugs, therapies, complications, etc.) can be identified.  
 
The following factors should also be considered:  
 
 The temporal sequence from study drug administration - The event should occur after 
the study drug is given. The length of time from study drug exposure to event should 
be evaluated in the clinical context of the event.  
 Underlying, concomitant, intercurrent diseases - Each report should be evaluated in the 
context of the natural history and course of the disease being treated and any other 
disease the subject may have.  
 Concomitant medication - The other medications the subject is taking or the treatment 
the subject receives should be examined to determine whether any of them might be 
recognized to cause the event in question.  
 Known response pattern for this class of study drug - Clinical and/or preclinical data 
may indicate whether a particular response is likely to be a class effect.  
 Exposure to physical and/or mental stresses - The exposure to stress might induce 
adverse changes in the recipient and provide a logical and better explanation for the 
event.  
 The pharmacology and pharmacokinetics of the study drug - The known pharmacologic 
properties (absorption, distribution, metabolism, and excretion) of the study drug 
should be considered.  
 
Assessment of Grade: 
 
The investigator will make an assessment of grade for each AE and SAE reported during the study, 
which will be recorded in the CRF. The assessment will be based on the National Cancer Institute’s 
CTCAE (Version 5.0) and graded as shown below: 
 Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
 Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living 


 
38
 Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care activities of daily living 
 Grade 4: Life-threatening consequences; urgent intervention indicated 
 Grade 5: Death related to AE 
 
Any AE that changes in grade during its course will be recorded in the CRF at the highest level 
experience by the subject. 
 
6.3. 
Expectedness 
 
Unexpected AE: An AE, which varies in nature, intensity or frequency from information on the 
investigational drug/agent provided in the product IB, package insert or safety reports. Any AE 
that is not included in the IB, package insert, safety reports or informed consent is considered 
“unexpected”. An expected AE with a fatal outcome should be considered unexpected unless the 
IB specifically states that the AE might be associated with a fatal outcome. 
 
Expected (known) AE: An AE, which has been reported in the IB, package insert or safety reports. 
An AE is considered “expected”, only if it is included in the IB document as a risk. 
 
6.4. 
Handling of Expedited Safety Reports 
 
In accordance with local regulations, the IND Sponsor (or designee) and BMS will notify 
investigators of all SAEs that are unexpected (i.e., not previously described in the IB), and related 
to nivolumab or relatlimab. An event meeting these criteria is termed a Suspected, Unexpected 
Serious Adverse Reaction (SUSAR). Investigator notification of these events will be in the form 
of a SUSAR Report that is to be e-mailed to the investigators and the study coordinators. Upon 
receiving such notices, the investigator must review and retain the notice with the IB and where 
required by local regulations, the investigator will submit the SUSAR to the appropriate IRB. The 
investigator and IRB will determine if the informed consent requires revision. The investigator 
should also comply with the IRB procedures for reporting any other safety information. 
 
6.5. 
Reporting 
 
6.5.1 Adverse Events (AEs) and Serious Adverse Events (SAEs) 
 
All AEs (both expected and unexpected) occurring from the first dose of study drug will 
be captured on the appropriate study-specific case report forms (CRFs).  
 
A non-serious adverse event is an AE not classified as serious. All non-serious AEs (not 
only those deemed to be treatment-related) should be collected continuously during the 
treatment period and for a minimum of 100 days (+14 day reporting window) following 
the last dose of study treatment or before initiation of a new antineoplastic treatment 
(whichever comes first). Non-serious AEs should be followed to resolution or stabilization, 
or reported as SAEs if they become serious. Follow-up is also required for non-serious AEs 
that cause interruption or discontinuation of study drug and for those present at the end of 


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39
study treatment as appropriate. Non-serious AEs are to be provided to BMS in aggregate 
via interim or final study reports as specified in the agreement or, if a regulatory 
requirement [e.g., IND US trial] as part of an annual reporting requirement. 
 
Subjects who experience a grade 2 or higher nivolumab or relatlimab-related AE should be 
discussed with the IND Sponsor.  
 
Report AEs to the IND Sponsor within 24 hours once identified as an unacceptable 
toxicity (defined in Section 4.7).   
 
 
Dung Le: 
  
 
All SAEs (including deaths) occurring from the first dose of study drug, throughout the 
study, and 100 days (+14 day reporting window) after the last dose of study drug or before 
initiation of a new antineoplastic treatment (whichever comes first) must be reported. All 
SAEs that the investigator considers related to the study drug occurring after the follow-up 
periods must be reported.  
 
SAEs will be reported promptly to the IND Sponsor, Regulatory Specialist, and BMS 
within 24 hours of recognition of the adverse event using the form found in Appendix E.  
If this falls on a weekend or holiday, an email notification is acceptable but must be 
followed by an SAE reporting form on the next business day. 
 
 
 
SAE reports and any other relevant safety information are to be sent to:  
 
Dung Le:  
 
 
Jennifer Durham  
 
BMS:  
 
 
 
6.5.2 Follow-up of Adverse Events and Serious Adverse Events 
 
After the initial AE or SAE report, the investigator is required to proactively follow each 
subject and provide further information to the safety department concerning the subject’s 
condition. 
 
All AE(s) and SAE(s) will be followed until: 
• 
Resolution 
• 
The condition stabilizes 
• 
The event is otherwise explained 
• 
The subject is lost to follow-up 
• 
Death 
 
As soon as relevant information is available, a follow-up SAE report will be submitted to 
the IND Sponsor and BMS. 


 
40
 
6.5.3 Reconciliation of SAEs 
 
The Principal Investigator will reconcile the clinical database SAE cases (case level only) 
transmitted 
to 
the 
IND 
Sponsor 
and 
BMS 
Global 
Pharmacovigilance 
. Frequency of reconciliation should be approximately 
every 3 months and prior to the database lock or final data summary. BMS GPV&E will 
email, upon request from the Principal Investigator, the reconciliation report. Requests for 
reconciliation should be sent to 
 and 
. The 
data elements listed on the BMS GPV&E reconciliation report will be used for case 
identification purposes. If the Principal Investigator determines a case was not transmitted 
to the IND Sponsor and BMS GPV&E, the case should be sent immediately to the IND 
Sponsor and BMS. 
 
6.5.4 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 SAEs.  
 
6.5.5 Potential Drug-Induced Liver Injury (DILI) 
 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities 
should occur prior to the reporting of a potential DILI event.  All occurrences of potential 
DILIs, meeting the defined criteria, must be reported as SAEs under the seriousness 
category checked as ‘other medically important event’. Potential drug induced liver injury 
is defined as: 
 
1) ALT or AST elevation > 3 times upper limit of normal (ULN)  
AND 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase) 
AND 
3) No other immediately apparent possible causes of AST/ALT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic 
or acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
 
6.5.6 Pregnancy Reporting 
 
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial or within 24 weeks following 
cessation of the study drugs, or pregnancy of a partner of a male subject within 33 weeks of 
cessation of the study drugs, must be reported by the investigator using the Pregnancy 
Surveillance Form. All subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, 


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41
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events).  If 
the pregnancy continues to term, the outcome (health of infant) must also be reported to the 
IND Sponsor and BMS. 
Any SAE occurring during pregnancy (pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth) must be recorded on the SAE report form and submitted to the 
IND Sponsor and BMS.   
 
6.5.7 Institutional Review Board (IRB) 
 
SAEs will be reported to the IRB per institutional guidelines. The following SAEs will be 
reported to the Johns Hopkins Medicine IRB per institutional guidelines: 
 
1. Deaths, regardless of causality 
2. Serious adverse events that are both related and unexpected 
 
Follow-up information will be submitted to the IRB as soon as relevant information is 
available. 
 
6.5.8 Food and Drug Administration (FDA) 
 
All reporting to the FDA for the trial will be completed by the IND Sponsor.  
 
6.5.8.1 Expedited IND Safety Reports 
 
7 Calendar-Day Telephone or Fax Report:   
The IND Sponsor is required to notify the FDA of any fatal or life-threatening adverse 
event that is unexpected and assessed by the investigator to be possibly related to the 
investigational agent.  Such reports are to be emailed to the regulatory project 
manager and faxed 
 to the FDA within 7 calendar days of first 
learning of the event. Follow-up information will be submitted to the FDA as soon 
as relevant information is available.  
 
15 Calendar-Day Written Report:   
The IND Sponsor is required to notify the FDA of any SAE that is unexpected and 
related to the investigational agent in a written IND Safety Report.   
 
Written IND Safety Reports should include an Analysis of Similar Events in 
accordance with regulation 21 CFR § 312.32.  All safety reports previously filed with 
the IND concerning similar events should be analyzed.  The new report should 
contain comments on the significance of the new event in light of the previous, 
similar reports.   
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the 
FDA within 15 calendar days of first learning of the event. Follow-up information 


 
42
will be submitted to the FDA as soon as relevant information is available. 
 
6.5.8.2 IND Annual Reports 
 
In accordance with the regulation 21 CFR § 312.33, the IND Sponsor shall within 60 
days of the anniversary date that the IND went into effect submit a brief report of the 
AEs and progress of the investigation.  Please refer to Code of Federal Regulations, 
21 CFR § 312.33 for a list of the elements required for the annual report.  All IND 
annual reports will be submitted to the FDA by the IND Sponsor. 
 
7. 
PHARMACEUTICAL INFORMATION 
 
7.1. Agent Accountability 
 
The IND sponsor or the IND Sponsor’s representative shall take responsibility for and shall take 
all steps to maintain appropriate records and ensure appropriate supply, storage, handling, 
distribution and usage of investigational product in accordance with the protocol and any 
applicable laws and regulations.  
At the end of the study period, Bristol-Myers Squibb Company will not continue to supply study 
drug to subjects/investigators unless the Sponsor-Investigator chooses to extend their study. The 
investigator is responsible to ensure that the subject receives appropriate standard of care or other 
appropriate treatment in the independent medical judgement of the Investigator to treat the 
condition under study. 
 
7.2. Mode of Action 
 
Nivolumab is a fully human monoclonal immunoglobulin (Ig) G4 antibody that binds to the PD-1 
cell surface membrane receptor, a negative regulatory molecule expressed by activated T and B 
lymphocytes. Inhibition of the interaction between PD-1 and its ligands promotes immune 
responses and antigen-specific T cell responses to both foreign antigens as well as self-antigens. 
 
Relatlimab is a fully human monoclonal immunoglobulin (Ig) G4 antibody that binds to the LAG-
3 cell surface membrane receptor. LAG-3 is expressed on activated T cells and binds MHC class 
II with higher affinity than CD4, thereby downregulating the T-cell response. Relatlimab binds to 
a defined epitope on LAG-3 with high affinity and specificity and potently blocks the interaction 
of LAG-3 with its ligand, MHC class II, resulting in a reversal of LAG-3-mediated T-cell 
downregulation. 
 


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44


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45
 


 
46
7.10. Returns and Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
BMS or designee, the amount dispensed to, and returned by 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 investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal have 
been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
 
 
 


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8. 
CORRELATIVE/SPECIAL STUDIES 
 
Research samples will be collected at the discretion of the PI based on availability of supplies and 
safety of patient and staff. Sample collection, processing, storage, and shipment instructions will 
be provided in the Laboratory Manual. 
 
8.1. 
Tumor Tissue Studies 
 
Blocks or slides (twenty five unstained slides) will be collected from the surgical resection of each 
subject’s primary tumor for CPM score determination as part of subject pre-screening (Cohort A 
and B only). CPM score determination for patients in Cohort C will be performed on archived 
samples at a later timepoint after enrollment. These slides will also be used for the evaluation of 
additional immune and tumor markers. Slides for CPM score determination will be stained with a 
hematoxylin and eosin (H&E) and PD-L1. See Section 3.4 and the Laboratory Manual for 
additional details regarding tissue collection, processing, storage, and shipment.  
 
Tumor biopsies will be collected (if the subject’s tumor is thought reasonably safe and easy to 
biopsy) per Section 9. If a biopsy was done within 28 days before first dose, archived tissue from 
this biopsy may be used as a baseline sample. Fine needle aspiration samples do not contain 
sufficient tissue contextual information and will not be obtained. Additional biopsies may be 
obtained later in course of therapy.  
 
To explore the association of the tumor microenvironment and clinical responses, archived tumor 
tissue and tumor tissue obtained at baseline and during treatment will be compared. PD-L1 
expression may predict response to anti-PD-1 therapy[19]; however, PD-L1 is also upregulated in 
response to IFN- released by infiltrating T cells and could potentially be a predictor of response 
to any active immunotherapy. Pre- and post-treatment tumor biopsies will also be analyzed with 
immunohistochemistry and gene expression analysis for expression of T cell subset markers (CD3, 
CD4, CD8, FoxP3, Granzyme A/B, CD69), immune regulation (PD-L1, PD-L2, CTLA4, LAG-3, 
IDO1, TIM-3), and immune cell population markers (NK, DC, B cell, MDSC, M1/M2 
macrophages). 
 
To explore genetic determinants of response, whole-exome sequencing will be performed on DNA 
from tumors and matched normal tissue. We will characterize the tumor mutational landscape 
through exomic sequencing for mutation analysis and MANA prediction. 
 
TCR sequencing will be undertaken to evaluate the T cell repertoire through next-generation 
sequencing in the tumor tissue for MANAFEST assay and to characterize peripheral immune 
responses to MANA. Gene expression profiling will also be employed to identify gene signatures 
within the tumor microenvironment (TME) associated with response and survival. 
 
8.2. 
Whole Blood  
 
Whole blood will be collected to assess the baseline characteristic of the subjects enrolled and to 
correlate these molecular and clinicopathologic criteria with treatment response and toxicity.  DNA 


 
48
will be extracted from whole blood and used to evaluate for any germline mutations that may 
correlate with response or toxicity. 
 
Detailed instructions for sample collection, processing, storage, and shipment are provided in the 
laboratory manual. 
 
8.3. 
Peripheral Blood Mononuclear Cells (PBMCs) 
 
PBMCs will be collected per the study calendar. Post-treatment changes in PBMCs including 
effector, helper, and regulatory T cells, NK cells and macrophages through cell phenotyping 
analysis and gene expression profiling will be measured. Post-treatment expression of PD-1 and 
other lymphocyte activation markers will be measured and correlated with OS.  
 
T cells will be isolated and co-cultured with synthetic peptide neoantigens and will undergo TCR 
sequencing to assess for clonal expansion as previously described[39]. Gene expression will also 
be conducted on pre- and on-treatment PBMCs. 
 
Detailed instructions for sample collection, processing, storage, and shipment are provided in the 
laboratory manual. 
 
8.4. 
Serum and Plasma Marker Studies 
 
Sera and plasma will be collected per the study calendar to identify potential therapeutic targets, 
biomarkers, and predictors of response (including sLAG-3) and autoimmune toxicity through 
proteomic approaches. DNA will be extracted from plasma samples and ctDNA levels commonly 
mutated genes will be assessed. 
 
Detailed instructions for sample collection, processing, storage, and shipment are provided in the 
laboratory manual. 
 
8.5. 
Diagnostic Tissue Samples 
 
Tissue, fluid, or blood may be collected from standard of care procedures used to treat or diagnoses 
immune related toxicities. Detailed instructions for sample collection, processing, storage, and 
shipment are provided in the laboratory manual.  
 
8.6. 
Microbiome Studies 
 
Stool and oral wash (and/or buccal mucosal) samples will be collected per the study calendar.  
Additional samples may be obtained if the patient has any drug-related toxicity at any point during 
the trial. 
 
Microbial DNA will be isolated from stool and oral wash (and/or buccal mucosal) samples and 
prepared for 16S rRNA V4 amplicon sequencing to profile microbial species represented in the 
gut pre- and post-treatment. In addition, microbial DNA will be subjected to whole genome 
metagenomics profiling of microbial species via shotgun sequencing for detailed functional and 


J18119/Amendment 8 / Version 9.0 / March 31, 2022 
49
pathway analysis to determine the change in the species and functions in response to treatment. 
Further bioinformatics analyses will be performed with these sequencing data to identify candidate 
microbial biomarkers, and predictors of response.  Detailed instructions for sample collection, 
processing, storage, and shipment are provided in the laboratory manual. 
 
8.7. 
Genomic Analysis 
 
Genomic sequencing library construction, whole genome/exome sequencing, whole transcriptome 
sequencing, microbial sequencing, neoepitope prediction, mutation burden, and bioinformatic 
analysis will be performed either at an on-campus laboratory or at an off-campus sequencing 
service. All the samples will be de-identified before sending to any laboratory for sequencing.  The 
FASTQ files, BAM files and VCF files will be generated and analyzed.  
 
Genomic sequencing data will be stored and computations conducted using a JH IT managed 
subscription of Azure. 
 
Clinical analysis   
 
Several CLIA-certified laboratories now offer molecular profiling of cancer specimens in 
commercial and noncommercial settings and provide these results to patients and their physicians 
(e.g. Foundation Medicine, PGDx, Michigan Center for Translational Pathology, or JHU CLIA 
Laboratories). It is possible, therefore, that some of our research analyses will be conducted in 
these CLIA-certified environments.  If tissue or cells are evaluated with next generation 
sequencing strategies to provide a molecular profile of individual cancer specimens in a CLIA-
certified facility, these results will be made available to the patient and their physician.  Patient 
confidentiality will be maintained, and the patient’s identity will not be publicly linked to any 
study results.  Researchers may use the data set generated in the CLIA assay setting to study 
genetic alterations across a large number of genes important in cancer. Germline mutations are 
only identified in punitive cancer genes. Researchers will use the data set for exploratory research 
to study cancer cell heterogeneity. Some of the sequencing data obtained from the NGS strategies 
will be uploaded to government sponsored databases, such as GEO and dbGAP.  The results of the 
research studies may be published but subjects will not be identified in any publication. 
 
If a germline alteration of clinical importance (as judged by the Investigator) to the subject and his 
or her family members is identified by a CLIA-certified test in the course of this analysis, attempts 
will be made in writing to contact the subject and/or family members for genetic counseling 
referral. 
 
 
 


 
50
9. 
STUDY CALENDAR 
9.1. Cohorts A and B 
Study Procedures 
Pre-
screen 
Screen 
Cycle (28 days)21 EOT22 Safety 
FU23 
Clinical 
FU24 
Survival 
FU25 
Visit Windows (days)1 
N/A 
-28 to D1 
± 3 
± 7 
+14 
± 14 
± 14 
Nivolumab/ Relatlimab 
 
 
X 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
X 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
Medical, Cancer, & Con Med History2 
 
X 
 
 
 
 
 
Mucin/PD-L1 CPM 
X 
 
 
 
 
 
 
Con Meds, Adverse Events3 
 
 
X 
X 
X 
X 
 
Physical Exam, ECOG  PS3 
 
X 
X 
X 
 
X 
 
Vitals4 
 
X 
X 
X 
 
X 
 
Height5 
 
X 
 
 
 
 
 
Weight 
 
X 
X 
X 
 
X 
 
Oxygen Saturation 
 
X 
X 
X 
 
 
 
Virology6 
 
X 
 
 
 
 
 
Hematology, Chemistry7, 12 
 
X 
X 
X 
 
X 
 
Endocrine8, 12 
 
X 
X 
X 
 
 
 
Cardiac Troponin9, 12 
 
X 
X 
 
 
 
 
Urinalysis10, 12 
 
X 
 
 
 
 
 
Pregnancy Test11, 12 
 
X 
X 
 
 
 
 
CEA12 
 
X 
X 
X 
 
X 
 
ECG13 
 
X 
 
 
 
 
 
Echocardiogram14 
 
X 
 
 
 
 
 
CT/MRI, RECIST/iRECIST15 
 
X 
X 
X 
 
X 
 
Whole Blood (up to 10cc) 16, 26 
 
 
X 
 
 
 
 
PBMC17, 18, 26 
 
 
X (see footnote for schedule) 
 
 
 
Plasma (up to 20cc)17, 26 
 
 
X (see footnote for schedule) 
 
 
 
Serum (up to 5cc)17, 26 
 
 
X (see footnote for schedule) 
 
 
 
Stool and Oral Wash Samples19, 26 
 
 
X (see footnote for schedule) 
 
 
 
Microbiome Questionnaire19 
 
 
X (see footnote for schedule) 
 
 
 
Tumor Biopsies20, 26 
 
X 
X 
 
 
 
 
Archival Tissue26 
X 
 
 
 
 
 
 
Survival Follow-up 
 
 
 
 
 
 
X 


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51
In order to minimize the need for research-only in-person visits, telemedicine visits may be substituted 
for in person clinical trial visits or portions of clinical trial visits where determined to be appropriate 
and where determined by the investigator not to increase the participants risks. Prior to initiating 
telemedicine for study visits the study team will explain to the participant, what a telemedicine visit 
entails and confirm that the study participant is in agreement and able to proceed with this method. 
Telemedicine acknowledgement will be obtained in accordance with the Guidance for Use of 
Telemedicine in Research. In the event telemedicine is not deemed feasible, the study visit will proceed 
as an in-person visit. Telemedicine visits will be conducted using HIPAA compliant method approved 
by the Health System and within licensing restrictions. 
 
1:   If necessary, a scheduled cycle may be delayed for up to 1 week. Longer delays to be approved by 
the IND Sponsor. 
2: Cancer history includes: primary site of cancer, gross location of primary tumor, secondary sites 
of cancer, histology, histologic grade, date of initial diagnosis, date of metastatic diagnosis, prior 
cancer therapy regimens, MSI testing, and tumor mutation testing. 
3: Complete physical examination and assessment of ECOG PS will be completed at baseline; 
focused physical examinations and assessment of ECOG PS will be conducted thereafter. Exams, 
concomitant medication, AE assessments, and ECOG PS can be evaluated up to 3 days prior to 
infusion.  
4: Blood pressure, pulse, and temperature. Vitals will be collected prior to and at the end of the 
nivolumab/relatlimab infusion (+ 15 minutes).  
5: Height will be obtained at or prior to baseline only.  
6: Virology screen: HIV antibody, hepatitis B surface antigen and hepatitis C antibody; additional 
virology may also be evaluated. Subjects who are hepatitis C antibody positive and confirmed 
negative viral load at screening will be allowed to enroll. 
7:  Clinical hematology: CBC with differential ANC, ALC, AEC, and platelet count; serum chemistry: 
sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, ALT, AST, alkaline 
phosphatase, total bilirubin, direct bilirubin, amylase, lipase, total protein, albumin, calcium, 
magnesium, and phosphorus. LDH at baseline only. 
8:   TSH (Total T3 and free T4 if TSH abnormal and clinically indicated). 
9: T (cTnt) or I (cTnI). To be obtained on C1D1, C2D1, and C3D1 only. Troponin elevations will 
require the participant to undergo a cardiac evaluation per Section 5.2. Following this evaluation, 
determination of further treatment will be based on the discussion with the IND Sponsor.  
10: Bilirubin, blood, glucose, ketones, leukocytes, nitrite, pH, color, protein, RBC and WBC count, 
and specific gravity. 
11: Pregnancy tests will be administered to WOCBP: serum pregnancy test is required at screening; 
serum or urine pregnancy tests are required before doses on Day 1 of dosing weeks.  
12: Labs may be collected within a window of up to 3 days prior to dosing.  
13: ECG should be performed at baseline (within 14 days prior to first dose on C1D1), if clinically 
indicated, or at elevation of troponin levels per Section 5.2.  
14: LVEF assessment with documented LVEF > 50% by either TTE or MUGA (TTE preferred test) 
within 6 months from first study drug administration. 
15: Spiral CT of thorax, abdomen and pelvis (and other imaging studies as clinically indicated to 
evaluate suspected sites of metastatic disease). If a subject cannot have a CT scan (e.g., allergy to 
contrast dye), an MRI should be performed. On study radiologic evaluations and tumor 
measurements (RECIST/iRECIST per Appendix C and D) will be at baseline, 12 weeks (+/- 2 
week), every 8 weeks (+/- 2 week) through week 52, and then every 12 weeks (+/- 2 week) 
thereafter including the EOT evaluation (± 4 weeks). The EOT scans do not need to be repeated if 


 
52
one has been done within the past 6 weeks. Weeks are in reference to calendar week and should 
not be adjusted due to dosing delays. 
16: Baseline only (any time prior to the first dose after eligibility is met) 
17: Whole blood for PBMC, plasma, and serum will be collected at baseline (any time prior to the first 
dose after eligibility is met), 4 weeks (+/- 1 week), every 16 weeks (+/- 2 week) through week 52, 
and then every 24 weeks (+/- 2 week) thereafter including the EOT evaluation. Weeks are in 
reference to calendar week and should not be adjusted due to dosing delays. 
18: Up to 120cc of whole blood for PBMC isolation will be collected at baseline (any time prior to the 
first dose after eligibility is met) and at week 4. Up to 150 cc will be collected at subsequent time 
points. 
19: Stool, oral wash (and/or buccal mucosal) specimens, and microbiome questionnaire will be 
obtained when available. All stool specimens should be collected within 72 hours (and ideally 
within 24 hours) of the patient's appointment. Baseline specimens may be obtained any time prior 
to the first dose after eligibility is met. On study stool specimens will be obtained every 12 weeks 
(+/- 2 week) through week 52, and then annually thereafter including the EOT evaluation (± 4 
weeks). Oral wash and/or buccal swab will be collected at baseline, once during treatment and 
annually thereafter including the EOT evaluation (± 4 weeks). Additional samples may be obtained 
if the patient has any drug-related toxicity at any point during the trial. Detailed instructions for 
stool and oral wash collection and shipment are provided in the Laboratory Manual.  
20: Tumor biopsies to be taken (if a subject’s tumor is thought to be reasonably safe and easy to biopsy) 
at baseline (any time prior to the first dose after eligibility is met) and at Cycle 2 (4-6 cores per 
time point). The Cycle 2 biopsy has a ± 1 week window. Additional optional biopsies may be 
obtained later in the course of study treatment. Fine needle aspiration will not be acceptable. 
Detailed instructions for tissue collection, processing and shipment are provided in the Laboratory 
Manual.  
21: Cycle 1 Day 1 evaluations do not need to be repeated if they were conducted within 3 days of the 
pre-study evaluations. Window of +7 days is for cycle 2 and beyond. 
22: EOT visit will occur 30 (±7) days after the final dose (or within 7 days prior to initiation of a new 
anti-cancer treatment, whichever comes first). NOTE: CT scan assessment at EOT will occur 30 
days (± 4 weeks) after the final dose. If the EOT visit occurs early, an assessment for AEs should 
be made by telephone or email on day 30 (±1) after last study dose. 
23: Subjects who discontinue treatment should be contacted by telephone or email at 100 days (+ 14 
day reporting window) from their last dose of study drug or within 7 days before initiation of a 
new antineoplastic treatment (whichever comes first) to assess for treatment related toxicities. In 
addition, all SAEs occurring during this time should be reported as well. 
24: Subjects who discontinue treatment without disease progression (Section 4.12.2) will enter the 
clinical follow-up portion of the trial. Clinical follow-up visits will occur every 12 weeks (± 2 
weeks) until progression. After disease progression, subjects will enter the survival follow-up 
portion of the trial. 
25: Subjects who discontinue treatment and have disease progression (Section 4.12.3) will enter the 
survival follow-up portion of the trial. Subjects should be contacted every 12 weeks (± 2 weeks) 
to monitor overall survival. Information of other cancer therapies after discontinuation from the 
study treatment will be collected as well.  
26: Research samples will be collected at the discretion of the PI based on availability of supplies and 
safety of patient and staff. 
 
 
 


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53
9.2. Cohort C 
  
Study Procedures 
Screen 
Cycle (28 days)21 EOT22 Safety 
FU23 
Clinical 
FU24 
Survival 
FU25 
Visit Windows (days)1 
-28 to D1 
± 3 
± 7 
+14 
± 14 
± 14 
Nivolumab/ Relatlimab 
 
X27 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical, Cancer, & Con Med History2 
X 
 
 
 
 
 
Con Meds, Adverse Events3 
 
X 
X 
X 
X 
 
Physical Exam, ECOG  PS3 
X 
X 
X 
 
X 
 
Vitals4 
X 
X 
X 
 
X 
 
Height5 
X 
 
 
 
 
 
Weight 
X 
X 
X 
 
X 
 
Oxygen Saturation 
X 
X 
X 
 
 
 
Virology6 
X 
 
 
 
 
 
Hematology, Chemistry7, 12 
X 
X 
X 
 
X 
 
Endocrine8, 12 
X 
X 
X 
 
 
 
Cardiac Troponin, CPK9, 12 
X 
X 
 
 
 
 
Urinalysis10, 12 
X 
 
 
 
 
 
Pregnancy Test11, 12 
X 
X 
 
 
 
 
CEA12 
X 
X 
X 
 
X 
 
ECG13 
X 
 
 
 
 
 
Echocardiogram14 
X 
 
 
 
 
 
CT/MRI, RECIST/iRECIST15 
X 
X 
X 
 
X 
 
Whole Blood (up to 10cc) 16, 26 
 
X 
 
 
 
 
PBMC17, 18, 26 
 
X (see footnote for schedule) 
 
 
 
Plasma (up to 20cc)17, 26 
 
X (see footnote for schedule) 
 
 
 
Serum (up to 5cc)17, 26 
 
X (see footnote for schedule) 
 
 
 
Stool and Oral Wash Samples19, 26 
 
X (see footnote for schedule) 
 
 
 
Microbiome Questionnaire19 
 
X (see footnote for schedule) 
 
 
 
Tumor Biopsies20, 26 
X 
X 
 
 
 
 
Archival Tissue26 
X 
Survival Follow-up 
 
 
 
 
 
 
X 
 


 
54
In order to minimize the need for research-only in-person visits, telemedicine visits may be substituted for 
in person clinical trial visits or portions of clinical trial visits where determined to be appropriate and 
where determined by the investigator not to increase the participants risks. Prior to initiating telemedicine 
for study visits the study team will explain to the participant, what a telemedicine visit entails and confirm 
that the study participant is in agreement and able to proceed with this method. Telemedicine 
acknowledgement will be obtained in accordance with the Guidance for Use of Telemedicine in Research. 
In the event telemedicine is not deemed feasible, the study visit will proceed as an in-person visit. 
Telemedicine visits will be conducted using HIPAA compliant method approved by the Health System and 
within licensing restrictions. 
 
1:   If necessary, a scheduled cycle may be delayed for up to 1 week. Longer delays to be approved by the 
IND Sponsor. 
2: Cancer history includes: primary site of cancer, gross location of primary tumor, secondary sites of 
cancer, histology, histologic grade, date of initial diagnosis, date of metastatic diagnosis, prior cancer 
therapy regimens, MSI testing, and tumor mutation testing. 
3: Complete physical examination and assessment of ECOG PS will be completed at baseline; focused 
physical examinations and assessment of ECOG PS will be conducted thereafter. Exams, concomitant 
medication, AE assessments, and ECOG PS can be evaluated up to 3 days prior to infusion. Additional 
weekly visits with AE assessment will occur through Week 8 (C3D1) for patients that received the 
480mg or 960mg dose of relatlimab. 
4: Blood pressure, pulse, and temperature. Vitals will be collected prior to and at the end of the 
nivolumab/relatlimab infusion (+ 15 minutes).  
5: Height will be obtained at or prior to baseline only.  
6: Virology screen: HIV antibody, hepatitis B surface antigen and hepatitis C antibody; additional 
virology may also be evaluated. Subjects who are hepatitis C antibody positive and confirmed negative 
viral load at screening will be allowed to enroll. 
7:  Clinical hematology: CBC with differential ANC, ALC, AEC, and platelet count; serum chemistry: 
sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, ALT, AST, alkaline phosphatase, 
total bilirubin, direct bilirubin, amylase, lipase, total protein, albumin, calcium, magnesium, and 
phosphorus. LDH at baseline only. 
8:   TSH (Total T3 and free T4 if TSH abnormal and clinically indicated). 
9: T (cTnt) or I (cTnI). To be obtained on C1D1, C2D1, and C3D1 only. For patients receiving 480mg or 
960mg dose of Relatlimab, cTnt or cTnI AND CPK will also be obtained weekly (± 3 day window) 
through and including C3D1. Troponin elevations will require the participant to undergo a cardiac 
evaluation per Section 5.2. Following this evaluation, determination of further treatment will be based 
on the discussion with the IND Sponsor.   
10: Bilirubin, blood, glucose, ketones, leukocytes, nitrite, pH, color, protein, RBC and WBC count, and 
specific gravity. 
11: Pregnancy tests will be administered to WOCBP: serum pregnancy test is required at screening; serum 
or urine pregnancy tests are required before doses on Day 1 of dosing weeks.  
12: Labs may be collected within a window of up to 3 days prior to dosing.  
13: ECG should be performed at baseline (within 14 days prior to first dose on C1D1), if clinically indicated, 
or at elevation of troponin levels per Section 5.2.  
14: LVEF assessment with documented LVEF > 50% by either TTE or MUGA (TTE preferred test) within 
6 months from first study drug administration. 
15: Spiral CT of thorax, abdomen and pelvis (and other imaging studies as clinically indicated to evaluate 
suspected sites of metastatic disease). If a subject cannot have a CT scan (e.g., allergy to contrast dye), 
an MRI should be performed. On study radiologic evaluations and tumor measurements 
(RECIST/iRECIST per Appendix C and D) will be at baseline, 12 weeks (+/- 2 week), every 8 weeks 
(+/- 2 week) through week 52, and then every 12 weeks (+/- 2 week) thereafter including the EOT 


J18119/Amendment 8 / Version 9.0 / March 31, 2022 
55
evaluation (± 4 weeks). The EOT scans do not need to be repeated if one has been done within the past 
6 weeks. Weeks are in reference to calendar week and should not be adjusted due to dosing delays. 
16: Baseline only (any time prior to the first dose after eligibility is met) 
17: Whole blood for PBMC, plasma, and serum will be collected at baseline (any time prior to the first dose 
after eligibility is met), 4 weeks (+/- 1 week), every 16 weeks (+/- 2 week) through week 52, and then 
every 24 weeks (+/- 2 week) thereafter including the EOT evaluation. Weeks are in reference to 
calendar week and should not be adjusted due to dosing delays. 
18: Up to 120cc of whole blood for PBMC isolation will be collected at baseline (any time prior to the first 
dose after eligibility is met) and at weeks 2 and 4. Up to 150 cc will be collected at subsequent time 
points. 
19: Stool, oral wash (and/or buccal mucosal) specimens, and microbiome questionnaire will be obtained 
when available. All stool specimens should be collected within 72 hours (and ideally within 24 hours) 
of the patient's appointment. Baseline specimens may be obtained any time prior to the first dose after 
eligibility is met. On study stool specimens will be obtained every 12 weeks (+/- 2 week) through week 
52, and then annually thereafter including the EOT evaluation (± 4 weeks). Oral wash and/or buccal 
swab will be collected at baseline, once during treatment and annually thereafter including the EOT 
evaluation (± 4 weeks). Additional samples may be obtained if the patient has any drug-related toxicity 
at any point during the trial. Detailed instructions for stool and oral wash collection and shipment are 
provided in the Laboratory Manual.  
20: Tumor biopsies to be taken (if a subject’s tumor is thought to be reasonably safe and easy to biopsy) at 
baseline (any time prior to the first dose after eligibility is met) and at Cycle 2 (4-6 cores per time point). 
The Cycle 2 biopsy has a ± 1 week window. Additional optional biopsies may be obtained later in the 
course of study treatment. Fine needle aspiration will not be acceptable. Detailed instructions for tissue 
collection, processing and shipment are provided in the Laboratory Manual.  
21: Cycle 1 Day 1 evaluations do not need to be repeated if they were conducted within 3 days of the pre-
study evaluations. Window of +7 days is for cycle 2 and beyond. 
22: EOT visit will occur 30 (±7) days after the final dose (or within 7 days prior to initiation of a new anti-
cancer treatment, whichever comes first). NOTE: CT scan assessment at EOT will occur 30 days (± 4 
weeks) after the final dose. If the EOT visit occurs early, an assessment for AEs should be made by 
telephone or email on day 30 (±1) after last study dose. 
23: Subjects who discontinue treatment should be contacted by telephone or email at 100 days (+ 14 day 
reporting window) from their last dose of study drug or within 7 days before initiation of a new 
antineoplastic treatment (whichever comes first) to assess for treatment related toxicities. In addition, 
all SAEs occurring during this time should be reported as well. 
24: Subjects who discontinue treatment without disease progression (Section 4.12.2) will enter the clinical 
follow-up portion of the trial. Clinical follow-up visits will occur every 12 weeks (± 2 weeks) until 
progression. After disease progression, subjects will enter the survival follow-up portion of the trial. 
25: Subjects who discontinue treatment and have disease progression (Section 4.12.3) will enter the 
survival follow-up portion of the trial. Subjects should be contacted every 12 weeks (± 2 weeks) to 
monitor overall survival. Information of other cancer therapies after discontinuation from the study 
treatment will be collected as well.  
26: Research samples will be collected at the discretion of the PI based on availability of supplies and safety 
of patient and staff. 
27: If nivolumab and relatlimab are being administered sequentially (due to Relatlimab 480 or 960mg dose), 
the order of administration is nivolumab followed by relatlimab. Subjects should be observed for a 
minimum of 30 minutes between each infusion. 
 
 
 


 
56
10. 
STUDY ENDPOINTS 
 
10.1. Primary Endpoint 
 
The primary endpoint is ORR, which is defined as the proportion of subjects with PR or CR 
according to RECIST 1.1. Subjects who discontinue due to toxicity or clinical progression prior to 
post-baseline tumor assessments will be considered as non-responders.  Subjects who discontinue 
for reasons other than toxicity or clinical progression prior to the post-baseline tumor assessments 
or for other reasons prior to their first dose of study drug will be replaced and not included in the 
primary efficacy analysis. 
 
10.2. Secondary Endpoint 
 
The secondary endpoint is as follows: 
 
Safety assessed by the following measures: 
– Number of patients who have grade 3 or higher drug-related toxicities  
– Frequency of drug-related toxicity by grade  
– Nivolumab- and relatlimab-related infusion reactions 
– Immune-related AEs 
– Unacceptable toxicities 
– Vital signs: BP, pulse, respiratory rate, temperature 
– Physical examination 
– Changes in ECG readings  
– Clinical hematology: complete blood count (CBC) with differential ANC, ALC, AEC, 
and platelet count 
– Clinical serum chemistry: sodium, potassium, chloride, bicarbonate, glucose, BUN, 
creatinine, LDH, ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, 
amylase, lipase, total protein, albumin, calcium, magnesium, and phosphorus 
– TSH, T3, Free T4 
– Cardiac troponin 
 
10.3. Exploratory Endpoints 
 
Exploratory endpoints are as follows: 
 
 Overall survival (OS), progression free survival (PFS), time to-progression (TTP), disease 
control rate (DCR), best overall response (BOR), duration of response (DOR), duration of 
clinical benefit (DCB), and time to objective response (TTOR) measured by RECIST 1.1 
(Appendix C).  
 
Overall survival (OS) is defined as the number of months from the date of first 
treatment until death or end of follow-up (OS will be censored on the date the 
subject was last known to be alive for subjects without documentation of death at 
the time of analysis). 
 
Progression-free survival (PFS) is defined as the number of months from the date 
of first treatment to disease progression (PD or relapse from CR as assessed using 


J18119/Amendment 8 / Version 9.0 / March 31, 2022 
57
RECIST 1.1 criteria) or death due to any cause. PFS will be censored at the date of 
the last scan for subjects without documentation of disease progression at the time 
of analysis. iPFS is defined as the time to iUPD if the next scan (4-8 weeks later) 
confirms PD (state change from iUPD to iCPD, time to progression defined in this 
instance as iUPD). 
 
Disease Control Rate (DCR) is defined as the percentage of subjects achieving 
stable disease or better (SD + PR + CR). 
 
Best Overall Response (BOR) is defined in Appendix C. 
 
Duration of Response (DOR) is defined as the number of months from the first 
documentation of a response to date of disease progression.  
 
Duration of Clinical Benefit (DCB) is defined as the number of months from the 
date of first treatment to date of disease progression in those achieving a PR or CR. 
 
Time to Objective Response (TTOR) is defined as the number of months from the 
date of first treatment to the date of documented partial or complete response. 
 
Time to-progression (TTP) is defined as the number of months from the date of 
first treatment to the date of documented disease progression (PD or relapse from 
CR as assessed using RECIST 1.1 criteria). It differs from PFS in that it does not 
include death in the definition of an event.  TTP will be censored at the date of the 
last scan for subjects without documentation of disease progression at the time of 
analysis. 
 iORR by immune-related RECIST criteria (iRECIST). 
 Immune subset analysis by IHC and gene expression profiling of the tumor  
– Sequencing of tumor 
– Assessment of tumor burden dynamics using standard protein biomarkers when 
available as well as circulating biomarkers (i.e. ctDNA). 
– Immune subset analyses by FACS in PBMCs including effector, helper, and 
regulatory T cells, NK cells and macrophages 
– T cell receptor (TCR) repertoire analysis in PBMCs and tumors 
– Gene expression analysis of PBMCs 
– Microbial community analysis and whole metagenome functional profiling analysis 
of stool and oral wash samples. 
 
11. 
DATA REPORTING/ REGULATORY REQUIREMENTS 
 
AE guidelines and instructions for AE reporting can be found in Section 6 (Adverse Events: List 
and Reporting Requirements). 
 
Dr. Dung Le will be holding the IND for this study.  She will comply with all regulated reporting 
requirements to the FDA. 
 
11.1. Data Collection and Processing 
 
All information will be collected on study-specific CRFs by study staff. These data will be 
reviewed for completeness and accuracy by the Principal Investigator at each site.  
 


 
58
CRFs will be used to capture study results and data. The study coordinator or other authorized 
study personnel will transcribe data from source documents onto eCRFs. Before or between visits, 
the IND Sponsor, or designee may request copies of the CRFs for preliminary medical review. 
Once the CRFs are complete and source-verified, the investigator must sign and date all required 
pages, verifying the accuracy of all data contained within the CRF.  
 
11.2. Safety Meetings 
 
Scheduled meetings will take place weekly and will include the protocol principal investigator, 
study coordinator(s), data manager(s), sub-investigators (as appropriate), collaborators (as 
appropriate), and biostatisticians (as appropriate) involved with the conduct of the protocol. During 
these meetings matters related to the following will be discussed: safety of protocol participants, 
validity and integrity of the data, enrollment rate relative to expectation, characteristics of 
participants, retention of participants, adherence to protocol (potential or real protocol violations), 
data completeness, and progress of data for objectives. 
 
11.3. Monitoring 
 
The SKCCC Compliance Monitoring Program will provide external monitoring for JHU-affiliated 
sites in accordance with SKCCC DSMP (Version 6.0, 02/21/2019). The SMC Subcommittee will 
determine the level of patient safety risk and level/frequency of monitoring. The PI shall internally 
monitor the progress of the trial, including review and confirmation of all safety/treatment-related 
outcomes, response assessments, safety reports and/or any related source documentation. The 
protocol will be monitored externally by the SKCCC CRO QA Office. Additional data and safety 
monitoring oversight will also be performed by the SKCCC Safety Monitoring Committee (SMC 
- as defined in the DSMP).  
 
Dr. Le is holding the IND for this study.  She will comply with all regulated reporting requirements 
to the FDA.  
 
11.4. Study Documentation 
 
11.4.1 Informed Consent and Authorization for use and Disclosure of Protected 
Health Information 
 
Written informed consent and authorization of use and disclosure of protected health 
information (PHI) must be obtained from each subject (or the subject’s legally authorized 
representative) before performing any study-specific screening/baseline period 
evaluations. The ICF and authorization for use and disclosure of PHI, which is prepared by 
the investigator or the site, must be reviewed and approved by the IND Sponsor, the study 
monitor (if applicable), and the site’s IRB before the initiation of the study.  
 
11.4.2 Investigator Study Files 
 
Documentation about the investigator and study staff, the IRB and the institution, is 
required before study site initiation. A list of required documents will be provided by the 


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IND Sponsor or designee to each participating investigator. Copies of these documents as 
well as supplemental information, such as the investigator’s obligations, IB, clinical study 
protocol and amendments, safety information, investigational agent information, biological 
samples and laboratory procedures, SRM, study logs and IND Sponsor/investigator/study 
monitor correspondence will be kept on-site in study site-specific binders. 
 
The IND Sponsor or designee will be responsible for maintaining original and backup of 
all CRF data. The investigator is responsible for maintaining backup of all electronic data 
systems used for primary documentation or source documentation. Backup of electronic 
data will be performed periodically as described in the site-specific SOPs. Backup records 
must be stored at a secure location on site and backup and recovery logs must be maintained 
to facilitate data recovery. If an electronic medical records system that is not supported by 
the IND Sponsor or designee (or is discontinued or decommissioned) is used, the 
investigator must maintain a system to retrieve these records or arrange for the transfer of 
these records to an alternate electronic format or to paper. 
 
Changes to any electronic records require an audit trail, in accordance with 21 CFR 
11.10(e), and should include who made the changes and when and why the changes were 
made. An audit trail is defined as a secure, computer-generated, time-stamped electronic 
record that will allow reconstruction of the course of events relating to the creation, 
modification and deletion of an electronic record. Audit trails must be created 
incrementally, in chronological order and in a manner that does not allow new audit trail 
information to overwrite existing data. Audit trails should be in a readable format and 
readily available at the study site and any other location where electronic study records are 
maintained. 
 
Audit trails are generated automatically for eCRFs. The investigator is responsible for 
maintaining audit trails of all electronic data systems used for primary documentation or 
source documentation. 
 
11.4.3 Case Report Forms and Source Documentation 
 
The investigator must make study data accessible to the site monitor, to other authorized 
representatives of the IND Sponsor (or designee) and to the appropriate regulatory 
authority inspectors. The original CRF for each subject will be checked against source 
documents at the study site by the site monitor. 
 
11.4.4 Retention of Study Documents 
 
According to ICH E6, Section 4.9, all CRFs, as well as supporting paper and electronic 
documentation and administrative records, must be retained for at least 2 years after the 
last approval of a marketing application and until there are no pending or contemplated 
marketing applications, or at least 2 years have elapsed since the formal discontinuation of 
clinical development of an individual product. Longer retention periods may apply. The 
IND Sponsor will notify investigators as to when documents no longer need to be retained. 
No study documents will be destroyed or moved to a new location without prior written 


 
60
approval from the IND Sponsor. If the investigator relocates, retires or withdraws from the 
clinical study for any reason, all records required to be maintained for the study should be 
transferred to an agreed-upon designee, such as another investigator at the institution where 
the study was conducted. 
 
Audit trails for electronic documents must be retained for a period at least as long as that 
required for the subject electronic records to which they pertain. The investigator must 
retain either the original or a certified copy of audit trails. 
 
11.4.5 Data Confidentiality and Subject Anonymity 
 
All information about the nature of the proposed investigation provided by the IND 
Sponsor or their representative to the investigator (with the exception of information 
required by law or regulations to be disclosed to the IRB, the subject or the appropriate 
regulatory authority) must be kept in confidence by the investigator. 
 
The anonymity of participating subjects must be maintained. Subjects will be identified by 
their assigned subject number on CRFs and other documents retrieved from the site or sent 
to the IND Sponsor, study monitor, BMS, regulatory agencies, or central 
laboratories/reviewers. Documents that identify the subject (e.g., the signed ICF) must be 
maintained in strict confidence by the investigator, except to the extent necessary to allow 
auditing by the appropriate regulatory authority, the study monitor, IND Sponsor or their 
representative. 
 
12. 
STATISTICAL CONSIDERATIONS 
 
12.1. Study Design/Endpoints 
 
Sample Size 
 
This is an open-label, two stage, phase 2 study to evaluate the safety and clinical activity of 
nivolumab and relatlimab in patients with metastatic or locally advanced microsatellite stable 
(MSS) colorectal cancer that have a positive and negative composite PD-L1/Mucin (CPM). The 
primary endpoint is objective response rate (ORR) assessed using RECIST 1.1.   
 
The trial will enroll two cohorts of MSS mCRC patients receiving 480mg nivolumab/160mg 
relatlimab: patients with MSS colorectal adenocarcinomas who have a positive CPM score (Cohort 
A); and patients with MSS colorectal adenocarcinomas who have a negative CPM score (Cohort 
B). The cut-off threshold > 15% of CPM will be used to determine CPM positivity. An additional 
cohort of MSS mCRC patients without biomarker selection will be enrolled to receive 480mg 
nivolumab/960mg relatlimab or 480mg nivolumab/480mg relatlimab (Cohort C). 
 
Each cohort will enroll up to 32 evaluable patients. The primary endpoint is objective response 
rate (ORR) per RECIST 1.1, and the three cohorts will be analyzed separately for the primary 
analysis of rate of ORR. For each cohort, the treatment will be considered inactive and of no 
interest for further evaluation if the ORR is 5% or less and considered active if the ORR is 20% or 


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greater. This design allows for evaluating the efficacy of the treatment and CPM as a predictive 
marker simultaneously.   
  
Simon two-stage minimax design is planned for each cohort.  Initially, 18 patients per cohort will 
be treated in stage 1. Patients will be considered evaluable if they receive at least one dose of study 
treatment. If there is at least 1 response in that cohort then an additional 14 patients will be enrolled 
in stage 2 for a total of 32 patients in that cohort. If a total of 4 or more responses are observed in 
stage 1 and 2 combined, we conclude the regimen is promising and warrant further study. This 
design has 90% power to reject the null response rate of 5% in favor of 20% response rate, with 
one-sided type 1 error 0.1.   
 
We expect that the prevalence of a positive CPM score is 10-15% among MSS CRC patients. 
Therefore, we will need to screen 220-320 MSS CRC patients in order to identify 32 marker 
positive MSS CRC patients. Assuming 95% of CRC patients are MSS, we will screen a total of 
235-340 CRC patients. 
 
Statistical Analyses 
 
The primary endpoint is objective response rate, defined as complete response (CR) or partial 
response (PR) per RECIST 1.1. Objective response rate (ORR) will be estimated as the proportion 
of subjects whose best overall response is either a CR or PR with corresponding 95% CI. The 
primary population for the analysis is all subjects who receive at least one dose of study drug, and 
have at least one post-baseline tumor assessments or discontinue due to toxicity or clinical 
progression prior to post-baseline tumor assessments.   
 
Exploratory endpoints include progression-free survival (PFS), overall survival (OS), and duration 
of response (DOR). PFS is defined as the time from the first day of study treatment to the date of 
the first documented tumor progression or death due to any cause, whichever occurs first. Subjects 
who did not progress or die will be censored on the date of their last tumor assessment. Kaplan-
Meier curves will be used to summarize PFS. Overall survival (OS) is the time from the first day 
of study treatment to the date of death due to any cause. A subject who has not died will be censored 
at last known date alive. Kaplan-Meier curves will be used to summarize OS. Among patients with 
an objective response, DOR is defined as the time between the date of initial complete or partial 
response to the date of the first documented tumor progression or death due to any cause. Subjects 
who neither progress nor die will be censored on the date of their last tumor assessment. Summary 
statistics will be presented for DOR. 
 
For biomarkers, potential relationships between biomarker data and efficacy or safety endpoints 
will be investigated aimed at identifying baseline biomarkers that may be used to prospectively 
identify subjects likely (or not likely) to respond to the treatment and to identify subjects who may 
be predisposed to having adverse reactions to treatment. These exploratory biomarker analyses 
will be completed with biomarkers measured in blood and in tumor samples.  
 
The performance of the PD-L1/mucin composite score (CPM) in predicting treatment response 
will be further evaluated. ROC analysis based on logistic regression will be used to assess the 


 
62
prediction accuracy, and the cutoff threshold for identifying patients who may benefit the therapy 
will be validated.    
 
Genomic sequencing library construction, whole genome/exome sequencing, whole transcriptome 
sequencing, microbial sequencing, neoepitope prediction, mutation burden, and bioinformatic 
analysis will be performed either at an on-campus laboratory or at an off-campus sequencing 
service. All the samples will be de-identified before sending to any laboratory for sequencing.  The 
FASTQ files, BAM files and VCF files will be generated and analyzed. 
 
Genomic sequencing data will be stored and computations conducted using a JH IT managed 
subscription of Azure. 
 
12.2. Safety Analysis 
 
The safety analysis will be performed in all treated subjects. AE data will be listed individually 
and incidence of AEs summarized by system organ class and preferred terms within a system organ 
class for each cohort.  When calculating the incidence of AEs, each AE (based on preferred 
terminology defined by CTCAE version 5.0) will be counted only once for a given subject.  In 
analyses of grade and causality, if the same AE occurs on multiple occasions, the highest grade 
and strongest relationship to study drug will be assumed.  If 2 or more AEs are reported as a unit, 
the individual terms will be reported as separate experiences.   
 
Changes in vital signs, hematology and clinical chemistry parameters from baseline to the end of 
the study will be examined.  Toxicity will be tabulated by type and grade. Toxicities will be 
characterized according to the CTCAE version 5.0.  Treatment-emergent changes from normal to 
abnormal values in key laboratory parameters will be identified. 
 
 
 


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13. REFERENCES 
 
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3. 
Coca, S., et al., The prognostic significance of intratumoral natural killer cells in patients 
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Naito, Y., et al., CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in 
human colorectal cancer. Cancer Res, 1998. 58(16): p. 3491-4. 
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Ropponen, K.M., et al., Prognostic value of tumour-infiltrating lymphocytes (TILs) in 
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Liljefors, M., et al., Natural killer (NK) cell function is a strong prognostic factor in 
colorectal carcinoma patients treated with the monoclonal antibody 17-1A. Int J Cancer, 
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7. 
Galon, J., et al., Type, density, and location of immune cells within human colorectal 
tumors predict clinical outcome. Science, 2006. 313(5795): p. 1960-4. 
8. 
Pages, F., et al., Effector memory T cells, early metastasis, and survival in colorectal 
cancer. N Engl J Med, 2005. 353(25): p. 2654-66. 
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Funada, Y., et al., Prognostic significance of CD8+ T cell and macrophage peritumoral 
infiltration in colorectal cancer. Oncol Rep, 2003. 10(2): p. 309-13. 
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Pages, F., et al., In situ cytotoxic and memory T cells predict outcome in patients with 
early-stage colorectal cancer. J Clin Oncol, 2009. 27(35): p. 5944-51. 
11. 
Halama, N., et al., Localization and density of immune cells in the invasive margin of 
human colorectal cancer liver metastases are prognostic for response to chemotherapy. 
Cancer Res, 2011. 71(17): p. 5670-7. 
12. 
Topalian, S.L., et al., Survival, durable tumor remission, and long-term safety in patients 
with advanced melanoma receiving nivolumab. J Clin Oncol, 2014. 32(10): p. 1020-30. 
13. 
Brahmer, J.R., et al., Safety and activity of anti-PD-L1 antibody in patients with advanced 
cancer. N Engl J Med, 2012. 366(26): p. 2455-65. 
14. 
Hodi, F.S., et al., Improved survival with ipilimumab in patients with metastatic 
melanoma. N Engl J Med, 2010. 363(8): p. 711-23. 
15. 
Wolchok, J.D., et al., Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med, 
2013. 369(2): p. 122-33. 
16. 
Gettinger, S.N., et al., Overall Survival and Long-Term Safety of Nivolumab (Anti-
Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously 
Treated Advanced Non-Small-Cell Lung Cancer. J Clin Oncol, 2015. 33(18): p. 2004-12. 
17. 
Gajewski, T.F., et al., Molecular profiling to identify relevant immune resistance 
mechanisms in the tumor microenvironment. Curr Opin Immunol, 2011. 23(2): p. 286-92. 
18. 
Tumeh, P.C., et al., PD-1 blockade induces responses by inhibiting adaptive immune 
resistance. Nature, 2014. 515(7528): p. 568-71. 


 
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19. 
Taube, J.M., et al., Association of PD-1, PD-1 ligands, and other features of the tumor 
immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res, 2014. 
20(19): p. 5064-74. 
20. 
Herbst, R.S., et al., Predictive correlates of response to the anti-PD-L1 antibody 
MPDL3280A in cancer patients. Nature, 2014. 515(7528): p. 563-7. 
21. 
Topalian, S.L., et al., Safety, activity, and immune correlates of anti-PD-1 antibody in 
cancer. N Engl J Med, 2012. 366(26): p. 2443-54. 
22. 
Lipson, E.J., et al., Durable cancer regression off-treatment and effective reinduction 
therapy with an anti-PD-1 antibody. Clin Cancer Res, 2013. 19(2): p. 462-8. 
23. 
Ascierto, P.A., et al., Initial efficacy of anti-lymphocyte activation gene-3 (anti-LAG-3; 
BMS-986016) in combination with nivolumab (nivo) in pts with melanoma (MEL) 
previously treated with anti-PD-1/PD-L1 therapy. Abstract at 2017 ASCO Annual 
Meeting. 
24. 
Relatlimab Investigator's Brochure. 
25. 
Rizvi, N.A., et al., Cancer immunology. Mutational landscape determines sensitivity to 
PD-1 blockade in non-small cell lung cancer. Science, 2015. 348(6230): p. 124-8. 
26. 
van Rooij, N., et al., Tumor exome analysis reveals neoantigen-specific T-cell reactivity in 
an ipilimumab-responsive melanoma. J Clin Oncol, 2013. 31(32): p. e439-42. 
27. 
Le, D.T., et al., PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med, 
2015. 372(26): p. 2509-20. 
28. 
Le, D.T., et al., Mismatch repair deficiency predicts response of solid tumors to PD-1 
blockade. Science, 2017. 357(6349): p. 409-413. 
29. 
Overman, M.J., et al., Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA 
Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. J 
Clin Oncol, 2018: p. JCO2017769901. 
30. 
Overman, M.J., et al., Nivolumab in patients with metastatic DNA mismatch repair-
deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-
label, multicentre, phase 2 study. Lancet Oncol, 2017. 18(9): p. 1182-1191. 
31. 
Llosa, N.J., et al., The vigorous immune microenvironment of microsatellite instable colon 
cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov, 2015. 5(1): 
p. 43-51. 
32. 
Yoon, Y.S., et al., Clinical implications of mucinous components correlated with 
microsatellite instability in patients with colorectal cancer. Colorectal Dis, 2015. 17(8): p. 
O161-7. 
33. 
Alexander, J., et al., Histopathological identification of colon cancer with microsatellite 
instability. Am J Pathol, 2001. 158(2): p. 527-35. 
34. 
Reggiani Bonetti, L., et al., Do pathological variables have prognostic significance in 
rectal adenocarcinoma treated with neoadjuvant chemoradiotherapy and surgery? 
World J Gastroenterol, 2017. 23(8): p. 1412-1423. 
35. 
Carbognin, L., et al., Differential Activity of Nivolumab, Pembrolizumab and MPDL3280A 
according to the Tumor Expression of Programmed Death-Ligand-1 (PD-L1): Sensitivity 
Analysis of Trials in Melanoma, Lung and Genitourinary Cancers. PLoS One, 2015. 10(6): 
p. e0130142. 


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36. 
Gettinger, S.N., et al., First-line nivolumab (anti-PD-1; BMS-936558, ONO-4538) 
monotherapy in advanced NSCLC: Safety, efficacy, and correlation of outcomes with PD-
L1 status. Journal of Clinical Oncology, 2014. 32(15_suppl): p. 8024-8024. 
37. 
Grosso, J., et al., Association of tumor PD-L1 expression and immune biomarkers with 
clinical activity in patients (pts) with advanced solid tumors treated with nivolumab 
(anti-PD-1; BMS-936558; ONO-4538). Journal of Clinical Oncology, 2013. 31(15_suppl): 
p. 3016-3016. 
38. 
Wolchok, J.D., et al., Guidelines for the evaluation of immune therapy activity in solid 
tumors: immune-related response criteria. Clin Cancer Res, 2009. 15(23): p. 7412-20. 
39. 
Le, D.T., et al., Mismatch-repair deficiency predicts response of solid tumors to PD-1 
blockade. Science, 2017. 
40. 
Seymour, L., et al., iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics. Lancet Oncol, 2017. 18(3): p. e143-e152. 
 
 
 


 
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APPENDIX A: PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 


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APPENDIX B: MANAGEMENT ALGORITHMS 
 
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the IND Sponsor. The guidance applies to all immuno-oncology (I-O) agents and 
regimens. 
 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated. 
 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory subjects with low-
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids. 
 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. 
 
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used. 
 
 


 
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APPENDIX C: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 
1.1 CRITERIA FOR EVALUATING RESPONSE IN SOLID TUMORS 
 
RECIST version 1.1 will be used in this study for assessment of tumor response.  While either CT 
or MRI may be used utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study.   
Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm 
with CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable unless there is evidence of progression in the irradiated site. Malignant 
lymph nodes.  To be considered pathologically enlarged and measurable, a lymph node must 
be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured 
and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions 
are present in the same subject, these are preferred for selection as target lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements.  It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected.  A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum.  The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease. 
 


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Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study).  In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also considered 
progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a subject 
to be considered in complete clinical response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions.  Unequivocal progression should not normally trump target lesion 
status.  It must be representative of overall disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the review panel (or Principal Investigator). 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 


 
78
recorded since the treatment started).  The subject's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
For Subjects with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall 
Response when 
Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. 
Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. 
Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least 
once >4 wks. from 
baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of 
a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: Subjects with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
Reference 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. 
Verweij. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 
1.1).  Eur J Cancer. 2009 Jan;45(2):228-47. 
 
 
 


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APPENDIX D: DESCRIPTION OF THE IRECIST PROCESS FOR ASSESSMENT OF 
DISEASE PROGRESSION  
 
Assessment at Screening and Prior to RECIST 1.1 Progression 
 
Until radiographic progression based on RECIST 1.1, there is no distinct iRECIST assessment. 
 
Assessment and Decision at RECIST 1.1 Progression 
 
In participants who show evidence of radiological PD by RECIST 1.1 the Investigator will decide 
whether to continue a participant on study treatment until repeat imaging is obtained using the 
criteria outlined in Section 4.10.1. 
 
If the Investigator decides to continue treatment, the participant may continue to receive study 
treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by 
iRECIST, per Investigator assessment. 
 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including: 
 Increase in the sum of diameters of target lesion(s) identified at baseline to ≥ 20% and 
≥ 5 mm from nadir 
o Please note: the iRECIST publication uses the terminology “sum of measurements”, 
but “sum of diameters” will be used in this protocol, consistent with the original 
RECIST 1.1 terminology. 
 Unequivocal progression of non-target lesion(s) identified at baseline 
 Development of new lesion(s) 
iRECIST defines new response categories, including iUPD (unconfirmed progressive disease) and 
iCPD (confirmed progressive disease).  For purposes of iRECIST assessment, the first visit 
showing progression according to RECIST 1.1 will be assigned a visit (overall) response of iUPD, 
regardless of which factors caused the progression. 
At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be assessed as 
usual. 
New lesions will be classified as measurable or non-measurable, using the same size thresholds 
and rules as for baseline lesion assessment in RECIST 1.1.  From measurable new lesions, up to 5 
lesions total (up to 2 per organ), may be selected as New Lesions – Target.  The sum of diameters 
of these lesions will be calculated, and kept distinct from the sum of diameters for target lesions at 
baseline.  All other new lesions will be followed qualitatively as New Lesions – Non-target. 
Assessment at the Confirmatory Imaging 
On the confirmatory imaging, the participant will be classified as progression confirmed (with an 
overall response of iCPD), or as showing persistent unconfirmed progression (with an overall 
response of iUPD), or as showing disease stability or response (iSD/iPR/iCR). 


 
80
Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs: 
 Any of the factors that were the basis for the initial iUPD show worsening 
o For target lesions, worsening is a further increase in the sum of diameters of ≥ 5 mm, 
compared to any prior iUPD time point 
o For non-target lesions, worsening is any significant growth in lesions overall, compared 
to a prior iUPD time point; this does not have to meet the “unequivocal” standard of 
RECIST 1.1 
o For new lesions, worsening is any of these: 
 An increase in the new lesion sum of diameters by ≥ 5 mm from a prior iUPD time 
point  
 Visible growth of new non-target lesions  
 The appearance of additional new lesions 
 Any new factor appears that would have triggered PD by RECIST 1.1 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
 None of the progression-confirming factors identified above occurs AND 
 The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1) 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the scan on which 
iUPD is seen.  This may correspond to the next visit in the original visit schedule.  The assessment 
of the subsequent confirmation scan proceeds in an identical manner, with possible outcomes of 
iCPD, iUPD, and iSD/iPR/iCR. 
Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
 None of the progression-confirming factors identified above occurs, AND 
 The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.  
The response is classified as iSD or iPR (depending on the sum of diameters of the target lesions), 
or iCR if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudo-progression, and the level of suspicion for 
progression is “reset”.  This means that the next visit that shows radiographic progression, 


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81
whenever it occurs, is again classified as iUPD by iRECIST, and the confirmation process is 
repeated before a response of iCPD can be assigned.  
Detection of Progression at Visits After Pseudo-progression Resolves 
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated by 
any of the following events: 
 Target lesions 
o Sum of diameters reaches the PD threshold (≥ 20% and ≥ 5 mm increase from nadir) 
either for the first time, or after resolution of previous pseudo-progression.  The nadir 
is always the smallest sum of diameters seen during the entire trial, either before or 
after an instance of pseudo-progression. 
 Non-target lesions 
o If non-target lesions have never shown unequivocal progression, their doing so for the 
first time results in iUPD. 
o If non-target lesions had shown previous unequivocal progression, and this progression 
has not resolved, iUPD results from any significant further growth of non-target 
lesions, taken as a whole. 
 New lesions 
o New lesions appear for the first time 
o Additional new lesions appear 
o Previously identified new target lesions show an increase of ≥ 5 mm in the new lesion 
sum of diameters, from the nadir value of that sum 
o Previously identified non-target lesions show any significant growth 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated.  Progression 
must be confirmed before iCPD can occur. 
The decision process is identical to the iUPD confirmation process for the initial PD, except in one 
respect. If new lesions occurred at a prior instance of iUPD, and at the confirmatory scan the 
burden of new lesions has increased from its smallest value (for new target lesions, their sum of 
diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to iSD or iPR. It will 
remain iUPD until either a decrease in the new lesion burden allows resolution to iSD or iPR, or 
until a confirmatory factor causes iCPD. 
Additional details about iRECIST are provided in the iRECIST publication[40]. 
 
 
 
 
 


 
82
Table 3: Comparison between RECIST 1.1 and iRECIST 
 
 
RECIST 1.1 
iRECIST 
Definitions of disease: 
numbers, sites and 
target or non 
Measurable are diameters greater 
than 10 mm (15 for nodes 
maximum of 5 (2 per organ) 
No change from RECIST 1.1 
CR, PR or SD 
Cannot have met criteria for 
progression 
Can have had iUPD (more than 
once) but not iCPD before iCR, 
iPR or iSD 
Confirmation of CR or 
PR 
Only in non-randomized studies 
As per RECIST 1.1 
Confirmation of SD 
Not required 
As per RECIST 1.1 
New lesions 
Progression: recorded but not 
measured 
iUPD but only becomes iCPD if 
on the next scan there are new 
lesions or the size increases by 
greater than 5 mm 
Confirmation of 
progression 
Not required 
Required 
Consideration of 
clinical status 
Not required 
Clinical stability considered at 
iUPD to decide treatment 
continuation 
 
Table 4:    Trajectory of progression in iRECIST 
 
Target Lesions: iCR, Non-
target: iCR, no new lesions 
iCR 
iCR 
Target lesions: iCR, Non-
target: non iCR/non iUPD, no 
new lesions 
iPR 
iPR 
Target Lesions: iPR, Non-
target: non iCR/non iUPD, no 
new lesions 
iPR 
iPR 
Target lesions: iSD, Non-
target: non iCR/non iUPD, no 
new lesions 
iSD 
iSD 
Target lesions: iUPD with no 
change or with a decrease 
from the last time point, Non-
target: iUPD with no change 
or decrease from last time 
point, new lesions 
NA 
 
 
New lesions confirm iCPD if 
new lesions previously 
identified and increased in 
size (≥ 5 mm in sum of 
measures for new lesions or 
any increase for new lesion 
non-target) or increase in 
number. If no change is seen 
in new lesions assignment 
remains iUPD 


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83
Target lesions: iSD, iPR, 
iCR, non-target: iUPD, no 
new lesions 
iUPD 
Remains iUPD unless iCPD 
is confirmed by increase in 
the size of non-targets (does 
not need to meet RECIST 1.1 
criteria) 
Target lesions: iUPD, non-
target: non iCR/non iUPD, no 
new lesions 
iUPD 
Remains iUPD unless iCPD 
confirmed on the basis of 
further increase ≥ 5 mm; 
otherwise stays as iUPD 
Target lesions: iUPD, non-
target: iUPD, no new lesions 
iUPD 
Remains iUPD unless iCPD 
confirmed on previously 
identified targets iUPD ≥ 5 
mm or non-target iUPD 
Target lesions: iUPD, non-
targets: iUPD, new lesions 
iUPD 
Remains iUPD unless iCPD 
confirmed by increase of ≥ 5 
mm previously identified 
target, or non-target or an 
increase in size or number of 
new lesions 
Target lesions non iUPD or 
progression, non-targets: non 
iUPD or progression, new 
lesions 
iUPD 
Remains iUPD unless iCPD 
confirmed by increase in size 
or number of new lesions 
previously identified. 
Target lesions, non-target lesions and new lesions are defined according to RECIST 1.1 criteria: if 
no pseudoprogression occurs, RECIST 1.1 and iRECIST categories for CR, PR and SD are the 
same. * Previously identified in the assessment prior to this time point. ‘I’ indicates immune 
responses assigned using iRECIST 
 
 
 
 


 
84
APPENDIX E: SAE REPORTING FORM 
 
 


J18119/Amendment 8 / Version 9.0 / March 31, 2022 
85
FAX 
TO: 
BMS Worldwide Safety 
FROM:  
FAX: 
 
PAGES:  
PHONE:  
DATE:  
RE:  
 
CC: 
 
 
Study:  
A Phase 2 study Evaluating Response and Biomarkers in Patients with Microsatellite Stable (MSS) 
Advanced Colorectal Cancer treated with Nivolumab in Combination with Relatlimab (J18119, CA224-
068) 
 
Comments:   
 
Please confirm receipt to:  
 
 
 


 
86
Serious Adverse Event Reporting Form 
 
 
 
Protocol Title: 
 
 
A Phase 2 study Evaluating Response and Biomarkers in Patients with 
Microsatellite Stable (MSS) Advanced Colorectal Cancer treated with 
Nivolumab in Combination with Relatlimab 
Protocol 
Number: 
CA224-068 
J18119 
Signature of PI: 
 
 
 
Principal Investigator: 
 
Dr. Dung Le 
Date of 
Report: 
 
 
 
Report Type: 
Initial    
Follow-up 
Final Follow-up 
Death 
Addendum to: 
 
Serious Criteria (check all 
that apply): 
Death    
Life-threatening 
 Hospitalization or Elongation of 
Existing Hospitalization 
 Other Important Medical Event 
 Cancer 
 Overdose 
 Other:______________________ 
Hospital Admission 
Date: 
Date Event 
Discovered: 
Hospital Discharge 
Date:   
Section A: Subject Information 
Subject ID: 
Subject Gender: 
Male 
Female 
 
Subject Age: 
Section B: Event Information 
Event diagnosis or 
symptoms: 
 
Event Grade: 
Cause of death (if 
applicable): 
Event Outcome: 
 Not Recovered 
 Recovering 
 Recovered 
 Recovered with 
sequelae 
 Death 
 Unknown 
Event Onset Date (or Date of Death): 
 
Event End Date: 
Section C: Study Drug Information 
 
Investigational Product: Nivolumab (480 mg) and Relatlimab (160 mg, 480 mg, or 960 mg) IV 
every 28 days 
 
Indication: Metastatic or locally advanced microsatellite stable (MSS) colorectal adenocarcinoma 


J18119/Amendment 8 / Version 9.0 / March 31, 2022 
87
Relatlimab Formulation: 
 With pentetic acid  
 Without pentetic acid 
 
Number of Total Cycles: 
 
Action taken with the study drug: 
 
 None 
 Interrupted 
 Delayed  
 Discontinued  
 
Relatlimab Dose: 
 160 mg (Cohort A/B) 
 480 mg (Cohort C) 
 960 mg (Cohort C) 
 
Date of First Dose: 
 
Date of Last Dose prior to 
Event: 
 
Relationship to: 
Nivolumab 
Relatlimab 
Underlying Disease 
Unrelated 
 
 
 
Related 
 
 
 
Section D: Brief Description of the Event: 
 
Section E: Relevant Tests/Laboratory Data 
 
Section F: Relevant Medical History 
 
Section G: Concomitant Drug (Not related to SAE) 
Name of the Drug 
Start Date 
Stop Date 
Route 
Dose 
Frequency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section H: Comments 
 
Additional Documents: 
 Please specify