Neoadjuvant and Adjuvant Checkpoint Blockade in Patients With Clinical Stage III or Oligometastatic Stage IV Melanoma
Phase: PHASE2
Conditions: Cutaneous Melanoma, Mucosal Melanoma, Ocular Melanoma, Stage III Acral Lentiginous Melanoma AJCC v7, Stage IIIB Cutaneous Melanoma AJCC v7, Stage IIIB Uveal Melanoma AJCC v7, Stage IIIC Cutaneous Melanoma AJCC v7, Stage IIIC Uveal Melanoma AJCC v7, Stage IV Acral Lentiginous Melanoma AJCC v6 and v7, Stage IV Cutaneous Melanoma AJCC v6 and v7, Stage IV Uveal Melanoma AJCC v7
Sponsor: M.D. Anderson Cancer Center

 
PROTOCOL 
TITLE: A Multicenter Study with Neoadjuvant and Adjuvant 
Checkpoint Blockade in Patients with Clinical Stage III 
or Oligometastatic Stage IV Melanoma 
STUDY NUMBER: MDACC: 2015-0041; BMS: CA209-291 
VERSION NUMBER: 8 
PROTOCOL DATE: 29 MAY 2018 
AMENDMENT: Amendment 7 
TEST PRODUCTS: Nivolumab 
Ipilimumab 
Relatlimab 
PRINCIPAL INVESTIGATOR: Rodabe N. Amaria, MD 
Assistant Professor 
Melanoma Medical Oncology 
1515 Holcombe Boulevard 
Houston, Texas 77030 
CO-INVESTIGATOR: Jennifer A. Wargo, MD (MDACC) 
SUB-INVESTIGATORS: Charlotte E. Ariyan, MD. PhD (MSKCC) 
Michael A. Postow, MD (MSKCC) 
IND NUMBER: 127,886 
SUPPORT PROVIDED BY: Bristol-Myers Squibb (BMS) 
 
 
CONFIDENTIAL 
This is a University of Texas MD Anderson Cancer Center document that contains confidential 
information. It is intended solely for the recipient clinical investigator(s) and must not be disclosed to 
any other party. This material may be used only for evaluating or conducting clinical investigations; any 
other proposed use requires written consent from University of Texas MD Anderson Cancer Center. 
 
Protocol 2015-0041, Version 8 

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Protocol Amendments 
 
Protocol Version and Date 
Amendment Number 
Approval Date 
Version 1 – 1 June 2015 
Initial 
23 April 2015 
Version 2 – 18 August 2015 
Amendment 1 
30 August 2015 
Version 3 – 19 November 2015 
Amendment 2 
14 December 2015 
Version 4 – 9 May 2016 
Amendment 3 
15 June 2016 
Version 5 – 20 June 2016 
Amendment 4 
18 July 2016 
Version 6 – 9 August 2016 
Amendment 5 
29 September 2016 
Version 7 – 19 April 2017 
Amendment 6 
12 June 2017 

3 
 
Table of Contents 
1 
Trial Summary .......................................................................................................... 7 
1.1 
Trial Summary Table ............................................................................................... 7 
2 
Background & Rationale ......................................................................................... 11 
2.1 
Introduction ............................................................................................................ 11 
2.2 
Ipilimumab ............................................................................................................. 11 
2.3 
Nivolumab ............................................................................................................. 13 
2.4 
Relatlimab (anti-LAG-3) ......................................................................................... 15 
2.5 
Safety of Combination Checkpoint Blockade ......................................................... 16 
2.6 
Neoadjuvant Approach .......................................................................................... 18 
3 
Objectives & Endpoints ........................................................................................... 19 
3.1 
Primary Objective .................................................................................................. 19 
3.2 
Secondary Objectives ............................................................................................ 19 
3.3 
Exploratory Objectives ........................................................................................... 20 
4 
Ethical Considerations ............................................................................................ 20 
4.1 
Good Clinical Practice ........................................................................................... 20 
4.2 
Institutional Review Board/Independent Ethics Committee .................................... 21 
4.3 
Informed Consent .................................................................................................. 21 
5 
Investigational Plan ................................................................................................. 22 
5.1 
Study Design ......................................................................................................... 22 
5.2 
Study Assessments ............................................................................................... 24 
5.3 
Treatment Assignment ........................................................................................... 25 
5.4 
Eligibility Criteria .................................................................................................... 25 
5.4.1 
Inclusion Criteria ............................................................................................. 25 
5.4.2 
Exclusion Criteria ............................................................................................ 28 
6 
Treatment Plan ....................................................................................................... 30 
6.1 
Investigational Product .......................................................................................... 30 
6.2 
Handling and Dispensing ....................................................................................... 31 
6.3 
Destruction ............................................................................................................ 31 
6.4 
Product Descriptions.............................................................................................. 32 
6.4.1 
Nivolumab (BMS-936558) .............................................................................. 32 
6.4.2 
Ipilimumab ...................................................................................................... 32 
6.4.3 
Relatlimab (BMS-986016) .............................................................................. 33 
6.5 
Dose Calculations and Administration .................................................................... 34 
6.5.1 
Dose Modifications ......................................................................................... 35 
6.5.2 
Dose Delay Criteria ........................................................................................ 35 

4 
 
6.5.3 
Study-Drug Discontinuation Criteria ................................................................ 37 
6.5.4 
Treatment of Immunotherapy-Related Infusion Reactions ............................... 38 
6.6 
Permanent Discontinuation from Study Treatment and Subject Completion Criteria 
39 
6.6.1 
Subject Completion Criteria ............................................................................ 39 
6.6.2 
Permanent Discontinuation from Study Treatment .......................................... 39 
6.7 
Prohibited Medications and Non-Drug Therapies ................................................... 40 
7 
Schedule of Assessments ....................................................................................... 41 
7.1 
Study Procedure Tables ........................................................................................ 41 
7.2 
Critical Baseline Assessments ............................................................................... 46 
7.3 
Safety Evaluations on Therapy .............................................................................. 46 
7.3.1 
Physical Exam/ECOG/Vital Signs/Concomitant Medications ........................... 46 
7.3.2 
Adverse Event Assessment ............................................................................ 47 
7.3.3 
Laboratory Assessments ................................................................................ 47 
7.4 
Biospecimen Collections ........................................................................................ 48 
7.4.1 
Peripheral Blood and Serum Samples ............................................................ 48 
7.4.2 
Tumor Biopsies and Surgical Specimen ......................................................... 48 
7.5 
Disease Assessments ........................................................................................... 49 
7.5.1 
Pathologic Assessments ................................................................................. 49 
7.5.2 
Imaging Assessments .................................................................................... 50 
7.5.3 
Translational Research/Biomarker Analysis .................................................... 50 
8 
Safety and Reporting .............................................................................................. 52 
8.1 
Sponsor SAE Reporting......................................................................................... 54 
8.2 
Non-Serious Adverse Event Collection and Reporting ........................................... 56 
8.3 
Laboratory Test Abnormalities ............................................................................... 57 
8.4 
Pregnancy ............................................................................................................. 57 
8.5 
Overdose ............................................................................................................... 57 
8.6 
Other Safety Considerations .................................................................................. 57 
9 
Statistical Considerations ........................................................................................ 58 
9.1 
Sample Size and Power ........................................................................................ 58 
Arm A and Arm B.......................................................................................................... 58 
Arm C ........................................................................................................................... 58 
9.2 
Study Populations .................................................................................................. 58 
9.2.1 
Safety Population ........................................................................................... 58 
9.3 
Stopping Rule ........................................................................................................ 59 
9.4 
Patient Characteristics ........................................................................................... 61 
9.5 
Primary Efficacy Measure ...................................................................................... 61 

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9.6 
Secondary Efficacy Measures ............................................................................... 62 
9.6.1 
Immunologic Response .................................................................................. 62 
9.6.2 
Objective Response ....................................................................................... 62 
9.6.3 
Recurrence-Free and Overall Survival ............................................................ 62 
9.7 
Exploratory Efficacy Measures .............................................................................. 62 
9.8 
Safety Measures ................................................................................................... 62 
10 Study Management................................................................................................. 63 
10.1 Data Management ................................................................................................. 63 
10.1.1 
Enrollment ...................................................................................................... 63 
10.1.2 
Data Entry and Maintenance .......................................................................... 63 
10.1.3 
Records Retention .......................................................................................... 63 
11 References ............................................................................................................. 64 
12 Appendices ............................................................................................................. 70 
 
 
List of Figures 
 
Figures 1a and 1b Study Design Schema ............................................................................ 23 
 
List of Tables 
 
Table 1 Eligibility Guidelines of Organ and Marrow Function ................................................ 26 
Table 2 Product Descriptions ............................................................................................... 34 
Table 3 Study Procedure Table for Patients Randomized to Arm A (neoadjuvant and adjuvant 
nivolumab) ........................................................................................................................... 41 
Table 4 Study Procedure Table for Patients Randomized to Arm B (neoadjuvant ipilimumab 
and nivolumab, adjuvant nivolumab) .................................................................................... 42 
Table 5 Study Procedure Table for Patients Enrolled to Arm C (neoadjuvant and adjuvant 
nivolumab and relatlimab) .................................................................................................... 43 
Table 6 Adjuvant Therapy Study Procedure Table for Arm A and Arm B .............................. 44 
Table 7 Adjuvant Therapy Study Procedure Table for Arm C ............................................... 45 
Table 8 Required Laboratory Testing ................................................................................... 47 
Table 9 Stopping Boundaries for Arm A and Arm B ............................................................. 59 
Table 10 Operating Characteristics for Arm A and Arm B .................................................... 59 
Table 11 Stopping Criteria - Toxicity for Arm C .................................................................... 60 
Table 12 Stopping Criteria - Futility for Arm C ..................................................................... 60 
Table 13 Operating Characteristics for Arm C ..................................................................... 61 
 
Appendices 
 
Appendix 1 Melanoma of the Skin Aging .............................................................................. 70 
Appendix 2 RECIST 1.1 Criteria ......................................................................................... 71 
Appendix 3 Guidance on Contraception ............................................................................... 76 
Appendix 4: GI Adverse Event Management Algorithm ........................................................ 77 

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Appendix 5: Renal Adverse Event Management Algorithm .................................................. 78 
Appendix 6: Pulmonary Adverse Event Management Algorithm ........................................... 79 
Appendix 7: Hepatic Adverse Event Management Algorithm ................................................ 80 
Appendix 8: Endocrinopathy Adverse Event Management Algorithm ................................... 81 
Appendix 9: Skin Adverse Event Management Algorithm ..................................................... 82 
Appendix 10: Neurological Adverse Event Management Algorithm ...................................... 83 

7 
 
1 
Trial Summary 
1.1 
Trial Summary Table 
 
Investigational 
Products, 
Dose, 
Administration, 
Duration of 
Treatment: 
• 
Arm A: Nivolumab (BMS-936558) monotherapy administered IV over 30 
minutes at 3 mg/kg every 2 weeks for 4 doses (administered week 1, 
3, 5, 7) prior to surgical excision. Postoperative nivolumab administered 
IV over 30 minutes at 3 mg/kg every 2 weeks for 6 months (Closed to New 
Patient Enrollment (CNPE) as of 11 July 2017). 
• 
Arm B: Nivolumab administered IV over 60 minutes at 1 mg/kg combined 
with ipilimumab administered IV over 90 minutes at 3 mg/kg every 3 weeks 
for three doses (week 1, 4, 7) prior to surgical excision. Postoperative 
nivolumab administered IV over 30 minutes at 3 mg/kg every 2 weeks for 6 
months (Closed to New Patient Enrollment (CNPE) as of 11 July 2017). 
• 
Arm C: Relatlimab 160 mg IV and Nivolumab 480mg IV will be 
administered together over approximately 60 minutes every 28 days 
for 2 doses in the neoadjuvant setting. Post-operatively, Relatlimab 
160 mg IV together with Nivolumab 480 mg IV will be administered 
every 28 days for an additional 10 doses (Open to Enrollment). 
Research 
Hypothesis: 
Treatment with neoadjuvant immunotherapy will produce complete responses 
in high-risk resectable melanoma. 
Objectives: 
Primary: 
Arm A and Arm B 
• 
To assess the pathologic response of nivolumab monotherapy and 
nivolumab and ipilimumab dual therapy administered in the neoadjuvant 
setting in patients with high- risk resectable melanoma. Pathologic 
response will be assessed by percent viable tumor cells, percent tumor 
necrosis, presence of fibrosis and melanoma proliferation as assessed by 
phosphohistone H3 from baseline, to on-treatment and surgical specimens. 
Arm C 
• 
To assess the pathologic response rate of combination relatlimab with 
nivolumab in the neoadjuvant setting in patients with high- risk resectable 
Stage IIIB/C or oligometastatic Stage IV melanoma. Pathologic response 
will be assessed by percent viable tumor cells, percent tumor necrosis, 
presence of fibrosis and melanoma proliferation as assessed by 
phosphohistone H3 from baseline, to on-treatment and surgical specimens. 
• 
Secondary: 
Arm A and Arm B 
To assess the immunologic response of neoadjuvant nivolumab 
monotherapy and neoadjuvant nivolumab and ipilimumab dual therapy in 
patients with high-risk resectable melanoma. Immunologic response will be 

8 
 
determined by change in T cell infiltrate from baseline to on-treatment and 
surgical specimens in response to therapy 
To assess the objective response rate (ORR) of nivolumab monotherapy 
and nivolumab and ipilimumab dual therapy administered in the neoadjuvant 
setting as assessed by imaging (RECIST 1.1 criteria) in patients with high- 
risk resectable melanoma 
To assess the 12-month recurrence-free survival (RFS) and overall survival 
(OS) of patients with high-risk resectable melanoma treated with 
neoadjuvant nivolumab monotherapy or nivolumab and ipilimumab dual 
therapy followed by adjuvant nivolumab 
To evaluate the safety of nivolumab monotherapy and dual ipilimumab and 
nivolumab in the neoadjuvant setting and peri-operatively as well as assess 
the safety of adjuvant nivolumab. 
Arm C 
To evaluate the safety and feasibility of relatlimab with nivolumab delivered 
in the neoadjuvant setting 
To assess the objective response rate (ORR) of relatlimab with nivolumab 
administered in the neoadjuvant setting as assessed by imaging (RECIST 
1.1 criteria) in patients with high-risk resectable melanoma 
To assess the 12-month recurrence-free survival (RFS) and overall survival 
(OS) of patients with high-risk resectable melanoma treated with 
neoadjuvant and adjuvant relatlimab with nivolumab 
To evaluate immunologic and molecular mechanisms of response and 
resistance to relatlimab with nivolumab. 
Exploratory: 
• 
 Identification of immunologic and genomic markers correlating with clinical 
and pathological response and resistance. 
Study Design: 
This is a Phase 2, randomized non-comparative study of neoadjuvant nivolumab 
monotherapy or nivolumab combined with ipilimumab followed by adjuvant 
nivolumab or nivolumab combined with relatlimab in adult (≥18 years) subjects 
with resectable, high-risk melanoma. Patients with prior adjuvant therapy 
including use of prior interferon alpha, pegylated interferon or vaccine) will be 
eligible after a 28 day washout period. Subjects must have stage IIIB/IIIC or 
stage IV resectable, oligometastatic (less than or equal to 3 sites of disease, 
excluding bone and CNS) melanoma, as per the American Joint Committee 
on Cancer (AJCC) stagirng system. Subjects will be treated with one of the 
following: 
• 
Arm A: nivolumab 3 mg/kg (+/- 7 days) IV Q2W (4 doses) prior to surgical 
excision (CNPE). 

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• 
Arm B: nivolumab 1 mg/kg (+/- 7 days) IV combined with ipilimumab 3 mg/kg 
IV Q3W (3 doses) prior to surgical excision (CNPE). 
A new treatment (Arm C) has been incorporated in Amendment 7 of this protocol 
(BMS: CA209-291 and MDACC: 2015-0041). Patients will receive relatlimab 
(anti-LAG-3) in combination with Nivolumab for 2 doses in the neoadjuvant 
setting. An additional 10 doses of relatlimab with nivolumab will be administered 
to the patients in the adjuvant setting. 
• 
Arm C: nivolumab 480 mg combined with relatlimab 160 mg every 28 days 
for 2 doses prior to surgical excision, then 10 doses of nivolumab 480 mg 
with relatlimab 160mg, post-operatively. 
 
 
Study 
Population: 
Key Inclusion Criteria: 
• 
ECOG PS 0 or 1. 
• 
Histologically confirmed stage IIIB/IIIC (resectable) or oligometastatic 
(≤3), resectable stage IV melanoma, as per AJCC staging system. 
• 
Patients must have at least one tumor amenable to serial biopsy in 
clinic or be willing to undergo serial biopsies through image-guided 

10 
 
procedures. Baseline, on-treatment and surgical samples will be 
collected for analysis. 
• 
Tumor tissue must be assessed for PD-L1 expression via IHC. 
Key Exclusion Criteria: 
• 
Brain metastases, leptomeningeal or bone metastases. 
• 
Subjects with active, known or suspected autoimmune disease. 
Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism 
due to autoimmune condition only requiring hormone replacement, 
psoriasis not requiring systemic treatment, or conditions not expected 
to recur in the absence of an external trigger are permitted to enroll 
• 
 Subjects with a condition requiring systemic treatment with either 
corticosteroids (> 10 mg daily prednisone equivalents) or other 
immunosuppressive medications within 14 days of study drug 
administration. Inhaled or topical steroids, and adrenal replacement 
doses > 10 mg daily prednisone equivalents are permitted in the 
absence of active autoimmune disease. 
• 
Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA- 
4 antibody 
Study 
Assessments: 
Pathologic response to neoadjuvant therapy is primary endpoint of the study. 
This will be assessed by percentage of viable tumor cells, percent tumor 
necrosis, amount of fibrosis and proliferation by phosphohistone H3. These 
factors will be assessed in a continuum over serial time-points including 
baseline, prior to dose two (and potentially dose 3 when feasible) and 
surgical resection samples. 
Secondary objectives include immunologic response which will be assessed by 
change in immune infiltrate in tumor from baseline to on-treatment and 
surgical resection specimens. Additional secondary objectives include objective 
response rate to neoadjuvant therapy as assessed by RECIST 1.1 criteria. 
Recurrence free and overall survival will also be determined by long-term follow 
up of these patients. Safety assessments will also be made by CTCAE version 
4.0 criteria. 
Statistical 
Considerations 
: 
Sample Size: 
A total of 53 patients will be enrolled on this study. Prior to Amendment 7, 
patients were stratified by stage of disease (IIIB/IIIC/M1A vs. M1B/M1C) and 
PD-L1 tumor status and then randomized in a 1:1 ratio for Arms A and B. 
Twelve patients were randomized to Arm A, and 11 patients were randomized 
to Arm B. After approval of Amendment 7, thirty patients will be enrolled to Arm C 
without randomization, and Arms A and B will be closed to Enrollment. Patient 
enrollment is expected at a rate of 2-4 patients per month. 

11 
 
2 
Background & Rationale 
2.1 
Introduction 
Melanoma accounts for less than 2% of skin cancer cases but is responsible for the large 
majority of skin cancer deaths.1 Moreover, the incidence of melanoma has been increasing 
for the past 30 years worldwide. In the United States alone, the incidence has increased by 
an average of 4% per year since the early 1970s. 2 
Surgery has long been the mainstay of treating resectable melanoma. When there is not 
obvious distant metastatic disease, the initial treatment consists of widely excising the 
melanoma lesion and, often, sampling or removal of the draining lymph nodes. In its earliest 
stage (stage I), surgery alone provides good long-term survival, with over 90% of patients alive 
ten years after treatment. However, as the stage increases, the chance of recurrent or 
metastatic disease increases substantially. Less than half of patients with clinically detectable 
lymph node involvement and fewer than 15% of patients with distant disease will survive ten 
years. 3 
In the past, systemic options to decrease the risk of recurrence in patients with high-risk, 
resectable disease and to treat patients with metastatic disease have been limited. 
Historically, the best available treatment has been interferon alpha-2b therapy.4 Its use in 
treating patients with resected stage II/III disease has not consistently improved overall 
survival in multiple clinical trials and generally has poor tolerance secondary to significant 
treatment related toxicities. 5-10 Similarly, in the metastatic setting, high dose interleukin-2 
produces a low overall response rate (16%), and again, with serious toxicity, so that it is given 
only to selected patients.4 11 
More recently, systemic therapy for melanoma has undergone a seismic shift with the advent 
of two new drug classes. The first class is small molecule kinase inhibitors to BRAF 
(dabrafenib and vemurafenib) and MEK (trametinib), which have demonstrated a survival 
benefit and are FDA approved in BRAF V600 mutated metastatic melanoma. 12-14 The second 
new class of drugs is immune checkpoint inhibitors. Ipilimumab, a monoclonal antibody (mAb) 
antagonist to CTLA-4, has improved survival and is FDA approved in both treatment naïve 
and pretreated metastatic melanoma.15,16 A second immune checkpoint mAb, nivolumab, 
which targets PD-1, demonstrated promising initial results and the phase III study was 
stopped early due to clear benefit in overall survival associated with PD-1 blockade and is 
anticipated to be FDA approved by the end of 2014.17,18 The role of these new therapeutic 
options in the neoadjuvant and adjuvant settings remains to be fully elucidated and is an active 
area of investigation. The aim of this trial is to further clarify the benefit of PD-1 blockade 
(nivolumab) alone or in combination with CTLA-4 blockade (ipilimumab) given to patients with 
resectable, high- risk melanoma. 
 
2.2 
Ipilimumab 
Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4, CD152) was the first recognized and 
is the best characterized inhibitory immune checkpoint molecule. 19,20 CTLA-4 is the only 
checkpoint currently targeted with an FDA-approved therapeutic drug, ipilimumab. CTLA-4 
functions as a negative counterpart to CD28, the required costimulatulatory signal for the 

12 
 
activation and expansion of T-cells. CTLA-4 is an inhibitory checkpoint molecule expressed 
on activated T-cells and constitutively expressed on regulatory T- cells (Treg).20 After TCR- 
antigen mediated activation of T-lymphocytes, expression of CTLA-4 on the cell membrane 
increases dramatically.  CLTA-4 appears to suppress immune activation through multiple 
pathways and the relative importance of each in overall immune homeostasis and in disease- 
related autoimmunity and immune suppression is not clear.21 
Preclinical work with anti-CTLA-4 mAbs supported the notion of an inhibitory role for CTLA-4. 
22,23 Soon thereafter, work with anti-CTLA-4 blocking mAbs for therapeutic purposes 
proceeded. Initial animals studies confirmed that the mAbs could indeed augment immune 
response to peptide antigens.23 Not long after this, CTLA-4 mAbs were used to experimentally 
overcome antitumor immune tolerance.24 Preclinical data suggests and it stands to reason, 
that less immunogenic tumors are less likely to respond to CTLA-4 mAb blockade alone.25 
Given the known immunogenicity of melanoma, initial clinical development was focused in this 
malignancy. 
 
Initial phase I and II studies of ipilimumab monotherapy demonstrated encouraging results.26- 
27 The first phase III study of ipilimumab, sponsored by Bristol-Meyers Squibb, began enrolling 
patients in September 2004. The trial enrolled 676 HLA-A*0201+ patients with pretreated, 
unresectable stage III or IV melanoma. The patients were randomized 3:1:1 to receive either 
ipilimumab with gp100 peptide vaccine, ipilimumab alone, or gp100 alone. Ipilimumab was 
dosed at 3 mg/kg every three weeks for four doses. Patients were not routinely offered 
maintenance therapy, however, those who progressed after responding to therapy or who had 
stable disease after twelve weeks were allowed “reinduction” therapy. The primary endpoint 
of the trial was overall survival (OS). The trial demonstrated an OS benefit in all patients who 
received ipilimumab (median OS: 10.0 months for ipilimumab with gp100, 10.0 months for 
ipilimumab alone, and 6.4 months for gp100 alone; p<0.003). There was no difference in 
survival in patients who received ipilimumab with gp100 and those who received ipilimumab 
alone. There were four cases of complete responses and multiple cases of long-term disease 
control in patients who received ipilimumab in the initial report.28 Importantly, long-term follow- 
up has demonstrated that approximately 20% of patients achieve a long-term survival benefit 
from ipilimumab treatment, a finding that has been since replicated in multiple studies with 
ipilimumab in melanoma.29 Approximately 60% of patients treated with ipilimumab 
experienced an immune-related adverse event (irAE), with the rates of serious irAEs (≥ grade 
3) of 10% to 15% in the ipilimumab groups.15 Of the 31 patients who met criteria for and 
received “reinduction” therapy (progression after complete or partial response or stable 
disease), 19% achieved a complete or partial response and 68% achieved disease control 
with similar toxicity to the original induction therapy.30 Based on this study, ipilimumab 
achieved FDA approval at a dose of 3.0mg/kg to treat unresectable stage III and stage IV 
melanoma. 
 
Ipilimumab was further tested in treatment naïve melanoma patients in a randomized phase 
III trial evaluating ipilimumab with dacarbazine versus dacarbazine alone.27 A dose of 10 
mg/kg of ipilimumab was used in combination with dacarbazine. Five- hundred-two patients 
were enrolled and randomized 1:1 to receive ipilimumab plus dacarbazine every three weeks 
for four doses followed by dacarbazine every three weeks until week 22 or placebo plus 
dacarbazine at the same schedule. Patients with stable disease or Response Evaluation 
Criteria in Solid Tumor (RECIST) objective responses were able to receive maintenance 

13 
 
ipilimumab or placebo every 12 weeks. Of note, based on emerging consensus from previous 
work with CTLA-4 blockade and other immunotherapy, the primary endpoint was changed, 
with FDA approval, from progression-free survival to OS prior to unblinding of the treatment 
groups or data analysis. 31,32 Ultimately, the trial showed that patients who received the 
combination of ipilimumab with dacarbazine survived longer (11.2. months) compared to 
dacarbazine alone (9.2 months, p<0.001). The difference became more pronounced with time, 
as the combination arm had 20.8% of patients alive at three years compared to 12.2% in the 
chemotherapy only arm. The toxicities were greater in the combination arm and also greater 
than in many of the previous ipilimumab studies (56% ≥ grade 3), likely secondary to the higher 
dose (10 mg/kg) of ipilimumab used as well as the addition of chemotherapy. However, there 
were no treatment-related deaths reported.16 Based on the results of this study, the 
combination of ipilimumab and dacarbazine is approved for first-line therapy for unresectable 
melanoma. 
 
Ipilimumab is being evaluated as an adjuvant therapy in melanoma in two trials. ECOG 1609 
is an on-going randomized phase III trial comparing adjuvant ipilimumab 3mg/kg, ipilimumab 
10mg/kg, and interferon alpha-2b therapy in patients with resected high-risk stage III or stage 
IV melanoma.33 The EORTC 18071 phase III trial is a double-blind, randomized trial that has 
enrolled 951 patients with stage III melanoma to receive ipilimumab 10mg/kg or placebo every 
three weeks for four doses then every three months for up to three years until recurrence or 
unacceptable toxicity. Fifty-two percent of patients discontinued treatment due to adverse 
events. The most common grade III/IV immune-related toxicities in the ipilimumab and 
placebo arms were gastrointestinal (15.9% vs 0.8%), hepatic (10.6% vs 0.2%) and endocrine 
(8.5% vs 0%). Five (1.1%) died secondary to treatment related toxicity. The 3-year relapse- 
free survival rate was 46.5% in the ipilimumab arm, compared to 34.8% in the placebo arm 
(p=0.001). With a median follow up of 2.7 years, ipilimumab improved the relapse-free survival 
by a hazard ratio of 0.75.34 
2.3 
Nivolumab 
Programmed death 1 (PD-1) is a more recently discovered immune checkpoint receptor that 
has generated considerable excitement based on favorable preclinical profiling and initial 
clinical results. Like CLTA-4, PD-1 is a transmembrane protein expressed on effector immune 
cells.35 Also like CLTA-4, expression of PD-1 is inducibly expressed with lymphocyte 
activation, although it is expressed more broadly than CTLA-4 as it is also found on activated 
B lymphocytes and natural killer cells. 36-38 PD-1 is bound principally by programmed death 
ligand 1 (PD-L1, B7-H1) but also, to a lesser degree, by programmed death ligand 2 (PD-L2, 
B7-DC).39 
The PD-1 receptor pathway is an important negative regulator of the immune system. The PD- 
1 pathway appears to also have a primary role in cancer tolerance and immune escape. 
Higher expression of PD-L1 on tumor cells is associated with a worse prognosis, more 
aggressive features, and/or resistance to immunotherapy in the large majority of cancers that 
it has been characterized in. 40-48 Furthermore, preclinical data demonstrates that increasing 
tumor expression of PD-L1 makes it less susceptible to immunotherapy, while blocking it 
increases its vulnerability to immune-mediated destruction. 49-52 
Based on promising preclinical therapeutic results, PD-1 blocking mAbs have proceeded to 
human clinical trials. 49,50,52-54 Nivolumab (MDX-1106, BMS-936558, Bristol-Myers Squibb, 

14 
 
New York, NY) is a fully humanized IgG4 monocolonal antibody that binds to PD-1, blocking 
its binding site. It was initially tested in a phase I, dose escalation trial in 296 patients with 
heavily pretreated advanced melanoma (n=104), colorectal cancer (n=19), CRPC (n=17), 
NSCLC (n=122), and renal cell carcinoma (n=34). Nivolumab was given at 0.3, 1, 3, or 10 
mg/kg in six patient cohorts followed by expansion cohorts at 10mg/kg. Patients were initially 
given a single dose and allowed additional doses if they demonstrated clinical benefit, 
however, the trial transitioned into a phase Ib where patients were dosed every two weeks 
and reassessed every eight weeks. Treatment was continued for up to 96 weeks or until 
disease progression or complete response. Treatment with nivolumab was better tolerated 
overall than treatment with CTLA-4 blocking antibodies with no maximum tolerated dose 
achieved. Only 14% experienced serious (≥ grade 3) drug toxicity and only 5% had to 
discontinue therapy secondary to this. 
 
Nivolumab treatment demonstrated substantial antitumor effect, with partial or complete 
responses (by RECIST criteria) observed in patients with melanoma, NSCLC, and renal cell 
carcinoma but not colorectal cancer or CRPC. Responses were observed across various 
doses at rates of 19 to 41% in melanoma, 6 to 32% in NSCLC, and 24 to 31% in renal cell 
carcinoma. In addition, disease stability and mixed response were observed in a substantial 
portion of patients. In melanoma patients two and three year OS were 48% and 41%, 
respectively and the median duration of response in patients with an objective response was 
an impressive 22.9 months.55 Further analysis of PD-L1 expression from 61 patients who had 
pretreatment specimens available demonstrated an objective response in 36% of tumors 
expressing PD-L1 and none in PD-L1-negative tumors.17 
Nivolumab monotherapy has been extensively studied in a number of tumor types including 
non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), and colorectal 
cancer (CRC) with body weight normalized dosing (mg/kg). Nivolumab pharmacokinetics (PK) 
and exposures of subjects in these studies have been characterized by population 
pharmacokinetic (PPK) analysis of data collected in these studies, together with PK data from 
several Phase 1, 2, and 3 clinical studies of nivolumab monotherapy in solid tumors. PPK 
analyses have shown that the PK of nivolumab are linear, with dose proportional exposures 
over a dose range of 0.1 mg/kg to 10 mg/kg, and are similar across tumor types. Nivolumab 
clearance and volume of distribution were found to increase with increasing body weight, but 
the increase was less than proportional, indicating that a mg/kg dose represents an over- 
adjustment for the effect of body weight on nivolumab PK. Given the relationship between 
nivolumab PK and body weight, a flat dose is expected to lead to lower exposures in heavier 
patients, relative to the exposures in lighter patients. 
 
Using the PPK model, nivolumab steady-state trough, peak and time-averaged concentration 
(Cminss, Cmaxss, and Cavgss, respectively) were predicted for a flat nivolumab dose of 240 
mg Q2W and compared to those following administration of 3 mg/kg Q2W in NSCLC, 
melanoma, and RCC subjects. A dose of 240 mg nivolumab is identical to a dose of 3 mg/kg 
for subjects weighing ~ 80 kg, which is the approximate median body weight of subjects in the 
Phase 2 and 3 BMS clinical studies of nivolumab monotherapy. From the simulations, the 
geometric mean values of Cminss, Cmaxss, and Cavgss with flat dosing are slightly (< 15%) 
higher than that produced by a 3 mg/kg dose, and the coefficient of variation (cv%) in these 
measures of exposure are only slightly (< 10%) greater than that of 3 mg/kg dosing. Given 
the similarity of nivolumab PK across tumor types and the similar exposures predicted 
following administration of a 240 mg flat dose compared to 3 mg/kg, it is expected that the 

15 
 
safety and efficacy profile of nivolumab following a flat dose will be similar to that of 3 mg/kg 
nivolumab dose. 
 
Across the various tumor types in the BMS clinical program, nivolumab has been shown to be 
safe and well tolerated up to a dose level of 10 mg/kg, and the relationship between Nivolumab 
exposure produced by 3 mg/kg and efficacy has been found to be relatively flat. Taken 
together, the PK, safety, and efficacy data indicate that the safety and efficacy profile of flat 
nivolumab dose every 2 weeks will be similar to that of a 3 mg/kg nivolumab every 2 weeks. 
 
In Arm C of this study after completion of the combination portion of the study, all subjects 
will receive flat dose 480 mg nivolumab every 4 weeks (Q4W), which provides a more 
convenient dosing regimen for subjects. Based on PK modeling and simulations, 
administration of nivolumab 480 mg Q4W will be started after steady state is achieved with 
the combination regimen. While 480 mg Q4W is predicted to provide greater (approximately 
20%) maximum steady state concentrations and lower (approximately 10%) steady state 
trough concentrations, these exposures are predicted to be within the exposure ranges 
observed at doses up to 10 mg/kg Q2W used in the Phase 1 nivolumab clinical program, and 
are not considered to put subjects at increased risk. Similar to the nivolumab Q2W dosing 
monotherapy regimen, the exposures predicted following administration of nivolumab 480 mg 
Q4W, are on the flat part of the exposure-response curves for previously investigated tumors, 
melanoma and NSCLC, and are not predicted to affect efficacy. Based on these data, 
nivolumab 480 mg Q4W is expected to have similar efficacy and safety profiles to nivolumab 
3 mg/kg Q2W. 
 
Hence, doubling the dose of nivolumab from 240 mg to 480 mg would extend the dosing 
interval from 2 weeks to 4 weeks. Thus a flat dose of 480 mg every 4 weeks is recommended 
for Arm C of this study. FDA approval of Nivolumab 480mg IV every 4 weeks was obtained 
on March 6, 2018. 
 
2.4 
Relatlimab (anti-LAG-3) 
LAG-3 is an inhibitory checkpoint molecule found on the surface of antigen presenting cells 
which may limit the anti-tumor activity of PD-1 blockade. 
 
Relatlimab as a single agent has had an acceptable safety profile at all tested doses: 20, 80, 
240, and 800 mg, flat dose. The MTD was not reached up to 800 mg relatlimab Q2W. The 
combination therapy of relatlimab and nivolumab when administered sequentially (nivolumab 
30-minute IV infusion followed by relatlimab 1-hour IV infusion) has an acceptable safety 
profile of all dose combinations that have completed safety testing, up to relatlimab 160 
mg/nivolumab 240 mg Q2W. In addition, safety evaluation with alternative less frequent 
regimen (Q4W) dose escalation cohorts are currently under investigation in Study CA224020. 
The less frequent dosing regimens of relatlimab are designed to afford more convenience to 
the target patient population and allow combination with less frequent nivolumab dosing 
regimens. To date, the sequential administration of relatlimab 160 mg/nivolumab 480 mg Q4W 
has been shown safe (1 DLT out of six evaluable subject) to move to the next cohort of 
relatlimab 240 mg/nivolumab 480 mg Q4W. 

16 
 
Results from a Phase 1 trial using both LAG-3 (BMS-986016) and PD-1 blockade (nivolumab) 
have been shown to be safe with clinical activity in advanced solid tumor patients 
(NCT01968109). 
 
Neoadjvuant therapy is a powerful platform to inform efficacy, toxicity and biomarkers of 
treatment response and resistance. We believe that biomarker driven neoadjuvant clinical 
trials provide critical insights into immunologic and molecular mechanisms of response and 
resistance that are essential for each novel combination therapy regimen. These trials 
combine the practical advantages of limited patient numbers with the ability to use each 
patient’s biospecimens as a robust learning resource. 
 
Prior to Amendment 7, this neoadjuvant trial randomized to single agent nivolumab vs the 
combination of ipilimumab and nivolumab (BMS CA209-291), showed suboptimal responses 
with single agent nivolumab with 22% of treated patients progressing to no longer be surgically 
resectable during the 8 week duration of neoadjuvant treatment but also grade 3 toxicity rate 
of 89% during neoadjuvant ipilimumab with nivolumab. It is hypothesized that use of LAG-3 
with PD-1 blockade may provide optimal efficacy with limited toxicity in the neoadjuvant 
treatment setting based on the below Phase 1 trial data. 
 
Study CA224020 is a Phase 1 dose escalation and cohort expansion study of the safety, 
tolerability, and efficacy of relatlimab administered alone and in combination with nivolumab 
in advanced solid tumors. As of cut-off date of 07-Apr-17, preliminary proof-of-concept 
efficacy has been revealed in Part C in the combination treatment expansion cohort of 
advanced melanoma with prior treatment with anti-PD-1/PD-L1. All subjects were treated with 
relatlimab 80 mg + nivolumab 240 mg every 2 weeks. The overall ORR was 11.5% (n=61 
response evaluable) with a disease control rate of 49%. Biomarker analyses showed that 
patients whose tumor associated immune cells expressed more LAG-3 had a higher 
response rate, with a greater than 3-fold increase in ORR observed in patients with evidence 
of LAG-3 expression in at least 1% of nucleated cells within the tumor margin, compared to 
less than 1% LAG-3 expression (ORRs of 18.2% [6/33] and 5.0% [1/20], respectively). PD- 
L1 expression did not appear to enrich for response. 
 
The treatment group had the following characteristics: 1) Most patients had M1C disease 
(69%), 2) the cohort was heavily pretreated (76% with 2 or more prior therapies), 3) all 
patients had progressed while receiving anti-PD-1/PD-L1, and 4) progressive disease was 
the best response to prior anti-PD-1/PD-L1 in 40% of patients. Overall, relatlimab in 
combination with nivolumab demonstrated encouraging initial efficacy with a safety profile 
similar to nivolumab monotherapy. 
In summary, relatlimab in combination with nivolumab has shown the capacity to induce 
responses in heavily treated advanced solid tumors, with the added ability to trigger responses 
in tumors that have demonstrated resistance to nivolumab therapy. It is hypothesized that 
response rates will be higher in the neoadjuvant setting this therapy will be applied to patients 
who are not exposed to prior anti PD-1 or PD-L1 blockade. 
 
2.5 
Safety of Combination Checkpoint Blockade 
There is ample preclinical data supporting dual checkpoint blockade in murine cancer 
models.56-61 Based on these principles, investigators have initiated trials of dual checkpoint 
blockade for multiple malignancies. 

17 
 
Preliminary phase I results of combination of nivolumab and ipilimumab in patients with 
advanced melanoma demonstrate the potential of this combination.62 The trial treated 86 
patients with concurrent (n=53) dose-escalation of the two agents or sequenced treatment 
(n=33) with nivolimumab in patients previously treated with ipilimumab. In the concurrent arm, 
treatment was dosed at 0.3 mg/kg of nivolumab and 3 mg/kg of ipilimumab (cohort 1), 1 mg/kg 
of nivolumab and 3mg/kg of ipilimumab (cohort 2), 3 mg/kg of nivolumab and 1 mg/kg of 
ipilimumab (cohort 2a), 3mg/kg of nivolumab and 3 mg/kg of ipilimumab (cohort 3). Dose- 
limited toxicity was observed in cohort 3, so cohort 2 was treated as the maximum tolerated 
dose. The concurrent treatment demonstrated considerably higher rates of adverse events 
than previous trials of either drug in monotherapy. Treatment-related adverse events were 
noted in 93% of patients, serious treatment-related adverse events (≥ grade 3) were seen in 
53% of patients, and 21% of patients discontinued therapy secondary to these toxicities. The 
types of irAEs observed were similar to those seen in both nivolumab and ipilimumab 
monotherapy trials. The adverse events were well managed with immunosuppressant 
medication and hormonal replacement therapy (for endocrinopathies) and there were no 
treatment-related deaths observed. In the concurrent arm, 21 of the 53 patients (40%) were 
noted to have a response by mWHO criteria (the primary endpoint) with the suggestion of a 
higher response rate when irRC and unconfirmed responses are included. Remarkably, 16 
(76%) of those with an objective response had a tumor reduction of 80% or more with five 
complete responses noted. 62 Longer-term follow up has demonstrated a complete response 
rate of 17% and a 1 and 2 year OS of 82% and 75%, respectively. Furthermore, the 2a cohort 
(3mg/kg nivolumab and 1mg/kg of ipilimumab) has demonstrated a 1 and 2 year OS of 94% 
and 88%, respectively. This dosing group has been selected for further study with expanded 
enrollment and on-going follow-up.63 
Two additional trials of ipilimumab and nivolumab in combination are being conducted in non- 
small cell lung cancer (NSCLC) and metastatic renal cell carcinoma. In both trials patients 
were given either nivolumab 3mg/kg with ipilimumab 1mg/kg or nivolumab 1mg/kg and 
ipilimumab 3mg/kg for every 3 weeks for four cycles followed by nivolumab 3mg/kg every two 
weeks until progression or unacceptable toxicity. In NSCLC, 46 treatment naïve patients were 
enrolled at initial reporting. Grade 3-4 toxicity was seen in 48% of patients with 3 treatment 
related deaths and 16 discontinuing treatment secondary to toxicity.  Overall, 22% of 
patients achieved an objective response and, at the interim reporting of results, three of the 
dosing cohorts had not achieved median duration of response due to ongoing responses (9+- 
21+ weeks).64 In the metastatic renal cell carcinoma trial, 44 patients were enrolled at initial 
reporting. Grade 3-4 toxicity was seen in 43% of patients. No patients died from treatment 
related toxicity and seven discontinued treatment due to toxicity. An objective response was 
seen in 34% of patients with 14/15 responses on-going (4.1+-21+ weeks) at the time of last 
reporting.65 
On September 30, 2015 the FDA granted accelerated approval to the use of ipilimumab in 
conjunction with nivolumab for patients with BRAF wild type, unresectable or metastatic 
melanoma. This was based on a randomized double blinded clinical trial showing response 
rates of 60% for combination treated patients vs. 11% for ipilimumab treated patients. PFS for 
patients on the combination was 8.9 months vs. 4.7 months for ipilimumab treated patients.66 
Safety of the combination of nivolumab and relatlimab was assessed in study CA224020. 
Overall, based on preliminary data as of the clinical cutoff date of 15-Jun-2017, the safety 
profile of relatlimab in combination with nivolumab is manageable, with no maximum tolerated 
dose (MTD) reached at the tested doses up to 160 mg relatlimab and 240 mg nivolumab (flat 

18 
 
dose, every 2 weeks [Q2W]), with evaluation of the 240 mg relatlimab/240 mg nivolumab 
combination doselevel ongoing. At the time of the clinical cutoff date (15-Jun-2017) one dose- 
limiting toxicity (DLT) of Grade 5 myocarditis was observed at the 240 mg relatlimab/240 mg 
nivolumab combination dose level among five evaluable subjects. There was no dose 
relationship between the incidence, severity, or causality of adverse events (AEs) to 
combination therapy. In the nine expansion cohorts, a total of 262 subjects were treated with 
80 mg relatlimab and 240 mg nivolumab Q2W. Most AEs were low grade (Grade 1 to Grade 
2) with a total of 26 subjects experiencing a drug-related serious adverse event (SAE). All 
AEs, except for one Grade 5 myocarditis and one Grade 4 drug-induced liver injury (DILI), 
were reversible and manageable by withholding study drug administration providing standard 
medical care, and/or following immunerelated AE algorithms. In summary the safety profile 
of the combination of relatlimab and nivolumab appears similar to nivolumab monotherapy in 
terms of both frequency and severity of AEs. 
A pattern of immune-related adverse events has been defined for treatment with nivolumab 
monotherapy and nivolumab in combination with other immune-targeting agents such as 
relatlimab. Management algorithms have been developed for these events and are provided 
in the Appendix. Most high-grade events are manageable with the use of corticosteroids or 
hormone replacement therapy (endocrinopathies) as instructed in these algorithms. 
Myocarditis has been observed with nivolumab monotherapy treatment (see nivolumab IB). 
Given the grade 5 myocarditis event in the CA224020 study, and the known nonclinical 
mouse double LAG-3/PD-1 knockout myocarditis phenotype, increased cardiac surveillance 
with troponin measurements were instituted. As of the clinical cutoff date of 15-Jun-2017 
there have been four grade 1 myocarditis cases (asymptomatic troponin elevations with 
imaging correlate of myocardial inflammation but without evidence of cardiac dysfunction). 
Treatment was delayed in all cases, and precautionary steroid treatment was given without 
any of the participants developing evidence of cardiac dysfunction. 
Additional details on the safety profiles of relatlimab and nivolumab, including guidance 
regarding myocarditis and other potential risks, as well as results from other clinical studies, 
are available in the relatlimab and nivolumab IBs. 
 
2.6 
Neoadjuvant Approach 
Increasingly, systemic therapy is being given in the neoadjuvant setting (prior to surgery) in a 
variety of cancer types including breast, rectal, and esophageal cancers. There are many 
practical and theoretical advantages to giving systemic therapy up front. First, giving systemic 
therapy prior to surgery allows patients to receive and complete the entire course of systemic 
therapy because there are no potential complications and deconditioning that are inherent to 
major operative interventions. Second, up front systemic treatment can shrink the tumor and 
increase the likelihood that the entire tumor is removed. Next, obtaining the tumor specimen 
after it has been exposed to systemic treatment allows for an assessment of response to 
treatment which can be used as a prognostic marker or, potentially, to direct further systemic 
therapy. From a scientific standpoint, this tissue can also be used to help elucidate drug 
mechanism of action and determine biomarkers that can predict responsiveness to therapy. 
 
In immunotherapy, in general, and checkpoint blockade, in particular, there are theoretical 
advantages to giving therapy prior to tumor removal. Neoadjuvant immunotherapy may be 
more effective than immunotherapy given in the immediate postoperative period as patients 
will experience some level immunosuppression as a consequence of surgery.67 Additionally, 
more robust antitumor immune responses are expected with checkpoint blockade when the 

19 
 
tumor microenvironment is intact within the host as there is potential exposure to tumor- 
specific antigens, immuno-adaptability (antigenic epitope spreading) of the immune system to 
changes in tumor cells, and cytokine signaling that may enhance the immune response. 
Checkpoint inhibitors augment the body’s inherent antitumor immune response by 
counteracting cancer-related immunosuppression. This allows the immune system to 
recognize tumor associated antigens and mount an effective response against them. Having 
the intact tumor in place will allow the immune system greater exposure to the full range of 
immunogenic tumor epitopes and, thus may lead to a more effective response. 
 
3 
Objectives & Endpoints 
3.1 
Primary Objective 
Arm A and Arm B 
 
To assess the pathologic response of nivolumab monotherapy and nivolumab and 
ipilimumab dual therapy administered in the neoadjuvant setting in patients with clinical 
stage III or oligometastatic stage IV melanoma. Pathologic response will be assessed by 
percent viable tumor cells, percent tumor necrosis, presence of fibrosis and melanoma 
proliferation as assessed by phosphohistone H3 from baseline, to on- treatment and surgical 
specimen 
 
Arm C 
 
To assess the pathologic response rate of combination relatlimab with nivolumab in the 
neoadjuvant setting in patients with high-risk resectable Stage IIIB/C or oligometastatic Stage 
IV melanoma. Pathologic response will be assessed by percent viable tumor cells, percent 
tumor necrosis, presence of fibrosis and melanoma proliferation as assessed by 
phosphohistone H3 from baseline, to on- treatment and surgical specimens. 
 
 
3.2 
Secondary Objectives 
Arm A and Arm B 
 
• 
 To assess the immunologic response of neoadjuvant nivolumab monotherapy and 
neoadjuvant nivolumab and ipilimumab dual therapy in patients with high-risk 
resectable melanoma. Immunologic response will be determined by change in T cell 
infiltrate from baseline to on-treatment and surgical specimens in response to therapy 
 
• 
 To assess the objective response rate (ORR) of nivolumab monotherapy and 
nivolumab and ipilimumab dual therapy administered in the neoadjuvant setting as 
assessed by imaging (RECIST 1.1 criteria) in patients with high-risk resectable 
melanoma 
 
• 
To assess the 12-month recurrence-free survival (RFS) and overall survival (OS) 
of patients with high-risk resectable melanoma treated with neoadjuvant nivolumab 

20 
 
monotherapy or nivolumab and ipilimumab dual therapy followed by adjuvant 
nivolumab 
 
• 
To evaluate the safety of nivolumab monotherapy and dual ipilimumab and 
nivolumab in the neoadjuvant setting and peri-operatively as well as assess the 
safety of adjuvant nivolumab. 
 
Arm C 
 
• 
To evaluate safety and feasibility of relatlimab with nivolumab delivered in the 
neoadjuvant setting 
 
• 
To assess the objective response rate (ORR) of relatlimab with nivolumab 
administered in the neoadjuvant setting as assessed by imaging (RECIST 1.1 criteria) 
in patients with high-risk resectable melanoma. 
 
• 
To assess the 12-month recurrence-free survival (RFS) and overall survival (OS) 
of patients with high-risk resectable melanoma treated with neoadjuvant and adjuvant 
relatlimab with nivolumab 
 
• 
To evaluate immunologic and molecular mechanisms of response and resistance to 
relatlimab with nivolumab. 
 
 
3.3 
Exploratory Objectives 
Identification of immunologic and genomic markers correlating with clinical and pathological 
response and resistance 
 
4 
Ethical Considerations 
4.1 
Good Clinical Practice 
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by 
the International Conference on Harmonisation (ICH) and in accordance with the ethical 
principles underlying European Union Directive 2001/20/EC and the United States Code of 
Federal Regulations, Title 21, Part 50 (21CFR50). The study will be conducted in 
compliance with the protocol. The protocol and any amendments and the subject informed 
consent will receive Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
approval/favorable opinion prior to initiation of the study. All potential serious breaches 
must be reported to BMS immediately. A serious breach is a breach of the conditions and 
principles of GCP in connection with the study or the protocol, which is likely to affect, to 
a significant degree, the safety or physical or mental integrity of the subjects of the study 
or the scientific value of the study. Personnel involved in conducting this study will be 
qualified by education, training, and experience to perform their respective tasks. This study 
will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment). 

21 
 
4.2 
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable 
opinion from the IRB/IEC for the protocol, consent form, subject recruitment materials (e.g., 
advertisements), and any other written information to be provided to subjects. The 
investigator or BMS should also provide the IRB/IEC with a copy of the Investigator 
Brochure or product labeling information to be provided to subjects and any updates. The 
investigator or BMS should provide the IRB/IEC with reports, updates and other information 
(e.g., expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures. 
 
4.3 
Informed Consent 
Investigators must ensure that subjects are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer to 
participate. 
 
In situations where consent cannot be given to subjects, their legally acceptable 
representatives are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the subject volunteers to participate. BMS 
will provide the investigator with an appropriate (i.e., Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that 
have their origin in the Declaration of Helsinki. 
 
Investigators must: 
 
1. Provide a copy of the consent form and written information about the study in the 
language in which the subject is most proficient prior to clinical study participation. 
The language must be non-technical and easily understood. 
 
2. Allow time necessary for subject or subject's legally acceptable representative to 
inquire about the details of the study. 
 
3. Obtain an informed consent signed and personally dated by the subject or the 
subject's legally acceptable representative and by the person who conducted the 
informed consent discussion. 
 
4. Obtain the IRB/IEC’s written approval/favorable opinion of the written informed 
consent form and any other information to be provided to the subjects, prior to 
the beginning of the study, and after any revisions are completed for new information. 
 
5. If informed consent is initially given by a subject’s legally acceptable representative 
or legal guardian, and the subject subsequently becomes capable of 
making and communicating his or her informed consent during the study, consent 
must additionally be obtained from the subject. 
 
Revise the informed consent whenever important new information becomes available that 
is relevant to the subject's consent. The investigator, or a person designated by the 
investigator, should fully inform the subject or the subject's legally acceptable 
representative or legal guardian, of all pertinent aspects of the study and of any new 

22 
 
information relevant to the subject's willingness to continue participation in the study. This 
communication should be documented. 
 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects' signed 
ICF and, in the US, the subjects’ signed HIPAA Authorization. 
 
The consent form must also include a statement that BMS and regulatory authorities have 
direct access to subject records. Subjects unable to give their written consent (e.g., stroke or 
subjects with or severe dementia) may only be enrolled in the study with the consent of a 
legally acceptable representative. The subject must also be informed about the nature of the 
study to the extent compatible with his or her understanding, and should this subject become 
capable, he or she should personally sign and date the consent form as soon as possible. 
The explicit wish of a subject who is unable to give his or her written consent, but who is 
capable of forming an opinion and assessing information to refuse participation in or to be 
withdrawn from, the clinical study at any time should be considered by the investigator. The 
rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society. 
 
5 
Investigational Plan 
5.1 
Study Design 
This is a randomized Phase II study designed to detect pathologic and immunologic 
biomarkers of response to checkpoint blockade in melanoma. In Arm A, 12 patients received 
up to four upfront doses of nivolumab and in Arm B 11 patients received up to three 
doses of upfront ipilimumab combined with nivolumab. Both groups of patients will have a 
baseline biopsy and blood for genomic and immunologic analyses. On-treatment biopsies 
and blood for biomarker analysis will be obtained in both groups around dose 2 and dose 
3 (if feasible). Neoadjuvant therapy will be administered over 7 weeks and will then be 
followed by restaging scans. If at any point during the course of neoadjuvant therapy there is 
clinical (worsening performance status) and/or objective evidence (new imaging data) to 
suggest rapid disease progression, the patient will be taken off study and offered immediate 
surgery or other alternative treatment plan. If disease remains resectable based on the 
updated scans and the assessment of the treating surgical oncologist, patients in both 
groups will undergo definitive surgical excision of visible disease. Preliminary assessment 
of surgical margins will be obtained by intra-operative frozen section when appropriate. If 
surgical margins are found to be microscopically involved, patients will still be eligible for 
initiation of adjuvant therapy and no adjuvant radiation will be administered. 
 
All acquired tissue samples (baseline, on-treatment and surgical resection) will be used for 
biomarker analyses. Patients will be reassessed for initiation of adjuvant nivolumab once 
adequate wound healing has been achieved within 4-6 weeks of surgical procedure. Both 
groups of patients will then initiate on six months of adjuvant nivolumab administered every 
two weeks. Restaging scans will be obtained every 12 weeks. 
 
Patients with clinical stage III (IIIB/IIIC) or oligometastatic stage IV disease will be 
screened for eligibility. Patients with disease that is determined to be surgically resectable as 
agreed upon by a multidisciplinary consensus conference will be eligible to be screened for 
the protocol. Disease will be considered unresectable if there is significant vascular, neural 

23 
 
or bony involvement and in cases where a complete surgical resection with negative 
margins cannot be safely performed. Prior to Amendment 7, forty patients were expected to 
be randomized in a 1:1 ratio between Arm A and Arm B. Subjects would then be stratified by 
stage of disease (IIIB, IIIC, M1A vs. M1B/M1C) and by PD-L1 + or PD-L1 – tumor status). 
After approval of Amendment 7, Arms A and B were closed to new patient entry and Arm C 
was opened to enrollment. Thirty patients will be enrolled to Arm C without randomization. 
 
Figures 1a and 1b Study Design Schema 
 
 
 
 
Based on analysis by Data Safety Monitoring Board at a meeting on July 11, 2017, enrollment 
on Arm A and B was closed based on efficacy (Arm A) and safety (Arm B) concerns. At the 
time of study closure, 23 total patients were enrolled and treated; 12 in Arm A and 11 in Arm 
B. In Arm A, 22% of patients experienced disease progression and were ineligible for surgery 
prompting closure of this Arm. In Arm B, all patients have been able to proceed to surgery, 
however the grade 3 toxicity rate was 89% and 33% required delay in surgery related to 
toxicity. This Arm was closed due to concerns of toxicity and patient safety. Based on the 
above results, Arm C was created to explore the safety and efficacy of alternative dosing 
strategies to maximize efficacy while minimizing toxicity. 
 
In Arm C, 30 patients will receive relatlimab combined with nivolumab every 28 days for 2 
doses prior to surgery. The biospecimen collection plan will include blood and tumor 
collections at day 14 and day 28. Neoadjuvant therapy will be administered and will then be 
followed by restaging scans. If at any point during the course of neoadjuvant therapy there is 
clinical (worsening performance status) and/or objective evidence (new imaging data) to 
suggest rapid disease progression, the patient will be taken off study and offered immediate 
surgery or other alternative treatment plan. If disease remains resectable based on the 
updated scans and the assessment of the treating surgical oncologist, patients will undergo 
definitive surgical excision of visible disease. In the adjuvant setting, patients will receive 

24 
 
relatlimab and nivolumab every 28 days for an additional 10 doses. Restaging scans will be 
obtained every 12 weeks in the adjuvant setting. 
 
 
 
5.2 
Study Assessments 
The primary objective of this study is assessment of pathologic changes from baseline to on- 
treatment samples within each treatment arm. Blood and tumor collections are required at 
baseline (samples must be obtained within 28 days of treatment initiation), around dose 2 
and dose 3 of neoadjuvant therapy in Arms A and B, and again at the time of definitive 
surgical excision. Biopsies around dose 3 for Arms A and B and at relapse are optional and 
will be done if medically safe and feasible. Patients in arms A and B will undergo adjuvant 
nivolumab. Biopsies around dose 3 for Arms A and B and at relapse are optional and will be 
done if medically safe and feasible. 
 
In Arm C, blood and tumor are required at baseline (samples must be obtained within 28 days 
of treatment initiation), at day 14 and day 28 of neoadjuvant therapy and at the time of definitive 
surgical excision. Patients in Arm C will then undergo 10 months of adjuvant relatlimab and 
nivolumab. 
 
For all treatment arms, research blood will be obtained every three months during the 
duration of adjuvant therapy. Blood and tumor will also be collected at the time of 
relapse for all treatment arms when possible. 
 
Secondary objectives of this study include assessment of immunologic changes in the 
tumor microenvironment and blood, treatment response based on imaging in response to 
neoadjuvant therapy, toxicity, RFS and OS. Subjects will be assessed with computed 
tomography (CT) or magnetic resonance imaging (MRI) at screening, after completion of 
neoadjuvant therapy and during the post-treatment follow-up period (refer to the Study 
Procedure Tables in Section 7.1 for scanning frequency). Subjects will also be followed for 
survival. Subjects will be followed for a minimum of two years. Safety will be evaluated 
by clinical assessments including vital signs and complete physical examinations, chemistry 
and hematology laboratory values and formal assessments of adverse events (AEs). 

25 
 
5.3 
Treatment Assignment 
Subjects will be approved for treatment after a consensus panel of medical and surgical 
oncologists have determined that the disease is amenable to surgical resection and after the 
subject has passed screening evaluations (see Section 5.4). Subjects will then be assigned a 
subject number and will be eligible for randomization to Arm A or Arm B. Subject 
randomization will be implemented by the Clinical Trial Conduct website maintained by the 
Department of Biostatistics at the University of Texas M.D. Anderson Cancer Center 
(https://biostatistics.mdanderson.org/ClinicalTrialConduct). Once a subject number has been 
assigned, it cannot be reassigned to any other patient. If the subject is prematurely 
discontinued from the study without having received the prescribed treatment, an additional 
subject may be enrolled as a replacement subject. 
 
There will be no randomization for patients in Arm C. 
 
5.4 
Eligibility Criteria 
5.4.1 
Inclusion Criteria 
 
A subject will be eligible for inclusion in this study only if all of the following criteria apply: 
 
1. Capable of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form 
 
2.  Patients must have histologically or cytologicaly confirmed Stage IIIB/C or Stage IV 
oligometastatic melanoma. Oligometastatic melanoma is defined as three or fewer 
areas of resectable disease excluding central nervous system and bone 
involvement. Patients with cutaneous, mucosal, acral, ocular or unknown primary 
melanomas are eligible for enrollment. For patients with stage IV disease with distant 
lymph nodes (stage M1a), a maximum of three separate lymph node sites fit the 
definition of oligometastatic disease. Resectable tumors are defined as having no 
significant vascular, neural or bony involvement. Only cases where a complete 
surgical resection with tumor-free margins can safely be achieved are defined as 
resectable. Details on melanoma staging per the American Joint Committee on 
Cancer Version 7 can be found in Appendix 1. 
 
3. Patients will have at least one melanoma deposit that can undergo serial biopsy 
(at least 2 time points) during the neoadjuvant phase of the protocol. Patients must 
be willing to provide tumor samples at the time points specified in the Study 
Procedure Tables (Section 7.1). 
 
4.  All patients must undergo a baseline tumor biopsy. In Arms A and B, tumor biopsy 
for PD-L1 testing (PD-L1 positivity is determined by greater than or equal to 1% of 
cells staining in the membrane by immunohistochemistry) is required for stratification. 
PD-L1 status is not required for enrollment on Arm C. The 28-8 clone for PD-L1 testing 
is required for assessment of PD-L1 status. For patients with stage IV disease, site 
of tumor biopsy will preferably be from non-lymph node disease site. For PD-L1 testing, 
the biopsy should contain sufficient tumor content (>100 tumor cells/4-micron tissue 
section). If a sample contains insufficient tumor content, a re-biopsy will be required 
to obtain a sample with sufficient tumor content prior to treatment. 

26 
 
5. Patients must be medically fit enough to undergo surgery as determined by the 
treating medical and surgical oncology team 
 
6. Patients who have been previously treated in the adjuvant setting for melanoma will 
be eligible for treatment after a 28 day wash-out period 
 
7. Patients must have measurable disease, defined by RECIST 1.1 (Appendix 2) 
 
8. Age ≥ 18 years 
 
9. ECOG performance status 0-1 
 
10. Patients must have organ and marrow function as defined below within 28 days of first 
study treatment: 
 
Table 1 Eligibility Guidelines of Organ and Marrow Function 
 
System 
Laboratory Values 
Hematologic 
Absolute neutrophil count (ANC)† 
≥ 1.5 X 109/L 
Hemoglobin‡ 
≥ 8.5 g/dL 
Platelets‡ 
≥ 100 X 109/L (≥ 60 for HCC) 
PT/INR and PTT 
≤ 1.5 X ULN 
WBC† 
≥ 2.0 x 109/L 
Hepatic 
Total bilirubin 
≤ 1.5 X ULN (except subjects with Gilbert’s Syndrome 
who must have normal direct bilirubin) [3 mg/dL for HCC] 
AST and ALT 
Albumin 
≤ 3.0 X ULN (≤ 5 x ULN for HCC) 
≥2.5 g/dL 
Renal 
Creatinine 
OR 
Calculated creatinine clearance 
OR 
24-hour urine creatinine clearance 
≤1.5 X ULN 
≥ 40 mL/min 
≥ 50 mL/min 
Other 

27 
 
Lipase 
Amylase 
Normal Thyroid Function (or stable 
on hormone supplementation) 
LVEF 
< 1.5 X ULN 
< 1.5 X ULN 
0.27 – 10 X 109/L 
Assessment with documented LVEF ≥ 50% by either 
TTE (preferred test) or MUGA within 6 months from first 
study drug administration 
† = stable off any growth factor within 28 days of first study drug administration. 
‡ = transfusion to achieve this level is not permitted within 2 weeks of first study drug 
administration 
Women are eligible if: 
 
11.  Non-childbearing potential defined as pre-menopausal females with a documented 
tubal ligation or hysterectomy; or postmenopausal defined as 12 months of 
spontaneous amenorrhea [in questionable cases a blood sample with simultaneous 
follicle stimulating hormone (FSH) > 40 MlU/mL and estradiol < 40 pg/mL (<140 
pmol/L) is confirmatory]. Females on hormone replacement therapy (HRT) and 
whose menopausal status is in doubt will be required to use one of the 
contraception methods in Appendix 3 if they wish to continue their HRT during the 
study. Otherwise, they must discontinue HRT to allow confirmation of post- 
menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 
weeks will elapse between the cessation of therapy and the blood draw; this interval 
depends on the type and dosage of HRT. Following confirmation of their post- 
menopausal status, they can resume use of HRT during the study without use of a 
contraceptive method. 
 
12.  Childbearing potential and agrees to use method(s) of contraception. For a 
teratogenic study drug and/or when there is insufficient information to assess 
teratogenicity (preclinical studies have not been done), a highly effective method(s) 
of contraception (failure rate of less than 1% per year) is required. 
 
The individual methods of contraception and duration should be determined 
in consultation with the investigator. Women of childbearing potential (WOCBP) 
must follow instructions for birth control when the half-life of the investigational 
drug is greater than 24 hours, contraception should be continued for a period of 30 
days plus the time required for the investigational drug to undergo five half-lives. 
The half-life of nivolumab and ipilimumab is up to 25 days and 18 days, respectively. 
WOCBP should use an adequate method to avoid pregnancy for 24 weeks (30 days 
plus the time required for nivolumab and/or relatlimab to undergo five half-lives) 
after the last dose of investigational drug. WOCBP must have a negative serum 
or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) 
within 24 hours prior to the start of investigational product 
 
13. Women must not be breastfeeding 
 
14. Men who are sexually active with WOCBP must use any contraceptive method with 
a failure rate of less than 1% per year The investigator shall review contraception 
methods and the time period that contraception must be followed. Men who are 

28 
 
sexually active with WOCBP must follow instructions for birth control when the half- 
life of the investigational drug is greater than 24 hours, contraception should be 
continued for a period of 90 days plus the time required for the investigational drug to 
undergo five half-lives. The half-life of nivolumab and ipilimumab is up to 25 days and 
18 days, respectively. Therefore, men who are sexually active with WOCBP must 
continue contraception for 33 weeks (90 days plus the time required for nivolumab 
and/or relatlimab to undergo five half-lives) after the last dose of investigational drug. 
In addition, male participants must be willing to refrain from sperm donation during this 
time. 
 
Men who are sexually active with women who are not of childbearing potential (i.e., 
who are postmenopausal or surgically sterile and azoospermic men) do not require 
contraception. 
 
Further guidance on contraception practices can be found in Appendix 3. 
 
15. For Arm C: Cardiac assessment at baseline by trans-thoracic echocardiogram (TTE) 
with LVEF≥ 50%. 
 
 
5.4.2 
Exclusion Criteria 
 
A subject will not be eligible for inclusion in this study if any of the following criteria apply: 
 
1. Currently 
receiving 
cancer 
therapy 
(chemotherapy, 
radiation 
therapy, 
immunotherapy, or biologic therapy) or investigational anti-cancer drug 
 
2. Any major surgery within the last 3 weeks 
 
3. Brain metastases, leptomeningeal disease or bone metastases 
 
4. Pregnant or lactating female 
 
5. Unwillingness or inability to follow the procedures required in the protocol 
 
6. Current use of anticoagulants (warfarin, heparin, direct thrombin inhibitors) at 
therapeutic levels 
 
7.  Any serious or uncontrolled medical disorder that, in the opinion of the investigator, 
may increase the risk associated with study participation or study drug 
administration, impair the ability of the subject to receive protocol therapy, or interfere 
with the interpretation of study results. 
 
8. Prior malignancy active within the previous 3 years except for patient’s prior 
diagnosis of melanoma and locally curable cancers that have been apparently 
cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or 
carcinoma in situ of the prostate, cervix, or breast with local control measures 
(surgery, radiation). 
 
9. Subjects with active, known or suspected autoimmune disease. Subjects with 
vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune 

29 
 
condition only requiring hormone replacement, psoriasis not requiring systemic 
treatment, or conditions not expected to recur in the absence of an external trigger are 
permitted to enroll. 
 
10.  Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 
mg daily prednisone equivalents) or other immunosuppressive medications within 14 
days of study drug administration. Inhaled or topical steroids and adrenal 
replacement doses > 10 mg daily prednisone equivalents are permitted in the 
absence of active autoimmune disease. 
 
11. Prior treatment with an anti-PD-1, anti-PD-L1, anti-LAG-3 or anti-CTLA-4 antibody 
 
12. Any positive test result for hepatitis B or C virus indicating acute or chronic 
infection 
 
13. Known history of testing positive for human immunodeficiency virus or known 
acquired immunodeficiency syndrome 
 
14. History of severe hypersensitivity reaction to any monoclonal antibody 
 
15. Prisoners or subjects who are involuntarily incarcerated 
 
16. Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(infection disease) illness 
 
17. A known or underlying medical condition that, in the opinion of the Investigator, could 
make the administration of the study drug hazardous to the subject or could adversely 
affect the ability of the subject to comply with or tolerate the study. 
 
18. A confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year 
prior to informed consent. 
 
19. Evidence of active infection that requires systemic antibacterial, antiviral, or antifungal 
therapy ≤ 7 days prior to initiation of study drug therapy. 
 
20. Any other acute or chronic medical illness. 
 
21. Subjects who are unable to undergo venipuncture and/or tolerate venous access. 
 
22. Any other sound medical, psychiatric, and/or social reason as determined by the 
Investigator 
 
23. Any of the following procedures or medications: 
 
a. Within 2 weeks prior to time of study treatment: 
 
i. Systemic or topical corticosteroids at immunosuppressive doses (> 10 
mg/day of prednisone or equivalent). Inhaled or topical steroids, and 
adrenal replacement steroid doses of > 10 mg daily prednisone 
equivalent, are permitted in the absence of active autoimmune disease. 
 
ii. Palliative radiation or gamma 

30 
 
b. Within 4 weeks prior to study drug administration: 
 
i. 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 Sponsor/Medical 
Monitor is mandatory. 
 
24. Subjects with history of life-threatening toxicity related to prior immune therapy (e.g., 
anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically 
targeting T-cell co-stimulation or immune checkpoint pathways) except those that are 
unlikely to re-occur with standard countermeasures (e.g., hormone replacement after 
endocrinopathy). 
 
25. Troponin T (TnT) or I (TnI) > 2 x institutional upper limit of normal (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 subject 
may undergo a cardiac evaluation and be considered for treatment, following a 
discussion with the investigator or designee. 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 a cardiac 
evaluation and be considered for treatment, following a discussion with the investigator 
or designee. 
 
26. For Arm C: Uncontrolled or significant cardiovascular disease including, but not limited 
to, any of the following: i) Myocardial infarction (MI) or stroke/transient ischemic attack 
(TIA) within the 6 months prior to consent ii) Uncontrolled angina within the 3 months 
prior to consent iii) Any history of clinically significant arrhythmias (such as ventricular 
tachycardia, ventricular fibrillation, or torsades de pointes) iv) QTc prolongation > 480 
msec v) History of other clinically 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, deep venous thrombosis, etc ) vi) Cardiovascular disease- 
related requirement for daily supplemental oxygen vii) History of two or more MIs OR 
two or more coronary revascularization procedures viii) Subjects with history of 
myocarditis, regardless of etiology 
 
6 
Treatment Plan 
6.1 
Investigational Product 
The investigational products are supplied by BMS. The investigational products should be 
stored in a secure area according to local regulations. It is the responsibility of the 
investigator to ensure that investigational product is only dispensed to study subjects. The 
investigational product must be dispensed only from official study sites by authorized 
personnel according to local regulations. 
 
In this protocol, investigational products are: nivolumab ( BMS-936558), ipilimumab (BMS- 
734016), and relatlimab (BMS-986016). 

31 
 
6.2 
Handling and Dispensing 
The product storage manager should ensure that the study drug is stored in accordance 
with the environmental conditions (temperature, light, and humidity) as determined by BMS. 
If concerns regarding the quality or appearance of the study drug arise, the study drug 
should not be dispensed and contact BMS immediately. 
 
Investigational product documentation must be maintained that includes all processes 
required to ensure drug is accurately administered. This includes documentation of drug 
storage, administration and, as applicable, storage temperatures, reconstitution, and use of 
required processes (e.g., required diluents, administration sets). 
 
Infusion-related supplies (e.g., IV bags, in-line filters, 0.9% NaCl solution) will not be 
supplied by the sponsor and should be purchased locally if permitted by local regulations. 
 
Please refer to the current version of the Investigator Brochure and/or pharmacy reference 
sheets for complete storage, handling, dispensing, and infusion information for BMS- 
936558 (nivolumab) and ipilimumab. 
 
6.3 
Destruction 
Investigator drug destruction is allowed provided the following minimal standards are met: 
 
• 
On-site disposal practices must not expose humans to risks from the drug. 
 
• 
 On-site disposal practices and procedures are in agreement with applicable laws 
and regulations, including any special requirements for controlled or hazardous 
substances 
 
• 
Written procedures for on-site disposal are available and followed. The 
procedures must be filed with the Sponsor SOPs and a copy provided to BMS 
upon request. 
 
• 
 Records are maintained that allow for traceability of each container, including the 
date disposed of, quantity disposed, and identification of the person disposing the 
containers. The method of disposal, i.e., incinerator, licensed sanitary landfill, or 
licensed waste disposal vendor must be documented. 
 
• 
Accountability and disposal records are complete, up-to-date, and available for 
BMS to review throughout the clinical trial period as per the study agreement. 
 
• 
 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. 

32 
 
6.4 
Product Descriptions 
6.4.1 
Nivolumab (BMS-936558) 
 
Nivolumab (BMS-936558) vials must be stored at a temperature of 2°C to 8°C and 
should be protected from light and freezing, and shaking. If stored in a glass front 
refrigerator, vials should be stored in the carton. Recommended safety measures for 
preparation and handling of nivolumab include laboratory coats and gloves. 
 
For details on prepared drug storage and use time of nivolumab under room 
temperature/light and refrigeration, please refer to the BMS-936558 (nivolumab) 
Investigator Brochure. 
 
Care must be taken to assure sterility of the prepared solution as the product does not 
contain any anti-microbial preservative or bacteriostatic agent. No incompatibilities between 
nivolumab and polyolefin bags have been observed. 
 
Nivolumab is to be administered approximately as a 30-minute IV infusion with a 0.2- 1.2 
micron in-line filter at the protocol-specified dose when administered as a single agent. It is 
administered for 60 minutes when given with ipilimumab or relatlimab. The drug can be diluted 
with 0.9% normal saline or 5% dextrose injection for delivery but the total drug concentration 
of the solution cannot be below 0.35 mg/ml. It is not to be administered as an IV push or 
bolus injection. At the end of the infusion, flush the line with a sufficient quantity of normal 
saline. For further details, please refer to the current BMS-936558 (nivolumab) Investigator 
Brochure. 
 
6.4.2 
Ipilimumab 
 
Ipilimumab injection can be used for IV administration without dilution after transferring to a 
PVC (polyvinyl chloride), non-PVC/non-DEHP (di-(2-ethylhexyl)phthalate) or glass containers 
and is stable for 24 hours at 2-8ºC or room temperature/room light (RT/RL). For ipilimumab 
storage instructions, refer to ipilimumab IB and/or pharmacy reference sheets. 
 
Recommended safety measures for preparation and handling include protective clothing, 
gloves, and safety cabinets. 
 
Ipilimumab is to be administered approximately as a 90-minute IV infusion, using a 
volumetric pump with a 0.2 to 1.2 micron in-line filter at the protocol-specified dose. The drug 
can be diluted with 0.9% normal saline or 5% Dextrose Injection to concentrations between 
1 mg/mL and 4 mg/mL. It is not to be administered as an IV push or bolus injection. 
Care must be taken to assure sterility of the prepared solutions, since the drug product does 
not contain any antimicrobial preservatives or bacteriostatic agents. At the end of the 
infusion, flush the line with a sufficient quantity of normal saline or 5% dextrose solution. 
Please also refer to the current ipilimumab Investigator brochure for further details. 
 
When both study drugs are to be administered on the same day, separate infusion bags 
and filters must be used for each infusion. Nivolumab is to be administered first. The 
nivolumab infusion must be promptly followed by a saline flush to clear the line of 
nivolumab before starting the ipilimumab infusion. 

33 
 
If concerns regarding the quality or appearance of the investigational product arise, the 
investigational product will not be administered and BMS will be contacted immediately. If the 
study drug(s) are to be destroyed on site, it is the investigator’s responsibility to ensure 
that arrangements have been made for disposal, and that procedures for proper disposal 
have been established according to applicable regulations, guidelines, and institutional 
procedures. 
 
6.4.3 
Relatlimab (BMS-986016) 
 
Relatlimab should be stored at 2°C to 8°C (36oF to 46oF) with protection from light. Do not 
freeze the drug product. 
 
Relatlimab is to be administered as a 60 minute IV infusion through a 0.2/1.2-µm pore size, 
low-protein-binding polyethersulfone membrane in-line filter at the protocol-specified doses. 
When dosing sequentially with nivolumab, relatlimab should begin within 15-30 minutes after 
the end of the nivolumab infusion. Relatlimab injection and nivolumab injection can be diluted 
with 0.9% sodium chloride injection (normal saline), to protein concentrations no lower than 
1.33 mg/mL. Detailed instructions for drug product dilution and administration are provided in 
the pharmacy manual for the clinical study. 
 
Care must be taken to assure sterility of the prepared solution, as the products do not contain 
any anti-microbial preservative or bacteriostatic agent. No incompatibilities between the co- 
administered drug products and polyolefin or PVC bags, or non-DEHP or PVC infusion sets 
have been observed. 
 
The administration of relatlimab and nivolumab must be completed within 24 hours of 
preparation. If not used immediately, the infusion solution may be stored in a refrigerator at 
2°C to 8°C (36oF to 46oF) for up to 24 hours and a maximum of 8 hours of the total 24 hours 
can be at room temperature (20°C to 25°C; 68oF to 77oF) and exposed to room light. The 
maximum 8-hour period under room temperature and room light conditions includes the 
product administration period. 

34 
 
Table 2 Product Descriptions 
 
Product 
Description and 
Dosage Form 
Potency 
Primary 
Packaging 
(Volume)/Label 
Type 
Secondary 
Packaging 
(Qty)/Label Type 
Appearance 
Storage 
Conditions (per 
label) 
Nivolumab 
100mg 
(10mg/mL) 
10mL vial 
Open-Label 
5 or 10 vials 
per carton 
Open- label 
Clear to opalescent, 
colorless to pale 
yellow liquid. 
May contain particles 
2 to 8ºC. Protect 
from light and 
freezing 
Ipilimumab 
200mg 
(5mg/mL) 
40mL vial 
Open-Label 
5 vials per carton 
Open- label 
Clear, colorless to 
pale yellow liquid. 
May contain particles 
2 to 8ºC. Protect 
from light and 
freezing 
Relatlimab 
100mg 
(10mg/mL) 
10mL vial 
Open-Label 
4 vials per carton 
Open- label 
Clear to opalescent, 
colorless to pale 
yellow liquid. 
May contain particles 
2 to 8ºC. Protect 
from light and 
freezing 
 
 
 
 
 
6.5 
Dose Calculations and Administration 
The first dose of study medication(s) is to be administered within 7 days of randomization. 
 
For Arms A and B prior to Amendment 7, a total of 40 patients were expected to be 
randomized 1:1 on two different treatment arms. After approval of Amendment 7, Arms A and 
B will be closed and Arm C will be added. A total of 30 patients will be treated with nivolumab 
and relatlimab without randomization. There will be two different phases of drug 
administration. 
 
1) Neoadjuvant phase: 
 
• 
Arm A: nivolumab 3 mg/kg IV every 2 weeks (+/-7 days) on weeks 1, 3, 5 and 7 
 
• 
Arm B: nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 
weeks (+/-7 days) on weeks 1, 4 and 7. 

35 
 
• 
Arm C: nivolumab 480 mg IV combined with relatlimab 160 mg IV every 28 days 
(±7 days) beginning on week 1 for 2 doses (Week 1 and Week 5) 
 
2) Adjuvant phase: 
 
• 
Patients in treatment arms A and B will receive nivolumab 3mg/kg IV every 2 
weeks (±7 days) for a total of 24 weeks (13 doses) 
 
• 
Patients in Arm C will receive nivolumab 480 mg IV combined with relatlimab 160 
mg IV every 28 (+/-7 days) days for a total of 10 doses. 
 
For Treatment Arms A and B, the dosing calculations should be based on the actual body 
weight. If the subject’s weight on the day of dosing differs by > 10% from the weight used 
to calculate the original dose, the dose must be recalculated using the patient’s new actual 
body weight. All doses should be rounded to the nearest milligram. There will be no dose 
modifications allowed. Please refer to the current Investigator Brochure for additional 
details on administration. 
 
6.5.1 
Dose Modifications 
 
Dose reductions or dose escalations are not permitted. 
 
6.5.2 
Dose Delay Criteria 
 
Because of the potential for clinically meaningful treatment-related AEs requiring early 
recognition and prompt intervention, management algorithms have been developed for 
suspected AEs of selected categories. The PI or study doctor will proceed with surgery if still 
feasible despite side-effect related dose delay. 
 
Study drug administration should be interrupted and increased monitoring of subjects should 
ensue if any of the following drug related adverse event(s) occurs: 
 
• 
Grade ≥1 myocarditis 
 
o All troponin elevations require a dose delay to allow for prompt cardiac 
evaluations. Following this evaluation, determination of further treatment 
will be based on the discussion with the sponsor or designee. 
 
• 
Grade ≥2 non-skin, drug-related adverse events with the following exceptions: 
 
o Grade 2 drug-related fatigue or laboratory abnormalities do not require a 
treatment delay 
 
• 
Any Grade 3 skin, drug-related AE 
 
• 
Any Grade 3 drug-related laboratory abnormalities with the following exceptions 
for lymphopenia, leukopenia, AST, ALT, or total bilirubin 
 
o Grade 3 lymphopenia or leukopenia does not require dose delay 

36 
 
o If a subject has a baseline AST, ALT, or total bilirubin that is within normal 
limits, delay dosing for drug-related Grade ≥2 toxicity 
 
o If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 
toxicity range, delay dosing for drug-related Grade ≥3 toxicity 
 
• 
 Any adverse event, laboratory abnormalities, or intercurrent illness which in the 
judgment of the investigator, warrants delaying the dose of study medication. 
 
If dose delay is necessary, nivolumab (Arm A) or both nivolumab and ipilimumab 
(Arm B) must be delayed until treatment can resume. 
 
See current Investigator Brochure and Appendix 4 - Appendix 10 for citation 
examples. 
 
Dose delay criteria apply for all drug-related adverse events (regardless of 
whether or not the event is attributed to study drug). All study drugs must be 
delayed until treatment can resume. 
 
Subjects may resume treatment with study drug when the drug-related AE(s) 
resolve to Grade ≤ 1 or baseline value, with the following exceptions: 
 
o Subjects may resume treatment in the presence of Grade 2 fatigue 
 
o Subjects who have not experienced a Grade 3 drug-related skin AE may 
resume treatment in the presence of Grade 2 skin adverse event 
 
o Subjects with baseline Grade 1 AST/ALT or total bilirubin who require 
dose delays for reasons other than a 2-grade shift in AST/ALT or total 
bilirubin may resume treatment in the presence of Grade 2 AST/ALT OR 
total bilirubin 
 
o Subjects with combined Grade 2 AST/ALT AND total bilirubin values 
meeting discontinuation parameters should have treatment permanently 
discontinued 
 
o Drug-related pulmonary AEs, diarrhea, or colitis, must have resolved to 
baseline before treatment is resumed 
 
o Drug-related endocrinopathies adequately controlled with physiologic 
hormone replacement may resume treatment 
 
o  In the neoadjuvant phase of therapy, if a treatment delay of more than 
three weeks is required, the next dose(s) can be omitted for patient safety 
and patient can stay on protocol as long as the patient is deemed to be 
responding clinically and will be able to proceed with surgery as planned. 
 
o If a subject in Arm B experiences a severe adverse event during 
neoadjuvant combination therapy that subsequently becomes well 
managed (grade 1), initiating treatment with nivolumab in the adjuvant 
setting may be considered if the patient is deemed fit to initiate adjuvant 

37 
 
therapy within the appropriate treatment window (within 4-6 weeks of 
discharge from hospital for surgical excision). 
 
o In the adjuvant phase of therapy: if the criteria to resume treatment are 
met, the subject should restart treatment at the next scheduled time- 
point per protocol. 
 
However, if the treatment is delayed past the next scheduled time-point per 
protocol, the next scheduled time-point will be delayed until dosing 
resumes. If treatment is delayed > 6 weeks, the subject must be 
permanently discontinued from study therapy, except as specified below 
 
6.5.3 
Study-Drug Discontinuation Criteria 
 
Treatment should be permanently discontinued for the following: 
 
• 
Grade 3 troponin not associated with any other sign of cardiac toxicity (as determined 
by a cardiac evaluation) 
 
• 
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days in the 
neoadjuvant and adjuvant settings, including uveitis, pneumonitis, colitis, and 
neurologic adverse events. 
 
• 
Grade 
3 
drug-related 
laboratory 
abnormalities 
do 
not 
require 
treatment 
discontinuation except those noted below: 
 
o Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding 
requires discontinuation 
 
o Any drug-related liver function test (LFT) abnormality that meets the 
following criteria require discontinuation: 
 
 
AST or ALT > 8 x ULN 
 
 
Total bilirubin > 5 x ULN 
 
 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
 
• 
Grade 3 myocarditis 
 
• 
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
following events which do not require discontinuation: 
 
o Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to < Grade 
4 within 1 week of onset. 
 
o  Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated 
with clinical sequelae and are corrected with supplementation/appropriate 
management within 72 hours of their onset 

38 
 
• 
Any dosing delay of more than 2 weeks in the neoadjuvant phase of treatment and > 
6 weeks in the adjuvant phase of treatment with the following exceptions: 
 
o  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 Investigator must be 
consulted. Tumor assessments should continue as per protocol even if dosing 
is interrupted 
 
o  Dosing interruptions > 6 weeks that occur for non-drug-related reasons may 
be allowed if approved by the Investigator. Prior to re-initiating treatment in a 
subject with a dosing interruption lasting > 6 weeks, the Investigator must be 
consulted. Tumor assessments should continue as per protocol even if dosing 
is interrupted 
 
• 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the Investigator, presents a substantial clinical risk to the subject with 
continued nivolumab dosing. 
 
6.5.4 
Treatment of Immunotherapy-Related Infusion Reactions 
 
Since nivolumab, ipilimumab, and relatlimab contain only human immunoglobulin protein 
sequences, they are unlikely to be immunogenic and induce infusion or hypersensitivity 
reactions. However, if such a reaction were to occur, it might manifest with fever, chills, 
rigors, headache, rash, pruritus, arthralgias, hypo- or hypertension, bronchospasm, or other 
symptoms. All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria 
are met. Infusion reactions should be graded according to NCI CTCAE (version 4.0) 
guidelines. 
 
Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines as appropriate: 
 
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention 
not indicated) Remain at bedside and monitor subject until recovery from symptoms. The 
following 
prophylactic 
pre-medications 
are 
recommended 
for 
future 
infusions: 
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen) at least 30 minutes before additional nivolumab administrations. 
 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [e.g., antihistamines, non-steroidal anti- 
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for less than 24 hours). Stop the nivolumab or ipilimumab or 
relatlimab infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen); remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor subject closely. If symptoms recur 
then no further nivolumab or ipilimumab or relatlimab will be administered at that visit. 
Administer diphenhydramine 50 mg IV, and remain at bedside and monitor the subject 

39 
 
until resolution of symptoms. The following prophylactic pre-medications are recommended 
for future infusions: diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 
mg (acetaminophen) should be administered at least 30 minutes before additional 
nivolumab or ipilimumab administrations. If necessary, corticosteroids (recommended dose: 
up to 25 mg of IV hydrocortisone or equivalent) may be used. 
 
6.6 
Permanent Discontinuation from Study Treatment and Subject 
Completion Criteria 
6.6.1 
Subject Completion Criteria 
 
After subject has stopped receiving protocol therapy or if there is an intolerable effect, there 
will be an End of Treatment Visit. During this visit, a physical exam, blood about 6½ 
tablespoons will be drawn for routine tests and to test the immune system. 
 
Every 12 weeks after the subject’s last dose, a physical exam will be done. Six 
tablespoons of blood will be drawn for routine tests and to test the immune system; a CT 
scan, PET-CT scan, and/or MRI will be done to check the status of the disease. 
 
A subject will be considered to have completed the study if the subject is no longer receiving 
clinical benefit (i.e., has progressive disease per RECIST, has died, has shown 
unacceptable toxicity, or study completion criteria have been met). A subject will be 
considered to have withdrawn from the study if the subject, in the absence of disease 
progression or death, is lost to follow-up, has withdrawn consent, or is withdrawn at the 
investigator’s discretion. Patients enrolled will have completed the study after being followed 
for a minimum of two years after the time of surgical resection. Subjects who are ongoing at 
the time the study is closed/terminated will be considered to have completed the study. 
 
6.6.2 
Permanent Discontinuation from Study Treatment 
 
During the protocol defined treatment period study treatment(s) may be permanently 
discontinued for the following reasons: 
 
• 
Death 
 
• 
Unacceptable adverse event 
 
• 
Deviation(s) from the protocol 
 
• 
Request of the subject or proxy 
 
• 
Investigator’s Discretion 
 
• 
Subject is lost to follow-up 
 
• 
Study is closed or terminated 
 
The primary reason each study treatment was permanently discontinued must be 
documented in the subject’s medical records. 

40 
 
If disease recurs prior to the completion of the treatment period, study treatment should be 
discontinued and follow-up assessments should be conducted every three months. Follow 
up assessments may be performed in person, by mail or via phone conversation. 
 
If the subject voluntarily discontinues from treatment due to toxicity, ‘adverse event’ will 
be recorded as the primary reason for permanently discontinuation in the medical record. 
 
All subjects who permanently discontinue from study treatment will have assessments at 
the time of discontinuation and during post study treatment follow- up as specified in Time 
and Events Tables. In addition, all subjects who permanently discontinue study treatment 
without evidence of disease recurrence will also be followed for disease recurrence 
according to the protocol schedule until: 
 
• 
Withdrawal of consent 
 
• 
Death, or 
 
• 
Study completion (as defined in Section 7.5.1) 
 
Subjects that permanently discontinue from study treatment before the end of the treatment 
period without evidence of disease recurrence will return for disease assessment visits 
starting at the next regularly scheduled disease assessment visit (i.e. every 12 weeks for 
restaging scans). If a subject experiences disease recurrence at any time, subsequent 
follow up should be conducted every three months in person, by mail or by phone contact. 
 
Follow-up for survival, new anti-cancer therapy (including radiotherapy) and response to new 
anti-cancer therapy will continue for all subjects including those with disease recurrence for 
2 years after the surgery after which all protocol- required assessments and procedures 
will be discontinued. Follow-up contact to assess survival and new anti- cancer therapy 
may be made via clinic visit or another form of communication (e.g. phone, email, mail 
etc.). 
 
6.7 
Prohibited Medications and Non-Drug Therapies 
The use of illicit drugs within 28 days or 5 half-lives, whichever is shorter, prior to 
randomization and for the duration of the study will not be allowed. 
 
The following medications or non-drug therapies are also prohibited while on treatment in 
this study: 
 
• 
Other anti-cancer therapies; 
 
• 
Other investigational drugs; 
 
• 
Antiretroviral drugs (Note: Subjects with known HIV are ineligible for study 
participation); 
 
Herbal remedies (e.g., St. John’s wort) 

41 
 
7 
Schedule of Assessments 
7.1 
Study Procedure Tables 
Table 3 Study Procedure Table for Patients Randomized to Arm A (neoadjuvant and 
adjuvant nivolumab) 
 
Procedures 
Screening 
28 Days 
Week 1 
Week 3 
Week 5 
Week 7 
Week 9 
Day 1 
Day 15 h 
Day 29 i 
Day 43 j 
Day 57 k 
Informed Consent 
X 
Demographics 
X 
Medical History 
X 
Concurrent 
Medications 
X 
X 
X 
X 
X 
X 
Adverse Events (AEs) 
X 
X 
X 
X 
X 
X 
PE/Vitals/ECOG a 
X 
X 
X 
X 
X 
X 
Pregnancy Test b 
X 
X 
CBC with Diff 
X 
X 
X 
X 
X 
X 
Serum Chemistry c 
X 
X 
X 
X 
X 
X 
TSH, Free T4 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
Hepatitis B and C 
X 
12-Lead EKG 
X 
X 
Biopsy d 
X 
X 
X l 
Research Blood e 
X 
X 
X 
X 
Disease Assessment f 
X 
X 
Surgical Resection g 
X 
Nivolumab 3mg/kg 
X 
X m 
X m 
X m 
a. 
Systolic and diastolic blood pressure, pulse rate, and temperature. Must include full skin examination. Documentation 
of Eastern Cooperative Oncology Group status is required within 48 hours of each dose of drug administration 
b. 
Serum or urine β-hCG - For women of childbearing potential only within 24 hours of start of study drugs and at week 
9 visit 
c. 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, 
LDH, magnesium, phosphorus, potassium, total protein, AST, ALT, sodium. Amylase and lipase will be 
done if clinically indicated. 
d. 
 Minimal 5mm punch biopsy or core biopsy of safely accessible lesion. Additional biopsies will be performed 
around dose 2 (+/- 3 days) for patients in both treatment arms. When medically safe and feasible and subject 
agrees additional biopsies will be obtained around dose 3 (+/- 3 days) for both groups. Baseline biopsies are 
required for all enrolled patients. Week 5 biopsy is strongly encouraged but will be optional for patients with 
oligometastatic disease that is not safely amenable to serial biopsies 
e. 
40cc of blood will be obtained at each time point for immunologic and genomic correlative studies 
f. 
PET/CT or CT of the chest, abdomen, pelvis (neck if clinically indicated) and brain MRI (or CT of the head with 
contrast if MRI is contraindicated) 
g. 
Surgical resection of residual tumor if restaging scans show disease stability, favorable response to treatment, or 
progression of disease that is still deemed surgically resectable. A sample of the tumor will be obtained at the time 
of surgery to test for any residual melanoma cells and/or progression of disease. 
h. 
Day 15 +/- 7 days 
i. 
Day 29 +/- 7 days 
j. 
Day 43 +/- 7 days 
k. 
Day 57 +/- 7 days 
l. 
Week 5 biopsy will be performed if subject has consented and if biopsy is deemed safe and feasible by study team 
m. 
If a treatment delay of more than two weeks is required for patient safety, the next dose(s) can be omitted and patient 
can stay on protocol as long as the patient is deemed to be responding clinically and will be able to proceed with 
surgery as planned. 

42 
 
Table 4 Study Procedure Table for Patients Randomized to Arm B (neoadjuvant 
ipilimumab and nivolumab, adjuvant nivolumab) 
 
Procedures 
Screening 
28 Days 
Week 1 
Week 4 
Week 7 
Week 9 
Day 1 
Day 22 h 
Day 43 i 
Day 57 j 
Informed Consent 
X 
Demographics 
X 
Medical History 
X 
Concurrent 
Medications 
X 
X 
X 
X 
X 
Adverse Events (AEs) 
X 
X 
X 
X 
X 
PE/Vitals/ECOG a 
X 
X 
X 
X 
X 
Pregnancy Test b 
X 
X 
CBC with Diff 
X 
X 
X 
X 
X 
Serum Chemistry c 
X 
X 
X 
X 
X 
TSH, Free T4 
X 
X 
X 
X 
Coagulation 
X 
X 
Hepatitis B and C 
X 
12-Lead EKG 
X 
X 
Biopsy d 
X 
X 
X k 
Research Blood e 
X 
X 
X 
X 
Disease Assessment f 
X 
X 
Surgical Resection g 
X 
Nivolumab 1mg/kg 
X 
X l 
X l 
Ipilimumab 3mg/kg 
X 
X 
X 
a. 
Systolic and diastolic blood pressure, pulse rate, and temperature. Must include full skin examination. Documentation 
of Eastern Cooperative Oncology Group status is required within 48 hours of each dose of drug administration 
b. 
Serum or urine β-hCG - For women of childbearing potential only within 24 hours of start of study drugs and at week 9 
visit 
c. 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
magnesium, phosphorus, potassium, total protein, AST, ALT, sodium. Amylase and lipase will be done if 
clinically indicated. 
d. 
 Minimal 5mm punch biopsy or core biopsy of safely accessible lesion. Additional biopsies will be performed around 
dose 2 (+/- 3 days) for patients in both treatment arms. When medically safe and feasible and subject agrees 
additional biopsies will be obtained around dose 3 (+/- 3 days) for both groups. Baseline biopsies are required for 
all enrolled patients. Week 7 biopsy is strongly encouraged but will be optional for patients with oligometastatic 
disease that is not safely amenable to serial biopsies 
e. 
40cc of blood will be obtained at each time point for immunologic and genomic correlative studies 
f. 
PET/CT or CT of the chest, abdomen, pelvis (neck if clinically indicated) and brain mri (or CT of the head with 
contrast if MRI is contraindicated) 
g. 
 Surgical resection of residual tumor if restaging scans show disease stability, favorable response to treatment, or 
progression of disease that is still deemed surgically resectable. A sample of the tumor will be obtained at the 
time of surgery to test for any residual melanoma cells and/or progression of disease. 
h. 
Day 22 +/- 7 days 
i. 
Day 43 +/- 7 days 
j. 
Day 57 +/- 7 days 
k. 
Week 7 biopsy will be performed if subject has consented and if biopsy is deemed safe and feasible by study team 
l. 
If a treatment delay of more than two weeks is required for patient safety, the next dose(s) can be omitted and patient 
can stay on protocol as long as the patient is deemed to be responding clinically and will be able to proceed with 
surgery as planned. 

43 
 
Table 5 Study Procedure Table for Patients Enrolled to Arm C (neoadjuvant and 
adjuvant nivolumab and relatlimab) 
 
Procedures 
Screening 
28 Days 
Week 1 
Week 3 
Week 5 
Week 9 
Day 1 
Day 14 h 
Day 28 i 
Day 57 j 
Informed Consent 
X 
Demographics 
X 
Medical History 
X 
Concurrent Medications 
X 
X 
X 
X 
X 
Adverse Events (AEs) 
X 
X 
X 
X 
X 
PE/Vitals/ECOG a 
X 
X 
X 
X 
X 
Pregnancy Test b 
X 
X 
CBC with Diff 
X 
X 
X 
X 
X 
Serum Chemistry c 
X m 
X 
X 
X 
X 
TSH, Free T4 
X m 
X 
X 
X 
Cardiac Troponin Level 
X m 
X 
X 
Coagulation o 
X 
X 
Hepatitis B and C 
X 
12-Lead EKG 
X 
X 
Echocardiogram n 
X 
Biopsy d 
X 
X 
X k 
Research Blood e 
X 
X 
X 
X 
Disease Assessment f 
X 
X 
Surgical Resection g 
X 
Nivolumab 480 mg and 
Relatlimab 160mg 
X 
X l 
a. 
Systolic and diastolic blood pressure, pulse rate, and temperature. Must include full skin examination. Documentation 
of Eastern Cooperative Oncology Group status is required within 48 hours of each dose of drug administration 
b. 
Serum or urine β-hCG - For women of childbearing potential only within 24 hours of start of study drugs and at week 9 
visit 
c. 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
magnesium, phosphorus, potassium, total protein, AST, ALT, sodium. Amylase and lipase will be done if 
clinically indicated. 
d. 
Minimal 5mm punch biopsy or core biopsy of safely accessible lesion. Additional biopsies will be performed around 
day 14 (+/- 3 days) and day 28 (+/-3 days) 
e. 
40cc of blood will be obtained at each time point for immunologic and genomic correlative studies 
f. 
PET/CT or CT of the chest, abdomen, pelvis (neck if clinically indicated) and brain mri (or CT of the head with 
contrast if MRI is contraindicated) 
g. 
 Surgical resection of residual tumor if restaging scans show disease stability, favorable response to treatment, or 
progression of disease that is still deemed surgically resectable. A sample of the tumor will be obtained at the 
time of surgery to test for any residual melanoma cells and/or progression of disease. 
h. 
Day 14 +/- 7 days 
i. 
Day 28 +/- 7 days 
j. 
Day 57 +/- 7 days 
k. 
Week 5 biopsy will be performed if subject has consented and if biopsy is deemed safe and feasible by study team 
l. 
If a treatment delay of more than two weeks is required for patient safety, the next dose(s) can be omitted and patient 
can stay on protocol as long as the patient is deemed to be responding clinically and will be able to proceed with 
surgery as planned. 
m. 
Subjects with controlled hyperthyroidism must be negative for thyroglobulin and thyroid peroxidase antibodies and 
thyroid-stimulating immunoglobulin. Subjects with Type 2 Diabetes must have HbA1c to establish baseline. Elevated 
troponin levels require cardiac evaluation. 
n. 
Trans-thoracic echocardiogram (TTE) or Multigated Acquisition (MUGA) scan (TTE is preferred) performed within 6 
months prior to initial study treatment. 
o. 
Prothrombin time/International Normalized Ratio (PT/INR), Activated Partial thromboplastin time (aPTT). 

44 
 
 
Table 6 Adjuvant Therapy Study Procedure Table for Arm A and Arm B 
 
Procedures 
Week 
10 
Week 
12 
Week 
14 i 
Week 
16 
Week 
18 i 
Week 
20 
Week 
22 
Week 
24 i 
Week 
26 
Week 
28 i 
Week 
30 
Week 
32 i 
Week 
34 
Week 
46, 58, 
70, 82, 
94, 
106 g 
EOT h 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events (AEs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PE/Vitals/ECOG a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with Diff 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TSH, Free T4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Research Blood c 
X 
X 
X 
X 
X 
Disease Assessment d 
X 
X 
X 
X 
X 
Nivolumab 3mg/kg e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biopsy f 
If evidence of disease recurrence or metastasis 
a. 
Systolic and diastolic blood pressure, pulse rate, and temperature. Must include full skin examination. Documentation of Eastern Cooperative Oncology Group status 
b. 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, magnesium, phosphorus, potassium, total protein, 
AST, ALT, sodium. Amylase and lipase will be done if clinically indicated. 
c. 
40cc of blood will be obtained at each time point for immunologic and genomic correlative studies. 
d. 
PET/CT or CT of the chest, abdomen, and pelvis are required but additional imaging of affected areas (neck or extremities) may be required for documentation of target 
lesions. Brain MRI (or CT of the head with contrast if MRI is contraindicated). MRI/CT imaging of the brain will be ordered but may be deferred in the setting of 
insurance company denial 
e. 
Nivolumab treatment should resume within 4-6 weeks of discharge from the hospital for surgical excision. Patients will have a physical exam; blood will be drawn for routine 
tests and to test the immune system. Patients with involved margins after surgical excision will be allowed to initiate adjuvant therapy. Week 10 visit = start of adjuvant 
nivolumab treatment after recovery and wound healing post-surgical intervention. 
f. 
Minimal 5mm punch biopsy or core biopsy of accessible lesion if there is disease recurrence or new metastasis. Biopsies at relapse are optional. 
g. 
All time points are +/-7 days. Subjects will be followed every 12 weeks for 2 years after surgery For subjects who complete study treatment or subjects who discontinue 
study treatment early without disease recurrence, f/u will be done by clinic visit 12 months from last dosage (for PE, labs, research blood, restaging assessments etc). For 
subjects who discontinue study treatment early due to disease recurrence or subjects who cannot return to MDACC, f/u will be done by phone call, e -mail or letter etc. 
Follow-up for survival, new anti-cancer therapy and response to new anti-cancer therapy will continue for all subjects for 2 years after surgery. 
h. 
End of treatment is defined as completion of 24 weeks (week 34 in the trial) of adjuvant nivolumab, experiencing SAE or intolerable AE mandating discontinuation of 
treatment or the development of recurrent disease 
i. 
Patient to receive phone call to assess concomitant medications and AEs prior to infusion 

45 
 
 
Table 7 Adjuvant Therapy Study Procedure Table for Arm C 
 
Week 
10 g 
Week 
12 i g 
Week 
14 g 
Week 
16 i g 
Week 
18 g 
Week 
20 i g 
Week 
22 g 
Week 
24 i g 
Week 
26 g 
Week 
28 i g 
Week 
30 g 
Week 
32 i g 
Week g 
34, 36 i 
Week g 
58, 70, 
EOT h 
38, 40 i 
82, 94, 
42, 44 i 
106 
Procedures 
46 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events (AEs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PE/Vitals/ECOG a 
X 
X 
X 
X 
X 
X 
X 
X j 
X 
X 
CBC with Diff 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test l 
X 
X 
X 
X 
X 
TSH, Free T4 k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cardiac Troponin 
Level 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Research Blood c 
X 
X 
X 
X 
X 
Disease Assessment d 
X 
X 
X 
X 
X 
Nivolumab 480 mg and 
Relatlimab 160 mge 
X 
X 
X 
X 
X 
X 
X 
Biopsy f 
If evidence of disease recurrence or metastasis 
a. 
Systolic and diastolic blood pressure, pulse rate, and temperature. Must include full skin examination. Documentation of Eastern Cooperative Oncology Group status 
b. 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, magnesium, phosphorus, potassium, total protein, 
AST, ALT, sodium. Amylase and lipase will be done if clinically indicated. 
c. 
40cc of blood will be obtained at each time point for immunologic and genomic correlative studies. 
d. 
PET/CT or CT of the chest, abdomen, and pelvis are required but additional imaging of affected areas (neck or extremities) may be required for documentation of target 
lesions. Brain MRI (or CT of the head with contrast if MRI is contraindicated). MRI/CT imaging of the brain will be ordered but may be deferred in the setting of 
insurance company denial. Performed every 12 weeks after Week 22. 
e. 
Treatment should resume within 4-6 weeks of discharge from the hospital for surgical excision. Patients will have a physical exam; blood will be drawn for routine tests and to 
test the immune system. Patients with involved margins after surgical excision will be allowed to initiate adjuvant therapy. Week 10 visit = start of adjuvant treatment after 
recovery and wound healing post-surgical intervention. Administered every 4 weeks for 10 doses I the adjuvant setting. 
f. 
Minimal 5mm punch biopsy or core biopsy of accessible lesion if there is disease recurrence or new metastasis. Biopsies at relapse are optional. 
g. 
All time points are +/-7 days. Subjects will be followed every 12 weeks for 2 years after surgery For subjects who complete study treatment or subjects who discontinue 
study treatment early without disease recurrence, f/u will be done by clinic visit 12 months from last dosage (for PE, labs, research blood, restaging assessments etc). For 
subjects who discontinue study treatment early due to disease recurrence or subjects who cannot return to MDACC, f/u will be done by phone call, e -mail or letter etc. 
Follow-up for survival, new anti-cancer therapy and response to new anti-cancer therapy will continue for all subjects for 2 years after surgery. 
h. 
End of treatment is defined as completion of 10 doses of relatlimab (Week 46 in the trial) of adjuvant treatment, experiencing SAE or intolerable AE mandating 
discontinuation of treatment or the development of recurrent disease 
i. 
Patient to receive phone call to assess concomitant medications and AEs prior to infusion 
j. 
PE/Vitals/ECOG will occur on Treatment Visit days 
k. 
Thyroid function testing will be performed every 4 weeks through Week 106 
l. 
Pregnancy testing will be performed every 12 weeks through Week 106. 

46 
 
Every 12 weeks after the last dose of study drug, a complete physical exam will be done. The 
subject will also have blood drawn for routine tests and to test the immune system. A CT scan, 
PET-CT scan, or MRI will be done to check the status of the disease. 
 
7.2 
Critical Baseline Assessments 
Baseline (Screening) assessments will be obtained within 28 days of treatment initiation and 
will include: 
 
• 
Complete physical examination, including height (in cm) and weight (in kg) 
 
• 
Vital signs: blood pressure, temperature, respiratory rate, pulse rate 
 
• 
Eastern Cooperative Oncology Group (ECOG) performance status 
 
• 
Clinical laboratory tests: hematology, clinical chemistry, and thyroid function, 
coagulation, and Hepatitis B and C. Cardiac troponin level will be assessed for patients 
in Arm C. 
 
• 
 Serum or urine beta-human chorionic gonadotropin (β-HCG) pregnancy test for 
female subjects of childbearing potential only 
 
• 
12-lead electrocardiogram (ECG) 
 
• 
Trans-thoracic echocardiogram (TTE) for patients enrolled to Arm C 
 
• 
Dermatologic exam by attending physician or mid-level provider 
 
• 
 Brain magnetic resonance imaging (MRI) with contrast or a computed tomography 
(CT) scan (with contrast) if MRI is contraindicated 
 
• 
PET/CT or CT of the chest, abdomen and pelvis with contrast. CT of neck or 
extremity if clinically indicated 
 
• 
Review of concomitant medications 
 
• 
Assessment of baseline adverse events 
 
• 
Biopsy of accessible tumor and acquisition of research blood for immune correlates 
 
7.3 
Safety Evaluations on Therapy 
7.3.1 
Physical Exam/ECOG/Vital Signs/Concomitant Medications 
 
A complete physical examination will be performed by a qualified physician or a midlevel 
provider (physician’s assistant, nurse practitioner). Documentation of Eastern Cooperative 
Oncology Group status is required within 48 hours of each dose of drug administration. Vital 
sign measurements will include systolic and diastolic blood pressure, pulse rate, and 
temperature. Assessment of concomitant medications will be obtained at each clinic visit. 

47 
 
7.3.2 
Adverse Event Assessment 
 
Assessment of adverse events will be performed by the research nurse, treating physician 
or mid-level provider. 
 
7.3.3 
Laboratory Assessments 
 
Hematology, clinical chemistry, and additional parameters as per the Study Procedure Tables 
in Section 7.1 to be tested are listed below in Table 8 Required Laboratory Testing. 
Laboratory studies must be obtained within 48 hours of each time administration. 
 
Table 8 Required Laboratory Testing 
 
Hematology 
Platelet Count 
RBC Indices: 
Automated WBC Differential: 
WBC Count (absolute) 
MCV 
Neutrophils 
Hemoglobin 
Lymphocytes 
Hematocrit 
Monocytes 
Eosinophils 
Basophils 
Clinical Chemistry 
BUN 
Potassium 
AST (SGOT) 
Total Bilirubin 
Creatinine 
Chloride 
ALT (SGPT) 
Total Protein 
Glucose 
Total CO2 
Lactate 
Dehydrogenase (LDH( 
Albumin 
Sodium 
Calcium 
Alkaline Phosphatase 
Magnesium 
Phosphorus 
Other Tests 
β-hCG (urine or serum at screening for females of child bearing potential) 
coagulation tests (PT/INR, PTT at screening and week 9) 
TSH, free T4 
Cardiac Troponin Levels 

48 
 
7.4 
Biospecimen Collections 
For blood and tissue correlative studies, specimens will be collected as part of the protocol as 
specified in the Study Procedure Tables (Section 7.1) and stored for later analysis. 
 
Samples will be stored with the coded identification number or by tissue accession number. All 
samples and clinical data will be tracked by means of a unique research tracking number that 
will not be related to any patient identifying information. The link between research tracking 
numbers and patient identifiers will be kept in a secure application. More than one sample 
(each sample with a unique research tracking number) may be associated with a single medical 
record number in the database. Assays will be performed in research laboratories at MD Anderson, 
M.D. Anderson Immune Monitoring Core Facility and sub-investigating sites. Tumor tissue 
obtained for this protocol may be sent to the Parker Institute for Cancer Immunotherapy for 
research analysis. Results of all assays and other collected data will be maintained in the 
secure research application. 
 
Tissue will be procured from blood and tumor biopsies. 
 
7.4.1 
Peripheral Blood and Serum Samples 
 
Blood processing for PBMC, plasma and storage: 30ml of venous peripheral blood will 
be collected in sodium heparin vacutainers, at the time points as described in Section 7. 1 . 
The blood will be processed and stored, according to standard operating procedures, for 
PBMC, cell pellet and plasma for subsequent immune and molecular evaluation. 
 
 
7.4.2 
Tumor Biopsies and Surgical Specimen 
 
All patients will have biopsies performed safely on accessible tumors before starting 
treatment (unless biopsy is not safe and tissue blocks are available for analysis). 
These biopsy samples should be excisional, incisional or core needle. Fine needle 
aspirates or other cytology specimens are insufficient for downstream biomarker 
analyses. The pre-treatment tumor biopsy must contain sufficient tumor content (≥100 
tumor cells/4-micron tissue section) for PD-L1 immunohistochemistry testing prior to 
randomization in Arm A and B. Additional biopsies will be performed around dose 2 (+/- 
7 days) for patients in Arms A and B. When medically safe and feasible, additional 
biopsies will be obtained around dose 3 (+/- 7 days) for Arms A and B. In addition, 
local surgery of isolated symptomatic lesions and biopsy prior to re-treatment in the 
setting of interrupted active treatment is strongly encouraged, if deemed clinically safe. 
For Arm C, tumor biopsy will be performed at baseline, day 14 (+/- 7 days) and day 28 (+/- 
7 days. PD-L1 and LAG-3 testing will be performed on pre-treatment tumor biopsy but 
results are not needed prior to treatment initiation. Surgical resection samples for all 
groups will also be included for research analyses. In addition, any patient with 
accessible tumor at the time of relapse may have a tumor biopsy performed. Available 
paraffin embedded tumor tissue or excision may also be collected as pre-treatment 
comparator samples, so long as the patient provides consent for use in this study. 
Preferred archival material includes tissue obtained in the same manner as specified in 
this trial and with no systemic anti-tumor treatment received by the patient between the 

49 
 
biopsy and their enrollment on this protocol. However, other archival tissue may also be 
collected. 
 
In order to accommodate all downstream biomarker analyses, incisional/excisional biopsies 
are strongly encouraged for this study, however, if incisional/excisional biopsies are not 
possible, core needle biopsies are acceptable as an alternative. Collection of a minimum of 
4 core needle biopsies at least 10 mm in length using a needle gauge of 18 or larger will 
be used when feasible for all on treatment biopsies to accommodate PD-L1 staining and 
correlative research as indicated in the protocol. 
 
For tissue obtained from MD Anderson participants, each set of core biopsies (up to four) or 
surgical specimen may be divided into portions and processed as below for later analysis. 
Specific instructions for processing may be provided in the event that four cores cannot be 
obtained. 
 
1. FFPE for histology and IHC (25% of the specimen.) 
 
2. 50% of the specimen in RPMI (Roswell Park Memorial Institute) media 
 
3. 25% Snap frozen tumor in a cryovial 
 
For tissue obtained from MSKCC participants, each set of core biopsies (up to four) or 
surgical specimen may be divided into portions and processed as below for later analysis. 
Specific instructions for processing may be provided in the event that four cores cannot be 
obtained. 
 
1. 50% FFPE for histology and IHC 
 
2. 50% snap frozen tumor in a cryovial 
 
7.5 
Disease Assessments 
7.5.1 
Pathologic Assessments 
 
All patients will be evaluated with imaging after 7 weeks of neoadjuvant therapy prior to the 
planned surgical resection. Tumor samples will be collected within 28 days of treatment 
initiation, around dose 2 and dose 3 if feasible and medically safe and at the time of the 
surgical resection and all of these samples will be utilized for the primary endpoint 
analyses. All patients who experience a PR or SD will be eligible for surgical resection. 
Those patients who develop PD who no longer have disease amenable to gross total 
surgical resection will no longer be eligible for protocol therapy. Patients who initially had 
lymph node involvement but appear to have achieved a CR on imaging will proceed on 
to completion lymph node dissection. Patients with visceral metastases who appear to 
have achieved a CR on imaging may forgo any surgical procedure and will immediately 
initiate the adjuvant portion of the protocol. 
 
Tumor specimens of patients undergoing evaluation for pathologic complete response (pCR), 
and pathologic partial response (pPR). pCR is defined as the absence of any residual 
invasive malignant cells on hematoxylin and eosin evaluation of the resected melanoma 

50 
 
specimen. pPR is defined as less than 50% viable tumor cells or more than 50% fibrosis on 
pathological evaluation. 
 
7.5.2 
Imaging Assessments 
 
Disease assessment will include imaging (computed tomography, magnetic resonance 
imaging) and physical examination (as indicated for palpable/superficial lesions). At 
screening, an MRI or CT of the head with contrast is required. At minimum, PET/CT or 
CT of the chest, abdomen and pelvis are required but additional imaging of affected areas 
(neck or extremities) may be required for documentation of target lesions. 
 
Disease assessment will be completed within 28 days prior to the first dose of study drug, 
then as indicated in the Study Procedure Tables (Section 7.1). More frequent disease 
assessments may be performed at the discretion of the investigator. To ensure 
comparability between baseline and subsequent assessments, the same method of 
assessment and the same technique will be used when assessing response. 
 
Disease response will be recorded as complete response (CR), partial response (PR), 
stable disease (SD), or progressive disease (PD) according to RECIST 1.1 criteria (Appendix 
2). 
 
7.5.3 
Translational Research/Biomarker Analysis 
 
Serum samples may be assessed by such techniques as ELISA, seromics or other multiplex- 
based assay methods to measure soluble factors. Such factors likely will include, IFN-Ɣ and 
interferon inducible factors, including CXCL9 and CXCL10, however, numerous serum-based 
biomarkers are currently under investigation for their potential to associate with efficacy to 
ipilimumab, nivolumab or other immunotherapy agents. These biomarkers include levels of 
soluble PD-L1, PD-1, anti-tumor antibodies, microRNAs (such as, but not limited to, miR-513, 
and miR19b), IL-12, TNFα, IL-10, TGF-β, VEGF, IL-6, IL-8, IL-17, IL-18, C-reactive protein 
and, as well as many other cytokines, chemokines, inflammatory factors and immune 
mediators. Such factors may be assessed in the context of the current study. Blood may also 
be collected at clinically relevant time points such as the occurrence of a ≥Grade 3 drug- 
related AEs. 
 
PBMC samples may be used for immunophenotyping or characterization of the immune cell 
subsets in the periphery, including, but not limited to, T cells, B cells, NK cells, or 
subpopulations of the aforementioned immune cell types. These samples may also be used 
to assess immune cell function or antigen specific T cell proliferation or activation pending 
emerging information from other nivolumab or ipilimumab studies or sub-studies. 
 
The MDACC Immunotherapy Platform (IMT) will perform immune monitoring of correlative 
samples collected at MD Anderson, including but not limited to evaluation of CD4 and CD8 T 
cells in peripheral blood (PBMCs) and available tumor samples as previously published. All 
samples that are provided to the IMT platform will be collected and analyzed as per a separate 
IRB-approved lab protocol. 
 
Pre-treatment tumor tissue specimens in the form of a paraffin embedded block or a minimum 
of 3unstained slides, with a single section on positively charged slides will be submitted for 
PD-L1 immunohistochemistry (IHC) assessment. 

51 
 
Tumor samples may be assessed for the expression of other immune or melanoma related 
genes, RNAs and/or proteins, as well as, the presence of immune cell populations using 
a variety of methodologies inclusive of, but not limited to immunohistochemistry (IHC), 
qRT-PCR, genetic mutation detection and fluorescent in-situ hybridization (FISH). Various 
molecular markers with potential predictive value for the treatment of melanoma with 
ipilimumab and nivolumab, and other immunotherapies are currently under investigation and 
may be assessed in this study. These tumor tissue biomarkers include, but are not 
limited to PD-1, PD-L2, tumor infiltrating lymphocytes (TILs) or subpopulations of TILs and a 
Th1 immune mRNA expression signature. 
 
Pending tissue availability other detailed analyses may include: 
 
a) Assess changes in the extent of T cell infiltrate over time. FFPE tumor 
specimens will be stained for CD3, CD4, CD8, CD20, FoxP3 using 
commercial antibodies. Staining frequency for each antibody will be quantified 
and ratio of various T cell components (CD4/CD8, Treg/CD8 etc) will be 
calculated over time. 
 
b) Assess activation status of infiltrating T cells: Studies will include IHC and 
multiparameter flow cytometry: 
 
c) IHC: In the TIL infiltrate, cells staining for Ki67, granzyme B, IFN-γ, TGF-beta, 
GATA-3, RORgt, BCL2 will be enumerated to estimate T cell activation, 
and Th1/Th2/Th17 bias. 
 
d) Flow cytometry: TIL isolated from serial tumor specimens will be assessed 
for expression of immunoregulatory and co-stimulatory markers PD1, 
CTLA4, LAG3, 41BB using available antibodies, and TCR zeta chain 
expression using flow. Baseline status and PBMC will serve as controls 
 
e) Assess via Nanostring for conversion to immune/inflammatory expression 
pattern 
 
f) RNA will be extracted from tumor tissue and analyzed for the presence or 
absence of an immune gene expression signature via our Nanostring 
codeset. Specimens will be run in duplicate. Previous positive and negative 
expressing tumors will be used as controls. 
 
g) Obtain pilot data on association between extent of TIL or other parameters 
with extent of tumor regression on week 8 tumor measurements and PFS. 
 
h)  Patients will undergo tumor measurements pre-treatment and 9 weeks into 
therapy. Response will be calculated by RECIST 1.1. Percent tumor 
shrinkage relative to baseline will be analyzed. Extent of tumor shrinkage 
and individual patient PFS will be examined for association with measures 
of immune infiltration at various time points. 

52 
 
8 
Safety and Reporting 
The investigator and site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an adverse event (AE) or serious adverse event (SAE) 
as documented in Sections 8. 1 and 8. 2 respectively. Effective with approval of 
Amendment 7, this study will be a single arm trial, therefore the MD Anderson Data Safety 
Monitoring Board (MDACC DSMB) can be removed as the monitor. 
 
Serious Adverse Event Reporting (SAE) for M. D. Anderson-sponsored Multicenter IND 
Protocols 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes: 
 
• 
Death 
 
• 
A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it 
occurred in a more severe form, might have caused death. 
 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
 
• 
A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse (21 CFR 
312.32). 
 
• 
Important medical events as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if deemed 
appropriate by the Principal Investigator or the IND Sponsor, MDACC IND Office. 
 
• 
All events occurring during the conduct of a protocol and meeting the definition of a 
SAE must be reported to the IRB in accordance with the timeframes and procedures 
outlined in “University of Texas M. D. Anderson Cancer Center Institutional Review 
Board Policy for Investigators on Reporting Unanticipated Adverse Events for Drugs 
and Devices”. 
 
Unless stated otherwise in the protocol, all SAEs, expected or unexpected, must be 
reported to the IND Office, regardless of attribution (within 5 working days of 
knowledge of the event). 

53 
 
Reporting for all sites: 
 
• 
A written report should be submitted to the Institutional Review Board (IRB) according 
to the requirements of the assigned IRB for patients enrolled at each site. (The MD 
Anderson site will utilize the electronic SAE application (eSAE) for reporting SAEs.) 
 
• 
SAEs will be reported to the sponsor on a template form that will be provided to each 
site. If needed, a copy of all relevant examinations that have been carried out and the 
dates on which these examinations were performed should be attached. For laboratory 
results, normal ranges should be included. Patient name should be marked out and 
initials and study number included on all attachments. 
 
• 
In case of a serious adverse event, the following actions must be undertaken by the 
investigator: (Please note that these are in addition to reporting that is required by the 
local IRB and supporting company.) Complete the SAE form immediately and then fax 
and overnight mail the signed and dated SAE form to the sponsor representative within 
two working days to the following address: 
 
The University of Texas M.D. Anderson Cancer Center 
IND Office 
Georgina Melendez. Proj. Mgr., Medical Affairs and Safety 
IND Office 
7007 Bertner, 1MC12.2227 
Houston, Texas 77030 
Tel no.: 713-563-8772 
Fax no.: 713-563-5468 
e-mail: mdaccsafetyreports@mdanderson.org 
 
• 
A copy of the tracking receipt should be kept and filed in the study regulatory binder at 
the site. The research team may e-mail or call the sponsor to confirm receipt of the 
SAE fax or mailed form. 
 
• 
Death or life-threatening events that are possibly, probably or definitely related 
to drug must be reported within 24 hours. The sponsor IND safety coordinator 
must be notified by phone immediately, in addition to fax or overnight mail as listed 
above. 
 
• 
All life-threatening or fatal events, expected or unexpected, and regardless of 
attribution to the study drug, must have a written report submitted within 24 hours 
(next working day) of knowledge of the event to the Safety Project Manager in the IND 
Office. 
 
• 
Serious adverse events will be captured from the time of the first protocol- 
specific intervention, unless the protocol states otherwise, and be reported until 
30 days after the last dose of drug. Serious adverse events must be followed 
until clinical recovery is complete and laboratory tests have returned to 
baseline, progression of the event has stabilized, or there has been acceptable 
resolution of the event. 

54 
 
• 
Additionally, any serious adverse events that occur after the 30 day time period 
that are related to the study treatment must be reported to the IND Office. This 
may include the development of a secondary malignancy. 
 
• 
All events reported the supporting company must also be report to the IND 
Office. 
 
Reporting to FDA: 
 
• 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events 
are reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
Investigator Communication with Supporting Companies: 
 
8.1 
Sponsor SAE Reporting 
• 
All Serious Adverse Events (SAEs) that occur following the subject’s written consent 
to participate in the study through 100 days of discontinuation of dosing must be 
reported to BMS Worldwide Safety. 
 
• 
 If the BMS safety address is not included in the protocol document (e.g. 
multicenter studies where events are reported centrally), the procedure for safety 
reporting must be reviewed/approved by the BMS Protocol Manager. Procedures 
for such reporting must be reviewed and approved by BMS prior to study activation. 
 
• 
The BMS SAE form should be used to report SAEs. If the BMS form cannot be 
used, another acceptable form (i.e CIOMS or Medwatch) must be reviewed and 
approved by BMS. The BMS protocol ID number must be included on whatever form 
is submitted by the Sponsor/Investigator. 
 
• 
 Following the subject’s written consent to participate in the study, all SAEs, 
whether related or not related to study drug, are collected, including those thought to 
be associated with protocol-specified procedures. The investigator should report 
any SAE occurring after these time periods that is believed to be related to study 
drug or protocol-specified procedure. 
 
• 
 In accordance with local regulations, BMS will notify investigators of all reported SAEs 
that are suspected (related to the investigational product) and unexpected (i.e., not 
previously described in the IB). In the European Union (EU), 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 an expedited 
safety report (ESR). 
 
o Other important findings which may be reported by the as an ESR include: 
increased frequency of a clinically significant expected SAE, an SAE 
considered associated with study procedures that could modify the conduct of 
the study, lack of efficacy that poses significant hazard to study subjects, 

55 
 
clinically significant safety finding from a nonclinical (e.g., animal) study, 
important safety recommendations from a study data monitoring committee, or 
sponsor decision to end or temporarily halt a clinical study for safety reasons. 
 
o  Upon receiving an ESR from BMS, the investigator must review and retain 
the ESR with the IB. Where required by local regulations or when there is a 
central IRB/IEC for the study, the sponsor will submit the ESR to the 
appropriate IRB/IEC. The investigator and IRB/IEC will determine if the 
informed consent requires revision. The investigator should also comply 
with the IRB/IEC procedures for reporting any other safety information. 
 
o  In addition, suspected serious adverse reactions (whether expected or 
unexpected) shall be reported by BMS to the relevant competent health 
authorities in all concerned countries according to local regulations (either 
as expedited and/or in aggregate reports). 
 
Serious Adverse Event Collection and Reporting 
 
Following the subject’s written consent to participate in the study, all SAEs, whether 
related or not related to study drug, must be collected, including those thought to be 
associated with protocol-specified procedures. All SAEs must be collected that occur 
within 100 days of discontinuation of dosing. 
 
All SAEs must be collected that occur during the screening period. If applicable, SAEs must 
be collected that relate to any protocol-specified procedure (e.g., a follow-up skin biopsy). 
The investigator should report any SAE that occurs after these time periods that is believed 
to be related to study drug or protocol-specified procedure. 
 
SAEs, whether related or not related to study drug, and pregnancies must be reported to 
BMS within 24 hours. SAEs must be recorded on BMS or an approved form; pregnancies on 
a Pregnancy Surveillance Form. 
 
SAE Email Address: Worldwide.Safety@BMS.com 
 
SAE Facsimile Number: 609-818-3804 
 
If only limited information is initially available, follow-up reports are required. (Note: Follow- 
up SAE reports should include the same investigator term(s) initially reported.) 
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 hours to the 
BMS (or designee) using the same procedure used for transmitting the initial SAE report. 
 
All SAEs should be followed to resolution or stabilization. 
 
For studies conducted under an Investigator IND in the US include the following: 
 
For studies conducted under an Investigator IND in the US, any event that is both serious 
and unexpected must be reported to the Food and Drug Administration (FDA) as soon as 
possible and no later than 7 days (for a death or life-threatening event) or 15 days (for all 

56 
 
other SAEs) after the investigator’s or institution’s initial receipt of the information. BMS will be 
provided with a simultaneous copy of all adverse events filed with the FDA. 
 
SAEs should be reported on MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/medwatch/ 
 
MedWatch SAE forms should be sent to the FDA at: 
 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
• 
An SAE report should be completed for any event where doubt exists regarding 
its seriousness. 
 
• 
For studies with long-term follow-up periods in which safety data are being 
reported, include the timing of SAE collection in the protocol. 
 
• 
If the investigator believes that an SAE is not related to study drug, but is potentially 
related to the conditions of the study (such as withdrawal of previous therapy or 
a complication of a study procedure), the relationship should be specified in the 
narrative section of the SAE Report Form. 
 
• 
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports should include the same investigator term(s) initially reported.) 
 
• 
 If an ongoing SAE changes in its intensity or relationship to study drug or if 
new information becomes available, a follow-up SAE report should be sent within 24 
hours to BMS using the same procedure used for transmitting the initial SAE report. 
All SAEs should be followed to resolution or stabilization. All SAEs should be followed 
to resolution or stabilization. 
 
8.2 
Non-Serious Adverse Event Collection and Reporting 
The collection of non-serious AE information should begin at initiation of study drug. All 
non-serious adverse events (not only those deemed to be treatment-related) should 
be collected continuously during the treatment period and for a minimum of 30 days following 
the last dose of study treatment. 
 
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if 
they become serious. Follow-up is also required for non-serious AEs that cause interruption 

57 
 
or discontinuation of study drug and for those present at the end of study treatment as 
appropriate. 
 
8.3 
Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following 
institutional procedures. Test results that constitute SAEs should be documented and 
reported as such. 
 
The following laboratory abnormalities should be documented and reported appropriately: 
 
• 
any laboratory test result that is clinically significant or meets the definition of an SAE 
 
• 
 any laboratory abnormality that required the subject to have study drug discontinued 
or interrupted 
 
• 
any laboratory 
abnormality that 
required 
the subject to 
receive specific 
corrective therapy. 
 
8.4 
Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a 
study subject is pregnant or may have been pregnant at the time of investigational product 
exposure, including during at least 6 half-lives after product administration, the investigational 
product will be permanently discontinued in an appropriate manner (e.g., dose tapering if 
necessary for subject safety). 
 
The investigator must immediately notify Worldwide Safety @BMS of this event via the 
Pregnancy Surveillance Form in accordance with SAE reporting procedures. 
 
Follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome and, where applicable, offspring information must be reported on the 
Pregnancy Surveillance Form [provided upon request from BMS] 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported 
to BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance 
Form. 
 
8.5 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must 
be reported as an SAE. 
 
8.6 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a nonserious or serious 
AE, as appropriate, and reported accordingly. 

58 
 
9 
Statistical Considerations 
9.1 
Sample Size and Power 
Arm A and Arm B 
 
Patients with, stage IIIB/IIIC or stage IV resectable, oligometastatic melanoma will be enrolled 
in this phase 2 study. Patients with prior adjuvant therapy including use of prior interferon 
alpha, pegylated interferon or vaccine will be eligible after a 28 day washout period. This is 
an exploratory biomarker study and no statistical comparisons will be made between the two 
treatment arms. The primary objective is to assess pathologic response of neoadjuvant 
nivolumab monotherapy (Arm A) and nivolumab and ipilimumab combination therapy (Arm B). 
pCR is defined as the absence of any residual invasive malignant cells on hematoxylin and 
eosin evaluation of the resected melanoma specimen. pPR is defined as less than 50% viable 
tumor cells or more than 50% fibrosis on pathological evaluation. 
 
We assume the pathologic complete response rate will be 5% for patients in Arm A and 15% 
for Arm B. These data are extrapolated from the imaging CR rates from previously published 
data. 17, 18, 62, 63, 66 Thus, assuming the true pathologic complete response rate in Arm A is 
5%, the probability of at least 1 out of 20 patients experiencing a response is 0.64. For 
treatment Arm B, the probability of at least 1 out of 20 patients experiencing a pathologic 
response is 0.96 assuming a true response rate of 15%. 
 
Arm C 
 
Thirty patients will be enrolled to Arm C.. The primary objective is to assess the pathologic 
response rate of neoadjuvant relatlimab with nivolumab. Pathologic complete response is 
defined as the absence of any residual invasive malignant cells on hematoxylin and eosin 
evaluation of the resected melanoma surgical specimen. Pathologic partial response is 
defined as less than 50% viable tumor cells or more than 50% fibrosis on pathologic evaluation 
of the surgical sample. All tumor samples are evaluated by a single dermatopathology certified 
collaborator. 
 
We assume the pathologic response rate will be 30% for patients in Arm C. Assuming this true 
pathologic response rate, the probability of at least 5 out of 30 patients experiencing a 
response is 0.97. 
 
 
9.2 
Study Populations 
Intent-to-treat (ITT) population: All patients randomized to Arm A or B, and treated in Arm C 
in the study will be included in the analysis regardless of their adherence to entry criteria, 
treatment they actually received, compliance, and subsequent withdrawal from treatment or 
protocol deviation. 
 
9.2.1 
Safety Population 
 
All patients who receive at least one dose of study treatment will be evaluable from the time 
of their first treatment. 

59 
 
9.3 
Stopping Rule 
Continuous monitoring of disease progression will be performed for all patients in treatment 
Arm A and Arm B, beginning with the first four patients. Assuming a prior beta distribution of 
(0.4, 1.6), the treatment arm will terminate if the Pr (δdp > 0.20 | data) > 0.85, where δdp is 
the proportion of patients experiencing disease progression within the treatment arm. 
Disease progression is defined as progression such that disease is no longer resectable 
based on week 9 imaging. The decision rule for discontinuing enrollment in a specific 
treatment arm is presented in Table 9 and the operating characteristics for this rule are 
presented in Table 10. 
 
Continuous monitoring of toxicity and futility will be performed for all patients in Arm C, 
beginning with the first six patients. Assuming a prior beta distribution of (1, 1), corresponding 
to a toxicity rate of 50%, the treatment arm will terminate if the Pr (δT > 0.50 | data) > 0.975, 
where δT is the proportion of patients experiencing ≥ grade 3 toxicities. For futility, a prior beta 
distribution of (0.6, 1.4) will be assumed, corresponding to a pRR of 30%. Patient enrollment 
will terminate if the Pr (δpRR < 0.30 | data) > 0.975, where δpRR is the pRR attributable to the 
treatment combination. The decision rule for terminating for toxicity is presented in Table 11 
while the decision rule for terminating for futility is presented in Table 12 and the operating 
characteristics for these rules are presented in Table 13. The method used to produce the 
decision rules and operating characteristics was designed by Thall, Simon, and Estey72,73 as 
extended by Thall and Sung74. 
 
 
Table 9 Stopping Boundaries for Arm A and Arm B 
 
Total number of patients 
Stop enrollment in treatment arm if 
there are this many patients with 
disease progression 
1-3 
Never stop with this many patients 
4-7 
3-7 
8-11 
4-11 
12-15 
5-15 
16-19 
6-19 
20 
Always stop with this many patients 
 
Table 10 Operating Characteristics for Arm A and Arm B 
 
True % of 
DLTs 
Pr (stopping early) 
Median Sample Size 
(interquartile) 
0.05 
0.0 
20 (20, 20) 
0.10 
0.0 
20 (20, 20) 
0.20 
0.2 
20 (17, 20) 
0.30 
0.6 
13 (6, 20) 
0.40 
0.8 
7 (5, 13) 
0.60 
1.0 
5 (4, 6) 

60 
 
 
 
Table 11 Stopping Criteria - Toxicity for Arm C 
 
Total number of patients 
Stop enrollment in treatment Arm C if 
there are this many patients with ≥ 
grade 3 toxicities 
1-5 
Never stop with this many patients 
6 
6 
7-8 
7-8 
9 
8-9 
10-11 
9-11 
12 
10-12 
13-14 
11-14 
15-16 
12-16 
17 
13-17 
18-19 
14-19 
20 
15-20 
21-22 
16-22 
23-24 
17-24 
25 
18-25 
26-27 
19-27 
28-29 
20-29 
30 
End of Enrollment 
 
 
 
Table 12 Stopping Criteria - Futility for Arm C 
 
Total number of patients 
Stop enrollment if there are this many 
patients responding 
1-6 
Never stop with this many patients 
7-12 
0 
13-18 
0-1 
19-23 
0-2 
24-27 
0-3 
28-29 
0-4 
30 
End of Enrollment 

61 
 
Table 13 Operating Characteristics for Arm C 
 
True Toxicity 
Rate 
True pRR 
Pr (stopping early) 
Average # of 
Patients Treated 
0.20 
0.10 
0.90 
14 
0.20 
0.46 
23 
0.30 
0.14 
27 
0.40 
0.04 
29 
0.60 
0.002 
30 
0.30 
0.10 
0.90 
14 
0.20 
0.46 
23 
0.30 
0.15 
27 
0.40 
0.04 
29 
0.60 
0.004 
30 
0.50 
0.10 
0.91 
14 
0.20 
0.51 
21 
0.30 
0.23 
26 
0.40 
0.13 
28 
0.60 
0.10 
28 
0.60 
0.10 
0.94 
13 
0.20 
0.64 
19 
0.30 
0.44 
23 
0.40 
0.37 
24 
0.60 
0.34 
25 
0.80 
0.10 
1.00 
9 
0.20 
0.98 
10 
0.30 
0.97 
11 
0.40 
0.97 
12 
0.60 
0.97 
12 
 
 
 
9.4 
Patient Characteristics 
Demographic and baseline characteristics of the ITT population will be summarized for 
all patients and by treatment arm. Categorical measures will be summarized using 
frequencies and percentages while continuous variables will be summarized using mean, 
standard deviation, median, minimum, and maximum. 
 
9.5 
Primary Efficacy Measure 
The primary efficacy measure in this study is pathologic response. The proportion of patients 
experiencing pathologic response will be computed with associated 95% CI for each treatment 
arm. 

62 
 
9.6 
Secondary Efficacy Measures 
9.6.1 
Immunologic Response 
 
Immunologic response will be assessed by change in T cell infiltrate from baseline to each 
study procedure visit (approximately 9 weeks). The change in T cell infiltrate will be assessed 
over time for each treatment arm using a generalized linear mixed model with terms for 
visit, stage of disease, and PD-L1 tumor status. 
 
9.6.2 
Objective Response 
 
Objective response (i.e., CR, PR, SD, and PD) will be categorized based on criteria specified 
in Appendix 2. The proportion of patients experiencing objective response will be computed 
with associated 95% CI for each treatment arm. 
 
9.6.3 
Recurrence-Free and Overall Survival 
 
Recurrence-free survival (RFS) will be defined from time of surgical resection to the date of 
documented disease recurrence. Patients who are still alive without disease progression 
after 12 months of treatment start date will be censored. Overall survival (OS) will be defined 
from treatment start date to date of death. Patients who are still alive after 12 months of 
treatment start date will be censored. RFS and OS will be estimated using the Kaplan-Meier 
method for each treatment arm. 
 
9.7 
Exploratory Efficacy Measures 
Various molecular markers with potential predictive value for the treatment of melanoma may 
be assessed. The association between change in tumor size and immune infiltration within 
each treatment arm will be assessed using a generalized linear mixed model where change 
in tumor size will be the dependent variable and gene expression, visit, and gene expression- 
by-visit interaction will be the independent variables. The association between RFS and 
immune infiltration within each treatment arm will be determined by a Cox proportional hazards 
regression model. 
 
9.8 
Safety Measures 
Safety and tolerability within each treatment arm will be assessed by vital signs, laboratory 
assessments, adverse events, and serious adverse events for the safety population. 
Adverse events will be graded by the CTCAE version 4.0. Categorical measures will be 
summarized using frequencies and percentages while continuous variables will be 
summarized using mean, standard deviation, median, minimum, and maximum. 

63 
 
10 
Study Management 
10.1 
Data Management 
10.1.1 
Enrollment 
 
For the purposes of this study at M. D. Anderson Cancer Center, the Protocol Data 
Management System (PDMS) will be employed. All patients will be registered in the Clinical 
Oncology Research system (CORe) before any study specific tests are performed. 
Registration in CORe will be performed by MDACC study staff after eligibility is confirmed for 
each potential subject at either site. 
 
10.1.2 
Data Entry and Maintenance 
 
Data for this protocol will be entered into a secure electronic data capture (EDC), such as 
Prometheus. All participating sites will use this EDC. The Parker Institute will also have access 
to the study data for data analysis purposes. 
 
The investigator is required to retain, in a confidential manner, the data pertinent to the study 
for the duration of the study or the maximum period required by applicable regulations and 
guidelines or institutional procedures. If the investigator withdraws from the study (e.g., 
relocation, retirement), the records shall be transferred to a mutually agreed upon designee 
(e.g., another investigator or IRB). 
 
The concomitant medications will not be captured in the case report form (PDMS). They will 
be captured in the subject’s medical records. 
 
Posting of Information on Clinicaltrials.gov 
 
Study information from this protocol will be posted on clinicaltrials.gov before 
enrollment of subjects begins. 
 
10.1.3 
Records Retention 
 
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe and 
secure location. The records must be easily accessible when needed and must be available 
for review in conjunction with assessment of the facility, supporting systems, and relevant site 
staff. 

64 
 
11 
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(1998). 

70 
 
12 
Appendices 
Appendix 1 Melanoma of the Skin Aging 
 
 
Reference: American Joint Committee on Cancer. (2009). 7th Edition of AJCC Melanoma 
Staging 
System. 
Retrieved 
19 
April 
2012 
from 
http://www.cancerstaging.org/staging/posters/melanoma8.5x11.pdf. 

71 
 
Appendix 2 RECIST 1.1 Criteria 
 
Measurability of Tumor Lesions at Baseline 
Measurable lesion: 
 
• 
A non nodal lesion that can be accurately measured in at least one dimension (longest 
dimension) of 
 
o ≥10 mm with MRI or CT when the scan slice thickness is no greater than 5mm. 
If the slice thickness is greater than 5mm, the minimum size of a measurable 
lesion must be at least double the slice thickness (e.g., if the slice thickness is 
10 mm, a measurable lesion must be ≥20 mm). 
 
o ≥10 mm caliper/ruler measurement by clinical exam or medical photography. 
o ≥20 mm by chest x-ray. 
• 
 Additionally lymph nodes can be considered pathologically enlarged and measurable 
if 
 
o ≥15mm in the short axis when assessed by CT or MRI (slice thickness 
recommended to be no more than 5mm). At baseline and follow-up, only the 
short axis will be measured [Eisenhauer, 2009]. 
 
Non-measurable lesion: 
 
• 
All other lesions including lesions too small to be considered measurable (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 mm and <15 mm short 
axis) as well as truly non-measurable lesions, which include: leptomeningeal 
disease, ascites, pleural or pericardial effusions, inflammatory breast disease, 
lymphangitic involvement of the skin or lung, abdominal masses/abdominal 
organomegaly identified by physical exam that is not measurable by reproducible 
imaging techniques [Eisenhauer, 2009]. 
 
Measurable disease: 
 
• 
The presence of at least one measurable lesion. Palpable lesions that are not 
measurable by radiologic or photographic evaluations may not be utilized as the 
only measurable lesion. 
 
Non-Measurable only disease: 
 
• 
The presence of only non-measurable lesions. 
 
Specifications by Methods of Measurements: 
 
• 
The same diagnostic method, including use of contrast when applicable, 
must be used throughout the study to evaluate a lesion. 

72 
 
• 
All measurements should be taken and recorded in millimeters (mm), using a ruler or 
calipers. 
 
• 
Ultrasound is not a suitable modality of disease assessment. If new lesions are 
identified by ultrasound, confirmation by CT or MRI is required. 
 
• 
Fluorodeoxyglucose (FDG)-PET is generally not suitable for ongoing assessments of 
disease. However FDG-PET can be useful in confirming new sites of disease where 
a positive FDG-PET scans correlates with the new site of disease present on CT/MRI 
or when a baseline FDG-PET was previously negative for the site of the new lesion. 
FDG-PET may also be used in lieu of a standard bone scan providing coverage allows 
interrogation of all likely sites of bone disease and FDG-PET is performed at all 
assessments. 
 
• 
If PET/CT is performed then the CT component can only be used for standard 
response assessments if performed to diagnostic quality, which includes the required 
anatomical coverage and prescribed use of contrast. The method of assessment 
should be noted as CT on the CRF. 
 
Clinical Examination: 
 
• 
Clinically detected lesions will only be considered measurable when they are 
superficial (e.g., skin nodules). In the case of skin lesions, documentation by color 
photography, including a ruler/calipers to measure the size of the lesion, is required. 
 
CT and MRI: Contrast enhanced CT with 5mm contiguous slices is 
recommended. 
 
Minimum size of a measurable baseline lesion should be twice the slice thickness, 
with a minimum lesion size of 10 mm when the slice thickness is 5 mm. MRI is 
acceptable, but when used, the technical specification of the scanning sequences 
should be optimized for the evaluation of the type and site of disease and lesions must 
be measured in the same anatomic plane by use of the same imaging examinations. 
Whenever possible the same scanner should be used. [Eisenhauer, 2009]. 
 
X-ray: Should not be used for target lesion measurements owing to poor lesion 
definition. Lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung; however chest CT is preferred over chest X- 
ray [Eisenhauer, 2009]. 
 
Evaluation of target lesions: 
 
• 
Definitions for assessment of response for target lesion(s) are as follows: 
 
o Complete Response (CR): Disappearance of all target lesions. Any 
pathological lymph nodes must be <10mm in the short axis. 
o Partial Response (PR): At least a 30% decrease in the sum of the 
diameters of target lesions, taking as a reference, the baseline sum of 
the diameters (e.g. percent change from baseline). 
o Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for progressive disease. 

73 
 
o Progressive Disease (PD): At least a 20% increase in the sum of the 
diameters of target lesions, taking as a reference, the smallest sum of 
diameters recorded since the treatment started (e.g. percent change from 
nadir, where nadir is defined as the smallest sum of diameters recorded 
since treatment start). In addition, the sum must have an absolute 
increase from nadir of 5mm. 
o Not Applicable (NA): No target lesions at baseline. 
o Not Evaluable (NE): Cannot be classified by one of the five preceding 
definitions. 
 
• 
Note: 
 
o If lymph nodes are documented as target lesions the short axis is added 
into the sum of the diameters (e.g. sum of diameters is the sum of the 
longest diameters for non-nodal lesions and the short axis for nodal 
lesions). When lymph nodes decrease to non-pathological size (short axis 
<10mm) they should still have a measurement reported in order not to 
overstate progression. 
 
o If at a given assessment time point all target lesions identified at baseline 
are not assessed, sum of the diameters cannot be calculated for purposes 
of assessing CR, PR, or SD, or for use as the nadir for future assessments. 
However, the sum of the diameters of the assessed lesions and the 
percent change from nadir should be calculated to ensure that progression 
has not been documented. If an assessment of PD cannot be made, the 
response assessment should be NE. 
 
o All lesions (nodal and non-nodal) should have their measurements 
recorded even when very small (e.g 2 mm). If lesions are present but too 
small to measure, 5 mm should be recorded and should contribute to the 
sum of the diameters, unless it is likely that the lesion has disappeared in 
which case 0 mm should be reported. 
 
o If a lesion disappears and reappears at a subsequent time point it should 
continue to be measured. The response at the time when the lesion 
reappears will depend upon the status of the other lesions. For example, if 
the disease had reached a CR status then PD would be documented at the 
time of reappearance. However, if the response status was PR or SD, the 
diameter of the reappearing lesion should be added to the remaining 
diameters and response determined based on percent change from 
baseline and percent change from nadir 
 
 
Evaluation of non-target lesions: 
 
• 
Definitions for assessment of response for non-target lesions are as follows: 
 
o Complete Response (CR): The disappearance of all non-target lesions. All 
lymph nodes identified as a site of disease at baseline must be non- 
pathological (e.g. <10 mm short axis). 

74 
 
Note: 
o Non-CR/Non-PD: The persistence of 1 or more non-target lesion(s) or 
lymph nodes identified as a site of disease at baseline ≥ 10 mm short axis. 
 
o Progressive Disease (PD): Unequivocal progression of existing non-target 
lesions. 
 
o Not Applicable (NA): No non-target lesions at baseline. 
 
o Not Evaluable (NE): Cannot be classified by one of the four preceding 
definitions. 
 
• 
Note: 
 
o In the presence of measurable disease, progression on the basis of solely 
non-target disease requires substantial worsening such that even in the 
presence of SD or PR in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. 
 
o  In the presence of non-measurable only disease consideration should be 
given to whether or not the increase in overall disease burden is comparable 
in magnitude to the increase that would be required to declare PD for 
measurable disease. 
 
o Sites of non-target lesions, which are not assessed at a particular time point 
based on the assessment schedule, should be excluded from the response 
determination (e.g. non-target response does not have to be "Not Evaluable"). 
 
Confirmation of Response: 
 
• 
To be assigned a status of PR or CR, a confirmatory disease assessment should be 
performed no less than 4 weeks (28 days) after the criteria for response are first met. 
 
Overall Response Criteria: 
 
• 
 Table 7 presents the overall response at an individual time point for all possible 
combinations of tumor responses in target and non-target lesions with or without the 
appearance of new lesions for subjects with measurable disease at baseline. 
 
Table 7 Evaluation of Overall Response for Subjects with Measurable Disease at Baseline 
 
 
 
 
 

75 
 
• 
Note: 
 
o Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be classified as having "symptomatic deterioration." Objective response status 
is determined by evaluations of disease burden. Every effort should be made to 
document the objective progression even after discontinuation of treatment. 
 
o In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue. 
 
When the evaluation of CR depends on this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR. 

76 
 
Appendix 3 Guidance on Contraception 
 
 
Guidance on Contraception 
ACCEPTABLE METHODS FOR PROTOCOLS WITH A TERATOGENIC DRUG OR WHEN 
THERE IS INSUFFICIENT INFORMATION TO DETERMINE TERATOGENICITY 
 
(CHOOSE ONE OF THE FOLLOWING 3 OPTIONS) 
 
OPTION 1: Any TWO of the following methods 
 
□ Hormonal Methods of Contraception 
□ IUD 
□ Vasectomy 
□ Tubal Ligation 
□ A barrier method (Female of Male condom with spermicide, cervical cap with 
spermicide, or diaphragm with spermicide) 
 
OPTION 2: Male condom (with spermicide) and diaphragm 
OPTION 3: Male condom (with spermicide) and cervical cap 
UNACCEPTABLE METHODS OF CONTRACEPTION: 
• 
Abstinence (including periodic abstinence) 
• 
No method 
• 
Withdrawal 
• 
Rhythm 
• 
Vaginal Sponge 
• 
Any barrier method without spermicide 
• 
Spermicide 
• 
Progestin-Only Pills 
Concomitant Use of Female and Male CondomIn countries where spermicide is not available, 
use of a male condom without spermicide in conjunction with a hormonal method, IUD, or 
tubal ligation will be acceptable to fulfill this recommendation. Any barrier method when 
used alone (without spermicide) or the concomitant use of a female and male condom, 
are not considered sufficient methods of contraception, as they carry a failure rate of > 1%. 
 
Women of childbearing potential (WOCBP) receiving nivolumab will be instructed to 
adhere to contraception for a period of 24 weeks after the last dose of investigational 
product. Men receiving nivolumab and/or relatlimab and who are sexually active with 
WOCBP will be instructed to adhere to contraception for a period of 33 weeks after the 
last dose of investigational product. These durations have been calculated using the upper 
limit of the half-life for nivolumab (25 days) and are based on the protocol requirement that 
WOCBP use contraception for 5 half-lives plus 30 days and men who are sexually 
active with WOCBP use contraception for 5 half-lives plus 90 days. 

77 
 
 
 
Appendix 4: GI Adverse Event Management Algorithm 
 
 

78 
 
 
 
Appendix 5: Renal Adverse Event Management Algorithm 
 

79 
 
 
 
Appendix 6: Pulmonary Adverse Event Management Algorithm 
 

80 
 
 
 
 
Appendix 7: Hepatic Adverse Event Management Algorithm 
 

81 
 
 
 
Appendix 8: Endocrinopathy Adverse Event Management Algorithm 
 

82 
 
 
 
 
Appendix 9: Skin Adverse Event Management Algorithm 
 

83 
 
 
 
Appendix 10: Neurological Adverse Event Management Algorithm