Parallel Proof of Concept Phase 2 Study of Nivolumab and Metformin Combination Treatment in Advanced Non-small Cell Lung Cancer With and Without Prior Treatment With PD-1/PD-L1 Inhibitors
Phase: PHASE2
Conditions: Recurrent Non-Small Cell Lung Carcinoma, Stage III Non-Small Cell Lung Cancer, Stage IIIA Non-Small Cell Lung Cancer, Stage IIIB Non-Small Cell Lung Cancer, Stage IV Non-Small Cell Lung Cancer
Sponsor: Northwestern University

NU Study Number: NU 16L04
Other Study Number: CA 209-801
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Parallel proof of concept phase 2 study of nivolumab and metformin 
combination treatment in advanced non-small cell lung cancer with 
and without prior treatment with PD-1/PD-L1 inhibitors 
Principal Investigator:
Young Kwang Chae, MD, MPH, MBA
Assistant Professor, 
Division of Hematology and Oncology, 
Department of Medicine, Feinberg School of Medicine, Robert H. Lurie 
Comprehensive Cancer Center of Northwestern University
251 East Huron Street, Galter Suite 3-150
Chicago, IL 60611
Phone: 312-926-6895
Email: young.chae@northwestern.edu
Sub-Investigator(s):
Nisha Mohindra, MD
Victoria Villaflor, MD
Valerie Nelson, MD
Timothy Taxter, MD
Biostatistician:
Borko Jovanovic, PhD
borko@northwestern.edu
Study Intervention(s):
Nivolumab, Metformin
IND Number:
133341
IND Holder:
Young Kwang Chae, MD, MPH, MBA
 
Funding Source: 
Rare Population Malignancy Program (RPMP) grant from BMS 
Version Date:
4.22.19 (Amendment 5)
Coordinating Center:
Clinical Research Office
Robert H. Lurie Comprehensive Cancer Center 
Northwestern University
676 N. St. Clair, Suite 1200
Chicago, IL  60611
www.cancertrials.northwestern.edu
IRB #: STU00204354-CR0003 Approved by NU IRB for use on or after 11/11/2019 through 11/10/2020.

NU Study Number: NU 16L04
Other Study Number: CA 209-801
2
TABLE OF CONTENTS
LIST OF ABBREVIATIONS ............................................................................................................5
STUDY SCHEMA ............................................................................................................................7
STUDY SUMMARY .........................................................................................................................8
1.0
INTRODUCTION – BACKGROUND & RATIONALE....................................................11
1.1 Significant unmet need in treatments of advanced non-small cell lung cancers.........11
1.2 Immune stimulating properties of Metformin:..............................................................11
1.3 Metformin ....................................................................................................................15
1.4 Exploratory Studies.....................................................................................................15
2.0
OBJECTIVES & ENDPOINTS.......................................................................................15
2.1 Primary Objective & Endpoint .....................................................................................15
2.2 Secondary Objectives & Endpoints.............................................................................15
2.3 Exploratory Objectives & Endpoints............................................................................16
3.0
PATIENT ELIGIBILITY..................................................................................................16
3.1 Inclusion Criteria .........................................................................................................16
3.2 Exclusion Criteria ........................................................................................................18
4.0
TREATMENT PLAN ......................................................................................................20
4.1 Overview .....................................................................................................................20
4.2 Treatment Administration............................................................................................20
4.3 Toxicity Management & Dose Delays/Modifications ...................................................21
4.4 Continuation of Investigational Therapy after Progression .........................................26
4.5 Concomitant Medications/Treatments.........................................................................26
4.6 Duration of Therapy ....................................................................................................27
4.7 Duration of Follow Up..................................................................................................27
4.8 Removal of Subjects from Study Treatment and/or Study as a Whole.......................27
4.9 Patient Replacement...................................................................................................28
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NU Study Number: NU 16L04
Other Study Number: CA 209-801
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5.0
STUDY PROCEDURES TABLE....................................................................................29
6.0
ENDPOINT ASSESSMENT...........................................................................................31
6.1 Solid Tumors...............................................................................................................31
6.2 Immune-related RECIST (irRECIST) ..........................................................................31
6.3 Primary Endpoint.........................................................................................................32
6.4 Secondary Endpoints..................................................................................................32
6.5 Exploratory end points ................................................................................................33
7.0
ADVERSE EVENTS ......................................................................................................33
7.1 Adverse Event Monitoring...........................................................................................33
7.2 Definitions & Descriptions ...........................................................................................33
7.3 Reporting of pregnancy and lactation .........................................................................35
7.4 Adverse events Reporting...........................................................................................36
8.0
DRUG INFORMATION ..................................................................................................37
8.1 Nivolumab ...................................................................................................................37
8.2 Metformin ....................................................................................................................41
8.3 Combination of metformin and nivolumab ...................................................................42
9.0
CORRELATIVES/SPECIAL STUDIES..........................................................................42
9.1 Sample Collection Guidelines .....................................................................................42
9.2 Sample Processing, Storage, and Shipment ..............................................................42
9.3 Assay Methodology.....................................................................................................42
10.0        STATISTICAL CONSIDERATIONS ................................................................................43
10.1 Study Design/Study Endpoints..................................................................................43
10.2 Sample Size and Accrual..........................................................................................44
10.3 Data Analyses Plans.................................................................................................44
11.0      STUDY MANAGEMENT ...................................................................................................45
11.1 Institutional Review Board (IRB) Approval and Consent...........................................45
IRB #: STU00204354-CR0003 Approved by NU IRB for use on or after 11/11/2019 through 11/10/2020.

NU Study Number: NU 16L04
Other Study Number: CA 209-801
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11.2 Amendments.............................................................................................................46
11.3 Registration Procedures............................................................................................46
11.4 Data Management and Monitoring/Auditing..............................................................47
11.5 Adherence to the Protocol.........................................................................................47
11.6 Investigator Obligations.............................................................................................47
11.7 Publication Policy......................................................................................................48
REFERENCES ..............................................................................................................................49
Appendices...................................................................................................................................50
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NU Study Number: NU 16L04
Other Study Number: CA 209-801
Amendment 5: 4.22.19
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LIST OF ABBREVIATIONS
AE
Adverse Event
ALC
Absolute Lymphocyte Count
ALK
Anaplastic Lymphoma Kinase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CMP
Comprehensive Metabolic Panel
CR
Complete Response
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLT
Dose Limiting Toxicity
DSMB
Data and Safety Monitoring Board
ECOG
Eastern Cooperative Oncology Group
EGFR
Epidermal Growth Factor Receptor
GI
Gastrointestinal
H&PE
History & Physical Exam
HunMab
Human Monoclonal Antibody
IGF-1
Insulin like Growth Factor-1
IgG4
Immunoglobulin G4
IV (or iv)
Intravenously
MSI
Microsatellite Instability
MTD
Maximum Tolerated Dose
mTOR
Mammalian Target of Rapamycin
NCI
National Cancer Institute
NSCLC
Non Small Cell Lung Cancer
ORR
Overall Response Rate or Objective Response Rate
OS
Overall Survival
PBMCs
Peripheral Blood Mononuclear Cells
PD
Progressive Disease
PD-(L)1
Programmed Death- (Ligand) 1
PFS
Progression Free Survival
PO (or p.o.)
Per os/by mouth/orally
PR
Partial Response
RCC
Renal Cell Carcinoma
SAE
Serious Adverse Event
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
SPGT
Serum Glutamic Pyruvic Transaminase
TCM
Central Memory T Cells
TEM
Effector Memory T Cells
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NU Study Number: NU 16L04
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TNBC
Triple Negative Breast Cancer
Tregs
Regulatory T Cells
TSC 1/2
Tuberous Sclerosis Complex 1/2
VEGF
Vascular Endothelial Growth Factor
WBC
White Blood Cells
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NU Study Number: NU 16L04
Other Study Number: CA 209-801
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STUDY SCHEMA
 
Group A
Patients without prior treatment 
with PD-1/PD-L1 inhibitor
Nivolumab, 240 mg every 14 days (Cycle 1-4, Day 1 & 15) then 
nivolumab 480mg every 28 days (Day 1 of Cycle 5+)
+
Metformin (Glucophage XR), 2,000 mg by mouth once daily*
Response assessment every 2 cycles (8 weeks)
Response or Stable 
Disease
Continue treatment 
assessment
Disease Progression or 
Intolerability
Discontinue treatment
Group B
Patients with prior treatment 
with  PD-1/PD-L1 inhibitor given as 
either a single agent or in combination 
with chemotherapy
Advanced
Non-small cell lung cancer
* Metformin: start at 1,000 mg daily and escalate incrementally to 2,000 mg/day 
as tolerated (see section 4.0 for details)
Induction:
Treatment with metformin monotherapy (Glucophage 
XR, 1,000mg PO QD) will begin 7 days before 
combination therapy
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NU Study Number: NU 16L04
Other Study Number: CA 209-801
Amendment 5: 4.22.19
8
STUDY SUMMARY
Title
Parallel proof of concept phase 2 study of nivolumab and metformin 
combination treatment in advanced non-small cell lung cancer with and 
without prior treatment with PD-1/PD-L1 inhibitors 
Version
4.22.19 (Amendment 5)
Study Design
Phase II proof of concept study with two parallel groups
Study Center(s)
Northwestern University
Objectives
Primary Objective:  
To assess anti-tumor activity of the combination treatment of metformin 
with nivolumab in patients with non-small cell lung cancer with and 
without prior exposure to PD-1/PD-L1 inhibitors: Anti-tumor activity will 
be assessed by objective response rate (ORR, complete response and 
partial response) using RECIST criteria (version 1.1)
Secondary Objectives:
(1) To assess the efficacy of the combination treatment of metformin with 
nivolumab according to depth, duration, and persistence of response, 
disease control rate (DCR; CR, PR, and SD at 24 weeks), progression-
free survival (PFS), and overall survival (OS) in patients with non-small 
cell lung cancer with and without prior exposure to PD-1/PD-L1 inhibitors 
using RECIST criteria
(2) To assess the efficacy of the combination treatment of metformin with 
nivolumab according to depth, duration, and persistence of response, 
ORR, DCR, PFS, and OS in the above population using immune-related 
RECIST (irRECIST) criteria
(3) To assess the safety and tolerability profile of the combination 
treatment of metformin with nivolumab in the above population using 
CTCAE version 4.03
Exploratory objective:
(1) To assess the immune-related tumor and blood biomarkers including 
T cell markers and their association with treatment response in the 
above population
(2) To assess the dynamic change in both immune and genomic 
biomarkers in blood that may correlate with response to treatment.
Sample Size
Up to 51 patients (minimum of 21 patients) 
Based on optimal Simon two stage design;
- Arm A: If stopped earlier 9 patients will be enrolled to arm A, if 
continued, 24 patients will be enrolled.
- Arm B: If stopped earlier 12 patients will be enrolled to arm B, if 
continued 25 patients will be enrolled.  
Total maximum number of evaluable patients=49
Given possible inevaluable patient and drop out from study, we will aim 
for 51 patients for total enrollment.
This will be a single institution trial with duration of enrollment estimated 
to be 2 years.
Estimated accrual rate will 25.5 per year, approximately 2 per month.
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NU Study Number: NU 16L04
Other Study Number: CA 209-801
Amendment 5: 4.22.19
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Diagnosis & Key 
Eligibility Criteria
Study population will consist of patients age 18 or older, Eastern 
Cooperative Oncology Group (ECOG) performance status 0-2, with 
histologically confirmed, locally advanced or metastatic non-small cell 
lung cancer (arm A: naive to single agent PD-1/PD-L1 inhibitors that 
includes but not limited to durvalumab, pembrolizuamb, atezolizumab, 
nivolumab, avelumab; arm B: refractory to or progressed on one of the 
above agents; both cases are defined by initial PD or PD following CR, 
PR, or SD using RECIST criteria.). Patients need to have adequate 
kidney, bone marrow, and liver functions, and a measurable disease 
according to Response Evaluation Criteria of Solid Tumors (RECIST). 
Patient should not have received metformin within 6 months from the 
consent date. (Arm B: Patients who were on metformin while on PD-
1/PD-L1 inhibitors will be excluded). Patients with exposure to prior 
immunotherapy, including combination treatment with PD-1/PD-L1 
inhibitors are excluded from arm A. Immunotherapy agents include but 
are not limited to interleukin-2 and other immune checkpoint antagonist 
targeting CTLA-4, LAG-3, TIM-3, KIR etc. and/or agonists targeting 
OX40, ICOS, CD137, etc. Also, patients who are intolerant to PD-1/PD-
L1 inhibitors or metformin are also excluded. Prior cancer vaccine 
treatments are permitted for both arms. Of note, patients with prior 
exposure to single agent PD-1/PD-L1 inhibitors or combination treatment 
with PD-1/PD-L1 inhibitor and chemothrapy (such as carboplatin, 
pemetrexed, and pembrolizumab) are eligible for enrollment in arm B. 
Patients cannot have a history of clinically significant autoimmune 
diseases or a syndrome that requires systemic steroids (>10mg 
prednisone or equivalent, premedication for contrast allergy is permitted) 
or immunosuppressive agents. Autoimmune diseases include but are not 
limited to autoimmune hepatitis, systemic lupus erythematous, 
rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, 
vasculitis, or glomerulonephritis. Vitiligo, alopecia, hypothyroidism on 
stable doses of thyroid replacement therapy, psoriasis not requiring 
systemic therapy within the past 3 years is permitted.  Short-term steroid 
premedication for contrast allergy is permitted. Metastatic brain 
parenchymal disease must have been treated and patient must be off 
steroids for at least two weeks. Patients with another primary malignancy 
within 2 years prior to starting study treatment with the exception of 
adequately treated basal cell carcinoma, squamous cell carcinoma or 
other non-melanomatous skin cancer, or in-situ carcinoma of the uterine 
cervix, or any local cancers that are deemed to be cured from 
investigator’s point of view.
Treatment Plan
Patients will start metformin (Glucophage XR) at 1,000mg by mouth 
once daily during a 7-day induction period prior to starting nivolumab 
Cycle 1 Day 1 (1 cycle = 28 days). The dose will be increased by 500mg 
every 7 days (C1D1 and C1D8) until reaching the target dose of 
2000mg. Nivolumab will be administered at a fixed dose of 240 mg IV 
every14 days during Cycle 1-4 (Day 1 & 15) and 480mg IV every 28 
days starting with Cycle 5 Day 1. Treatment will continue until disease 
progression confirmed by RECIST criteria v1.1, intolerable toxicity or 
withdrawal of consent. Imaging by CT or MRI will be scheduled every 2 
cycles (8 weeks).
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NU Study Number: NU 16L04
Other Study Number: CA 209-801
Amendment 5: 4.22.19
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Statistical Methodology
Accounting for inevaluable patients and dropouts, up to 51 patients (Arm 
A=24, Arm B=25) will be entered into the trial based on optimal Simon 
two stage design as below.
Arm A: In the first stage, 9 patients will be entered.  If no patients show a 
response, then the trial will be terminated due to inactivity of the 
treatment.  If 1 or more of 9 show a response, then an additional 15 
patients will be added.  If 2 or fewer of 24 show a response, then the trial 
will conclude that the response rate could be as low as 5%.  If 3 or more 
respond, then the trial will conclude that the response rate is at least 
20%.  This design has a 20% chance of falsely concluding the rate is 5% 
(false negative Type II error rate = 20%, or power = 80%), and a 10% 
chance of falsely concluding that the rate is 20% (false positive Type I 
error rate = 10%).  There is a 63% probability of early termination of the 
trial when the true response rate is 5%.
Arm B: In the first stage, 12 patients will be entered.  If 2 or fewer 
patients show a response, then the trial will be terminated due to 
inactivity of the treatment.  If 3 or more of 12 show a response, then an 
additional 13 patients will be added.  If 7 or fewer of 25 show a response, 
then the trial will conclude that the response rate could be as low as 
20%.  If 8 or more respond, then the trial will conclude that the response 
rate is at least 40%.  This design has a 20% chance of falsely concluding 
the rate is 20% (false negative Type II error rate = 20%, or power = 
80%), and a 10% chance of falsely concluding that the rate is 40% (false 
positive Type I error rate = 10%).  There is a 56% probability of early 
termination of the trial when the true response rate is 5%.
IRB #: STU00204354-CR0003 Approved by NU IRB for use on or after 11/11/2019 through 11/10/2020.

NU Study Number: NU 16L04
Other Study Number: CA 209-801
Amendment 5: 4.22.19
11
1.0
INTRODUCTION – BACKGROUND & RATIONALE
1.1
Significant unmet need in treatments of advanced non-small cell lung cancers
Despite the recent success of immune checkpoint inhibitors, only a small proportion of 
patients with non-small cell lung cancer gain clinical benefit from such therapies. Many 
patients are either refractory to or relapse after such therapies. Since the FDA approval 
of PD-1 (programmed death receptor-1) inhibitors (nivolumab, pembrolizumab) in 
advanced non-small cell lung cancer as single agents or in combination with 
chemotherapy first-line in metastatic nonsquamous NSCLC (carboplatin, pemetrexed, 
and pembrolizumab), many patients have been treated with these drugs as a standard of 
care treatment. However, many of them were found to be refractory to or progressed on 
such treatments. Moreover, many patients with various types of cancers who had PD-
1/PD-L1 inhibitors administered as part of clinical trials are now refractory to such 
treatments. 
Therefore there is high unmet need in non-small cell lung cancer to increase the efficacy 
of immune checkpoint inhibitors. Also, since most of novel immunotherapy trials, whether 
in single agent or in combination, exclude patients who have previously been exposed to 
other forms of immunotherapy including PD-1/PD-L1 inhibitors, these patients have 
significantly limited access to investigational therapeutics. Therefore, there is substantial 
unmet need for treatment options for patients with non-small cell lung cancer refractory to 
PD-1/PD-L1 inhibitors. 
1.2
Immune stimulating properties of Metformin:
Metformin is one of the most commonly prescribed medications for the treatment of 
diabetes mellitus. Experiments in animal models of pancreatic cancer demonstrated anti-
tumor properties of metformin via various mechanisms including inhibition of insulin like 
growth factor-1 (IGF-1) and mTOR, along with activation of AMPK and tuberous sclerosis 
complex (TSC1, TSC2)1. Furthermore, epidemiologic data have repeatedly demonstrated 
decreased cancer incidence and mortality in patients taking metformin 2-5
 
Figure 1. Anti-cancer Mechanism of Metformin
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NU Study Number: NU 16L04
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Of note, recent experiments have also suggested that metformin has immune modulatory 
properties. Metformin inhibited immune exhaustion of CD8+ tumor induced lymphocytes 
(TIL), thereby enhancing T cell mediated immune response to tumor tissue. It decreased 
apoptosis of CD8+ tumor infiltrating lymphocytes (TILs), and also shifts the phenotype of 
CD8+ TILs expressing exhaustion markers (especially PD1 negative Tim3 positive) from 
central memory T cells (TCM, inactive against tumor cells) to effector memory T cells 
(TEM, active against tumor cells). The increase in TEM cell population has been found to 
correlate with regression of tumor cells 6. In a study evaluating an experimental cancer 
vaccine, administration of metformin after vaccination in animal models showed an 
increase in CD8+ memory T cells which conferred protective immunity upon subsequent 
tumor challenge 7. Figure 1 summarizes the effects of metformin on various cellular 
pathways. 
We have further explored the immune modulatory function of metformin. We have 
confirmed the positive effect of metformin on cytotoxic CD8+ T cells. Moreover, we also 
demonstrated for the first time that metformin inhibits regulatory T cells (Tregs) 
(unpublished data).
1.3
Rationale for the Current Study
    
1.3.1
Generating synergy and overcoming resistance to PD-1/PD-L1 inhibitors 
with the combination of nivolumab and metformin: 
Building upon the above scientific and clinical rationale supporting the use for 
metformin to maximize the benefit of immunotherapy and the high unmet need 
for more effective treatment options for patients with non-small cell lung cancer 
both with and without prior exposure to PD-1/PD-L1 inhibitors, we propose a 
proof-of-concept parallel phase 2 trial using the combination regimen of 
nivolumab and metformin.
We hypothesize that the combination of nivolumab and metformin will be 
synergistic in effect and also will overcome the resistance to single agent PD-
1/PD-L1 inhibitors. The fact that metformin activates CD8+ TILs, aids in 
formulation of TEMs and suppress Tregs at the same suggests that the 
combination of metformin and anti-PD1 monoclonal antibody, nivolumab may 
exert more robust immune modulatory anti-cancer effect than single agent PD-
1/PD-L1 inhibitors. In addition, non-immune anti-tumor property of metformin may 
have assist in providing additive anti-cancer effect.  
In Group B, this trial will enroll both patients who initially responded to PD-1/PD-
L1 inhibitors and progressed later on as well as patients had primary 
refractoriness to such agents. This trial will also serve as a proof of concept trial 
to later further explore the effectiveness of the metformin- immune check-point 
inhibition combination regimen in cancers that harbor primary or secondary 
resistance to PD-1/PD-L1 inhibitors. 
Given that the indications for PD-1/PD-L1 inhibitors in solid cancers will only 
expand in the near future, time is right for this proof-of-concept trial that will 
answer the important clinical questions in both increasing efficacy and 
overcoming the resistance in PD-1/PD-L1 inhibitors. This trial may pave way for 
the next pivotal phase 3 trial in non-small cell lung cancer or for proof of concept 
phase 2 trial in other cancer types where the combination treatment may be of 
significant clinical value.   
1.3.2
Rationale for the Study Design:
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Group A and Group B will address two clinical questions. Group A is designed to 
assess possible synergistic effect of the combination treatment in immunotherapy 
naïve patients whereas group B is designed to determine whether the 
combination treatment of metformin with immunotherapy can overcome 
resistance to single agent PD-1/PD-L1 inhibitors.
Group A: In order to demonstrate synergy in anti-tumor effect, ORR of the 
combination treatment will be compared to that of historical control (20%) 
reported in phase 3 single agent nivolumab trials in lung cancer (CheckMate057 
and CheckMate017). Optimal Simon’s two stage design will be used with target 
ORR of 40% versus control ORR of 20% (type 1 error rate of 0.1 and power of 
0.8)
 
Group B: In order to find signal in patients with prior exposure to single agent PD-
1/PD-L1 inhibitors, ORR of the combination treatment will be described. Optimal 
Simon’s two stage design will be used with target ORR of 20% versus control 
ORR of 5% (type 1 error rate of 0.1 and power of 0.8). 
1.4
Nivolumab Clinical development
The U. S. Food and Drug Administration approved nivolumab (Opdivo Injection, 
Bristol-Myers Squibb Company) for patients with unresectable or metastatic 
melanoma, non-small cell lung cancer, renal cell carcinoma, and Hodgkin’s 
lymphoma.
1.4.2
Clinical efficacy
In a phase 1 (1, 3, and 10 mg/kg nivolumab doses) dose-escalation study the 3 
mg/kg dose was chosen for expanded cohorts. Among 236 patients, objective 
responses (ORs) (complete or partial responses [CR or PR]) were seen in 
NSCLC, melanoma, and RCC. ORs were observed at all doses. Median OS was 
16.8 months across doses and 20.3 months at the 3 mg/kg dose. Heavily 
pretreated patients with NSCLC treated with nivolumab (1, 3, or 10mg/kg) 
achieved median OS across all dose cohorts of 9.9 months with response rates 
of 17% and median duration of response 17 months 8. In addition, responses 
were similar between both squamous and non-squamous carcinoma cohorts in 
this study. A subsequent phase 3 study compared nivolumab to docetaxel in 
second-line treatment setting of advanced squamous cell carcinoma among 272 
patients. Nivolumab arm demonstrated superior median OS (9 vs. 6 months), 1 
year survival rate (42 vs. 24%), response rates (20 vs. 9%), and significantly 
lower rates of grade 3-4 treatment related adverse events (7 vs. 55%) 9. These 
results supported the FDA approval of nivolumab for second-line treatment of 
advanced squamous cell carcinoma following treatment with platinum-based 
chemotherapy. 
Nivolumab also has clinically meaningful activity in RCC. A phase II study treated 
168 patients with advanced clear cell RCC with progression after agents 
targeting VEGF pathway at three doses of nivolumab (0.3, 2 and 10mg/kg) 10. 
Median overall survival was 18, 25, and 24 months for the three dose cohorts, 
respectively. More recently 821 patients previously treated with anti-angiogenic 
therapy were randomized to either nivolumab (3mg/Kg every 2 weeks) or 
everolimus (10mg daily).11 The median overall survival was 25.0 months (95% 
confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months 
(95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab 
versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the 
prespecified criterion for superiority (P≤0.0148). Response rates were in average 
20% with only 11% incidence of grade 3-4 treatment-related adverse events. 
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NU Study Number: NU 16L04
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1.4.3
Clinical Safety
For nivolumab monotherapy, the safety profile is similar across tumor types 
(investigator brochure v 2015). The only exception is pulmonary inflammation 
adverse events (AEs), which may be numerically greater in subjects with 
NSCLC, because in some cases, it can be difficult to distinguish between 
nivolumab-related and unrelated causes of pulmonary symptoms and 
radiographic changes. There is no pattern in the incidence, severity, or causality 
of AEs to nivolumab dose level. Safety data for subjects with previously treated 
advanced or metastatic NSCLC treated with nivolumab monotherapy in 
CA209017 (131 subjects), CA209057 (287 subjects), and CA209063 (117 
subjects) were pooled and safety analyses were performed for these pooled 
subjects who receiving nivolumab monotherapy (a total of 535 
subjects)(investigator brochure v 2015). Based on the pooled analyses, 
nivolumab monotherapy at a dose of 3 mg/kg administered IV Q2W has an 
acceptable safety profile, as demonstrated by the frequency, severity, and types 
of AEs, drug-related deaths, SAEs, and AEs leading to discontinuation. The most 
common adverse events were fatigue (19.6%), decreased appetite (12.3%), 
nausea (12.0%), and asthenia (10.5%). The majority of drug-related AEs were of 
Grade 1-2 in severity.
1.4.4
Nivolumab dosing and rationale for the flat dosing
Anti-tumor activity was observed in study CA209003 at dose levels ranging from 
1 to 10 mg/kg in RCC. The antitumor activity of nivolumab tended to increase 
with dose, as did the incidence of SAEs. The anti-tumor activity of nivolumab in 
RCC was investigated at dose levels 1 and 10 mg/kg, with the higher activity 
observed at 10 mg/kg. The observed anti-tumor activity in melanoma, and 
NSCLC was highest at 3 mg/kg, suggesting that anti-tumor activity approaches a 
plateau at dose levels of 3 mg/kg and above. Consistent with these observations, 
the results of the exposure-response analyses for these tumor types, show that 
the probability of a tumor response tended to approach a plateau for trough 
concentrations produced by 3 and 10 mg/kg every 2 week dosing. Nivolumab 
was adequately tolerated up to 10 mg/kg, the highest dose level tested, and no 
maximum tolerated dose (MTD) was identified. Although the spectrum, 
frequency, and severity of nivolumab-related AEs were generally similar across 
the dose levels tested, the 10 mg/kg doses level had numerically higher Grade 
3/4 drug-related SAEs and AEs leading to discontinuation. Based on the totality 
of the safety, efficacy, and exposure-response data, a dose of 3 mg/kg every two 
weeks was selected as the dose anticipated achieving an appropriate balance of 
benefit and risk. 
1.4.5
Nivolumab flat dose regimen
The safety and efficacy of 240 mg (monotherapy) Q2W flat dose of nivolumab 
has recently received FDA approval and is expected to be similar to 3 mg/kg 
Q2W dosing regimen. Using the PPK model, exposure of nivolumab at 240 mg 
flat dose is identical to a dose of 3 mg/kg for subjects weighing 80 kg, which is 
the approximate median body weight in nivolumab clinical trials. Across the 
various tumor types in the 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 and safety has 
been found to be relatively flat. Given the similarity of nivolumab PK across tumor 
types and the similar exposures predicted following administration of 240 mg flat 
dose compared to 3 mg/kg, it is expected that the safety and efficacy profile of 
240 mg nivolumab will be similar to that of 3 mg/kg nivolumab. 
In addition, nivolumab 480 mg administered once every 4 weeks (Q4W) is 
currently under investigation. The less frequent dosing regimen is designed to 
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afford more convenience to the target patient populations. The nivolumab dose of 
480 mg Q4W was selected based on clinical data and modeling and simulation 
approaches using PPK and exposure-response analyses of data from studies in 
multiple tumor types (melanoma, NSCLC, and RCC) to provide an approximately 
equivalent dose of nivolumab 3 mg/kg Q2W. Exposures following nivolumab
480 mg Q4W regimen are predicted to be within the exposure ranges observed 
at doses up to 10 mg/kg Q2W used in the nivolumab clinical program, and are 
not considered to put participants at increased risk. Hence, the flat dose of 
480mg nivolumab is under investigation , and will be administered in this study 
after 4 months at the 240mg dose.
1.5
Metformin
1.5.1
Clinical safety, Development and Efficacy
Metformin is a well-studied drug, utilized by a large number of adults with 
diabetes. The following are considered contraindications to the use of metformin: 
hypersensitivity to metformin or any component of the formulation; kidney 
dysfunction (serum creatinine ≥1.5 mg/dL in males or ≥1.4 mg/dL in females) or 
abnormal creatinine clearance from any cause (including shock, acute 
myocardial infarction, or septicemia); acute or chronic metabolic acidosis. In 
addition, it is generally recommended to temporarily discontinue metformin in 
patients undergoing radiologic studies in which intravascular iodinated contrast 
media are utilized. It is also recommended that metformin be used cautiously in 
patients with congestive heart failure requiring pharmacologic management, 
because the risk of lactic acidosis may be increased secondary to hypoperfusion.
Metformin was developed as an anti-diabetes drug. However, recent research 
have found interesting anti-tumor properites of metformin. Of note, the immune 
modulating properties leading to significant anti-tumor effect has not yet been 
explored in a clinical trial setting.
1.6
Exploratory Studies
Exploratory biomarker studies will be pursued involving tissue samples and peripheral 
blood. These studies will focus on the use of biomarkers to predict response to 
immunotherapy. Current body of evidence suggests that PD-L1 expression and TIL 
(tumor infiltrating lymphocyte) at tissue and peripheral blood lymphocyte phenotype 
markers may correlate with response to immunotherapy although still controversial. 
Tissue and blood samples will be stored to explore further molecular biomarkers 
including but not limited to genomic, immunologic or proteomic alterations.
 
2.0
OBJECTIVES & ENDPOINTS
2.1 Primary Objective & Endpoint
To assess anti-tumor activity of the combination treatment of metformin with nivolumab in 
patients with non-small cell lung cancer with and without prior exposure to PD-1/PD-L1 
inhibitors: Anti-tumor activity will be assessed by objective response rate (ORR, complete 
response and partial response) using RECIST criteria v1.1.
2.2 Secondary Objectives & Endpoints
2.2.1
To assess the efficacy of the combination treatment of metformin with nivolumab 
according to depth, duration, and persistence of response, disease control rate 
(DCR; CR, PR, and SD at 24 weeks), progression-free survival (PFS), and overall 
survival (OS) in patients with non-small cell lung cancer with and without prior 
exposure to PD-1/PD-L1 inhibitors using RECIST criteria v1.1. Depth of response 
(SD or PR) is defined as the change in the sum of the largest tumor diameters per 
RECIST.
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2.2.2
To assess the efficacy of the combination treatment of metformin with nivolumab 
according to depth, duration, and persistence of response, ORR, DCR, PFS, and 
OS in the above population using immune-related RECIST (irRECIST) criteria. 
Depth of response (SD or PR) is defined as the change in the sum of the largest 
tumor diameters per irRECIST.
2.2.3
To assess the safety and tolerability profile of the combination treatment 
of metformin with nivolumab in the above population using CTCAE 
version 4.03.
2.3 Exploratory Objectives & Endpoints
2.3.1
To assess the immune-related tumor and blood biomarkers including T 
cell markers and their association with treatment response in the above 
population  
2.3.2
To assess the dynamic change in both immune and genomic biomarkers 
in blood that may correlate with response to metformin.
3.0
PATIENT ELIGIBILITY
The target population for this study is all patients with advanced non-small cell lung cancer 
with and without prior exposure to PD-1 or PD-L1 inhibitors. This trial will be conducted at 
Northwestern University with the potential of opening the trial at other institutions. 
A total of 51 subjects will be needed for this trial. Approximately 4 potentially eligible patients 
are seen per month, and it is anticipated that at least 2 per month will be accrued. Potential 
patients may be referred to the Principal Investigator (PI) at Northwestern University, Dr. 
Young Chae, at 312-726-1234 or young.chae@northwestern.edu.
Eligibility will be evaluated by the study team according to the following criteria. Eligibility 
waivers are not permitted. Subjects must meet all of the inclusion and none of the exclusion 
criteria to be registered to the study. Study treatment may not begin until a subject is 
registered. Please refer to Section 11.3 for complete instructions regarding registration 
procedures.
3.1 Inclusion Criteria
3.1.1
Patients must have histologically confirmed, locally advanced or metastatic stage 
IV or non-resectable stage III non-small cell lung cancer (NSCLC). 
3.1.2
Patients may have received any number and type of prior treatment regimens for 
their NSCLC (aside from patients in Arm A, who cannot have had PD-1/PD-L1 
inhibitors). 
3.1.3
Arm A: patients must be treatment naive to PD-1/PD-L1 inhibitors including but 
not limited to durvalumab, pembrolizuamb, atezolizumab, nivolumab, and 
avelumab.
Arm B: patients’ tumor must be either refractory to or progressed on one of the 
above agents.
NOTE: Prior treatment may include any number of PD-1/PD-L1 inhibitor therapies 
given as either a single-agent or in combination with chemotherapy.. 
NOTE: Patients must be eligible to receive the next line of therapy and not be 
suspected of having pseudoprogression. Both cases are defined by initial PD or 
PD after CR, PR, or SD using RECIST criteria, respectively.  
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3.1.4
Patients must have measurable disease according to the standard RECIST 
version 1.1. 
NOTE: CT scans or MRIs used to assess the measurable disease must have 
been completed with 28 days prior to the study drug initiation.
3.1.5
Patients need to have adequate kidney, bone marrow, and liver functions ≤14 
days of registration as specified below:
absolute neutrophil 
≥ 1,000/mcL*
platelets
≥ 50,000/mcl*
hemoglobin
≥ 8 g/dL
total bilirubin
≤1.5 times the institutional upper limit of 
normal (ULN) (or ≤3 times ULN in case of 
liver metastasis or Gilbert Syndrome)
AST(SGOT)/ALT(SPGT)
≤ 2.5 X institutional ULN (or ≤5 times ULN in 
case of liver metastasis)
creatinine
≤ 1.4 ng/mL for females; ≤ 1.5 ng/mL for males** 
ng/ml
*Transfusion and/or growth factor are permitted within any timeframe.
**Patients with creatinine ≤ 2.0 ng/mL may still be eligible if in the opinion of 
the investigator, the benefits of treatment outweigh the risks.
3.1.6
Patients must be age ≥ 18 years; both male and female are eligible.
3.1.7
Patients must exhibit an ECOG performance status of ≤2.
3.1.8
Patients must have the ability to understand and the willingness to sign a written 
informed consent prior to registration on study.
3.1.9
Females of child-bearing potential (FOCBP) and men who are sexually active 
must agree to follow instructions for method(s) of contraception for the duration of 
treatment and the designated post-treatment period (see Appendix C for details 
on appropriate contraception methods) 
NOTE: A FOCBP is any woman (regardless of sexual orientation, having 
undergone a tubal ligation, or remaining celibate by choice) who meets the 
following criteria:

Has not undergone a hysterectomy or bilateral oophorectomy

Has had menses at any time in the preceding 12 consecutive months (and 
therefore has not been naturally postmenopausal for > 12 months)
3.1.10 FOCBP must have a negative pregnancy test ≤7 days prior to registration on 
study.
3.1.11 Patients with known history of central nervous system (CNS) metastases are 
eligible if CNS disease has been radiographically and neurologically stable for at 
least 6 weeks prior to study registration and do not require corticosteroids (of any 
dose) for symptomatic management.
NOTE: CNS imaging is only required at baseline for patients with known history of 
CNS metastases. 
3.1.12 Patients must have the ability to swallow oral medications.
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3.1.13 Patients who are known to be EGFR- or ALK-positive must have received prior 
EGFR- or ALK-targeted therapy, respectively.
NOTE: In such cases, documentation of EGFR mutation or ALK translocation 
status should be provided if available.
3.2 Exclusion Criteria
3.2.1
Both arms: Patients should not have received metformin within 6 months prior to 
registration. 
Arm B: Patients who were on metformin while on PD-1/PD-L1 inhibitors are not 
eligible.
3.2.2
Patients should not have received prior immunotherapies (exception: prior PD-
1/PD-L1 inhibitors are allowed for arm B only). 
NOTE: Prior cancer vaccine treatments are permitted. For arm B, exposure to PD-
1/PD-L1 inhibitors given as either a  single agentor in combination with 
chemotherapy are allowed ≥ 14 days from registration.
NOTE: Immunotherapies include but are not limited to interleukin-2 and other 
immune checkpoint antagonist targeting CTLA-4, LAG-3, TIM-3, KIR etc. and/or 
agonists targeting OX40, ICOS, CD137, etc.    
3.2.3
Patients who are intolerant to PD-1/PD-L1 inhibitors and/or metformin are 
excluded.
3.2.4
Patients with active autoimmune disease or history of autoimmune disease that 
might recur, which may affect vital organ function or require immune suppressive 
treatment including chronic prolonged systemic corticosteroids (defined as 
corticosteroid use of duration one month or greater), should be excluded. These 
include but are not limited to patients with a history of:

immune related neurologic disease

multiple sclerosis

autoimmune (demyelinating) neuropathy

Guillain-Barre syndrome

myasthenia gravis

systemic autoimmune disease such as SLE

connective tissue diseases

scleroderma

inflammatory bowel disease (IBD)

Crohn’s

ulcerative colitis

patients with a history of toxic epidermal necrolysis (TEN)

Stevens-Johnson syndrome

anti-phospholipid syndrome 
NOTE: 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.
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3.2.5
Patients are ineligible who have any condition requiring systemic treatment with 
corticosteroids (>10mg daily prednisone equivalents) or other immunosuppressive 
medications ≤14 days prior to registration. 
NOTE: Inhaled steroids and adrenal replacement steroid doses >10mg daily 
prednisone equivalents are permitted in the absence of active autoimmune 
disease. A brief (less than 3 weeks) course of corticosteroids for prophylaxis (eg, 
contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-
type hypersensitivity reaction caused by a contact allergen) is permitted. 
3.2.6
Patients who have an uncontrolled intercurrent illness including, but not limited to 
any of the following, are not eligible: 

Uncontrolled hypertension – blood pressure ≥ 150/90 mmHg despite medical 
therapy

Ongoing or active infection requiring systemic treatment

Symptomatic congestive heart failure

Unstable angina pectoris

Cardiac arrhythmia

Psychiatric illness/social situations that would limit compliance with study 
requirements

Any other illness or condition that the treating investigator feels would 
interfere with study compliance or would compromise the patient’s safety or 
study endpoints
3.2.7 Patients must not have had another primary malignancy within 2 years prior to 
starting study treatment with the exception of adequately treated basal cell 
carcinoma, squamous cell carcinoma or other non-melanomatous skin cancer, or 
in-situ carcinoma of the uterine cervix, or any local cancers that are deemed to be 
cured from investigator’s point of view. 
3.2.8
Patients may not be receiving any other investigational agents ≤ 14 days from 
registration.
3.2.9
Patients with known history of testing positive for human immunodeficiency virus 
(HIV) or known acquired immunodeficiency syndrome (AIDS) are excluded.
3.2.10 Patients who have any positive test for Hepatitis B or Hepatitis C virus indicating 
acute or chronic infection are excluded. 
3.2.11 Patients with known diabetes whose glucose control or general health condition 
may be adversely affected by the use of metformin as per the study protocol as 
deemed by either the study investigator or endocrinologist are excluded.  
3.2.12 Patients must not have any of the following contraindications to metformin: 

Hypersensitivity to metformin or any component of the formulation

Kidney dysfunction or abnormal creatinine (Cr < 2ng/mL) from any cause 

Acute or metabolic acidosis
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4.0
TREATMENT PLAN
4.1
Overview
Nivolumab and metformin combination will be administered intravenously and orally, 
respectively, until disease progression or intolerable toxicity. Metformin will be initiated 
during a 7-day Induction period at 1,000mg orally once daily. Metformin will then be 
escalated by 500mg every 7 days as tolerated (C1D1 and C1D8) until the full 2,000mg 
dose is reached. Extended release formulation - Glucophage XR will be used for the 
study and commercial supply will be used which will be purchased and dispensed by NU 
investigational pharmacy. During Cycle 1-4 (1 cycle = 28 days), nivolumab will be given 
at 240mg every 14 days (Day 1 & 15) over approximately 30 minutes (-5 / +15 minutes). 
Starting with Cycle 5 Day 1, nivolumab will be given at 480mg IV every 28 days over 
approximately 60 minutes (-10 / +15 minutes). Patients will be assessed for response 
every 8 weeks (2 cycles).
Note: Please refer to section 4.4 for patients who may continue treatment after initial 
progression.
Dosing schedule is summarized in the table below.
Table 4-1: Dosing of Nivolumab and Metformin
Drug
Dose
Route
Schedule
Nivolumab 
(Opdivo)
C1-4: 240mg
C5+: 480mg
IV
Cycle 1-4: every 14 days 
Cycle 5+: every 28 days until progression of disease, 
intolerable toxicity, or withdrawal of consent
Metformin 
hydrochloride 
(Glucophage 
XR)
2,000mg*
PO
daily with evening meal until progression of disease, 
intolerable toxicity, or withdrawal of consent

starting dose: 1,000mg

dose escalation plan: weekly by 500mg
*Metformin will be initiated at 1,000mg during the Induction period and escalate by 
500mg (1 tablet) every 7 days until the final dose of 2,000mg.
4.2
Treatment Administration
4.2.1
Nivolumab 
Treatment will be administered on an outpatient basis. Reported adverse events 
and potential risks are described below. No investigational or commercial agents 
or therapies other than those described below may be administered with the 
intent to treat the patient’s malignancy.
During Cycle 1-4, nivolumab will be administered at a fixed dose of 240 mg 
intravenously over approximately 30 minutes (-5 / +15 minutes) every 14 days. 
Starting with Cycle 5, nivolumab will be administered at 480mg IV over 60 
minutes (-10 / +15 minutes) every 28 days until disease progression, intolerable 
toxicity, or withdrawal of consent. 
There will be no dose escalations or reductions of nivolumab allowed. Subjects 
may be dosed no less than 12 days or 24 days from the previous dose (for 240 
mg and 480 mg doses, respectively). There are no pre-medications 
recommended for nivolumab on the first cycle. If an acute infusion reaction is 
noted, subjects should be managed according to Section 4.3.3.
Nivolumab is to be administered as a 30-minute (-5 / +15 minutes) or 60-minute 
(-10 / +15±± minutes) IV infusion (for 240mg and 480mg respectively), using a 
volumetric pump with a 0.2- 1.2 micron low-protein binding in-line filter at the 
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protocol-specified dose. The drug can be infused undiluted or diluted so as not to 
exceed a total infusion volume of 120mL. 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. 
Subjects will be monitored continuously for AEs while on study. Treatment delay 
or discontinuation will be based on specific laboratory and adverse event criteria. 
Early recognition and management may mitigate severe toxicity. Evaluation and 
Management Guidelines were developed to assist investigators and can be 
found in the Investigator Brochure: 

Suspected Pulmonary Toxicity  

Diarrhea and Colitis  

Suspected Hepatotoxicity (including asymptomatic liver function tests [LFT] 
elevations)  

Suspected Endocrinopathy

Nephrotoxicity
4.2.2
Metformin
Metformin will be administered orally once daily until disease progression, 
intolerable toxicity or withdrawal of consent. Extended release formulation - 
Glucophage XR, 500 mg will be used for the study. Two tablets (1,000 mg) PO 
once daily will be given for the first 7 days, then 3 tablets (1,500 mg) for the next 
7 days, then 4 tablets (2,000 mg) for the rest of the treatment period. Metformin 
should be taken with meals. This dose escalation plan is to minimize possible 
gastrointestinal toxicity of metformin. 2550mg of metformin is the FDA approved 
maximum dose of metformin. Tablets should not be cut, crushed, or chewed. 
Metformin will be held per institutional guidelines with IV contrast dye injection 
required for each imaging studies. Metformin dosing can occur independently of 
nivolumab dosing. No premedications are needed.  
Patients will maintain a drug diary throughout the study to monitor compliance of 
metformin dosing. Patients will return completed drug diaries, drug bottles, and 
any unused metformin tablets at each study visit.
4.3
Toxicity Management & Dose Delays/Modifications
Any patient who receives at least one dose of study therapy will be evaluable for toxicity 
endpoints. Each patient will be assessed for the development of toxicity according to the 
timeframe referenced in the Schedule of Events table. Toxicity will be assessed 
according to the NCI CTCAE v. 4.03. 
4.3.1
Dose delays: nivolumab
There will be no dose modifications allowed for management of toxicities.
Should the treating physician decide to delay treatment given suspicion for a 
drug-related side effect, the side effect should be attributed to one study drug to 
the best of the physician’s ability. Nivolumab should be delayed based on this 
attribution, or both drugs if a definite attribution is not possible. Nivolumab can be 
held for a maximum of 56 days.
Nivolumab administration should be delayed for the following until resolution to ≤ 
Grade 1 or baseline: 

Any Grade ≥ 2 non-skin, drug-related adverse event, with the following 
exceptions:
o
Grade 2 drug-related fatigue or laboratory abnormalities do not 
require a treatment delay 
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o
Any Grade 3 skin, drug-related adverse event
o
Any Grade 3 drug-related laboratory abnormality, with the following 
exceptions for  lymphopenia, leukopenia, AST, ALT, or total bilirubin:

Grade 3 lymphopenia or leukopenia does not require dose 
delay

If a subject has a baseline AST, ALT or total bilirubin that is 
within normal limits, delay dosing for drug-related Grade ≥ 2 
toxicity 

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 abnormality, or intercurrent illness which, in the 
judgment of the investigator, warrants delaying the dose of study medication. 
4.3.2
Treatment discontinuation: nivolumab
Should the treating physician decide to discontinue treatment given suspicion for 
a drug-related side effect, the side effect should be attributed to one study drug 
to the best of the physician’s ability. Nivolumab should be discontinued based on 
this attribution, and the patient must come off study treatment. The patient may 
not receive metformin monotherapy on-study.
Nivolumab should be discontinued permanently for the following:

 Any Grade 2 drug-related uveitis, eye pain, or blurred vision that does not 
respond to topical therapy and does not improve to Grade 1 severity within 
the re-treatment period OR requires systemic treatment

Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the 
following exceptions for laboratory abnormalities, drug-related uveitis, 
pneumonitis, bronchospasm, hypersensitivity reactions, infusion reactions, 
and endocrinopathies:
o
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, 
hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation
o
Grade 3 drug endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation
o
Grade 3 drug-related laboratory abnormalities do not require 
treatment discontinuation except:

Grade 3 drug-related thrombocytopenia > 7 days or associated 
with bleeding (aside from minor bleeds ≤ Grade 1) requires 
discontinuation

Any drug-related liver function test (LFT) abnormality that meets 
the following criteria require discontinuation:

AST or ALT > 5-10 x ULN for > 2 weeks

AST or ALT > 10 xUL

Total bilirubin > 5 x ULN

Concurrent AST or ALT > 3 xULN and total bilirubin > 2 
x ULN
 

Any Grade 4 drug-related adverse event or laboratory abnormality, except for 
the following events which do not require discontinuation:
o
Grade 4 neutropenia < 7 days
o
Grade 4 lymphopenia or leukopenia
o
Isolated Grade 4 amylase or lipase abnormalities that are not associated 
with symptoms or clinical manifestations of pancreatitis. PI and Data and 
Safety Monitoring Committee (DSMC) should be consulted for Grade 4 
amylase or lipase abnormalities.
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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

Grade 4 drug-related endocrinopathy adverse events, such as adrenal 
insufficiency, ACTH deficiency, hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-
controlling agents, respectively, may not require discontinuation.
 

Any event that leads to interruption in dosing lasting > 4 weeks from the 
previous dose requires discontinuation, 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 interruptions lasting > 4 weeks from the previous 
dose, the PI and DSMC must be consulted. Tumor assessments should 
continue as per protocol even if dosing is interrupted. Periodic study 
visits to assess safety and laboratory studies should also continue every 
4 weeks or more frequently if clinically indicated during such dosing 
interruptions.
o
Dosing interruptions lasting > 4 weeks from the previous dose that occur 
for non-drug- related reasons may be allowed if approved by the PI and 
DSMC. Prior to re-initiating treatment in a subject with a dosing 
interruption lasting > 4 weeks, the PI and DSMC must be consulted. 
Tumor assessments should continue as per protocol even if dosing is 
interrupted. Periodic study visits to assess safety and laboratory studies 
should also continue every 4 weeks or more frequently if clinically 
indicated during such dosing interrupted.
o
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.
o
If the patient is still receiving clinical benefit, he or she can hold drug for 
a maximum of 8 weeks (56 days) and subsequently continue therapy 
following the original treatment schedule.
4.3.3
Treatment of Nivolumab-related infusion reactions
Since nivolumab contains only human immunoglobulin protein sequences, it is 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. 
However, if such a reaction were to occur, it might manifest with fever, chills, 
rigors, headache, rash, pruritus, arthralgias, hypotension, hypertension, 
bronchospasm, or other allergic-like reactions. 
Treatment recommendations are provided below and may be modified based on 
local treatment standards and guidelines, as appropriate: 
Table 4-2: Nivolumab Infusion Reactions
NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Remain at bedside and monitor 
subject until recovery from 
symptoms. 
The following prophylactic pre-
medications are recommended 
for future infusions: 

Diphenhydramine 50 mg 
(or equivalent) and/or

Acetaminophen 325 to 
1000 mg at least 30 
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Table 4-2: Nivolumab Infusion Reactions
NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
minutes before 
additional nivolumab  
administrations
Grade 2
Moderate reaction requires 
therapy or infusion interruption 
but responds promptly to 
symptomatic treatment [eg, 
antihistamines, non-steroidal 
anti- inflammatory drugs, 
narcotics, corticosteroids, 
bronchodilators, IV fluids]; 
prophylactic medications 
indicated for < 24 hours
Stop the nivolumab infusion, 
begin an IV infusion of normal 
saline, and treat the subject with 
diphenhydramine 50 mg IV (or 
equivalent) and/or acetaminophen 
325 to 1000 mg; 
 
Remain at bedside and monitor 
subject until resolution of 
symptoms. 
Corticosteroid and/or 
bronchodilator therapy may also 
be administered as appropriate. If 
the infusion is interrupted, then 
restart the infusion at 50% of the 
original infusion rate when 
symptoms resolve; if no further 
complications ensue after 30 
minutes, the rate may be 
increased to 100% of the original 
infusion rate. 
Monitor subject closely. If 
symptoms recur, then no further 
nivolumab will be administered at 
that visit.
For future infusions, the following 
prophylactic pre-medications are 
recommended: 

Diphenhydramine 50 mg (or 
equivalent) and/or

Acetaminophen 325 to 1000 
mg should be administered 
at least 30 minutes before 
nivolumab infusions. If 
necessary, corticosteroids 
(up to 25 mg of SoluCortef or 
equivalent) may be used.
Grades 3 or 4
Severe reaction, Grade 3: 
prolonged [ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion]; 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae [eg, 
renal impairment, pulmonary 
infiltrates]. Grade 4: Life-
threatening; pressor or 
ventilatory support indicated
Immediately discontinue infusion 
of nivolumab infusion. Begin an IV 
infusion of normal saline and treat 
the subject as follows: 
Recommend bronchodilators, 
epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous 
administration or 0.1 to 0.25 mg of 
a 1:10,000 solution injected slowly 
for IV administration, and/or 
diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or 
equivalent), as needed. 
Subject should be monitored until 
the Investigator is comfortable 
that the symptoms will not recur. 
Nivolumab will be permanently 
discontinued. Investigators should 
follow their institutional guidelines 
for the treatment of anaphylaxis. 
Remain at bedside and monitor 
No subsequent dosing
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Table 4-2: Nivolumab Infusion Reactions
NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
subject until recovery of the 
symptoms
In case of late-occurring 
hypersensitivity symptoms (eg, 
appearance of a localized or 
generalized pruritus within 1 week 
after treatment), symptomatic 
treatment may be given (eg, oral 
antihistamine or corticosteroids
Immunotherapy agents such as nivolumab are associated with AEs that can differ in 
severity and duration compared to other therapeutic classes of medications. Early 
recognition and management of AEs associated with nivolumab can mitigate severe 
toxicity. Corticosteroids are the primary therapy for drug-related AEs. Management 
algorithms have been developed to assist investigators in assessing and managing 
nivolumab associated AEs, which can be found in Appendix D of this protocol. The 
guidance provided in these algorithms should not replace the Investigator’s medical 
judgment.
4.3.4
Metformin  
The most common adverse reactions to metformin are diarrhea, nausea/vomiting, 
flatulence, indigestion, and headaches.  These side effects occur most commonly upon 
initiation of therapy and are short lived.  These effects are mitigated by dose escalation 
regimens that are used in this trial.  Dose reduction or discontinuation will be applied in 
patients with persistent gastrointestinal symptoms related to metformin.  A rare but 
serious side effect of metformin is lactic acidosis, which is most common in patients with 
renal insufficiency and congestive heart failure.  Lactic acidosis can be evaluated by 
checking a patient’s renal function in addition to their serum lactic levels.  Any clinical or 
laboratory indication of metabolic acidosis will lead to immediate discontinuation of 
metformin.  
For commonly observed gastrointestinal AEs of metformin such as nausea, vomiting and 
diarrhea the dose should be withheld. Metformin should be held until the AE resolves to ≤ 
Grade 1 or baseline and restarted at a lower dose level as per Table 4-3. Metformin can 
be held for a maximum of 28 days. Patients who permanently discontinue metformin for 
toxicity must come off study treatment – they may not receive nivolumab monotherapy 
on-study.
Metformin-induced side effects as determined by the study investigator should be 
managed as listed below in tables 4-3 and 4-4.  
Table 4-3: Metformin-related toxicity dose reductions
CTCAE Grade
Metformin Dosing
0-2
No change from original starting dose
3 (1st occurrence)
Hold until resolved to ≤ grade 1 or 
baseline, then reduce to lower dose
3 (2nd occurrence)
Hold until resolved to ≤ grade 1 or 
baseline, then reduce to lower dose
3 (3rd occurrence) or 4
Discontinue treatment
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Table 4-4: Dose reduction of Metformin for toxicity
Current dose
Reduced dose
2000 mg
1500 mg
1500 mg
1000 mg
1000 mg
500 mg
500 mg
Discontinue*
Note: For the purpose of imaging with CT scan with IV contrast, metformin can be held 
according to the institution’s CT scan protocol.
*Patients will discontinue all study treatment
4.4
Continuation of Investigational Therapy after Progression
In the event of an initial assessment of progressive disease (PD, based on RECIST 
Version 1.1), a subject may continue to receive the assigned study treatment as long as 
the criteria listed below are met and eligibility to continue is documented in the medical 
record at the time the decision is made to continue treatment.
1. No confirmed PD: a subsequent scan obtained at least 4 weeks from prior scan is not 
suggestive of PD by RECIST 1.1 (see section 6.4.2), and the patient does not have 
clinical decline. 
NOTE: If PD is confirmed but the patient continues to have clinical benefit (e.g. 
improvement of symptoms and is tolerating treatment), the patient can continue 
treatment beyond PD per clinician’s discretion. 
2. Does not meet any of the other investigational product discontinuation criteria (Section 
4.4.2) 
3. Clinical symptoms or signs indicating significant PD such as the benefit-risk ratio of 
continuing therapy is no longer justified. 
4. No decline in ECOG performance status.
5. No threat to vital organs/critical anatomical sites (eg, spinal cord compression) 
requiring urgent alternative medical intervention, and continuation of study therapy 
would prevent institution of such intervention. 
If the lesions included in the tumor burden subsequently regress to the extent that the 
criteria for PD are no longer met, then treatment may continue according to the treatment 
schedule. 
4.5
Concomitant Medications/Treatments
4.5.1
Permitted Medications
All treatments that the investigator considers necessary for a subject’s welfare 
may be administered at the discretion of the investigator in keeping with the 
community standards of medical care. All concomitant medication will be 
recorded on the case report form (CRF) including all prescription, over-the-
counter (OTC), herbal supplements, and IV medications and fluids. If changes 
occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included on the CRF.
Subjects are permitted the use of topical, ocular, intra-articular, intranasal, and 
inhalational corticosteroids (with minimal systemic absorption). A brief (less than 
3 weeks) course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for 
treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity 
reaction caused by a contact allergen) is permitted. Inhaled or topical steroids, 
and adrenal replacement steroids are permitted at any dose in the absence of 
active autoimmune disease. 
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Concomitant palliative and supportive care for disease related symptoms 
(including bisphosphonates and RANK-L inhibitors) is allowed if initiated prior to 
first dose of study therapy. 
All concomitant medications received from informed consent until 30 days after 
the last dose of trial treatment should be recorded.  Concomitant medications 
administered past 30 days of treatment should be recorded if associated with an 
SAE.
4.5.2
Prohibited Medications
Subjects are prohibited from receiving the following therapies during the 
Screening and Treatment Phase of this trial:

Anti-cancer systemic chemotherapy or biological therapy (≤14 days prior 
to registration)

Immunotherapy not specified in this protocol (≤14 days prior to 
registration)

Investigational agents (≤14 days prior to registration)

Corticosteroids are not permitted ≤ 14 days prior to registration unless 
they fall under the criteria listed in 4.5.1

For the purpose of imaging with CT scan with IV contrast, metformin can 
be held according to the institution’s CT scan protocol.
4.6
Duration of Therapy
Patients may continue with treatment until any of the following occur:

Disease progression, unless the patient meets criteria for continuing treatment 
beyond progression. See section 4.4 for details.

Development of an inter-current illness that prevents further administration of 
treatment

Unacceptable adverse event(s) requiring discontinuation of at least one study drug

Patient decides to withdraw from either study treatment or the as a whole study

The treating investigator determines that the patient should be taken off treatment 
for any reason (i.e. changes in condition, inability to comply with study treatment or 
procedures)
4.7
Duration of Follow Up
All patients will be followed for adverse events for 30 days after last dose of study 
treatment (100 days for SAEs), or until the patient starts a new treatment, whichever 
occurs first. Patients who discontinue treatment for unacceptable adverse event(s) will be 
followed until resolution or stabilization of the adverse event (i.e. the grade is not 
changing). If a patient stops treatment due to unacceptable adverse event(s) but has not 
demonstrated disease progression, then the patient will be followed with imaging studies 
every 8 weeks until the time of progression radiographically according to RECIST 1.1 
criteria. In the event that a radiographic response is detected, then this event will be 
included as a response in the final analysis, and the time of progression used in 
calculation of the survival analysis. Patients will be followed for survival status every 3 
months for 1 year and every 6 months for a total of 3 years after treatment 
discontinuation for survival or progression of disease. 
4.8
Removal of Subjects from Study Treatment and/or Study as a Whole
Patients can be taken off the study treatment and/or study as a whole at any time at their 
own request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation must be clearly 
documented on the appropriate eCRF and may include:

Patient voluntarily withdraws from treatment (follow-up permitted)
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
Patient withdraws consent (no follow-up permitted)

Patient is unable to comply with protocol requirements

Patient demonstrates disease progression 

Patient experiences unacceptable toxicity 

Treating physician determines that continuation on the study would not be in the 
patient’s best interest

Patient becomes pregnant 

Patient develops a second malignancy that requires treatment which would interfere 
with this study

Patient becomes lost to follow-up (LTF) 
Patients who are permanently discontinued from receiving investigational product will be 
followed for disease progression and safety, including the collection of any protocol- 
specified blood specimens, unless consent is withdrawn or the subject is lost to follow-up 
or administered subsequent therapy. All subjects will be followed for survival and disease 
progression. Subjects who decline to return to the site for evaluations will be offered 
follow-up by phone every 3 months as an alternative.
4.9
Patient Replacement
If a patient is enrolled in the study but comes off study before cycle 1 day 1 of 
treatment, the patient may be replaced
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5.0
STUDY PROCEDURES TABLE
Table 5-1: Study Procedures
STUDY PROCEDURES 
Induction15
(7 days)
Cycle 1-4
(Cycle=28 days)
Cycle 5+
(Cycle = 28 days)
End of 
Treatment13
 Study window
Screening2,10
D1
D1 (±3 day)
D15 (±3 day)
D1 (± 3 days)
± 7 days
Follow Up16
Informed Consent1
X
Medical history
X
X
Physical Exam
X
X
X
X
X
X
Vital signs3
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
AE reporting
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
Chemistry panel4
X
X
X
X
X
X
CBC with differential5
X
X
X
X
X
X
Pregnancy test 6
X
X
X
Thyroid function test7
X
ECHO/ECG
X17
Imaging (CT or MRI)8
X
X8
X7
Biopsy tissue9,14
X
Blood biomarker14
X
X14
X
Nivolumab infusion11
X11
X11
X11
Metformin dispensing12
X
X
X
Survival
X
1.
Informed consent must be signed within 30 days of registration. If signature is outside that window a new consent should be signed.
2.
Pre-study H&P and all labs must be ≤ 14 days before registration. Tumor measurements and radiologic evaluations must be ≤28 days before 
registration. 
3.
Vital signs include pulse, blood pressure, and weight. Height will be recorded at baseline only.
4.
Serum Chemistry will include calcium, chloride, magnesium, phosphorus, creatinine, sodium, potassium, blood urea nitrogen, bicarbonate, 
glucose, total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), albumin, and total protein. 
5.
CBC: Performed at each study visit, prior to nivolumab. For patients experiencing significant drop in WBCs or platelets felt related to treatment, 
CBCs should be obtained more frequently (weekly or more frequently) to assess timing for retreatment or need for transfusion support.

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6.
Serum or urine test only for women of childbearing potential; must be tested within 7 days prior to registration and on Cycle 1 Day 1 (prior to 
nivolumab). 
7.
Thyroid function tests will include thyroid stimulating hormone and free T4. This will be done at baseline then only as clinically indicated thereafter. 
8.
The same modality used at baseline should be used throughout for imaging. CT imaging with contrast will occur every 2 cycles starting with Cycle 
3 Day 1 (± 7 days) and should include chest, abdomen, and pelvis. Neck will be included only if measurable lesions are present. Metformin should 
be held prior to scans per each institutional protocol. Tumor measurements will be performed using RECIST 1.1. Progressive Disease (PD) must 
be confirmed by repeat scan within 8 weeks at least after 4 weeks. Patients with a known history of CNS disease must have CNS imaging at 
screening to rule out activity.
9.
Patients will undergo a fresh tissue biopsy prior to study enrollment, unless deemed to be clinically inappropriate per PI. If not feasible, archived 
tissue will be used (if available).
10. The maximum time interval between registration and the first dose of study drug will be 14 days
11. Nivolumab will be given as follows:
Cycle 1-4: 240mg IV over 30 minutes (-5 / +15 minutes) every 14 days (Day 1 & 15, ±3 days)
Cycle 5+: 480mg IV over 60 minutes (-10 / +15 minutes) every 28 days (Day 1, ±3 days) until disease progression, intolerability, or withdrawal of 
consent. 
12. Metformin will be dispensed Day 1 of each cycle. Dosing will begin at 1,000mg po once daily and escalate by 500mg every 7 days until the final 
dose of 2,000mg is reached. Patients will return unused drug and drug bottles at each study visit and will maintain a drug diary to track 
compliance.
13. The end of treatment visit should occur 30 days after the last dose of study treatment (+/- 7 days) or before starting another line of treatment, 
whichever comes first. 
14. Correlatives from peripheral blood will be collected for all patients at Induction Day 1, C1D1, C3D1, and at the EOT. Biopsy samples (fresh or 
archived) will be collected for all patients if possible. See separate lab manual for specifications. See section 9.0 for details.  
15. Metformin monotherapy will be given at 1,000mg PO QD during the 7-day Induction period, prior to starting nivolumab on Cycle 1 Day 1. 
16. After patients come off treatment they will be followed up at 3, 6, 9, and 12 months (±7 days) and then every 6 months (±14 days) for 3 years for 
survival and progression of disease via either clinic visits or phone calls.
17. Echocardiogram and/or ECG should be performed at screening as clinically indicated for patients with a history of congestive heart failure or at 
risk because of underlying cardiovascular disease or exposure to cardiotoxic drugs. Cardiac toxicities should be closely monitored throughout 
treatment. 

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6.0
ENDPOINT ASSESSMENT
6.1
Solid Tumors
6.1.1 Response will be evaluated using the modified Response Evaluation Criteria in 
Solid Tumors, based on RECIST v1.1.12
6.1.2 Clinical evaluation and tumor assessments will be performed as indicated in Table 
7, based on physical examination and radiologic evaluation. 
6.1.3 Any lesion that has been previously treated with radiotherapy should be 
considered as a non-target lesion. However, if a lesion previously treated with 
radiotherapy has clearly progressed since the radiotherapy, it can be considered 
as a target lesion.
6.1.4 Definitions for measurable and non-measurable lesions, and criteria for response, 
should be based on RECIST v1.1.
6.1.5 Measurable Lesions
Must be accurately measured in at least one dimension (greatest diameter) with 
a minimum size of 10mm by CT scan (cuts of 5mm or less), MRI, or physical 
exam (ideally using calipers). Bone only disease is allowed, however, must have 
an osteoblastic component that can be easily measured.
6.1.6 Non-measurable Lesions
Defined as all other lesions less than 10mm. Examples of non-measurable 
lesions include leptomeningeal disease, ascites, pleural/pericardial effusions, 
inflammatory breast disease, lymphangitic involvement of skin or lung.
6.1.7 RECIST Response criteria (used for patient evaluation and treatment decisions)

Complete Response - Disappearance of all lesions.

Partial Response - At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters.

Objective Response Rate – the sum of complete responses and partial 
responses 

Progressive Disease - At least a 20% increase in the sum of diameters of 
target lesions, taking as reference the smallest sum on study (this includes 
the baseline sum if that is the smallest on study). In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of 
at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression.)

Stable Disease - Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of 
diameters while on study.
6.2
Immune-related RECIST (irRECIST)
6.2.1
In addition to above, tumor response will be assessed by the irRECIST for 
investigational purposes, not assessment of primary objective or treatment 
decisions.13 In RECIST v1.1, the appearance of new lesions indicates PD. 
However, in irRECIST, new measurable lesions are incorporated in the tumor 
burden, which is used to determine irPD, immune-related partial response (irPR), 
and immune-related complete response (irCR). New nonmeasurable lesions 
preclude irCR. Under RECST v1.1, there is no confirmation for PD. Under irRECIST, 
responses and irPDs must be confirmed by consecutive scans at least 4 weeks apart, 
assuming no clinical deterioration. We will define immune-related clinical benefit rate 
as immune-related stable disease (irSD), irPR, or irCR. 
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Table 6-1: Immune-related Response Evaluation Criteria: Overall Response
Tumor Burden
(Baseline and New)
Non-Target Lesions
(Baseline and New)
Response
Disappearance of non-
nodal lesions. All 
pathologic lymph nodes 
<10 mm (short axis)
Disappearance of non-
nodal lesions. All 
pathologic lymph nodes 
< 10 mm (short axis)
irCR
≥30% decrease from 
baseline
Any
irPR
≥20% increase from 
nadir and at least 5 mm
Any
irPD
Neither sufficient 
decrease to qualify for 
PR, nor sufficient 
increase to qualify for 
PD
Any
irSD
Disappearance of all 
non-nodal lesions. All 
pathologic lymph nodes 
<10 mm
Any other than 
disappearance of all 
non-nodal lesions and 
reduction of pathologic 
lymph nodes <10 mm
irPR
Not all evaluated
Any
irNE
irCR = immune-related complete response; irPD = immune-related progressive disease; 
irPR = immune-related partial response; irNE = immune-related not evaluable; irSD = 
immune-related stable disease; 
-Tumor burden is the sum of single diameters (short axis for nodal lesions, longest 
diameter for other lesions) for the target lesions. In subsequent scans, the diameters of 
new measurable lesions are added to the tumor burden. 
-Best overall response based on 2 consecutive measurements at least 4 weeks apart.
6.3
Primary Endpoint
To assess anti-tumor activity of the combination treatment of nivolumab and metformin in 
patients with advanced non-small cell lung cancer: Anti-tumor activity will be assessed by 
objective response rate (ORR, complete response and partial response) using RECIST 
criteria.  All patients who receive treatment will be considered evaluable except those 
removed from the study for adverse drug reactions.  
6.4
Secondary Endpoints
6.4.1
To assess the efficacy of the combination treatment of metformin with nivolumab 
according to depth, duration, and persistence of response, disease control rate 
(DCR; CR, PR, and SD at 24 weeks), progression-free survival (PFS), and overall 
survival (OS) in patients with non-small cell lung cancer with and without prior 
exposure to PD-1/PD-L1 inhibitors using RECIST criteria. Depth of response (SD 
or PR) is defined as the change in the sum of the largest tumor diameters per 
RECIST criteria.
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6.4.2
To assess the efficacy of the combination treatment of metformin with nivolumab 
according to depth, duration, and persistence of response, ORR, DCR, PFS, and 
OS in the above population using immune-related response criteria (irRC) criteria. 
Depth of response (SD or PR) is defined as the change in the sum of the largest 
tumor diameters per irRECIST.
6.4.3
To assess the safety and tolerability profile of the combination treatment of 
nivolumab and metformin in the above population using CTCAE version 4.03
6.5
Exploratory end points 
6.5.1
To assess the immune-related tumor and blood biomarkers including T 
cell markers and their association with treatment response in the above 
population
6.5.2
To assess the dynamic change in both immune and genomic biomarkers in blood 
that may correlate with response to metformin.  Blood will be collected prior to 
starting metformin and after 7 days of metformin treatment (C1D1, pre-dose).
7.0
ADVERSE EVENTS
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) of the 
Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please refer to 
Appendices for additional information). The level of risk attributed to this study requires high level 
monitoring, as outlined in the DSMP. In addition, the study will abide by all safety reporting 
regulations, as set forth in the Code of Federal Regulations.
7.1
Adverse Event Monitoring
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are reported in a 
routine manner at scheduled times during a trial (see Section 5 for time points). In 
addition, certain adverse events must be reported in an expedited manner to allow for 
optimal monitoring and patient safety and care. 
All patients experiencing an adverse event, regardless of its relationship to study drug, 
will be followed until: 

the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline; 

any abnormal laboratory values have returned to baseline; 

there is a satisfactory explanation other than the study drug for the changes 
observed; or

death.
7.2
Definitions & Descriptions
7.2.1
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an experimental intervention, whether or not related to 
the intervention. 
Recording of AEs should be done in a concise manner using standard, 
acceptable medical terms. In general, AEs are not procedures or measurements, 
but should reflect the reason for the procedure or the diagnosis based on the 
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abnormal measurement. Preexisting conditions that worsen in severity or 
frequency during the study should also be recorded (a preexisting condition that 
does not worsen is not an AE). Further, a procedure or surgery is not an AE; 
rather, the event leading to the procedure or surgery is considered an AE.
If a specific medical diagnosis has been made, that diagnosis or syndrome 
should be recorded as the AE whenever possible.  However, a complete 
description of the signs, symptoms and investigations which led to the diagnosis 
should be provided. For example, if clinically significant elevations of liver 
function tests are known to be secondary to hepatitis, “hepatitis” and not 
“elevated liver function tests” should be recorded. If the cause is not known, the 
abnormal test or finding should be recorded as an AE, using appropriate medical 
terminology (e/g/ thrombocytopenia, peripheral edema, QT prolongation).
7.2.2
Severity of AEs
All adverse events will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03. The CTCAE v4 is available at 
http://ctep.cancer.gov/reporting/ctc.html
If no CTCAE grading is available, the severity of an AE is graded as follows:

Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities.

Moderate (grade 2): the event causes discomfort that affects normal daily 
activities.

Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status.

Life-threatening (grade 4): the patient was at risk of death at the time of the 
event.

Fatal (grade 5): the event caused death.
7.2.3
Serious Adverse Events (SAEs)
All SAEs, regardless of attribution, occurring from time of signed informed 
consent, through 30 days after the last administration of study drug, must be 
reported upon discovery or occurrence.
An SAE is defined in regulatory terminology as any untoward medical occurrence 
that:

Results in death.
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself.

Is life-threatening.
The patient was at risk of death at the time of the event; it does not refer to 
an event that hypothetically might have caused death if it were more severe.

Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours.

Results in persistent or significant disability or incapacity.

Is a congenital anomaly/birth defect.

Is an important medical event.
Any event that does not meet the above criteria, but that in the judgment of 
the investigator jeopardizes the patient, may be considered for reporting as a 
serious adverse event. The event may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition of “Serious 
Adverse Event“. 
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency.
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7.2.4
Unanticipated Problems Involving Risks to Subject or Others
A UPIRSO is a type of SAE that includes events that meet ALL of the following 
criteria:

Is unanticipated in terms of nature, severity, or frequency

Places the research subject or others at a different or greater risk of harm

Is deemed to be at least possibly related to participation in the study.   
7.2.5
Hepatic Function Abnormality
Hepatic function abnormality is defined as any increase in ALT or AST to 
greater than 3 × ULN and concurrent increase in bilirubin to greater than 
2 × ULN. Concurrent findings are those that derive from a single blood draw or 
from separate blood draws taken within 8 days of each other. Follow-up 
investigations and inquiries will be initiated promptly by the investigational site 
to determine whether the findings are reproducible and/or whether there is 
objective evidence that clearly supports causation by a disease (eg, 
cholelithiasis and bile duct obstruction with distended gallbladder) or an agent 
other than the investigational product.
If the underlying diagnosis for the hepatic function abnormality is known 
(including progression of pre-existing disease such as primary or metastatic 
malignancy), the diagnosis should be recorded as an AE/SAE.
If the underlying diagnosis for the hepatic function abnormality remains 
unknown, the term “hepatic function abnormal” should be used to report the 
AE/SAE. Hepatic function abnormality of unknown etiology, or which is 
considered attributable to investigational product, is required to be reported as 
“hepatic function abnormal” within 24 hours of knowledge of the event. The 
investigator will review the data with the medical monitor. The investigator 
should then use clinical judgment to establish the cause based on local 
standard of care and follow the subject by conducting testing as clinically 
indicated.
7.2.6
Pneumonitis
Adverse events of pneumonitis are also of interest, as pneumonitis has 
been observed with anti-PD-1 and anti-PD-L1 mAbs. Initial work-up should 
include high-resolution CT scan, ruling out infection, and pulse oximetry. 
Pulmonary consultation is highly recommended.
7.2.7 
Other events requiring immediate reporting 
Overdose
An overdose is defined as a patient receiving a dose of investigational product 
in excess of dose detailed in this protocol.
Any overdose of a study patient with the investigational product, with or 
without associated AEs/SAEs, is required to be reported within 24 hours of 
knowledge of the event. If the overdose results in an AE, the AE must also be 
recorded on the AE eCRF. Overdose does not automatically make an AE 
serious, but if the consequences of the overdose are serious, for example 
death or hospitalization, the event is serious and must be reported as an 
SAE. The investigator will use clinical judgment to treat any overdose.
7.3
Reporting of pregnancy and lactation
Although pregnancy and lactation are not considered adverse events, it is the 
responsibility of investigators or their designees to report any pregnancy or lactation in a 
subject (spontaneously reported to them), including the pregnancy of a male subject's 
female partner that occurs during the trial or within 120 days of completing the trial 
completing the trial, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier.  All subjects and female partners of male 
subjects who become pregnant must be followed to the completion/termination of the 
IRB #: STU00204354-CR0003 Approved by NU IRB for use on or after 11/11/2019 through 11/10/2020.

NU Study Number: NU 16L04
Other Study Number: CA 209-801
Amendment 5: 4.22.19
36
pregnancy.  Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth 
must be reported as serious events (Important Medical Events).  If the pregnancy 
continues to term, the outcome (health of infant) must also be reported.
7.4
Adverse events Reporting
7.4.1
Routine Reporting
All routine adverse events, such as those that are expected, or are unlikely or 
definitely not related to study participation, are to be reported on the appropriate 
eCRF according to the time intervals noted in the appendices. Routine AEs will 
be reviewed by the Data and Safety Monitoring Committee (DSMC) according to 
the study’s phase and risk level, as outlined in the DSMP. 
7.4.2
Determining if Expedited Reporting is Required
This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the agent(s) must 
also be reported accordingly.
1)
Identify the type of adverse event using the NCI CTCAE v 4.03.
2)
Grade the adverse event using the NCI CTCAE v 4.03.
3)
Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows:

Definite: AE is clearly related to the study treatment.

Probable: AE is likely related to the study treatment.

Possible: AE may be related to the study treatment.

Unlikely: AE not likely to be related to the study treatment.

Unrelated: AE is clearly NOT related to the study treatment.
4)
Determine the prior experience of the adverse event.
Expected events are those that have been previously identified as 
resulting from administration of the agent. An adverse event is 
considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in:

the current protocol

the drug package insert

the current Investigator’s Brochure
7.4.3
Expedited Reporting of SAEs/Other Events
7.4.3.1 Reporting to the Northwestern University QAM/DSMC
All SAEs must be reported to the assigned QAM within 24 hours of 
becoming aware of the event. Completion of the NU CRO SAE Form, 
provided as a separate document, is required.
The completed form should assess whether or not the event qualifies as 
a UPIRSO. The report should also include:

Protocol description and number(s)

The patient’s identification number

A description of the event, severity, treatment, and outcome (if 
known)

Supportive laboratory results and diagnostics

The hospital discharge summary (if available/applicable)
All SAEs will be reported to, and reviewed by, the DSMC at their next 
meeting. See section 7.4.3.3 for instructions on reporting to BMS 
Global Safety.
IRB #: STU00204354-CR0003 Approved by NU IRB for use on or after 11/11/2019 through 11/10/2020.

NU Study Number: NU 16L04
Other Study Number: CA 209-801
Amendment 5: 4.22.19
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7.4.3.2 Reporting to the Northwestern University IRB

Any death of an NU subject that is unanticipated in nature and at 
least possibly related to study participation will be promptly reported 
to the NU IRB within 24 hours of notification. 

Any death of an NU subject that is actively on study treatment 
(regardless of whether or not the event is possibly related to study 
treatment) will be promptly reported to the NU IRB within 24 hours of 
notification, per Lurie Cancer Center policy.

Any death of a non-NU subject that is unanticipated and at least 
possibly related and any other UPIRSOs will be reported to the NU 
IRB within 5 working days of notification.

All other deaths of NU subjects not previously reported, other non-
NU subject deaths that were unanticipated and unrelated, and any 
other SAEs that were not previously reported as UPIRSOs will be 
reported to the NU IRB at the time of annual continuing review.
7.4.3.3 Reporting to BMS
SAE reports (including death by any cause), regardless of attribution will 
be reported within 24 hours to BMS Global Safety (using the NU CRO 
SAE Form and referencing the BMS study number, CA 209-801). The 
assigned study coordinator will facilitate all reporting to BMS Global 
Safety and email QA a copy of the report upon completion. BMS Global 
Safety can be notified at:
Email Address: Worldwide.Safety@BMS.com
8.0
DRUG INFORMATION
8.1
Nivolumab
8.1.1
Other names 
ONO-4538, BMS-936558, or MDX1106, Opdivo
8.1.2
Classification - type of agent
Human IgG4 anti-PD-1 monoclonal antibody
8.1.3
Mode of action
Nivolumab acts as an immunomodulator by blocking ligand activation of the 
programmed cell death 1 (PD-1) receptor on activated T cells anti-PD1.
8.1.4
Storage and stability
Nivolumab solution for infusion is a sterile, non-pyrogenic single-use, isotonic 
aqueous solution. Vials must be stored in a secure, limited-access location at 2 
to 8 degrees C (36 to 46 degrees F) and protected from light, freezing, and 
shaking. The product is a clear to opalescent solution, which may contain 
proteinaceous and extraneous particulates. The product is intended for IV 
administration. The drug product can be further diluted with normal saline in IV 
containers made of polyvinyl chloride (PVC) or non-PVC material. Opened or 
accessed vials should be immediately used to prepare the infusion solution in the 
IV bag and the infusion solution should be immediately administered.
After preparation, store the Nivolumab infusion either:

at room temperature for no more than 8 hours from the time of preparation. 
This includes room temperature storage of the infusion in the IV container 
and time for administration of the infusion or

under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours 
from the time of infusion preparation.
IRB #: STU00204354-CR0003 Approved by NU IRB for use on or after 11/11/2019 through 11/10/2020.

NU Study Number: NU 16L04
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Amendment 5: 4.22.19
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
Do not freeze.
8.1.5
Protocol dose specifics
A fixed dose of 240 mg IV every 2 weeks (Cycle 1-4) and 480mg IV every 4 
weeks (starting with Cycle 5 Day 1)  
8.1.6
Preparation

Nivolumab should be prepared in a laminar flow hood or safety cabinet using 
standard precautions for the safe handling of intravenous agents applying 
aseptic technique.

Visually inspect the drug product solution for particulate matter and 
discoloration prior to administration. Discard if solution is cloudy, if there is 
pronounced discoloration (solution may have a pale-yellow color), or if there 
is foreign particulate matter other than a few translucent-to-white amorphous 
particles.

Mix by gently inverting several times. Do not shake.

Aseptically withdraw the required volume of nivolumab solution into a 
syringe, and dispense into an IV bag.

If multiple vials are needed for a subject, it is important to use a separate 
sterile syringe and needle for each vial to prevent problems such as dulling of 
needle tip, stopper coring, repeated friction of plunger against syringe barrel 
wall.

Do not enter into each vial more than once. Do not administer as an IV push 
or bolus injection. 

Nivolumab injection can be infused undiluted or diluted so as not to exceed a 
total infusion volume of 120 mL.
8.1.7
Route of administration for this study
Intravenous infusion. Do not administer as an IV push or bolus injection. 
Administer nivolumab 240 mg as an intravenous infusion over 30 (-5/+15) 
minutes and 480mg as an intravenous infusion over 60 (-10/+15) through a 0.2 
micron to 1.2 micron pore size, low-protein binding polyethersulfone membrane 
in-line filter.
8.1.8
Incompatibilities: 
No incompatibilities between nivolumab injection and polyvinyl chloride (PVC), 
DEHP (di[2-ethylhexyl]phthalate), non-PVC/non-DEHP (di[2-ethylhexyl]phthalate) 
IV components, or glass bottles have been observed. Nivolumab should not be 
infused concomitantly in the same intravenous line with other medicinal products.
8.1.9 
Availability & Supply 
Nivolumab will be supplied by the study as 100 mg/Vial (10 mg/mL) clear to 
opalescent, colorless to pale yellow liquid in 10-cc Type 1 flint glass vials 
stoppered with butyl stoppers and sealed with aluminum seals.  May contain 
particles. 
A supply of nivolumab may be ordered from by completing a Drug Request Form 
provided by BMS. The first request may take place upon screening of the first 
patient. The initial order should be limited to 20 vials. Allow 5 business days for 
shipment of drug from BMS receipt of the Drug Request Form. Drug is protocol 
specific, but not patient specific. All drug product will be shipped by courier in a 
temperature-controlled container. It is imperative that only drug product 
designated for this protocol number be used for this study.
IRB #: STU00204354-CR0003 Approved by NU IRB for use on or after 11/11/2019 through 11/10/2020.

NU Study Number: NU 16L04
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Amendment 5: 4.22.19
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Drug re-supply request form should be submitted electronically 10 business days 
before the expected delivery date.  Deliveries will be made Tuesday through 
Friday.
When assessing need for resupply, keep in mind the number of vials used per 
treatment dose, and that shipments may take 14 business days from receipt of 
request. Drug is not patient-specific. 
8.1.10
Side effects
Nivolumab has been studied in over 8,600 subjects and is widely approved in 
multiple indications. Extensive details on the safety profile of nivolumab are 
available in the Investigator Brochure, and will not be repeated herein.
Overall, the safety profile of nivolumab monotherapy as well as combination 
therapy is manageable and generally consistent across completed and ongoing 
clinical trials with no MTD reached at any dose tested up to 10 mg/kg. Most AEs 
were low-grade (Grade 1 to 2) with relatively few related high-grade (Grade 3 to 
4) AEs. There was no pattern in the incidence, severity, or causality of AEs with 
respect to nivolumab dose level.
A pattern of immune-related adverse events has been defined, for which 
management algorithms have been developed; these are provided in Appendix 
D. Most high-grade events were manageable with the use of corticosteroids or 
hormone replacement therapy (endocrinopathies).
Below are safety data from 268 subjects with unresectable or metastatic 
melanoma and 117 patients with metastatic squamous NSCLC who received 
nivolumab alone. Related side effects reported in subjects receiving nivolumab 
alone were:
Very Frequent – Expected to occur in more than 20% of people (more than 20 
out of 100 people): Fatigue (50%), Dyspnea (38%), Musculoskeletal pain (36%), 
Rash (21%), Increased AST (28%), Increase alkaline phosphatase (22%), 
Hyponatremia (25-38%)
Frequent - Expected to occur in 10% to 20% of people (10 to 20 out of 100 
people): Pruritus (19%), Cough (17%), URI (11%), Peripheral edema (10%), 
Increased ALT (16%), Hyperkalemia (15%)
Not Frequent – Expected to occur in less than 10% of people (less than 10 out 
of 100 people): ventricular arrhythmia, iridocyclitis, infusion-related reactions, 
increased amylase, increased lipase, dizziness, peripheral and sensory 
neuropathy, exfoliative dermatitis, erythema multiforme, vitiligo, psoriasis
Deaths thought to be related to nivolumab when given alone were reported in 
approximately 0.5% of subjects treated (approximately 1 out 200 people).
8.1.11
Nursing implications
The first day of dosing is considered Day 1. Infusion duration for nivolumab will be 
approximately 30 minutes or 60 minutes for each individual infusion, for 240mg 
and 480mg doses, respectively.
Each dose of investigational product should be administered using the following 
guidelines:
1.
Investigational product must be administered at room temperature by 
controlled infusion via an infusion pump into a peripheral vein or central line. 
Prior to the start of the infusion, ensure that the bag contents are at room 
IRB #: STU00204354-CR0003 Approved by NU IRB for use on or after 11/11/2019 through 11/10/2020.

NU Study Number: NU 16L04
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temperature to avoid an infusion-related reaction due to the administration of 
the solution at low temperatures.
2.
A physician must be present at the site or immediately available to respond to 
emergencies during all administrations of investigational product. Fully 
functional resuscitation facilities should be available. Investigational product 
must not be administered via IV push or bolus but as a slow IV infusion. The 
entire content of each IV bag will be infused using an infusion pump. 
3.
The infusion lines should be attached only at time of use. Lines used for 
infusion during dose administration will need to be equipped with 0.22- or 0.2-
µm in-line filters.
4.
The duration of the investigational product administration will be recorded.
Nivolumab will be administered as an IV infusion over approximately 30 minutes. 
When an IV bag is used for the infusion, the IV line will be flushed with a volume 
of normal saline equal to the priming volume of the infusion set used after the 
contents of the IV bag are fully administered (unless prohibited by institutional 
practice).
8.1.12
Return and Retention of Study Drug
The clinical study team will be responsible for keeping accurate records of the 
clinical supplies received from BMS or designee, the amount dispensed to and 
returned not used by the subjects and the amount remaining at the conclusion of 
the trial. Upon completion or termination of the study, all unused and/or partially 
used investigational product will be destroyed at the site per institutional policy. It 
is the Investigator’s responsibility to arrange for disposal of all empty containers, 
provided that procedures for proper disposal have been established according to 
applicable federal, state, local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. 
Table 8-1 – Nivolumab Product Description:(Other names = MDX-1106, ONO-4538, anti-PD-1
Product 
Description 
and Dosage 
Form
Potency
   Primary 
Packaging
(Volume)/ 
Label Type
Appearance
Storage 
Conditions
(per label)
Nivolumab 
(BMS-
936558-01)*  
for Injection 
100 mg 
(10 
mg/Vial 
    10 mL vial
Clear to 
opalescent, 
colorless to 
pale yellow 
liquid.  May 
contain 
particles
BMS-936558-01 
Injection must be 
stored at 2 to 8 
degrees C (36 to 46 
degrees F) and 
protected from light 
and  freezing 
IRB #: STU00204354-CR0003 Approved by NU IRB for use on or after 11/11/2019 through 11/10/2020.

NU Study Number: NU 16L04
Other Study Number: CA 209-801
Amendment 5: 4.22.19
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8.2
Metformin
8.2.1
Other names 
Glucophage, N,N-dimethylimidodicarbonimidic diamide hydrochloride
8.2.2
Classification - type of agent
Oral antihyperglycemic drugs
8.2.3
Mode of action
Metformin is classified as an antidiabetic agent, a biguanide derivative. It 
decreases hepatic glucose production, decreases intestinal absorption of 
glucose, and improves insulin sensitivity by increasing peripheral glucose uptake 
and utilization. More recent data has revealed an immunomodulatory effect on 
cancer cells as described in section 1.2.
8.2.4
Storage and stability
Store at 20°–25° C (68°–77° F); excursions permitted to 15°–30° C (59°–86° F). 
[See USP Controlled Room Temperature.] Product will be dispensed in light-
resistant containers.
. 
8.2.5
Protocol dose specifics
Extended formulation  of  500 mg tablets will be used. Metformin will be initiated 
during a 7-day Induction period at 1,000mg orally once daily. Metformin will then 
be escalated by 500mg every 7 days as tolerated (C1D1 and C1D8) until the full 
2,000mg dose is reached. 
8.2.6
Preparation
None
8.2.7
Route of administration for this study
Oral
8.2.8
Incompatibilities
No formal drug-drug interactions have been reported with metformin and PD-1 or 
PD-L1 inhibitors. 

Cephalexin: May increase the serum concentration of metformin. 

Cimetidine: May decrease the excretion of metformin.

Corticosteroids (systemic): May diminish the hypoglycemic effect of 
antidiabetic agents. In some instances, corticosteroid-mediated HPA axis 
suppression has led to episodes of acute adrenal crisis, which may 
manifest as enhanced hypoglycemia, particularly in the setting of insulin 
or other antidiabetic agent use. 

Iodinated Contrast Agents: May enhance the adverse/toxic effect of 
metformin. Renal dysfunction that may be caused by iodinated contrast 
agents may lead to metformin-associated lactic acidosis.Use of these 
agents should be avoided while patients are receiving metformin and for 
48 hours after discontinuation; if it is necessary to conduct imaging while 
taking metformin, it should be performed with adequate hydration, and 
the use of mucomyst may be considered.
8.2.9
Availability & Supply 
As of January 2019, BMS will not provide Extended release Metformin tablets for 
the study. We will be switching from metformin supplied by BMS, to commercial 
supply of metformin which will be purchased and distributed through 
Northwestern University’s investigational pharmacy.
 It will be handled as an investigational agent and dispensed by the 
Investigational Pharmacy.
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NU Study Number: NU 16L04
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8.2.10
Side effects
Frequent (>10%)
Diarrhea, nausea, and flatulence.  These side effects typically subside after 
continued use of the medicine.  
Less Frequent (≤ 10%)
Asthenia, Indigestion, abdominal discomfort and Headache
Rare and serious
A rare severe side effect is lactic acidosis (1 in 33,000 patients).  The symptoms 
of lactic acidosis included feeling very weak, tired, or uncomfortable, unusual 
muscle pain, trouble breathing, unusual or unexpected stomach discomfort, 
feeling cold, feeling dizzy or lightheaded, and suddenly developing a slow or 
irregular heartbeat.
8.2.11
Nursing implications
Administer with food (to decrease GI upset) and with a full glass of water when 
feasible. Monitor bicarbonate levels on chemistry panels to ensure they stay 
within the normal range per institution. 
8.2.12
Return and Retention of Study Drug
Unused metformin, dispensed during previous visits, must be returned and drug 
accountability records updated. Returned capsules must be discarded and 
cannot be re-used in this study or outside the study. 
8.3
Combination of metformin and nivolumab
8.3.1
 Side Effects when nivolumab and metformin are given together
To our knowledge, no clinical trials combining metformin and nivolumab have 
been reported. Therefore, the side effects will be carefully monitored during 
the study.
9.0
CORRELATIVES/SPECIAL STUDIES
A fresh tissue biopsy of the primary tumor or a metastatic site at baseline will be collected if 
possible. If not feasible archived tissue will be used (if available). Fresh tissue biopsies will be 
performed using an image-guided core needle according to institutional practice. Tumor samples 
will be stored and may be used for additional correlative studies at a later date such as, but not 
limited to, immunohistochemistry, tumor mutation analysis, and proteomic analysis.
9.1
Sample Collection Guidelines
Blood samples are mandatory and will be collected for Flow and Biomarker analysis at 
Induction Day 1, C1D1, C3D1, and EOT. 
9.2
Sample Processing, Storage, and Shipment
Refer to the lab manual for sample processing, storage, and shipment information.
9.3
Assay Methodology
9.3.1
PD-L1 immunohistochemistry
Formalin-fixed, paraffin-embedded tumor specimens will be stained with anti-PD-
L1 monoclonal antibodies. PD-L1 will be scored as a percentage by two 
independent pathologists who are unaware of clinical data. PD-L1 staining as a 
predictive measure will be explored at various thresholds of positivity.
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9.3.2
Tumor infiltrating lymphocytes
TILs (CD8+, CD4+, nuclear FOXP3+) will be quantified by immunohistochemistry 
and assessed on hematoxylin and eosin stained tumor sections. TIL subsets will 
be classified as intraepithelial (iTILs) or stromal (sTILs), where iTILs are defined 
as the percentage of lymphocytes in direct contact with tumor cells, and sTILs 
are defined as the percentage of lymphocytes relative to the tumor stroma. 
Scoring, as a continuous percentage, will be performed by two independent 
pathologists who are unaware of clinical data.
9.3.3
T cell subpopulations
Population of CD4+, CD8+, and regulatory T cells (CD4+/CD25+) will be counted 
by cell sorting of PBMCs. Expression of CD4, CD8, and FOXP3 will be also 
examined in the tumor tissues to estimate relative ratio between T helper cells, 
killer T cells, and regulatory T cells. 
9.3.4
Immune and Genomic Biomarkers 
To assess the dynamic change in both immune and genomic biomarkers 
in blood that may correlate with response to metformin. Blood will be 
collected prior to starting metformin, pre-dose on C1D1, C3D1, and EOT. 
9.4
Specimen Banking
Patient samples collected for this study will be retained at Robert H Lurie Cancer Center 
of Northwestern University Pathology Core Facility. Specimens will be stored indefinitely 
or until they are used up, and such samples may be shared with researchers at other 
institutions. If future use is denied or withdrawn by the patient, best efforts will be made to 
stop any additional studies and to destroy the specimens. 
Dr. Young Chae will be responsible for reviewing and approving requests for clinical 
specimen from potential research collaborators outside of Northwestern University. 
Collaborators will be required to complete an agreement (a Material Transfer Agreement 
or recharge agreement) that states specimens will only be released for use in disclosed 
research. Any data obtained from the use of clinical specimen will be the property of 
Northwestern University for publication and any licensing agreement will be strictly 
adhered to.
The following information obtained from the subject's medical record may be provided to
research collaborators when specimens are made available:

Diagnosis

Collection time in relation to study treatment

Clinical outcome – if available

Demographic data
10.0
STATISTICAL CONSIDERATIONS
10.1
Study Design/Study Endpoints
This will be a phase II study of nivolumab and metformin in patients with advanced non-
small cell lung cancer.
The primary endpoint is objective response rate (ORR, complete response and partial 
response) using RECIST criteria v1.1 measured at 24 weeks from the start of treatment.
Secondary endpoints include assessing the efficacy of the combination treatment of 
nivolumab and metformin according to ORR, DCR, PFS, and OS in the above population 
using immune-related RECIST criteria (irRECIST) criteria in addition to RECIST criteria, 
and to assess assess the safety and tolerability profile of the combination treatment of 
nivolumab and metformin using CTCAE version 4. 
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Exploratory endpoints include biomarkers predictive of response from tissue and/or 
blood. They include but are not limited to assessment of tissue-based immunohistochemical 
expression of PD-L1; TILs; peripheral T cell subpopulations.
Clinical outcome will be analyzed according to three levels of PD-L1 expression:
<1%, 1-50%, and >50%.
Patients in Arm B (those who received prior PD-L1) will be categorized into two groups:
1.
Those who progressed while taking prior PD-L1 therapy (“checkpoint failures”)
2.
Those who responded to and failed or recurred after coming off PD-L1 therapy
10.2
Sample Size and Accrual
Up to 49 patients (Arm A=24, Arm B=25) will be entered into the trial based on optimal 
Simon two stage design as below.
Arm A: In the first stage, 9 patients will be entered.  If no patients show a response, then 
the trial will be terminated due to inactivity of the treatment.  If 1 or more of 9 show a 
response, then an additional 15 patients will be added.  If 2 or fewer of 24 show a response, 
then the trial will conclude that the response rate could be as low as 5%.  If 3 or more 
respond, then the trial will conclude that the response rate is at least 20%.  This design has 
a 20% chance of falsely concluding the rate is 5% (false negative Type II error rate = 20%, 
or power = 80%), and a 10% chance of falsely concluding that the rate is 20% (false positive 
Type I error rate = 10%).  There is a 63% probability of early termination of the trial when 
the true response rate is 5%.
Arm B: In the first stage, 12 patients will be entered.  If 2 or less patients show a response, 
then the trial will be terminated due to inactivity of the treatment.  If 3 or more of 12 show 
a response, then an additional 13 patients will be added.  If 7 or fewer of 25 show a 
response, then the trial will conclude that the response rate could be as low as 20%.  If 8 
or more respond, then the trial will conclude that the response rate is at least 40%.  This 
design has a 20% chance of falsely concluding the rate is 20% (false negative Type II error 
rate = 20%, or power = 80%), and a 10% chance of falsely concluding that the rate is 40% 
(false positive Type I error rate = 10%).  There is a 56% probability of early termination of 
the trial when the true response rate is 5%.
Due to inevaluable patients and dropout, target accrual will be 51 patients.  It is anticipated 
that 2 patients will be accrued per month so that accrual to this study will take 2 years.  
Thus, this study will be a single institution trial with duration of enrollment being 2 years.
The study will be done via both internal and external referral system. Being one of the 
busiest lung cancer programs in the area with good advertisement plan towards partnering 
institutions on this clinical trial, the above accrual plan is deemed to be a feasible one. 
10.3
Data Analyses Plans
Summary of Analytic plan for primary 
objective
Summary of Analytic plan for secondary 
objectives
Please refer to the below sample size 
justification for the parallel Simon’s two stage 
design which defines how the endpoints are 
met.
For Group A. Estimated ORR for historical 
control is 20% versus target ORR of 40% for 
niovulomab and metformin combination 
treatment.
Depth of response: waterfall plot
Duration and persistence of response: 
swimmer’s plot
   PFS: PFS at 1 and 2 years (Kaplan-Meier 
analysis)
   OS: OS at 1 and 2 years (Kaplan-Meier 
analysis)
   ORR, DCR by irRC (descriptive statistics, 
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For Group B. Estimated ORR for refractory 
patients is 5% versus target ORR of 40% for 
niovulomab and metformin combination 
treatment.
exact binomial confidence intervals)
We will use descriptive statistics and 
graphical displays to evaluate change in 
serum biomarkers between pre- and post-
treatment.  A Wilcoxon signed rank test will be 
used to determine if there is a statistically 
significant change in serum biomarkers.
Toxicities will be tabulated by type and grade.
The primary analysis will be on the evaluable analysis set, including all evaluable patients 
regardless of drug exposure. Clinical benefit rate will be defined as stable disease (for ≥12 
weeks), complete or partial response by both the Response Evaluation Criteria in Solid 
Tumors (RECIST) and irRECIST. Maximum response prior to disease progression will be 
used. The overall response rate will be estimated by the proportion of overall response, 
and its 80% confidence interval (CI) and 95% CI will be estimated using the exact 
binomial distribution.
Additionally, we will evaluate overall response rate, defined as complete or partial 
response using RECIST guidelines in a similar manner. We will also perform similar 
analyses using Immune Related RECIST (irRECIST). Duration of response, defined as 
the duration from the first documentation of clinical benefit to the first documented 
progressive disease or death of any cause, whichever occurs first, will also be analyzed. 
For patients alive and progression-free at the time of data cut off, duration of response 
will be censored as of the last tumor assessment date. Duration of response will only be 
evaluated for the subgroup of patients with a clinical benefit using the Kaplan-Meier 
method.
PFS is defined as the time from treatment initiation to documented disease progression. 
OS is defined as the time from the start of treatment until death due to any cause. For 
patients alive at the time of data cut-off, PFS and OS will be censored as of the last tumor 
assessment date or known to be alive, respectively. The PFS and OS will be estimated 
using the Kaplan-Meier method. The number, frequency, and severity of adverse events 
(as defined by the NCI Common Terminology Criteria for Adverse Events or CTCAE 
version 4.03) will be recorded.
Baseline percent PDL1 expression, TILs (sTILs, iTILs, and their ratio), and changes in T 
cell subpopulations will be used as a continuous variable to predict clinical benefit or 
overall response rates using appropriate statistical summaries. Cox proportional hazards 
regression will be used to compare how these biomarkers are associated with PFS and 
OS as well.
Changes in these biomarkers will also be analyzed to assess for pharmacodynamic 
effects of treatment. Continuous variables will be analyzed using either paired t-tests 
(normally distributed data), signed rank tests (non-normally distributed data) or repeated 
measures analysis of variance (correlated normally distributed data).
11.0
STUDY MANAGEMENT
11.1
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol.
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki.
IRB #: STU00204354-CR0003 Approved by NU IRB for use on or after 11/11/2019 through 11/10/2020.

NU Study Number: NU 16L04
Other Study Number: CA 209-801
Amendment 5: 4.22.19
46
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB approved consent form.
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the 
informed consent discussion.
11.2
Amendments
The Principal Investigator will formally initiate all amendments to the protocol and/or 
informed consent. All amendments will be subject to the review and approval of the 
appropriate local, institutional, and governmental regulatory bodies, as well as by BMS 
Scientific Affairs. Amendments will be distributed by the lead institution (Northwestern) to 
all affiliate sites upon approval by the Northwestern University IRB.
11.3
Registration Procedures
Patients may not begin protocol treatment prior to registration. All patient registrations will 
be registered centrally through the Clinical Research Office at Northwestern University 
before enrollment to study. Please contact the assigned Quality Assurance Monitor 
(QAM) or email the QA Department (croqualityassurance@northwestern.edu) for 
questions regarding patient registration.  
Prior to registration, eligibility criteria must be confirmed by the assigned QAM. The study 
coordinator will screen all subjects for potential registration via the web-based application 
NOTIS (Northwestern Oncology Trial Information System), which is available at: 
https://notis.nubic.northwestern.edu. Please note that a username and password is 
required to use this program, and will be provided during site activation prior to training 
on the NOTIS system.
BEFORE a patient can be treated on study, please complete and submit the following 
items to confirm eligibility and receive an identification number:

Patient’s signed and dated informed consent form (upload to NOTIS and keep 
original hard copy in a secure location/study chart)

Eligibility checklist (signed and dated by the treating physician – upload to NOTIS)

Eligibility eCRF (complete in NOTIS)

Copy of the pathology report (upload to NOTIS)
Training on eCRF completion will be provided at the time of site activation. Please refer 
to the eCRF demonstration videos on the CRO website for additional instructions on 
registering a patient.
The QAM will review the registration, register the patient, assign a subject identification 
number, and send a confirmation of registration to study personnel. Registration will then 
be complete and the patient may begin study treatment.
11.4
Data Submission
Once a subject is confirmed and registered to the study, eCRFs should be submitted 
according to the detailed data submission guidelines (provided in a separate document in 
NOTIS).  
IRB #: STU00204354-CR0003 Approved by NU IRB for use on or after 11/11/2019 through 11/10/2020.

NU Study Number: NU 16L04
Other Study Number: CA 209-801
Amendment 5: 4.22.19
47
11.5
Data Management and Monitoring/Auditing
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) 
of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please 
refer to Appendices for additional information). The level of risk attributed to this study 
requires high Intensity monitoring as outlined in the DSMP. The assigned QAM, with 
oversight from the Data Monitoring Committee, will monitor this study in accordance with 
the study phase and risk level. Please refer to the Appendices for additional data 
submission instructions.
11.6
Adherence to the Protocol
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol. 
11.6.1
Emergency Modifications
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval. 
For any such emergency modification implemented, an IRB modification form 
must be completed within 5 business days of making the change, and the QAM 
must be notified within 24 hours of such change. 
11.6.2
Other Protocol Deviations
All other deviations from the protocol must be reported to the assigned QAM 
using the appropriate form.
A protocol deviation is any unplanned variance from an IRB approved protocol 
that: 

Is generally noted or recognized after it occurs.

Has no substantive effect on the risks to research participants.

Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected.

Did not result from willful or knowing misconduct on the part of the 
investigator(s). 
A protocol deviation may be considered an instance of Reportable New 
Information (RNI) if it:

Has harmed or increased the risk of harm to one or more research 
participants.

Has damaged the scientific integrity of the data collected for the study.

Results from willful or knowing misconduct on the part of the investigator(s).

Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies.
11.7
Investigator Obligations
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The PI is responsible for personally overseeing the treatment of all study 
patients. The PI must assure that all study site personnel, including sub-investigators and 
other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion.
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected, entered onto the appropriate eCRFs, and submitted 
within the study-specific timeframes. Periodically, monitoring visits may be conducted and 
IRB #: STU00204354-CR0003 Approved by NU IRB for use on or after 11/11/2019 through 11/10/2020.

NU Study Number: NU 16L04
Other Study Number: CA 209-801
Amendment 5: 4.22.19
48
the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. The study may also be subject to routine audits by the 
Audit Committee, as outlined in the DSMP. 
11.8
Publication Policy
All potential publications and/or data for potential publications (e.g. manuscripts, 
abstracts, posters, clinicaltrials.gov releases) must be approved in accordance with the 
DSMC Data Release Policies and Processes. The assigned QAM will prepare a 
preliminary data set for DSMC approval no later than 3 months after the study reaches its 
primary completion date, as defined by ClinicalTrials.gov. This is the date that the final 
subject was examined or received an intervention for the purposes of final collection of 
data for the primary outcome, whether the clinical trial concluded according to the pre-
specified protocol or was terminated. If the investigator would like data release to be 
approved by the DSMC prior to when study design specifies, and/or prior to three months 
after a study’s primary completion date, the PI must send a written request for data 
approval to the QAM which includes justification. Requests must be made a minimum of 
six to eight weeks in advance of the expected deadline. The request will be presented to 
the DSMC at their next available meeting. Any DSMC decisions regarding data release 
will be provided to the PI. If the request is approved, the QAM will present the data set to 
the DSMC for approval. A final, DSMC-approved dataset, as applicable, will then be 
released 6-8 weeks after the request was made. The investigators are expected to use 
only DSMC-approved data and statistical analyses any time they are disseminating trial 
data. The investigators must send a copy of the draft abstract/poster/manuscript to the 
study’s biostatistician and assigned QAM to confirm that the DSMC-approved data and 
statistical analyses are used appropriately. Once the biostatistician and QAM gives final 
approval, the publication may be submitted to external publisher.
IRB #: STU00204354-CR0003 Approved by NU IRB for use on or after 11/11/2019 through 11/10/2020.

NU Study Number: NU 16L04
Other Study Number: CA 209-801
Amendment 5: 4.22.19
49
.
REFERENCES
 
1.
MOHAMMED A, JANAKIRAM NB, BREWER M, ET AL. ANTIDIABETIC DRUG METFORMIN 
PREVENTS PROGRESSION OF PANCREATIC CANCER BY TARGETING IN PART CANCER STEM 
CELLS AND MTOR SIGNALING. TRANSL ONCOL 2013; 6(6): 649-59.
2.
BO S, CICCONE G, ROSATO R, ET AL. CANCER MORTALITY REDUCTION AND 
METFORMIN: A RETROSPECTIVE COHORT STUDY IN TYPE 2 DIABETIC PATIENTS. DIABETES 
OBES METAB 2012; 14(1): 23-9.
3.
FRANCIOSI M, LUCISANO G, LAPICE E, STRIPPOLI GF, PELLEGRINI F, NICOLUCCI A. 
METFORMIN THERAPY AND RISK OF CANCER IN PATIENTS WITH TYPE 2 DIABETES: 
SYSTEMATIC REVIEW. PLOS ONE 2013; 8(8): E71583.
4.
CURRIE CJ, POOLE CD, JENKINS-JONES S, GALE EA, JOHNSON JA, MORGAN CL. 
MORTALITY AFTER INCIDENT CANCER IN PEOPLE WITH AND WITHOUT TYPE 2 DIABETES: 
IMPACT OF METFORMIN ON SURVIVAL. DIABETES CARE 2012; 35(2): 299-304.
5.
ZHANG ZJ, LI S. THE PROGNOSTIC VALUE OF METFORMIN FOR CANCER PATIENTS 
WITH CONCURRENT DIABETES: A SYSTEMATIC REVIEW AND META-ANALYSIS. DIABETES OBES 
METAB 2014; 16(8): 707-10.
6.
EIKAWA S, NISHIDA M, MIZUKAMI S, YAMAZAKI C, NAKAYAMA E, UDONO H. IMMUNE-
MEDIATED ANTITUMOR EFFECT BY TYPE 2 DIABETES DRUG, METFORMIN. PROC NATL ACAD 
SCI U S A 2015; 112(6): 1809-14.
7.
PEARCE EL, WALSH MC, CEJAS PJ, ET AL. ENHANCING CD8 T-CELL MEMORY BY 
MODULATING FATTY ACID METABOLISM. NATURE 2009; 460(7251): 103-7.
8.
GETTINGER SN, HORN L, GANDHI L, ET AL. OVERALL SURVIVAL AND LONG-TERM 
SAFETY OF NIVOLUMAB (ANTI-PROGRAMMED DEATH 1 ANTIBODY, BMS-936558, ONO-4538) IN 
PATIENTS WITH PREVIOUSLY TREATED ADVANCED NON-SMALL-CELL LUNG CANCER. J CLIN 
ONCOL 2015; 33(18): 2004-12.
9.
BRAHMER J, RECKAMP KL, BAAS P, ET AL. NIVOLUMAB VERSUS DOCETAXEL IN 
ADVANCED SQUAMOUS-CELL NON-SMALL-CELL LUNG CANCER. N ENGL J MED 2015; 373(2): 
123-35.
10.
MOTZER RJ, RINI BI, MCDERMOTT DF, ET AL. NIVOLUMAB FOR METASTATIC RENAL 
CELL CARCINOMA: RESULTS OF A RANDOMIZED PHASE II TRIAL. J CLIN ONCOL 2015; 33(13): 
1430-7.
11.
MOTZER RJ, ESCUDIER B, MCDERMOTT DF, ET AL. NIVOLUMAB VERSUS EVEROLIMUS 
IN ADVANCED RENAL-CELL CARCINOMA. N ENGL J MED 2015; 373(19): 1803-13.
12.
EISENHAUER EA, THERASSE P, BOGAERTS J, ET AL. NEW RESPONSE EVALUATION 
CRITERIA IN SOLID TUMOURS: REVISED RECIST GUIDELINE (VERSION 1.1). EUROPEAN 
JOURNAL OF CANCER 2009; 45(2): 228-47.
13.
NISHINO M, GIOBBIE-HURDER A, GARGANO M, SUDA M, RAMAIYA NH, HODI FS. 
DEVELOPING A COMMON LANGUAGE FOR TUMOR RESPONSE TO IMMUNOTHERAPY: IMMUNE-
RELATED RESPONSE CRITERIA USING UNIDIMENSIONAL MEASUREMENTS. CLINICAL CANCER 
RESEARCH : AN OFFICIAL JOURNAL OF THE AMERICAN ASSOCIATION FOR CANCER 
RESEARCH 2013; 19(14): 3936-43.
IRB #: STU00204354-CR0003 Approved by NU IRB for use on or after 11/11/2019 through 11/10/2020.

NU Study Number: NU 16L04
Other Study Number: CA 209-801
Amendment 5: 4.22.19
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APPENDICES
Appendix A.
Common Terminology Criteria for Adverse Events V4.0.3 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0.3 will be utilized for adverse event 
reporting. (http://ctep.cancer.gov/reporting/ctc.html)
IRB #: STU00204354-CR0003 Approved by NU IRB for use on or after 11/11/2019 through 11/10/2020.

NU Study Number: NU 16L04
Other Study Number: CA 209-801
Amendment 5: 4.22.19
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Appendix B – ECOG Performance Status
The Eastern Cooperative Oncology Group (ECOG) performance status scale
Grade
Description
0
Normal activity.  Fully active, a b l e   to  carry  on  all  pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% of 
waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self- care. 
Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, 
T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative 
Oncology Group, Robert Comis M.D., Group Chair.
IRB #: STU00204354-CR0003 Approved by NU IRB for use on or after 11/11/2019 through 11/10/2020.

NU Study Number: NU 16L04
Other Study Number: CA 209-801
Amendment 5: 4.22.19
52
Appendix C – Contraception Requirements
Investigators shall counsel FOCBP and male subjects who are sexually active with FOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy 
Investigators shall advise FOCBP and male subjects who are sexually active with FOCBP on the 
use of highly effective methods of contraception from the time of treatment initiation to 5 months 
(for FOCBP) or 7 months (for males with FOCBP partners) after the last dose of nivolumab. 
Highly effective methods of contraception have a failure rate of < 1% per year when used 
consistently and correctly.
At a minimum, subjects must agree to the use of two methods of contraception, with one method 
being highly effective and the other method being either highly effective or less effective as listed 
below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
a) 
Male condoms with spermicide
b)
Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants, and intrauterine devices (IUDs) such as Mirena® by FOCBP 
subject or male subject’s FOCBP partner. Female partners of male subjects participating 
in the study may use hormone based contraceptives as one of the acceptable methods of 
contraception since they will not be receiving study drug.
c)
Nonhormonal IUDs, such as ParaGard®
d)
Tubal ligation
e)
Vasectomy.
f)
Complete Abstinence*
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. Subjects who choose complete abstinence 
are not required to use a second method of contraception, but female subjects must continue to 
have pregnancy tests. Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete abstinence.
LESS EFFECTIVE METHODS OF CONTRACEPTION
a)
Diaphragm with spermicide
b)
Cervical cap with spermicide
c)
Vaginal sponge
d)
Male Condom without spermicide*
e)
Progestin only pills by FOCBP subject or male subject’s FOCBP partner
f)
Female Condom*
*A male and female condom must not be used together
IRB #: STU00204354-CR0003 Approved by NU IRB for use on or after 11/11/2019 through 11/10/2020.

NU Study Number: NU 16L04
Other Study Number: CA 209-801
Amendment 5: 4.22.19
53
Appendix D– Adverse Event Algorithms
Recommended management algorithms for suspected nivolumab related endocrinopathy, gastrointestinal toxicity, hepatotoxicity, 
neurologic toxicity, pulmonary toxicity, renal toxicity and skin toxicity.

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Other Study Number: CA 209-801
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Other Study Number: CA 209-801
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Other Study Number: CA 209-801
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Other Study Number: CA 209-801
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Other Study Number: CA 209-801
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Appendix E – Protocol Summary of Changes
IRB Response – January 11, 2017
Section(s) 
Affected
Prior Version
Response Changes
Rationale
3.1.3 (Inclusion 
Criteria)
n/a
Adds “NOTE: Patients must be 
eligible to receive the next line of 
therapy and not be suspected of 
having pseudoprogression.”
Clarification requested by IRB
3.1.5 (Inclusion 
Criteria)
n/a
Adds hemoglobin requirement 
≥8g/dL
Safety measure requested by 
IRB
Amendment 1 – February 16, 2017
Approved by Scientific Review Committee: March 15, 2017
Section(s) 
Affected
Prior Version
Response Changes
Rationale
Cover Page
IND Number: 
“TBD”
IND Number: 133341
Administrative; IND number 
now available
Study Schema
Metformin will 
“escalate to 
2,000 mg/day”
Metformin will “escalate 
incrementally to 2,000 mg/day”
Clarification to account for 
1,500 mg dose level
1.4.5 
(Nivolumab flat 
dose regimen)
Referred to 
240mg 
nivolumab being 
“under 
investigation
Updates 240mg nivolumab as 
being FDA approved
Clarification for updated 
information
4.1 (Overview); 
4.2.1 
(Nivolumab); 5.0 
(Study 
Procedures #11)
Nivolumab 
infusion 
windows were 
as follows:
Over 30 mins 
(±5 mins)
Over 60 mins 
(±10 mins)
Updates nivolumab infusion 
windows:
Over 30 mins (-5 / +15 mins)
Over 60 mins (-5 / +15 mins)
Allows for flexibility of infusion 
duration without compromising 
safe administration
5.0 (Study 
Procedures #9); 
9.0 
(Correlatives)
n/a
#9: Archived tissue will be used (if 
available)
Clarification; patients will still 
be eligible if tissue is not 
available
#7: Thyroid 
function test was 
to include TSH, 
free T3, and free 
T4
#7: Removes free T3 as 
requirement
Free T3 is not typically drawn 
and is not clinically relevant
#14: Blood 
biomarker was 
listed at Cycle 
5+ with a 
footnote “13”
#14: Removes Cycle 5+ time 
point; adds footnote “14” to Cycle 
1-4 time point;
Adds tube types to footnote 14 
Correction of error;
Clarification for easy 
referencing
5.0 (Study 
Procedures)
n/a
#17: Adds ECHO/ECG as clinically 
indicated at baseline for patients 
with underlying cardiovascular 
disease or history of CHF
CTEP recommendation for 
newly reported myocarditis 
toxicities associated with 
nivolumab
7.0 (Adverse 
Events); 7.4.1 
n/a
Adds relevant hyperlink to DSMP 
reference
Administrative; to align with 
current protocol template
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NU Study Number: NU 16L04
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Amendment 5: 4.22.19
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(Routine 
Reporting) 
7.2.2 (Severity 
of AE’s)
“All non-
hematologic 
adverse events” 
will use CTCAE 
4.03
Removes “non-hematologic”
Correction of error; all AE’s will 
follow CTCAE 4.03
9.1 (Sample 
Collection 
Guidelines)
Referenced 
section 5.0 for 
timing of 
correlatives
Lists tube types and timing of 
correlatives, removing references 
to 5.0.
Clarification for easy 
referencing.
9.3.4 (Immune 
and Genomic 
Biomarkers)
Blood was to be 
collected prior to 
metformin and 
C1D1.
Adds time points at C3D1 and 
EOT. Adds tube type (6mL EDTA 
tube)
Clarifications 
11.6.2 (Other 
Protocol 
Deviations)
“Promptly 
Reportable Non-
Compliance 
(PRNC)”
“Reportable New Information 
(RNI)”
Administrative; to align with 
current internal policies
Amendment 2 – June 21, 2017
Approved by Scientific Review Committee: June 26, 2017
Section(s) 
Affected
Prior Version
Response Changes
Rationale
Cover Page
Included Sachin 
Pai and Ricardo 
Costa as sub-
investigators
Removes Sachin Pai and Ricardo 
Costa as sub-investigators
Administrative; faculty no 
longer at Northwestern
5.0 (Study 
Procedures, #5)
CBC to be 
performed 
“every 2 weeks”
CBC to be performed “at each 
study visit, prior to nivolumab”
To fix discrepancy; table does 
not indicate study visits every 2 
weeks past Cycle 4
5.0 (Study 
Procedures, 
#14); 
9.1 (Sample 
Collection 
Guidelines)
Specified that 
correlative 
samples were to 
be collected in a 
6mL EDTA and 
6mL NaHep 
tube
Removes tube types from 
correlative instructions
Specific tube types will be 
delineated only in the lab 
manual to avoid the need for 
protocol amendments
8.2.5 (Protocol 
Dose Specifics)
Metformin was 
to be provided 
as 500mg and 
750mg tablets
Removes 750mg tablet
Correction; only the 500mg 
tablet will be supplied by BMS
Amendment 3 – December 6, 2017
Approved by Scientific Review Committee: 
Section(s) 
Affected
Prior Version
Amendment 3 Changes
Rationale
Study Schema; 
Study Summary; 
3.1.3 (Inclusion 
Criteria);
3.2.2 (Exclusion 
Criteria)
 Patients in Arm B may 
have been treated with 
prior single-agent PD-
1/PD-L1 inhibitors.  
Patients in Arm A must 
have been naïve to 
single-agent PD-1/PD-L1 
inhibitors. 
Eligibility was ambiguous 
for patients treated with 
Clarifies eligibility and 
stratification of patients:
Patients in Arm B may be 
treated with prior PD-
1/PD-L1 inhibitors, only 
as a single agent. 
Patients in Arm A must 
be naïve to any PD-
1/PD-L1 inhibitor.
Clarification of ambiguous 
language. 
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Amendment 5: 4.22.19
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PD-1/PD-L1 inhibitor in 
combination with 
chemotherapy, however 
it was interpretable that 
such patients were 
eligible for Arm A.
1.1 (Significant 
unmet needs in 
advanced 
NSCLC); 1.3 
(Rationale for the 
Current Study);
References FDA 
approvals of PD-1 
inhibitors, which 
previously only included 
single agents
References FDA 
approval of PD-1 
inhibitors as single 
agents or in combination 
with chemotherapy
Updated to reflect recent FDA 
approvals 
3.1.3 (Inclusion 
Criteria)
“Arm A: patients must be 
treatment naive to single-
agent PD-1/PD-L1 
inhibitors”
Removes “single agent”; 
Patients in Arm A must 
be treatment naïve to any 
PD-1/PD-L1 inhibitors.
Clarification of intended 
eligibility and stratification. 
4.2.1 
(Nivolumab)
“Subjects may be dosed 
no less than 25 days 
from the previous dose 
[of nivolumab].”
“Subjects may be dosed 
no less than 12 days or 
24 days from the 
previous dose (for 240 
mg and 480 mg doses, 
respectively).”
Correction to account for 240 
mg doses of nivolumab, which 
are scheduled every 14 days. 
This is consistent with other 
NU protocols involving 
nivolumab.
4.2.1 
(Nivolumab); 
8.1.6 
(Preparation)
“The drug can be diluted 
with 0.9% Sodium 
Chloride of 5% Dextrose 
for delivery but the total 
drug concentration of the 
solution cannot be below 
0.35 mg/mL.” 
“The drug can be infused 
undiluted or diluted so as 
not to exceed a total 
infusion volume of 120 
mL.”
Updated to align with new IB 
and flat dosing regimen. Prior 
language reflected instructions 
for weight-based dosing. 
4.3.2 (Treatment 
discontinuation: 
nivolumab); 7.4.1 
(Routine 
Reporting); 7.4.3 
(Expedited 
Reporting of 
SAE’s); 11.8 
(Publication 
Policy)
Referred to internal Data 
Monitoring Committee 
(DMC)
Changes to Data and 
Safety Monitoring 
Committee (DSMC)
To align with updated internal 
policies.
Visit window was set at 
±1 day, with a treatment 
window of ±7 days 
(footnote 11)
Updates all windows to 
±3 days
Updated for consistency within 
the table and with treatment 
window provided in section 
4.2.1
5.0 (Study 
Procedures 
Table)
#8: Imaging was marked 
at “Cycle 1-4, Day 1” with 
no footnote
Adds footnote 8 to 
Imaging at “Cycle 1-4, 
Day 1”
To clarify that imagining is only 
needed every 2 cycles starting 
with Cycle 3
8.1.4 (Storage 
and Stability); 
8.1.6 
(Preparation); 
8.1.8 
(Incompatibilities)
n/a
Replaces language with 
internal nivolumab 
template language (same 
content)
For consistency with other 
protocols involving nivolumab
8.1.7 (Route of 
administration for 
this study)
n/a
Adds infusion times and 
windows for nivolumab 
doses
To be thorough and consistent 
throughout the protocol
IRB #: STU00204354-CR0003 Approved by NU IRB for use on or after 11/11/2019 through 11/10/2020.

NU Study Number: NU 16L04
Other Study Number: CA 209-801
Amendment 5: 4.22.19
63
8.1.9 (Availability 
& Supply)
Did not specify timing for 
drug re-supply requests
Replaces language with 
internal nivolumab 
template language. Drug 
re-supply should be 
submitted 10 business 
days before the delivery 
date
Updated for accuracy per BMS
8.1.12 (Return & 
Retention of 
Study Drug)
n/a
Updates table to reflect 
accurate packaging of 
nivolumab product
Clarification 
9.4 (Specimen 
Banking)
n/a
Adds section on 
specimen banking with 
instructions for retention 
of samples at 
Northwestern. Specifies 
that samples may be 
shared with researchers 
at other institutions.
Updated to reflect the plan for 
samples to be collected for 
banking and possible future 
analysis.
Appendix C
n/a
Adds timeframe of 
contraception 
requirements for both 
females (5 months) and 
males (7 months) after 
the last dose of 
nivolumab
To align with BMS template 
and requirements
Appendix D
Contained outdated AE 
Management Algorithms. 
Specific outdated 
parameters include:
Hepatic:
Discontinue for 
AST/ALT >5xULN 
and/or Tbili >3xULN
Pulmonary (G3-4):
Includes example 
immunosuppression
Renal (G2-3):
“Consider renal 
biopsy”
Skin (G3-4):
n/a
Updates AE 
Management Algorithms 
to align with nivolumab IB 
v16. Specific changes to 
AE management include:
Hepatic:
Discontinue for 
AST/ALT > 5xULN or 
Tbili > 3xULN
Pulmonary (G3-4):
Removes examples of 
immunosuppression 
Renal (G2-3):
“Consider renal biopsy 
with nephrology 
consult”
Skin (G3-4):
Adds footnote: “If 
SJS/TEN is 
suspected, withhold I-
O therapy and refer 
patient for specialized 
care for assessment 
and treatment. If SJS 
or TEN is diagnosed, 
permanently 
discontinue I-O 
therapy.”
Updated per BMS for 
consistency with new 
nivolumab IB v16 and 
additional or clarified safety 
measures.
IRB #: STU00204354-CR0003 Approved by NU IRB for use on or after 11/11/2019 through 11/10/2020.

NU Study Number: NU 16L04
Other Study Number: CA 209-801
Amendment 5: 4.22.19
64
Amendment 4 – January 17, 2019
Section(s) 
Affected
Prior Version
Response Changes
Rationale
Section 8.2.9 
(Metformin drug 
availability and 
supply);
 Section 8.2.5
(Metformin dose 
specifics)
and 
Section 4.1 
(treatment) 
Language 
stating that 
Metformin 
extended 
release tablets 
will be used and 
will be supplied 
by BMS. 
Language updated to state that as 
of January 2019 BMS will NOT 
provide metformin. We will be 
switching from metformin supplied 
by BMS, to commercial supply of 
metformin which will be purchased 
and distributed through 
Northwestern University’s 
investigational pharmacy
As of December 31st 2018, 
BMS will no longer provide 
Metformin.
Section 8.2.5
(Metformin 
protocol dose 
specifics)
The starting 
dose of 
Metformin was 
listed as 500mg 
PO BID.
Language updated to state 
“Metformin will be initiated during a 
7-day Induction period at 1,000mg 
orally once daily. Metformin will 
then be escalated by 500mg every 
7 days as tolerated (C1D1 and 
C1D8) until the full 2,000mg dose 
is reached.”
To align with the rest of the 
protocol
(Correction of discrepancy 
within the protocol)
Section 11.8
Publication 
policy
Previous
template 
language
Updated with most current 
template language for publication 
policy
Template update
(administrative)
Amendment 5 dated 4.22.19
Section(s) 
Affected
Prior Version
Amendment 5 Changes
Rationale
Section 3.1.3
Inclusion criteria
and Study 
Schema
Arm B: patients’ 
tumor must be 
either refractory 
to or progressed 
on one of the 
above agents.
NOTE: Prior 
treatment may 
include any 
number of PD-
1/PD-L1 inhibitor 
therapies given 
as a single-agent 
The language in the note has 
been modified to state that PD-
1/PD-L1 inhibitor therapies can be 
given either as single agent or in 
combination with chemotherapy
Correction of discrepancy 
To be in alignment with 
language that already 
existed in the eligibility 
description in the Summary 
section of the protocol. This 
criteria has been approved 
by BMS. 
IRB #: STU00204354-CR0003 Approved by NU IRB for use on or after 11/11/2019 through 11/10/2020.

NU Study Number: NU 16L04
Other Study Number: CA 209-801
Amendment 5: 4.22.19
65
Section 3.2.2
Exclusion 
criteria
Patients 
receiving prior 
immunotherapies 
are excluded and 
the note stated 
the exception of 
allowing patients 
receiving PD-
1/PD-L1 
inhibitors as 
single agent. 
Modified the note to state that PD-
1/PD-L1 inhibitor therapies can be 
given either as single agent or in 
combination with chemotherapy
To align with modifications 
made to Section 3.1.3
Section 3.2.3
Exclusion 
criteria
The exclusion 
criteria stated 
that for arm B, 
patients must not 
have had prior 
exposure to 
combination 
treatment with 
PD-1/PD-L1 
inhibitors and 
another systemic 
treatment. 
This exclusion criterion has been 
removed, since it is in 
contradiction to the current 
modification to the inclusion 
criteria, which now allows 
PD-1/PD-L1 inhibitor therapies to 
be given either as single agent or 
in combination with chemotherapy
The rest of the exclusion criteria 
have been re-numbered 
accordingly. 
To align with modifications 
made to Section 3.1.3
IRB #: STU00204354-CR0003 Approved by NU IRB for use on or after 11/11/2019 through 11/10/2020.

NU Study Number: NU 16L04
Other Study Number: CA 209-801
Amendment 5: 4.22.19
66
Section 8.1.12
Table 8-1
Secondary 
packaging 
information 
present in the 
table
Secondary packaging information 
removed from the table
For flexibility
IRB #: STU00204354-CR0003 Approved by NU IRB for use on or after 11/11/2019 through 11/10/2020.