Phase II Trial of Nivolumab and Metformin in Patients With Treatment Refractory MSS Metastatic Colorectal Cancer
Phase: PHASE2
Conditions: Colorectal Adenocarcinoma, Metastatic Microsatellite Stable Colorectal Carcinoma, Refractory Colorectal Carcinoma, Stage IV Colorectal Cancer, Stage IVA Colorectal Cancer, Stage IVB Colorectal Cancer, Stage IVC Colorectal Cancer, Colorectal Cancer Metastatic
Sponsor: Emory University

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Winship Cancer Institute of Emory University
Phase II trial of Nivolumab and Metformin in patients with
treatment refractory MSS metastatic Colorectal Cancer
Principal Investigator:
Olumide Gbolahan, MD
1365 Clifton Road NE
Atlanta GA 30322
Telephone: 404-778-1900
Fax: 404-778-5520
e-mail address: ogbolah@emory.edu
Correlative PI:
Gregory Lesinski, PhD, MPH
Winship Cancer Institute of Emory University
Building C, Room C3090
1365 Clifton Road NE
Atlanta, GA 30322
Gregory.B.Lesinski@emory.edu
Co-Investigators:
Olatunji Alese MD
Statistician:
Zhengjia Chen PhD
IND sponsor: Olumide Gbolahan, MD
Supplied Agent(s): Nivolumab, BMS
Other Agent(s): Metformin ER, commercial, funding supplied by BMS

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TABLE OF CONTENTS
List of abbreviations ..................................................................................................................4
1.
Study Synopsis...............................................................................................................6
2.
Trial Diagram...............................................................................................................10
3.
OBJECTIVES..............................................................................................................10
3.1
Primary Objective and Hypotheses......................................................10
3.2
Secondary Objectives and Hypotheses................................................10
4.
BACKGROUND and rationale....................................................................................11
4.1
Study Disease.......................................................................................11
4.2
Investigational Agents .........................................................................11
4.3
Study Rationale....................................................................................13
4.4
Correlative Studies Background ..........................................................14
5.
PATIENT SELECTION..............................................................................................15
5.1
Eligibility Criteria................................................................................15
5.2
Exclusion Criteria ................................................................................17
6.
TREATMENT PLAN..................................................................................................19
6.2
DOSING DELAYS/DOSE MODIFICATIONS .................................21
6.3
General Concomitant Medication and Supportive Care Guidelines....25
6.4
Acceptable Concomitant Medications.................................................25
6.5
Prohibited Concomitant Medications ..................................................25
6.6
Rescue Medications & Supportive Care..............................................26
6.7
Diet/Activity/Other Considerations .....................................................29
6.8
Duration of Therapy.............................................................................31
6.9
Duration of Follow Up.........................................................................32
6.10
Criteria for Removal from Study.........................................................32
6.11
Discontinuation of Study Therapy after CR ........................................32
6.12
Subject Replacement Strategy .............................................................32
7.
STUDY CALENDAR .................................................................................................32
Study Flow Chart.............................................................................................33
8.
TRIAL PROCEDURES...............................................................................................35
8.1
Trial procedures ...................................................................................35
8.2
Assessing and Recording Adverse Events...........................................46
8.3
Expedited Adverse Event Reporting....................................................51
An investigator who is a qualified physician, will evaluate all adverse events as to: .............51
8.4
Routine Adverse Event Reporting .......................................................53
8.5
Secondary Malignancy.........................................................................53

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8.6
Second Malignancy..............................................................................54
9.
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES
......................................................................................................................................54
9.1
Investigational Product ........................................................................54
10.
STATISTICAL CONSIDERATIONS.........................................................................55
10.1
Study Design/Endpoints/ Determination of Sample Size....................55
10.2
Statistical and Analytical Plans............................................................55
10.3
Evaluation of Response........................................................................55
10.4
Analysis Sets........................................................................................56
10.5
Subject Disposition and Baseline Characteristics................................56
10.6
Safety Analysis ....................................................................................56
11.
ADMINISTRATIVE AND REGULATORY DETAILS............................................57
11.1
Compliance with Trial Registration and Results Posting Requirements.57
11.2
Pre-study Documentation.....................................................................57
11.3
Protocol Adherence..............................................................................57
11.4
Retention of Study Documents............................................................57
11.5
Data Management................................................................................57
12.
REFERENCES ............................................................................................................59
13.
APPENDICES .............................................................................................................61
13.1
APPENDIX A PERFORMANCE STATUS CRITERIA....................61
13.2
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)..62
13.3
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria
for Evaluating Response in Solid Tumors ...........................................62
13.4
APPENDIX BF....................................................................................63

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LIST OF ABBREVIATIONS
AE
adverse event/experience
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BP
blood pressure
CFR
Code of Federal Regulations
CR
CRC
complete response
colorectal cancer
CRO
contract research organization
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
D5W
dextrose 5% in water
DEHP
di(2-ethylhexyl) phthalate
DCR
disease control rate
dL
Deciliter
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
FDA
Food and Drug Administration
FFPE
GI
Formalin-fixed paraffin-embedded
Gastrointestinal
HIPAA
Health Insurance Portability Act
HIV
human immunodeficiency virus
HR
Heart rate
ICH
International Conference on Harmonisation
IEC
INR
Independent Ethics Committee
International normalized ratio
IRB
Institutional Review Board
IV
Intravenous
LC-MS/MS
liquid chromatography-mass spectrometry / mass spectrometry
LDH
lactate dehydrogenase
LMW
MDSC
MedDRA
Low molecular weight
Myeloid-derived suppressive cells
Medical Dictionary for Regulatory Activities
mg
Milligram

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MRI
MSI-high
MSS
magnetic resonance imaging
microsatellite instable-high
microsatellite stable
NCI
National Cancer Institute
PFS
Progression-free survival
PICCS
Peripherally-inserted central catheters
PK
Pharmacokinetic
PR
partial response
PVC
polyvinyl chloride
ORR
objective response rate
OS
overall survival
QT
cardiac interval from start of Q wave to end of T wave
RDC
remote data capture
RR
respiration rate
SD
stable disease
UGT
uridine-diphosphoglucuronosyltransferases
ULN
upper limit of normal
VADs
Vascular access devices
WHO
World Health Organization

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1. STUDY SYNOPSIS
Title of Study: Phase II trial of Nivolumab and Metformin in patients with treatment
refractory MSS metastatic Colorectal Cancer
Study Centers: Emory University Winship Cancer Institute
Study Phase: Phase II
Objectives:
Primary Objective:

The primary endpoint of this study is to Evaluate the effect of metformin in
combination with nivolumab on the overall response rate (ORR) (Primary Objective)
as assessed by RECIST.1.1
Secondary Objectives:

To determine the effect of the metformin and nivolumab combination on clinical
(PFS, OS) outcomes and biochemical (CEA) response.

To compare the effect metformin and nivolumab combination on immune and
metabolic biomarkers in the tumor microenvironment and systemic circulation
(pre and post treatment paired biopsies required).
Trial Design/Methodology: Single arm phase II study. 28 patients with previously treated
(previously treated with fluoropyrimidine, oxaliplatin, irinotecan and EGFR inhibitor – if
RAS wildtype) metastatic CRC will be started on metformin and nivolumab combination.
Treatment
1. Patients will start taking metformin 500 mg po BID for 3 days, then 500 mg am and
1000 mg pm for 4 days, then 1000 mg po bid for 1 week. Patients of the study will
get paired biopsies as outlined in study calendar.
2. If a patient cannot tolerate metformin 1000 mg po BID the patient will resume the
metformin dose which was tolerable
3. After 2 weeks of metformin only therapy (lead-in period) patients will start
nivolumab 480 mg IV q4 weeks and continue metformin 1000 mg PO BID (or the
tolerated dose of Metformin).
4. Restaging scans will be performed at the end of cycle 2, then every 8 weeks for 2
years.
5. Correlative assays will include- immune profiling of TILs and circulating
lymphocytes, plasma cytokine levels and metabolic biomarkers. These will be
performed at baseline at baseline, cycle 1 day 1, cycle 1 day 15, Cycle 3 Day 1and
at progression
Treatment regimen and trial diagram:

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Single arm Phase II treatment refractory MSS metastatic CRC
Nivolumab 480 mg IV q 4 weeks plus Metformin ER 1000 mg po BID D1-28
Screening
Biopsy, 28 patients
Blood
Metformin 1000
mg BID +
Nivolumab
Metformin 1000
mg plus
Nivolumab,
restage q8
weeks
3 days
Metformin 500
mg BID
Metformin 1000
mg po BID
4 days
2 weeks
Re- biopsy, 14 patients
Blood
Re-biopsy, 14 patients
Blood
Metformin 500
mg am, 1000
mg pm
1 week
Number of Subjects:
28 patients
Duration of treatment:
The treatment will be continued until progression of disease, unacceptable toxicity or
consent withdrawal for 2 years
Main criteria for inclusion:

Age ≥18 years old

Histological diagnosis of treatment refractory colorectal adenocarcinoma with
measurable disease

Prior
treatment
with
5
Fluorouracil, oxaliplatin and
irinotecan containing
chemotherapy (needs to be treated with anti-EGFR agent if extended RAS wild type)

ECOG 0 or 1

Adequate organ and hematologic function

Microsatellite stable tumor

No metformin use in the last 3 months

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Main criteria for exclusion:

MSI status

Autoimmune
conditions
that
may
require
systemic
steroids
or
other
immunosuppressive treatments

Pregnancy or breast feeding
Investigational product and administration:
Nivolumab will be provided intravenously and metformin will be provided in tablet form.
Eligible subjects will receive nivolumab 480 mg IV every 4 weeks and metformin 1000 mg
po BID according to the study design.
Control therapy, dose and administration: N/A
Efficacy evaluation/Endpoints:
Primary Endpoint: ORR
Secondary Endpoints: To determine PFS, OS, and biochemical response (CEA), immune
and metabolic biomarkers in tumor microenvironment and systemic circulation (pre and post
research biopsy required)
Safety evaluation/Endpoints:
NCI Common Toxicity Criteria Version 4.0
Rationale for number of subjects: Primary objective is to determine the overall
response rate. Historically ORR with single agent nivolumab in CRC is <5% and metformin
and nivolumab combination will have ORR of 15%. Simon’s MinMax two stage design is
employed for the study with power of 80% and alpha of 0.1. If there is 1 response in first 18
patients in the first stage of the study, then it will proceed with second stage to enroll total
of 28 patients. If there are 3 or more responders out of the 28 patients then it would be
positive study. This will enable us to evaluate clinical endpoints (ORR, CEA, RFS, OS) as
well as evaluate the impact on immune biomarkers.
Statistical methods: Phase II design

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Translational Research: Correlative assays will include- immune profiling of TILs and
circulating lymphocytes, plasma cytokine levels, and key metabolic biomarkers of relevance
to mechanism of metformin action when administered in combination with immunotherapy.
Paired biopsies will be obtained in all patients.

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2. TRIAL DIAGRAM
Single arm Phase II treatment refractory MSS metastatic CRC
Nivolumab 480 mg IV q 4 weeks plus Metformin ER 1000 mg po BID D1-28
Screening
Biopsy, 28 patients
Blood
Metformin 1000
mg BID +
Nivolumab
Metformin 1000
mg plus
Nivolumab,
restage q8
weeks
3 days
Metformin 500
mg BID
Metformin 1000
mg po BID
4 days
2 weeks
Re- biopsy, 14 patients
Blood
Re-biopsy, 14 patients
Blood
Metformin 500
mg am, 1000
mg pm
1 week
3. OBJECTIVES
3.1
Primary Objective and Hypotheses
1. Objective: To evaluate the effect of nivolumab and metformin combination on the
overall response rate (ORR) as assessed by RECIST 1.1.
Hypothesis: Metformin will impact the tumor microenvironment and potentiate the
anti-tumor effects of nivolumab in patients with treatment refractory, MSS metastatic
CRC patients.
3.2
Secondary Objectives and Hypotheses
1. Objective: To determine the effect of nivolumab and Metformin combination on
clinical outcomes, progression free survival and overall survival, and biochemical
response (CEA).
Hypothesis: Metformin plus nivolumab will affect overall response rate, progression
free survival, overall survival.
2. Objective: To compare the effect of nivolumab and metformin combination on
immune and metabolic biomarkers in the tumor microenvironment and systemic
circulation (pre and post treatment paired biopsies required).
Hypothesis: Metformin plus nivolumab will change the immune profile in the
peripheral blood as well as the tumor microenvironment.

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4. BACKGROUND AND RATIONALE
4.1
Study Disease
Colorectal cancer (CRC) is the third most common cancer in the US and it is estimated to cause
more than 50,000 deaths in 2018. [1] Approximately 20% of patients have metastatic CRC at
initial presentation who have a 5 year overall survival of 14%. [1] Clear majority of the CRCs
develop through chromosomal instability (CIN) pathway and approximately 15% develop
from the microsatellite instability (MSI) pathway which results from deficient DNA mismatch
repair (MMR). [2] While about 15% of all CRCs are MSI-H, about 4% of metastatic CRCs are
MSI-H. [3] Germline mutations in MMR genes such as MLH1, MSH2, MSH6, PMS2 or
epigenetic inactivation of MLH1 gene cause deficient MMR. MSI-H CRCs have better stage
adjusted prognosis compared to MSS CRCs. [2] Consensus molecular subtype (CMSs) system
classifies CRCs into 4 different gene expression-based molecular subtypes: CMS1 (14%,
microsatellite unstable with strong immune activation and hypermutated), CMS2 (canonical,
37%, epithelial differentiation, strong WNT and MYC Signaling activation), CMS3 (13%,
characterized with metabolic dysregulation and KRAS mutations) and CMS4 (mesenchymal,
23%, phenotype with strong transforming growth factor beta activation, stromal invasion and
angiogenesis), an unclassified group with mixed features represent 13% of remaining cases.
[4] The immunological signatures of tumor microenvironment (TME) and the molecular
subtypes were shown to be correlated. [Becht et al] CMS1 is the most immunogenic subtype
of all four subtypes while the CMS4 is the second most immunogenic. [4, 5] Immunotherapy
with checkpoint inhibitors has been proven to be very effective in the treatment of metastatic
CRC with high level of Microsatellite Instability (MSI-H), but ineffective in Microsatellite
Stable (MSS) CRC. [6] Immunotherapy with anti-PD-1 agents is approved only in MSI-H
metastatic CRC patients after failure of standard first line systemic chemotherapy. [7] MSI-H
tumors respond to check point inhibitors because of high mutational rate, up 20 times higher
compared to MSS CRC, as well as significant immune checkpoint expression [5]. At the
present time patients with MSI-H status, high expression of neo-antigens and TILs are good
candidates for check point inhibition whereas MSS CRC patients lack response to
immunotherapy due to opposite tumor features. [5] TME is essential for prognosis and is a
viable target for anti-cancer therapy by modulation of the TME composition. Only a small set
(4%) of metastatic CRCs would be candidate for anti-PD-1 therapy therefore there is
significant unmet need for innovative approaches to combine anti-PD1 therapy with other
agents to achieve manipulation of TME of CRCs and sensitize MSS CRCs to anti-PD-1
therapy. For example, by modulating the tumor microenvironment antitumor responses (ORR
17%, 4PR, 5SD) were reported in MSS patients when a checkpoint inhibitor was combined
with Cobimetinib in a phase Ib trial based on preclinical data showing increased intratumoral
CD8+ T cell infiltration and increased sensitivity to PDL-1 inhibition. [8] The preclinical
rationale was also confirmed in this phase Ib trial by showing increased CD8+ T cell
infiltration, MHC-I expression and PDL-1 upregulation in serial tumor biopsies on treatment.
4.2
Investigational Agents
4.2.1
Nivolumab in CRC:

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Immune checkpoint expression as programmed death 1 (PD-1) or cytotoxic T-lymphocyte-
associated antigen (CTLA-4) by tumor cells is one of the major immune evasion mechanisms.
[3, 9] PD-1, a member or B7/CD28 costimulatory receptor family, down regulates T-cell
activation by binding to its receptors programmed death ligand 1 (PD-L1) and programmed
death ligand 2 (PDL-2). Nivolumab is a fully humanized monoclonal IGG4 anti-PD-1 inhibitor
which is currently approved for MSI-H CRC after progression on systemic chemotherapy.
Nivolumab was studied as a single agent at doses of 0.3-10 mg/kg in the first phase I study in
39 patients with advanced solid tumors, 1/14 CRC patients achieved durable complete response
(CR), no maximum tolerated dose was determined. [10] That patient had MSI-H positive CRC.
In the following phase Ib study with single agent Nivolumab at a dose of 0.1-10 mg/kg IV in
296 patients with treatment refractory solid tumors none of the 19 CRC patients had objective
response. Of note these patients included predominantly MSS CRCs. [11]
CheckMate 142 Phase II study of single agent Nivolumab 3 mg/kg IV every 2 weeks in 74
treatment refractory MSI-H CRC patients revealed 31.1% objective response rate (ORR), 3%
complete response (CR) and 69% disease control rate (DCR) for 12 weeks or longer at a
median follow up of 12 months. [12] More updated results of the same study at median follow
up of 21 months revealed 34% ORR, 9% CR, and 62% DCR. [13] The response rates did not
differ between Tumor expression of PD-Ll≥1% and <1% in the same study. CheckMate142
trial currently has multiple arms with Nivolumab combined with other agents.
Most commonly reported grade 3 or 4 adverse events in CheckMate142 study included
elevated lipase (8%) elevated amylase (3%); and rest of grade 3 or 4 adverse events included
fatigue (1%), diarrhea (1%), maculopapular rash (1%), increased alanine aminotransferase
(1%), stomatitis (1%), abdominal pain (1%), increased creatinine (1%), decreased lymphocyte
count (1%), colitis (1%), acute kidney injury (1%), adrenal insufficiency (1%), esophagitis
(1%), increased gamma-glutamyltransferase (1%), gastritis (1%), pain (1%) No treatment
related deaths were reported.
Please refer to the Investigator’s Brochure for additional information for preclinical activity,
toxicology and potential adverse effects.
4.2.2
Metformin in CRC:
Metformin is a biguanide and decreases liver glucose production and increases insulin
sensitivity. It is the first line therapy and most commonly prescribed antidiabetic agent for
diabetes mellitus type II. It has favorable safety profile, weight neutral effects, low risk of
hypoglycemia and low cost. [14] Immediate release (IR) and extended release formulations
(ER) exist and extended release formulation provides better tolerability especially lower
gastrointestinal adverse events as well as improved patient adherence. ER formulation provides
gradual release of the drug into upper GI tract although it provides similar drug exposure at the
same daily total dose as immediate release formulation. [14] Maximum plasma concentration
of IR Metformin is reached at 2-3 hours and 7 hours for ER Metformin. [15] ER tablets cannot
be crashed or chewed and should be swallowed whole in order to maintain slow drug release.
The most common adverse events were reported as following in a 16-week, randomized,
double-blind, placebo-controlled study in patients with type II diabetes: upper respiratory tract

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infection (15%), diarrhea (12.9%), nausea/vomiting (8.2%), musculoskeletal pain (7.6%),
headache (7.1%), influenza (6.6%), dyspepsia/heartburn (5.3%), abdominal pain (5.1%), sinus
abnormality (3.7%), dizziness (3.4%), hypertension (3.1%), urinary tract infection (3.1%).That
particular study included 5 different treatment regimens including Metformin ER 1000 mg po
twice daily.
Please refer to the Investigator’s Brochure for additional information for preclinical activity,
toxicology and potential adverse effects.
Several epidemiological studies revealed decreased risk of cancer development and cancer
related mortality with use of metformin. A meta-analysis revealed decreased risk of colorectal
cancer incidence diabetic patients who are on metformin and improved overall mortality, CRC
specific mortality in CRC patients who are on metformin compared to those who are not. [16,
17] In meta-analysis by Meng et al. improved overall survival (OS), HR 0.75; 95% CI 0.65 to
0.87, was reported for metformin users compared to nonusers in patients with CRC and
diabetes although no cancer specific survival, HR 0.79, 95% CI 0.58 to 1.08, was detected.
[18] Anticancer properties of Metformin were attributed to mTOR inhibition through AMPK
pathway activation. [19] The positive therapeutic effects of metformin were shown in colon
cancer and lung cancer patients with diabetes on metformin versus other antidiabetic drugs in
a single institution retrospective study. [20] In that study colon cancer (104 on metformin, 98
non-metformin) and lung cancer (93 metformin and 87 non-metformin) patients with diabetes
were stratified according to being on metformin versus other antidiabetic medications between
1998 and 2012. 94.2% of patients were treated with surgery, 44.2% were treated with
chemotherapy, and 14.4% were treated with radiation therapy in colon cancer patients on
metformin as opposed to 89.8%, 48% an 18.4% in non-metformin cohort with colon cancer.
In the colon cancer group better OS (5.7 versus 4.1 years, p=0.001), better 5-year OS rates
(57% vs 37%, p=0.004), rate of CEA decrease (72% versus 47%, p=0.015), less metastasis
(23% versus 46%, p=0.001), less number of deaths (48% versus 76%, p<0.001) and less
recurrences (4% versus 19%, p=0.002) were seen in the metformin group compared to non-
metformin group. Additionally, better 5-year OS rates (29% versus 15%. P=0.023) and OS
(3.4 vs 1.8 years, p<0.001) were reported in patients on metformin compared to non-metformin
antidiabetic medication group in lung cancer cohort. 48.4% received surgery, 47.3% received
chemotherapy, and 40.9% received radiation therapy metformin cohort with lung cancer
patients compared to 40.2%, 42.5%, 47.1% in non-metformin cohort, respectively. No clinical
staging information was included for either colon cancer or lung cancer patients in this report.
In a nationwide population-based study from Taiwan including 47,597 patients with DMII
metformin use was associated with lower risk of CRC in a dose dependent manner. [21]
More recently multiple immunomodulatory effects of Metformin have been shown which
points to potential synergistic effect of Metformin with anti-PD-1 therapy in CRC. [22, 23]
4.3
Study Rationale
Preclinical studies suggest that metformin, by virtue of its impact on metabolic features in the

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tumor microenvironment has distinct immunomodulatory properties that could complement
PD-1 blockade and may potentially increase the sensitivity of MSS metastatic CRC patients to
PD-1 inhibition. [22, 23] Longer PFS and OS was reported in CRC patients with higher CD8+
T cell and memory T cell infiltration highlighting the potential role of immunomodulation as
a mechanism by which metformin elicits its effects.
Immune effects of Metformin in tumor microenvironment:
1. Metformin increased CD8+ tumor infiltrating T cells (TILs) and prevented apoptosis
and immune exhaustion of TILs. Metformin prevents apoptosis of CD 8+ tumor
infiltrating lymphocytes (TILs) and restored multi-functionality of PD1+, Tim3+
CD8+ TIL by promoting a phenotypic switch of T cells to adopt central memory and
effector phenotypes in murine tumor models. [22]
2. Metformin has metabolic properties that favor decreased intratumoral oxygen
consumption in vitro and in vivo, while it increased the oxygen consumption by CD 8+
TIL and improved the effector cytokine production by CD8+ TIL in B16 melanoma
and MC38 colon adenocarcinoma tumor models. [23]
3. Expression of coinhibitory molecules PD1 and Tim3 was modulated in metformin
treated mice compared to controls. [23]
4. The combination of metformin and PD1 inhibitor resulted in improved intratumoral T
cell function and increased anti-tumor activity. [23]
5. The metformin and PD-1 inhibitor combination improved antitumor activity and
intratumoral T cell function. [23]
Preclinical data strongly suggests that metformin can improve immune exhaustion of TIL and
potentiate the effects of immunotherapy. Based on this preclinical rationale, in this study
we propose evaluating the effects of metformin in potentiating the effects of
immunotherapy in patients with treatment refractory metastatic MSS CRC patients.
4.4
Correlative Studies Background
Abundant CD8+ T cell infiltration in the tumor microenvironment is associated with a survival
advantage in CRCs, independent of tumor stage. [24] Individual molecular subtypes of CRCs
have distinct immunological features. For example, CMS1 CRCs have upregulation of Th1
lymphocytes, cytotoxic T cells, NK cell infiltration and PD-1 expression. These features are
correlated with better clinical outcomes in CRCs. [25] In contrast, tumors displaying an
immune infiltration pattern with presence of Th17 cells, IL-17, Tregs, and MDSCs are
associated with poorer outcomes in CRCs. [24, 26] Preclinical studies demonstrated that
metformin could modulate the TME and improve CD8+ T cell infiltration and function,
decrease tumor cell oxygen consumption and increase CD8+ T cell oxygen consumption. [22,
23] The current study aims to harness the immunomodulatory effects of metformin, and
potential clinical benefit in combination with an anti-PD-1 agent, nivolumab, by modulating
the cellular composition within the TME. Therefore, we aim to analyze the immunogenic
profile of the tumors by paired biopsies and peripheral blood collection at the time points

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specified in the protocol. In the paired pre and post-treatment biopsy specimens, we will aim
to identify potential biomarkers for the combination therapy with Nivolumab and Metformin.
Pre and post biopsy tissue will be evaluated using IHC or immunofluorescence for relevant
lymphocyte, myeloid and stromal/vascular markers to provide a comprehensive view of the
cellular composition within the TME. Tissue will also be dissociated and flow cytometry will
be used to further define phenotypic properties of macrophages, lymphocytes or other cell
populations. In addition, we plan to perform on a subset of these patients, genomic analysis of
lymphocyte population.
Metformin is a mitochondrial electron transport chain Complex I inhibitor. The basis for co-
administration of metformin with anti-PD-1 therapy relies on inhibiting Complex I activity in
tumor cells, reducing oxygen consumption rates (OCR) in tumor cells while concomitantly
increasing oxygen in the surrounding microenvironment and oxidative metabolism of the
infiltrating T cell subsets. We will perform ex vivo studies to determine whether oxidative
metabolism is indeed regulated in the tumor and T cell subsets. Pre and post therapy tumor
sections will be evaluated for expression of the following: OCT-1 (metformin transporter), p-
AMPK (that is known to be activated with metformin), mTOR pathway (should be suppressed
as a consequence of AMPK activation), HIF1a, Caspase 3, and Ki67. Intracellular oxygen
levels in tumor and stroma will be evaluated using HypoxyprobeTM to confirm OXPHOS
inhibition. Sorted T cells populations will be evaluated for baseline OCR and OCR/ECAR
(extra-cellular acidification) with and without short-term exogenous metformin administration
using a Seahorse Bioenergetics bioanalyzer. In addition, viability of T cells with metformin or
specific complex I inhibitors (rotenone/piericidin) will be evaluated. Glycolytic gene
expression and OCT-1 expression in tumor samples prior to therapy and their correlation to
therapy response can prospectively help define biomarkers of sensitivity to the combinatorial
administration of metformin with anti-PD1. Evaluation of the outlined endpoints in pre- and
post-treatment samples will help assess the biology of an anti-tumor response.
5. PATIENT SELECTION
5.1
Eligibility Criteria
5.1.1
Patients must have histologically or cytologically confirmed stage IV colorectal
adenocarcinoma with measurable disease.
5.1.2
Prior treatment with 5 Fluorouracil (or capecitabine), oxaliplatin and irinotecan
containing chemotherapy (needs to be treated with anti-EGFR agent if extended RAS
wild type)
5.1.3
Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for non-
nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional techniques
or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam.

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5.1.4
Age ≥18 years.
5.1.5
ECOG performance status 0 or 1 (Karnofsky ≥70%, see Appendix A).
5.1.6
Life expectancy of greater than 3 months
5.1.7
Patients must have normal organ and marrow function as defined below

Absolute neutrophil count
≥1,500/mcL

Platelets
≥100,000/mcL

Hemoglobin
≥9 g/dL or ≥5.6 mmol/L without transfusion or
erythropoietin (EPO) dependency (within 7 days of
assessment)

Serum creatinine
≤1.5 x ULN
OR
creatinine clearance
≥60
mL/min/1.73
m2
for
patients
with
creatinine
levels
>1.5
x
ULN.
Creatinine
clearance
should
be
calculated
per
institutional standard

Serum total bilirubin
≤1.5 x the upper limit of normal (ULN) OR
direct
bilirubin ≤ULN for subjects with total bilirubin >1.5 ULN

AST(SGOT)/ALT(SGPT)
≤2.5 × institutional upper limit of normal

Serum Albumin
≥2.5 mg/dl

International normalized ratio (INR) or prothrombin time (PT) ≤1.5 x ULN unless
subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time
(PTT) is

within therapeutic range of intended use of anticoagulants

Activated partial thromboplastin time (aPTT) ≤1.5 x ULN unless subject is
receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of
intended use of anticoagulants
5.1.8
Patients with diabetes mellitus should be on a stable diabetic treatment regimen for at
least 1 month prior to trial enrollment and keep a blood glucose level log at home for
the first 4 weeks of the trial.
5.1.9
Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to receiving the first dose of study medication; if the
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will
be required.
5.1.10 Male subjects of childbearing potential must agree to use an adequate method of
contraception, starting with the first dose of study therapy through 120 days after the
last dose of study therapy.
o
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject

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5.1.11 Female subjects of childbearing potential must be willing to use an adequate method
of contraception for the course of the study through 120 days after the last dose of study
medication
o
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject
5.1.12 Ability to understand and the willingness to sign a written informed consent document.
5.2
Exclusion Criteria
5.2.1
Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering
the study or those who have not recovered from adverse events due to agents
administered more than 4 weeks earlier.
Note: Subjects with ≤grade 2 neuropathy are an exception to this criterion and may
qualify for the study
Note: If subject received major surgery, they must have recovered adequately from the
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5.2.2
Metformin use in the last 3 months
5.2.3
Patients who are receiving any other investigational agents.
5.2.4
Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis; subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
prior to the first dose of trial treatment and any neurologic symptoms have returned to
baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment; this exception does not include
carcinomatous meningitis which is excluded regardless of clinical stability.
5.2.5
History of allergic reactions attributed to compounds of similar chemical or biologic
composition to Nivolumab and Metformin.
5.2.6
Has a known history of active tuberculosis (TB) (Bacillus tuberculosis)
5.2.7
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment
5.2.8
Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs); replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form
of systemic treatment.
5.2.9
Has known history of, or any evidence of active, non-infectious pneumonitis.
5.2.10 Has an active infection requiring systemic therapy.
5.2.11 Has known substance abuse disorders that would interfere with cooperation with the
requirements of the trial.
5.2.12 Has received prior therapy with an anti-programmed death (PD)-1, anti-PD-L1, or anti-
PD-L2 agent.
5.2.13 Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
5.2.14 Has known active hepatitis B (e.g., hepatitis surface antigen [HBsAg] reactive) or
hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
detected).
5.2.15 Has received a live vaccine within 30 days of planned start of study therapy.
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines
and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated
vaccines, and are not allowed

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5.2.16 Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris or myocardial
infraction within 6 months of study entry, serious cardiac arrhythmia requiring
medications, baseline corrected QT (QTc) >450 mesc or previous history of QT
prolongation while taking other medications.
5.2.17 Other medications, or severe acute/chronic medical or psychiatric condition, or
laboratory abnormality that may increase the risk associated with study participation or
study drug administration, or may interfere with the interpretation of study results, and
in the judgment of the investigator would make the subject inappropriate for entry into
this study
5.2.18 Has a known additional malignancy that is progressing or requires active treatment;
exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer. Subjects
with prior malignancies are eligible if the subject has been disease free for >5 years.
5.2.19 Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the screening visit through 120 days after
the last dose of trial treatment.
5.3
Screen Failures
Minimal data for subjects who fail screening will be collected such as demographic
information and the reason for screen failure. Such subjects may be re-screened at the
discretion of the investigator after approval by the Data and Safety Monitoring Committee
(DSMC). The reason for the need to re-screen a subject will be documented in the subject’s
source documents.
6. TREATMENT PLAN
6.1.1
Agent Administration
Treatment will be administered on an outpatient basis. Reported adverse events and potential
risks are described in Section 7. Appropriate dose modifications are described in Section 6.
No investigational or commercial agents or therapies other than those described below may be
administered with the intent to treat the patient's malignancy.
Table 1: Cycle 1 only (Day -14 through 28) Lead-in period
Regimen Description
Agent
Premedications
; Precautions
Dose
Route
Schedule
Cycle
Length
42 days

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Metformin
Take with food
500
mg
tablet
am,
500 mg pm
PO
Twice daily
D-14
through -12
Metformin
Take with food
500
mg
tablet
am,
1000
mg
pm
PO
Twice daily
D
-11
through -8
Metformin
Take with food
1000
mg
tablet
am,
1000
mg
pm
PO
Twice daily
D
-7
through -1
Metformin*
Take with food
1000
mg
tablet and,
1000
mg
pm
PO
Twice
daily,
D1-
28
*If subject cannot tolerate 1000 mg po twice daily, will resume the highest tolerated dose of
Metformin.
NOTE:
The patient will be requested to maintain a medication diary of each dose of
medication (Metformin). The medication diary (Appendix B) will be returned to clinic staff
at the end of each course. Patients with diabetes mellitus will be requested to keep a blood
glucose log for the first 4 weeks of the trial (Appendix C)
Table 2: Cycle 2 and subsequent cycles (28 days)
Regimen Description
Agent
Premedications
; Precautions
Dose
Route
Schedule
Cycle
Length

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Nivolumab
Premedicate
with
Acetaminophen
650 mg po once
prior
to
Nivolumab,
optional
480 mg
IV
over
30
minutes
Day 1
Metformin*
Take with food
1000
mg
tablet and,
1000
mg
pm
PO
Twice
daily,
D1-
28
28 days
(4 weeks)
* If subject cannot tolerate 1000 mg po twice daily during Cycle 1, subject will continue the
maximum tolerated dose of Metformin as in cycle 1 for the subsequent cycles.
NOTE:
The patient will be requested to maintain a medication diary of each dose of
medication (Metformin). The medication diary (Appendix B) will be returned to clinic staff
at the end of each course.
6.1.2
Investigational Agent(s)
Nivolumab: No premedication indicated, may give Acetaminophen 500 mg po once
prior to Nivolumab administration, which is optional.
Metformin: No premedication indicated. AM dose should be taken with breakfast and
PM dose should be taken with dinner.
6.2
DOSING DELAYS/DOSE MODIFICATIONS
6.2.1
Metformin
The following guidelines are provided for the modification of the dose of metformin in the
event of toxicities attributed by the investigator to this study drug. Toxicities unrelated to
metformin will not ordinarily result in the modification of dose. AEs will be defined based on
the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events
(CTCAE) version 4.
In general, subjects experiencing Grade 1 and 2 drug related toxicities should not have the
dose of metformin modified. However, appropriate supportive care should be provided for the
management of drug related toxicities. Grade 2 toxicities may require dose or schedule
modifications (delaying or omitting individual doses) due to potentially greater clinical
significance; however, this should occur after discussion with study PI.
Dosing of metformin must be delayed if a subject experiences a Grade 3 non-hematologic
toxicity. If the toxicity resolves (returned to baseline or decreased to Grade ≤1) within 7 days,
dosing of metformin may be resumed one lower dose level (See section 6 Table 3). Exceptions
to this rule are as follows:

Grade 3 fatigue: dose modification is left to the PI’s discretion;

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
Grade 3 nausea, vomiting and diarrhea: dose modification only after optimal
prophylactic measures have failed to control the symptoms adequately;
In the case of Grade 4 non-hematologic toxicity, or persistent Grade 3 toxicity despite one
dose level reduction, metformin will be discontinued.
No dose adjustment of metformin will be performed for anemia.
No dose adjustment for Metformin will be performed for grade 1, 2, or 3 neutropenia or grade
1, 2, or 3(without bleeding) thrombocytopenia.
Dosing of metformin will be delayed if subjects develop grade 4 neutropenia or grade 3
thrombocytopenia complicated by bleeding or grade 4 thrombocytopenia. If the toxicity
resolves (returned to baseline or decreased to Grade ≤1) within 14 days, dosing of metformin
may be resumed one lower dose level (See section 6 Table 3).
Table 3: Dose reduction of Metformin
Dose Level
Metformin
1
1000 mg AM/1000 mg PM
-1
500 mg AM/1000mg mg PM
-2
500 mg AM/500mg mg PM
6.2.2
Nivolumab
Adverse events (both non-serious and serious) associated with nivolumab exposure may
represent an immunologic etiology. These adverse events may occur shortly after the first dose
or several months after the last dose of treatment. nivolumab must be withheld for drug-related
toxicities and severe or life-threatening AEs as per 3 below. See Section 6.6.1 for supportive
care guidelines, including use of corticosteroids.
Toxicities unrelated to nivolumab will not ordinarily result in the modification of nivolumab
dose. AEs will be defined based on the National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events (CTCAE) version 4.
Dose Modification Guidelines for Drug-Related Adverse Events- Nivolumab
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and
continue to taper over at least 4 weeks.
2. For situations where Nivolumab has been withheld, Nivolumab can be resumed after
AE has been reduced to Grade 1 or 0 and corticosteroid has been tapered. Nivolumab
should be permanently discontinued if AE does not resolve within 12 weeks of last
dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day
within 12 weeks.
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first
followed by oral steroid. Other immunosuppressive treatment should be initiated if
irAEs cannot be controlled by corticosteroids.

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4. Myocarditis: Withhold treatment for Grade 1 or 2. Permanently discontinue for Grade
3 or 4. Based on severity of AE administer corticosteroids.
5. Newly developed Type I diabetes mellitus: Follow endocrinopathy adverse event
management
algorithm.
Permanently
discontinue
Nivolumab
if
associated
hyperglycemia is grade 4.
6. Dosing interruptions are permitted in the case of medical / surgical events or logistical
reasons not related to study therapy (e.g., elective surgery, unrelated medical events,
patient vacation, and/or holidays). Subjects should be placed back on study therapy
within 3 weeks of the scheduled interruption, unless otherwise discussed with the
Sponsor-investigator. The reason for interruption should be documented in the patient's
study record.

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6.3
General Concomitant Medication and Supportive Care Guidelines
Because there is a potential for interaction of nivolumab and metformin with other
concomitantly administered drugs through the cytochrome P450 system, the case report form
must capture the concurrent use of all other drugs, over-the-counter medications, or alternative
therapies. The Principal Investigator should be alerted if the patient is taking any agent known
to affect or with the potential to affect selected CYP450 isoenzymes.
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during the ongoing trial. If there is a clinical indication for one of these or other medications
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or
vaccination may be required. The investigator should discuss any questions regarding this
with the PI.
The final decision on any supportive therapy or vaccination rests with the
investigator and/or the subject's primary physician
6.4
Acceptable Concomitant 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)

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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.
All concomitant medications received within 28 days before the first dose of trial treatment
and 30 days after the last dose of trial treatment should be recorded. Concomitant medications
administered after 30 days after the last dose of trial treatment should be recorded for SAEs
and ECIs (event of clinical interests) as defined in Section 8.2.
6.5
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and
Treatment Phase (including retreatment for post-complete response relapse) of this trial:

Antineoplastic systemic chemotherapy, monoclonal antibody or biological therapy

Immunotherapy not specified in this protocol

Investigational agents other than Nivolumab and Metformin

Radiation therapy
o
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may
be allowed at the investigator’s discretion.
Nivolumab will be held during
radiation and can be resumed after radiation is finished and patient is stable per
the treating physician. Metformin can be resumed during radiation.

Live vaccines within 30 days prior to the first dose of trial treatment and while
participating in the trial. Examples of live vaccines include, but are not limited to, the
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and
typhoid vaccine.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an
event of clinical interest of suspected immunologic etiology. The use of physiologic
doses of corticosteroids may be approved after consultation with the Sponsor -
investigator.

Inhibitors of CYP3A4 and/or PgP
Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole,
ritonavir) is prohibited.

Co-administration
with
moderate
CYP3A4
inhibitors
(e.g.,
erythromycin,
fluconazole) or PgP inhibitors should be avoided.. Co-administration with moderate
CYP3A4 can be done with caution and only if other alternatives are not available.

Lists
of
CYP3A4
inducers
and
inhibitors
can
be
found
on:
http://medicine.iupui.edu/clinpharm/ddis/table.aspx
and
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Dr
ugInteractionsLabeling/ucm080499.htm ).

Inducers of CYP3A4 and/or PgP

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Strong CYP3A4 inducers (i.e., phenytoin, carbamazepine, rifampin, rifabutin,
phenobarbital, St. John’s wort) should only be used if alternatives are not available.
Moderate inducers of CYP3A4 are allowed if alternatives are not available.
Subjects who, in the assessment by the investigator, require the use of any of the
aforementioned treatments for clinical management should be removed from the trial. Subjects
may receive other medications that the investigator deems to be medically necessary.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
6.6
Rescue Medications & Supportive Care
6.6.1
Supportive Care Guidelines
Subjects should receive appropriate supportive care measures as deemed necessary by the
treating investigator. Suggested supportive care measures for the management of adverse
events with potential immunologic etiology are outlined in Section 6.2. Where appropriate,
these guidelines include the use of oral or intravenous treatment with corticosteroids as well as
additional anti-inflammatory agents if symptoms do not improve with administration of
corticosteroids.
Note that several courses of steroid tapering may be necessary as symptoms
may worsen when the steroid dose is decreased. For each disorder, attempts should be made to
rule out other causes such as metastatic disease or bacterial or viral infection, which might
require additional supportive care. The treatment guidelines are intended to be applied when
the investigator determines the events to be related to nivolumab.
Note: if after the evaluation the event is determined not to be related, the investigator does not
need to follow the treatment guidance (as outlined below). Refer to Section 6.2 for dose
modification.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or
skin photography as part of evaluation of the event.
6.6.2
Management of Infusion Reactions: Signs and symptoms usually develop during or
shortly after drug infusion and generally resolve completely within 24 hours of
completion of infusion
Table 4 Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication
at
subsequent
dosing
Grade 1
Mild reaction; infusion interruption not
indicated; intervention not indicated
Increase monitoring of vital signs as medically
indicated until the subject is deemed medically
stable in the opinion of the investigator.
None
Grade 2
Requires
infusion
interruption
but
responds
promptly
to
symptomatic
treatment
(e.g.,
antihistamines,
NSAIDS,
narcotics,
IV
fluids);
prophylactic medications indicated for
< =24 hrs
Stop Infusion and monitor symptoms.
Additional
appropriate
medical
therapy
may
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Subject may be premedicated at
least 30 minutes prior to infusion of
nivolumab with:
Diphenhydramine 50 mg po (or
equivalent dose of antihistamine).
Acetaminophen 500-1000 mg po (or
equivalent dose of antipyretic).

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NCI CTCAE Grade
Treatment
Premedication
at
subsequent
dosing
Increase monitoring of vital signs as medically
indicated until the subject is deemed medically
stable in the opinion of the investigator.
If symptoms resolve within one hour of stopping
drug infusion, the infusion may be restarted at 50%
of the original infusion rate (e.g., from 100 mL/hr
to 50 mL/hr), if no further complications ensue
after 30 minutes, the rate may be increased to
100% of the original infusion rate. Monitor the
subject closely. If symptoms recur, then no further
study medication will be administered at that visit.
Otherwise dosing will be held until symptoms
resolve and the subject should be premedicated for
the next scheduled dose.
Subjects who develop Grade 2 toxicity despite
adequate
premedication
should
be
permanently discontinued from further trial
treatment administration.
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly responsive
to symptomatic medication and/or brief
interruption of infusion); recurrence of
symptoms
following
initial
improvement; hospitalization indicated
for other clinical sequelae (e.g., renal
impairment, pulmonary infiltrates)
Grade 4:
Life-threatening; pressor or ventilatory
support indicated
Stop Infusion.
Additional
appropriate
medical
therapy
may
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as medically
indicated until the subject is deemed medically
stable in the opinion of the investigator.
Hospitalization may be indicated.
Subject is permanently discontinued from
further trial treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug
administration.
6.7
Diet/Activity/Other Considerations
6.7.1
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE
such as diarrhea, nausea or vomiting. Seville orange, star fruit, grapefruit and their juices affect
P450 and PgP activity and concomitant use with nivolumab and metformin combination should
be avoided.
6.7.2
Contraception
Nivolumab and Metformin may have adverse effects on a fetus in utero. Furthermore, it is not
known if nivolumab and metformin have transient adverse effects on the composition of sperm.
For this trial, male subjects will be considered to be of non-reproductive potential if they have
azoospermia (whether due to having had a vasectomy or due to an underlying medical
condition).
Female subjects will be considered of non-reproductive potential if they are either:
(1) postmenopausal (defined as at least 12 months with no menses without
an alternative medical cause; in women < 45 years of age a high follicle

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stimulating hormone (FSH) level in the postmenopausal range may be
used to confirm a post-menopausal state in
women not using hormonal contraception or hormonal replacement
therapy. In the absence of 12 months of amenorrhea, a single FSH
measurement is insufficient.);
OR
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral
tubal ligation/occlusion, at least 6 weeks prior to screening;
OR
(3) has a congenital or acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or
impregnating a partner, respectively, while receiving study drug and for 120 days after the last
dose of study drug by complying with one of the following:
(1) practice abstinence† from heterosexual activity;
OR
(2) use (or have their partner use) acceptable contraception during heterosexual activity.
Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):

intrauterine device (IUD)

vasectomy of a female subject’s male partner

contraceptive rod implanted into the skin
Combination method (requires use of two of the following):

diaphragm
with
spermicide
(cannot
be
used
in
conjunction
with
cervical
cap/spermicide)

cervical cap with spermicide (nulliparous women only)

contraceptive sponge (nulliparous women only)

male condom or female condom (cannot be used together)

hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous
contraceptive injection
†Abstinence (relative to heterosexual activity) can be used as the sole method of
contraception if it is consistently employed as the subject’s preferred and usual
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation
methods, etc.) and withdrawal are not acceptable methods of contraception.
‡If a contraceptive method listed above is restricted by local regulations/guidelines,
then it does not qualify as an acceptable method of contraception for subjects
participating at sites in this country/region.
Subjects should be informed that taking the study medication may involve unknown risks to
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the study subjects of childbearing potential must adhere to the contraception requirement
(described above) from the day of study medication initiation (or 14 days prior to the initiation
of study medication for oral contraception) throughout the study period up to 120 days after
the last dose of trial therapy. If there is any question that a subject of childbearing potential
will not reliably comply with the requirements for contraception, that subject should not be
entered into the study.
6.7.3
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with Nivolumab and
Metformin, the subject will immediately be removed from the study. The site will contact the
subject at least monthly and document the subject’s status until the pregnancy has been
completed or terminated. The outcome of the pregnancy will be reported to BMS without
delay and within 24 hours to BMS and within 2 working days to Sponsor if the outcome is a
serious adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or life-
threatening complication to the mother or newborn).
The study investigator will make every effort to obtain permission to follow the outcome of
the pregnancy and report the condition of the fetus or newborn to the Sponsor.
If a male
subject impregnates his female partner the study personnel at the site must be informed
immediately and the pregnancy reported to Sponsor as described above and in Section 8.2.4.
6.7.4
Use in Nursing Women
It is unknown whether Nivolumab is excreted in human milk. Since many drugs are excreted
in human milk, and because of the potential for serious adverse reactions in the nursing infant,
subjects who are breast-feeding are not eligible for enrollment. Patients should be advised not
breastfeed while on Nivolumab and Metformin or for at least 3 months after discontinuation.
6.8
Duration of Therapy
In the absence of treatment delays due to adverse event(s), treatment may continue for 2 years
or until one of the following criteria applies:

Disease progression,

Intercurrent illness that prevents further administration of treatment,

Unacceptable adverse event(s),

Patient decides to withdraw from the study, or

General or specific changes in the patient's condition render the patient
unacceptable for further treatment in the judgment of the investigator.

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6.9
Duration of Follow Up
Patients will be followed as outlined in study calendar in section 7 after removal from study or
until death, whichever occurs first. Patients removed from study for unacceptable adverse
event(s) will be followed until resolution or stabilization of the adverse event.
6.10
Criteria for Removal from Study
Patients will be removed from study when any of the criteria listed in Section 5.4 applies. The
reason for study removal and the date the patient was removed must be documented in the
Case Report Form.
6.11
Discontinuation of Study Therapy after CR
Discontinuation of treatment may be considered for subjects who have attained a confirmed
CR that have been treated for at least 24 weeks with nivolumab and metformin and had at least
two treatments with nivolumab and metformin beyond the date when the initial CR was
declared. Subjects who then experience radiographic disease progression may be eligible for
additional treatment with nivolumab and metformin via the Second Course Phase at the
discretion of the investigator as detailed in Section 8.1.7.2.
6.12
Subject Replacement Strategy
Patients who do not complete the intended course of therapy due to reasons other than toxicity,
clinical or radiographic disease progression will be considered as in-evaluable for the primary
endpoint and will be replaced. Subject are not able to tolerate metformin despite 2 dose
reductions in the first 2 weeks of the trial (Metformin only phase) will be considered
inevaluable and replaced.
7. STUDY CALENDAR

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Study Flow Chart
Trial Period:
Treatment Cycles a
End
of
Treatme
nt
Post-Treatment
To be repeated
beyond 8 cycles
Treatment Cycle/Title:
Main
Study
Screeni
ng
(Visit
2)
1 a
2
3
4
5
6
7
8
Discon
Safety
Follow-
up
Follow
Up
Visitsb
Surviv
al
Follow
-Up
Day
D-
14
D-7
D1
D15
Scheduling Window (Days):
-28 to -
1
± 3
± 3*
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At
time
of Discon
30 days
post
discon
Every
8
weeks
post
discon
Every
12
weeks
Informed Consent
X
Inclusion/Exclusion Criteria
X
Demographics and Medical History
X
Prior and Concomitant Medication
Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Metformin Administration c
X
X
X
X
X
X
X
X
X
X
X
Drug
Diary
and
Pill
Count
(Metformin) section 13.5 c
X
X
X
X
X
X
X
X
X
X
X
Blood
glucose
log
for
diabetic
patients
X
X
X
X
Nivolumab administration c
X
X
X
X
X
X
X
X
Post-study anticancer therapy status
X
X
Survival Status
X
X
X
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
X
X
X
X
X
X
X
X
X
Directed Physical Examination
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status d
Xd
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test – Urine or Serum -
HCG
Xj
PT/INR and aPTT
X
CBC with Differential
X
Xe
X
X
X
X
X
X
X
X
X
X
X
X
Comprehensive
Serum
Chemistry
Panel
X
Xe
X
X
X
X
X
X
X
X
X
X
X
X
Fasting triglyceride, cholesterol and
glucose
X
X
X
CEA
X
X
X
X
X
X
Urinalysis
X
X
X
X
T3, FT4 and TSH
X
X
X
X
X
X
ECG
X

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Trial Period:
Treatment Cycles a
End
of
Treatme
nt
Post-Treatment
To be repeated
beyond 8 cycles
Treatment Cycle/Title:
Main
Study
Screeni
ng
(Visit
2)
1 a
2
3
4
5
6
7
8
Discon
Safety
Follow-
up
Follow
Up
Visitsb
Surviv
al
Follow
-Up
Day
D-
14
D-7
D1
D15
Scheduling Window (Days):
-28 to -
1
± 3
± 3*
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At
time
of Discon
30 days
post
discon
Every
8
weeks
post
discon
Every
12
weeks
Tumor Imaging
X
Xg
Xg
Xg
Xg
Newly Obtained Tissue Collection h
X
X h
X h
Correlative Studies Blood Collection i
X
Xi
Xi
Xi
Xi
a.
Each cycle is 4 weeks, and there is 14 days lead in period in cycle 1
b. Only for patients with ongoing treatment related toxicities
c.
Metformin will be taken 500 mg po BID for D-14 to-12, 500 mg am and 1000
mg pm for D-11 to 8, 1000 mg am and 1000 mg pm for D- 7 to -1, and continued
1000 mg BID for the rest of the study (if not able to tolerate 1000 mg BID
during D1-14 period subject will be on maximum tolerated dose). Study
coordinator will call the patient on Day -13 to confirm the subject is taking the
right dose of medication. Nivolumab will be given after biopsy#2 (same day or
up to 5 days later), and then repeated every 4 weeks.
d. ECOG performance status should be done within 14 days or less from day 1 of
cycle 1
e.
Lab results from screening may be used if completed within 1 week of day -1
f.
Baseline imaging within 4 weeks of day 1 is acceptable
g. Scans will be done at the end of cycle 2 (± 3 days), then repeated every 2 cycles
(q 8 weeks)
h. Paired biopsies (biopsy#1) will be obtained at baseline from all 28 patients
within 28 days before Cycle 1 day 1 after consent is signed, subject #1-9, 19-
23 (14 patients in total) will get post treatment biopsy (biopsy#2) cycle 1 Day
1 (same day or up to 5 days later) nivolumab will be given after biopsy#2 (same
day or up to 5 days later) and subject# 10-18, 24-28 (14 patients in total) will
get post treatment biopsy (biopsy#2) C1 Day 15 (same day or up to 5 days later).
Most accessible metastatic disease tumor site will be biopsied by Emory
Interventional Radiology. Same site will be biopsied at biopsy#1 and biopsy#2.
3 core biopsies will be obtained each time. If a patient undergoes biopsy#1 and
refuse biopsy#2 this subject will be replaced. Subjects continue metformin on
days of biopsy#2, and take metformin preferably 2 hours prior to the biopsy.

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i.
Correlative samples will be collected at baseline, cycle 1 day 1, cycle 1 day 15,
Cycle 3 Day 1 and at progression. Analysis will include phenotypic and
functional analysis of T and myeloid cell subsets.
j.
Must be within 72 hours of the study drug
*Unless otherwise specified

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8.
TRIAL PROCEDURES
8.1
Trial procedures
The Trial Flow Chart - Section 7.0 summarizes the trial procedures to be performed at each visit.
Individual trial procedures are described in detail below. It may be necessary to perform these
procedures at unscheduled time points if deemed clinically necessary by the investigator.
8.1.1
Administrative Procedures
8.1.1.1
Informed Consent
The Investigator must obtain documented consent from each potential subject prior to participating
in a clinical trial.
General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally acceptable
representative’s dated signature on a consent form along with the dated signature of the person
conducting the consent discussion.
A copy of the signed and dated consent form should be given to the subject before participation in
the trial.
The initial informed consent form, any subsequent revised written informed consent form and any
written information provided to the subject must receive the IRB/ERC’s approval/favorable
opinion in advance of use. The subject or his/her legally acceptable representative should be
informed in a timely manner if new information becomes available that may be relevant to the
subject’s willingness to continue participation in the trial. The communication of this information
will be provided and documented via a revised consent
form or addendum to the original consent form that captures the subject’s dated signature or by
the subject’s legally acceptable representative’s dated signature.
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and
Sponsor requirements.
8.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to
ensure that the subject qualifies for the trial.
8.1.1.3
Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history will
include all active conditions, and any condition diagnosed within the prior 10 years that are

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considered to be clinically significant by the Investigator. Details regarding the disease for which
the subject has enrolled in this study will be recorded separately and not listed as medical history.
8.1.1.4
Prior and Concomitant Medications Review
Prior Medications
The investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the subject within 28 days
before starting the trial. Treatment for the disease for which the subject has enrolled in this study
will be recorded separately and not listed as a prior medication.
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject during
the trial. All medications related to reportable SAEs and ECIs should be recorded as defined in
Section 8.2.
8.1.1.5
Disease Details and Treatments
Disease Details
The investigator or qualified designee will obtain prior and current details regarding disease status.
Prior Treatment Details
The investigator or qualified designee will review all prior cancer treatments including systemic
treatments, radiation and surgeries.
Subsequent Anti-Cancer Therapy Status
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after
the last dose of trial treatment. If a subject initiates a new anti-cancer therapy within 30 days after
the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the first dose
of the new therapy. Once new anti-cancer therapy has been initiated the subject will move into
survival follow-up.
8.1.1.6
Trial Compliance (Medication/Diet/Activity/Other)
Compliance with Metformin will be determined using drug diary and pill counts performed on day
1 of each cycle. Patients who take less than 80% of their prescribed dose of nivolumab and/or
metformin in the first 2 cycles due to reasons other than toxicity, clinical or radiographic disease
progression will be considered inevaluable for the primary endpoint and will be replaced.
8.1.2
Clinical Procedures/Assessments

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8.1.2.1
Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new or
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.
Adverse experiences will be graded and recorded throughout the study and during the follow-up
period according to NCI CTCAE Version 4.0 (see Section 11.2). Toxicities will be characterized
in terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial
treatment.
For subjects receiving treatment with nivolumab all AEs of unknown etiology associated with
nivolumab exposure should be evaluated to determine if it is possibly an event of clinical interest
(ECI) of a potentially immunologic etiology (termed immune-related adverse events, or irAEs, see
section 6.2.2).
Please refer to section 8.2 for detailed information regarding the assessment and recording of AEs.
Winship Cancer Institute’s Clinical Trials Office will perform the quality assurance and quality
control checks on this clinical trial. Before enrollment of any subject in this study, CTO personnel
and the Investigator will review the protocol; the Investigator’s Brochure; the CRFs/electronic
CRFs and instructions for completion; the informed consent process; and the procedure for
reporting AEs and SAEs.
8.1.2.2
Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the screening
period. Clinically significant abnormal findings should be recorded as medical history. A full
physical exam should be performed during screening,
8.1.2.3
Directed Physical Exam
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or
qualified designee will perform a directed physical exam as clinically indicated prior to trial
treatment administration.
8.1.2.4
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the administration
of each dose of trial treatment and at treatment discontinuation as specified in the Trial Flow Chart
(Section 6.0). Vital signs should include temperature, pulse, respiratory rate, weight and blood
pressure. Height will be measured at screening only.
8.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Section 11.1) at screening
(within 14 days of day 1 cycle 1), prior to the administration of each dose of trial treatment and
discontinuation of trial treatment as specified in the Trial Flow Chart.

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8.1.3
Tumor Imaging and Assessment of Disease
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for Evaluating Response in
Solid Tumors
RECIST version 1.1* will be used in this study for assessment of tumor response. While either
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this
study.
8.1.3.1
Tumor Tissue Collection and Correlative Studies Blood Sampling
Paired biopsies (biopsy#1) will be obtained at baseline from all 28 patients within 28 days before
Cycle 1 day 1 after consent is signed, subject #1-9, 19-23 (14 patients in total) will get post
treatment biopsy (biopsy#2) cycle 1 Day 1 (same day or up to 5 days later) and subject# 10-18,
24-28 (14 patients in total) will get post treatment biopsy (biopsy#2) C1 Day 15 (same day or up
to 5 days later). Most accessible metastatic disease tumor site will be biopsied by Emory
Interventional Radiology. Same site will be biopsied at biopsy#1 and biopsy#2. We don’t believe
biopsy site bias the study as any metastatic site which is deemed safe and accessible can be
biopsied. 3 core biopsies will be obtained each time. If a patient undergoes biopsy#1 and refuse
biopsy#2 this subject will be replaced. The obtained tissues will be handled in the following way:
1)
RNAlater for RNA stabilization and tissue storage
2)
Formalin-fixed paraffin block with one cut H&E stained slide
3)
Liquid nitrogen frozen tissue in cryo-preservation vials
All collected tissues are stabilized and stored in -80°C freezers (RNAlater stabilized, OCT
embedded, short term storage) or the vapor phase of a liquid nitrogen freezer (long term storage)
in single use aliquots. All FFPE tissue blocks are stored in a climate-controlled storage room that
is temperature (less than 27ºC) and humidity controlled.
Tissue will be evaluated using IHC or immunofluorescence to measure relevant immune markers
(i.e. CD3, CD4, CD8, CD163, PD-1, PD-2, PDL-1, MIF, TAM and stromal/ vascular markers).
When sufficient quantities of fresh tissue is available, it will also be dissociated and flow cytometry
will be used to determine the phenotypic characteristics of cell populations in the tumor
microenvironment. Tissue will be preserved for future exploratory studies including genomic
profiling.
Peripheral blood samples
Approximately 20 mL of peripheral blood will be collected prior to initiation of study therapy (at
baseline), cycle 1 day 1, cycle 1 day 15, Cycle 3 Day 1 and at progression. The peripheral blood
mononuclear cells will be isolated from these samples and stored in -80°C freezers until analysis.
Samples will be evaluated for:
i.
Determine whether there are phenotypic changes in of T-cell or myeloid cell surface
markers (including co-stimulatory/immune checkpoint molecules) in PBMCs after treatment.
Samples will be collected at baseline, cycle 1 day 1, cycle 1 day 15, Cycle 3 Day 1 and at
progression.
ii. Determine whether functional changes are evident in PBMCs in response to treatment and
whether these data correlate with clinical outcome measures. Samples will be collected at baseline
and week 10th. Pending quantity of cells a variety of assays may be performed, including but not
limited to intracellular cytokine production and expression of CD107.

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Shipping and handling instructions
After appropriate processing, the blood samples, tissue blocks, slides or frozen tissue samples
will be sent to:
Lesinski Laboratory
Suite C3038, Bay 34
1365-C Clifton Rd. NE
Winship Cancer Institute of Emory University
Atlanta, GA 30322
On the day that the specimens are to be shipped, notify Dr. Matthew Farren at
matthew.r.farren@emory.edu, and Dr. Gregory Lesinski at gregory.b.lesinski@emory.edu of the
pending specimen shipments. Include the Fed-Ex tracking number in the email.
Research blood contact Information:
Matthew Farren, Ph.D. 404-778-8230
Gregory B. Lesinski, Ph.D., MPH 404-778-3072
Methods and materials per Lab Manual
Table 5 Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum
β-human
chorionic
gonadotropin†
Hemoglobin
Alkaline phosphatase
Glucose
(β-hCG)†
Platelet count
Alanine aminotransferase (ALT)
Protein
PT (INR)
WBC (total and differential)
Aspartate aminotransferase (AST)
Specific gravity
aPTT
Red Blood Cell Count
Lactate dehydrogenase (LDH)
Microscopic exam (If abnormal)
Total thriiodothyronine (T3)
Absolute Neutrophil Count
Carbon Dioxide ‡
results are noted
Free tyroxine (T4)
Absolute Lymphocyte Count
(CO2 or biocarbonate)
Urine pregnancy test †
Thyroid stimulating hormone (TSH)
Calcium
Chloride
Blood for correlative studies
Glucose
Phosphorus
Potassium
Sodium
Magnesium
Total Bilirubin

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Hematology
Chemistry
Urinalysis
Other
Direct Bilirubin (If total bilirubin
is elevated above the upper limit of
normal)
Total protein
Blood Urea Nitrogen
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be
required.
‡ If considered standard of care in your region.
8.1.4
Other Procedures
Withdrawal/Discontinuation
When a subject discontinues/withdraws prior to trial completion, all applicable activities scheduled
for the final trial visit should be performed at the time of discontinuation. Any adverse events
which are present at the time of discontinuation/withdrawal should be followed in accordance with
the safety requirements outlined in Section 8.2 - Assessing and Recording Adverse Events.
Subjects who a) attain a CR or b) complete 24 months of treatment with nivolumab and metformin
combination may discontinue treatment with the option of restarting treatment if they meet the
criteria specified in Section 8.1.7.2 After discontinuing treatment following assessment of CR,
these subjects should return to the site for a Safety Follow-up Visit (described in Section 8.1.6)
and then proceed to the Follow-Up Period of the study (described in Section 8.1.7).
8.1.5
Visit Requirements
Visit requirements are outlined in Section 7.0 - Trial Flow Chart.
Specific procedure-related
details are provided above in Section 8.0 - Trial Procedures.
8.1.5.1
Screening
Screening Period
All subjects must sign an informed consent document prior to the initiation of any study related
procedures. The informed consent document must be signed within 28 days of Cycle 1 Day 1.
Screening procedures are to be conducted within 28 days of Cycle 1 Day 1.

Review of study eligibility criteria

Medical History

Record concomitant medications taken up to 28 days prior to day 1 cycle 1

Vitals [temperature, heart rate (HR), blood pressure (BP) and respiratory rate (RR)]

Physical Examination, including height and weight

ECOG Performance Status evaluation (within 14 days or less of cycle 1 day 1)

Laboratory Assessments

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o
Hematology: hemoglobin, hematocrit, red blood cell count, white blood cell
count with differential and platelet count
o
Serum chemistry: sodium, potassium, chloride, bicarbonate, magnesium,
calcium, phosphorus, blood urea nitrogen, creatinine, total bilirubin, LDH, total
protein, ALP, ALT, AST, and albumin. Fasting triglycerides, cholesterol and
glucose.
o
Serum or urine pregnancy test for women of childbearing potential. Must be
within 72 hours of study drug
o
Prothrombin time (PT) and activated partial thromboplastin time (aPTT)
o
Urinalysis
o
Tumor markers: CEA
o
T3, FT4, TSH

12-lead ECG

Radiologic imaging studies to evaluate tumor status. contrast computed tomography
(CT) or magnetic resonance imaging (MRI) of the chest and abdomen and pelvis.
Additional imaging may be obtained as clinically indicated. Baseline scans may be
done within 4 weeks prior to cycle 1 day 1.

Baseline fresh biopsy (in all patients, 28 total) will be obtained within 28 days of day
1 cycle 1 and after consent is signed.

Blood sample 20 cc for correlative work
8.1.5.2
Treatment Period
8.1.5.3
Lead in Cycle 1 Day -14

Record concomitant medications

Vitals (temperature, HR, BP and RR)

History and physical exam, pill diary and pill count, blood glucose log for diabetic
patients

ECOG performance status

Toxicity assessment

Laboratory Assessments
o
Hematology hemoglobin, hematocrit, red blood cell count, white blood cell
count with differential and platelet count
o
Chemistry sodium, potassium, chloride, bicarbonate, magnesium, calcium,
phosphorus, blood urea nitrogen, creatinine, glucose (random), total bilirubin,
LDH, total protein, ALP, ALT, AST, and albumin
o
For the cycle1 day -1 labs, lab results from the screening tests maybe used if
completed within 1 week of day -1

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o
Tumor marker – CEA

Metformin
8.1.5.4
Cycle 1 Day -7 phone call

Metformin

Review of adverse events, dosing compliance and concomitant medication (by clinical
trial coordinator via phone call
8.1.5.5
Cycle 1 Day 1

Record concomitant medications

Vitals (temperature, HR, BP and RR)

History and physical exam, pill diary and pill count, blood glucose log for diabetic
patients

ECOG performance status

Toxicity assessment

Laboratory Assessments
o
Hematology hemoglobin, hematocrit, red blood cell count, white blood cell
count with differential and platelet count
o
Chemistry sodium, potassium, chloride, bicarbonate, magnesium, calcium,
phosphorus, blood urea nitrogen, creatinine, glucose (random), total bilirubin,
LDH, total protein, ALP, ALT, AST, and albumin

Blood sample 20 cc for correlative work

Subject# 1-9, 19-23 (14 patients in total) will get biopsy#2 of paired biopsy (same day
or up to 5 days later)

Continue metformin

Nivolumab will be started after biopsy#2 (same day or up to 5 days later).

Nivolumab 480 mg will be administered as a 30-minute IV infusion in the infusion
center. Given the variability of infusion pumps, a window of -5 minutes and +10
minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).
8.1.5.6
Cycle 1 Day 15

Record concomitant medications

Vitals (temperature, HR, BP and RR)

History and physical exam, pill diary and pill count, blood glucose log for diabetic
patients

ECOG performance status

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
Toxicity assessment

Laboratory Assessments
o
Hematology hemoglobin, hematocrit, red blood cell count, white blood cell
count with differential and platelet count
o
Chemistry sodium, potassium, chloride, bicarbonate, magnesium, calcium,
phosphorus, blood urea nitrogen, creatinine, glucose (random), total bilirubin,
LDH, total protein, ALP, ALT, AST, and albumin
o
Tumor marker – CEA

Blood sample 20 cc for correlative work

The second half of the patients Subject #10-18, 24-28 (14 patients in total) will get
biopsy#2 of paired biopsy (same day or up to 5 days later)

Continue metformin
8.1.5.7
Cycle 2 Day 1

Record concomitant medications

Vitals (temperature, HR, BP and RR)

History and physical exam, pill diary and pill count

ECOG performance status

Toxicity assessment

Laboratory Assessments
o
Hematology hemoglobin, hematocrit, red blood cell count, white blood cell
count with differential and platelet count
o
Chemistry sodium, potassium, chloride, bicarbonate, magnesium, calcium,
phosphorus, blood urea nitrogen, creatinine, glucose (random), total bilirubin,
LDH, total protein, ALP, ALT, AST, and albumin
o
Tumor marker – CEA (every 2 cycles after cycle 2)
o
T3, FT4, TSH at cycle 2 and then after every 3 cycles

Metformin and Nivolumab combination

Cross sectional imaging (CT or MRI) for restaging at the end of C#2 (± 3 days), then
repeat every 2 cycles (every 8 weeks)
8.1.5.8
Cycle 3 Day 1 and Day 1 of each subsequent cycle

Record concomitant medications

Vitals (temperature, HR, BP and RR)

History and physical exam, pill diary and pill count

ECOG performance status

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
Toxicity assessment

Laboratory Assessments
o
Hematology hemoglobin, hematocrit, red blood cell count, white blood cell
count with differential and platelet count
o
Chemistry sodium, potassium, chloride, bicarbonate, magnesium, calcium,
phosphorus, blood urea nitrogen, creatinine, glucose (random), total bilirubin,
LDH, total protein, ALP, ALT, AST, and albumin
o
Fasting triglycerides, cholesterol and glucose (Cyle#3 and every 3 cycles)
o
Urinalysis (Cyle#3 and every 3 cycles)

Metformin and Nivolumab combination

Blood sample 20 cc for correlative work
8.1.5.9
End of treatment visit

Record concomitant medications

Vitals (temperature, HR, BP and RR)

History and physical exam

ECOG performance status

Toxicity assessment

Laboratory Assessments
o
Hematology hemoglobin, hematocrit, red blood cell count, white blood cell
count with differential and platelet count
o
Chemistry sodium, potassium, chloride, bicarbonate, magnesium, calcium,
phosphorus, blood urea nitrogen, creatinine, glucose (random), total bilirubin,
LDH, total protein, ALP, ALT, AST, and albumin
o
Tumor markers - when applicable.
o
Urinalysis
o
T3, FT4, TSH

Blood sample 20 cc for correlative work
8.1.6
Safety Follow-Up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last
dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes
first. All AEs that occur prior to the Safety Follow-Up Visit should be recorded. Subjects with an
AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 or until the beginning
of a new anti-neoplastic therapy, whichever occurs first. SAEs that occur within 90 days of the
end of treatment or before initiation of a new anti-cancer treatment should also be followed and
recorded. Subjects who are eligible for retreatment with nivolumab/metformin (as described in

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Section 8.1.7.2) may have up to two safety follow-up visits, one after the Treatment Period and
one after the Second Course Phase.
8.1.7
Follow-up Visits
Subjects who discontinue trial treatment for a reason other than disease progression will move into
the Follow-Up Phase and should be assessed every 8 weeks (± 7 days) by radiologic imaging to
monitor disease status. After 1 year, the imaging time point will occur every 9 weeks (± 7 days).
Every effort should be made to collect information regarding disease status until the start of new
anti-neoplastic therapy, disease progression, death, end of the study or if the subject begins
retreatment with nivolumab and metformin as detailed in Section 7.1.6.2. Information regarding
post-study anti-neoplastic treatment will be collected if new treatment is initiated. Details are
provided in Section 7.0 – Trial Flow Chart.
8.1.7.1
Survival Follow-up
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the
subject moves into the survival follow-up phase and should be contacted by telephone every 12
weeks to assess for survival status until death, withdrawal of consent, or the end of the study,
whichever occurs first.
8.1.7.2
Second Course Phase (Retreatment Period)
Subjects who stop nivolumab/metformin with SD or better may be eligible for up to one year of
additional nivolumab/metformin therapy if they progress after stopping study treatment. This
retreatment is termed the Second Course Phase of this study and is only available if the study
remains open and the subject meets the following conditions:

Either
o
Stopped initial treatment with nivolumab/metformin after attaining an investigator-
determined confirmed CR according to RECIST 1.1, and

Was treated for at least 24 weeks with nivolumab/metformin before discontinuing
therapy

Received at least two treatments with nivolumab/metformin beyond the date
when the initial CR was declared
OR
o
Had SD, PR or CR and stopped nivolumab/metformin treatment after 24 months of
study therapy for reasons other than disease progression or intolerability
AND

Experienced an investigator-determined confirmed radiographic disease progression after
stopping their initial treatment with nivolumab/metformin

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
Did not receive any anti-cancer treatment since the last dose of nivolumab/metformin

Has a performance status of 0 or 1 on the ECOG Performance Scale

Demonstrates adequate organ function as detailed in Section 5.1.7

Female subject of childbearing potential should have a negative serum or urine pregnancy
test within 72 hours prior to receiving retreatment with study medication.

Female subject of childbearing potential should be willing to use 2 methods of birth control
or be surgically sterile, or abstain from heterosexual activity for the course of the study
through 120 days after the last dose of study medication (Reference Section 5.1.10).
Subjects of child bearing potential are those who have not been surgically sterilized or have
been free from menses for > 1 year.

Male subject should agree to use an adequate method of contraception starting with the
first dose of study therapy through 120 days after the last dose of study therapy.

Does not have a history or current evidence of any condition, therapy, or laboratory
abnormality that might interfere with the subject’s participation for the full duration of the
trial or is not in the best interest of the subject to participate, in the opinion of the treating
investigator.
Subjects who restart treatment will be retreated at the same dose and dose interval as when they
last nivolumab/metformin. Treatment will be administered for up to one additional year.
Visit requirements are outlined in Section 7.0 – Trial Flow Chart
8.2
Assessing and Recording Adverse Events
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a
preexisting medical condition in a clinical investigation participant administered study drug and
that does not necessarily have a causal relationship with this treatment. An AE can therefore be
any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or
disease temporally associated with the use of investigational product, whether or not considered
related to the investigational product.
A non-serious adverse event is an AE not classified as serious.
8.2.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:

results in death

is life-threatening (defined as an event in which the participant was at risk of death at the time
of the event; it does not refer to an event which hypothetically might have caused death if it
were more severe)

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
requires inpatient hospitalization or causes prolongation of existing hospitalization (see
NOTE below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect

is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and
scientific judgment, may jeopardize the subject or may require intervention [eg, medical,
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples
of such events include, but are not limited to, intensive treatment in an emergency room or at
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in
hospitalization.)

Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study
drug is an SAE.

Unusual Failure in Efficacy (for Phase IV Canadian studies)
Although pregnancy and potential drug-induced liver injury (DILI), are not always serious by
regulatory definition, however, these events must be reported within the SAEs timeline.
Any component of a study endpoint that is considered related to study therapy should be reported
as an SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be
reported).
The following hospitalizations are not considered SAEs:

a visit to the emergency room or other hospital department < 24 hours, that does not result
in admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status (eg,
routine colonoscopy)

Medical/surgical admission other than to remedy ill health and planned prior to entry into
the study. Appropriate documentation is required in these cases.

Admission encountered for another life circumstance that carries no bearing on health status
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy,
caregiver respite, family circumstances, administrative reason).

Admission for administration of anticancer therapy in the absence of any other SAEs (applies
to oncology protocols)

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8.2.1.1
Reporting of Serious Adverse Events Associated with Nivolumab

All Serious Adverse Events (SAEs) that occur following the subject’s written consent to
participate in the study through 100 days for nivolumab of discontinuation of dosing must
be reported to BMS Worldwide Safety, whether related or not related to study drug. If
applicable, SAEs must be collected that relate to any later protocol-specified procedure (eg,
a follow-up skin biopsy).

Following the subject’s written consent to participate in the study, all SAEs, whether related
or not related to study drug, are collected, including those thought to be associated with
protocol-specified procedures. The investigator should report any SAE occurring after these
aforementioned time periods, which is believed to be related to study drug or protocol-
specified procedure to BMS.

An SAE report should be completed for any event where doubt exists regarding its
seriousness;

If the investigator believes that an SAE is not related to study drug, but is potentially related
to the conditions of the study (such as withdrawal of previous therapy or a complication of a
study procedure), the relationship should be specified in the narrative section of the SAE
Report Form.
An appropriate SAE form (e.g. ex-US = CIOMS form or USA = Medwatch form) should be used
to report SAEs to BMS. If you prefer to use your own Institutional form, it must be reviewed by
the BMS Protocol Manager prior to study initiation to ensure that at a minimum all of the data
elements on the CIOMS form are present. Note: Please include the BMS Protocol number on the
SAE form or on the cover sheet with the SAE form transmission.
The CIOMS form is available at: http://www.cioms.ch/index.php/cioms-form-i
The MedWatch form is available at: MedWatch 3500 Form


The Sponsor-investigator will reconcile the clinical database AE cases (case level only)
transmitted to BMS Global Pharmacovigilance (Worldwide.Safety@bms.com).

The
Investigator
will
request
from
BMS
GPV&E,
aepbusinessprocess@bms.com the SAE reconciliation report and include
the BMS protocol number every 3 months and prior to data base lock or
final data summary

GPV&E will send the investigator the report to verify and confirm all SAEs
have been transmitted to BMS GPV&E.

The data elements listed on the GPV&E reconciliation report will be used
for case identification purposes. If the Investigator determines a case was
not transmitted to BMS GPV&E, the case should be sent immediately to
BMS (Worldwide.Safety@bms.com).

In addition to the Sponsor Investigator’s responsibility to report events to the FDA ,
suspected serious adverse reactions (whether expected or unexpected) shall be reported by

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BMS to the relevant competent health authorities in all concerned countries according to
local regulations (either as expedited and/or in aggregate reports).

In accordance with local regulations, BMS will notify sponsor investigators of all reported
SAEs that are suspected (related to the investigational product) and unexpected (ie, not
previously described in the IB). An event meeting these criteria is termed a Suspected,
Unexpected Serious Adverse Reaction (SUSAR). Sponsor investigator notification of these
events will be in the form of either a SUSAR Report or a Semi-Annual SUSAR Report.
Other important findings which may be reported by BMS as an Expedited Safety Report
(ESR) include: increased frequency of a clinically significant expected SAE, an SAE
considered associated with study procedures that could modify the conduct of the study,
lack of efficacy that poses significant hazard to study subjects, clinically significant
safety finding from a nonclinical (eg, animal) study, important safety recommendations
from a study data monitoring committee, or sponsor or BMS decision to end or
temporarily halt a clinical study for safety reasons.
Upon receiving an ESR from BMS, the investigator must review and retain the ESR
with the IB. Where required by local regulations or when there is a central IRB/IEC for
the study, the sponsor will submit the ESR to the appropriate IRB/IEC. The investigator
and IRB/IEC will determine if the informed consent requires revision. The investigator
should also comply with the IRB/IEC procedures for reporting any other safety
information.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS
within 24 hours \ 1 Business Day of becoming aware of the event. SAEs must be recorded on either
CIOMS, MedWatch, or approved site SAE form.
Pregnancies must be reported and submitted to BMS. BMS will perform due diligence follow-up
using the BMS Pregnancy Form which the investigator must complete.
SAE Email Address: Worldwide.Safety@BMS.com
SAE Facsimile Number: +1 609-818-3804
If only limited information is initially available, follow-up reports are required. (Note: Follow-up
SAE reports should include the same investigator term(s) initially reported.)
If an ongoing SAE changes in its intensity or relationship to study drug or if new information
becomes available, a follow-up SAE report should be sent within 24 hours \ 1 Business Day to
BMS using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
The causal relationship to study drug is determined by a physician and should be used to assess all
adverse events (AE). The casual relationship can be one of the following:

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Related: There is a reasonable causal relationship between study drug administration and the AE.
Not related: There is not a reasonable causal relationship between study drug administration and
the AE.
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship.
Adverse events can be spontaneously reported or elicited during open-ended questioning,
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be
questioned regarding the specific occurrence of one or more AEs.)
8.2.2
Nonserious Adverse Event

Non-serious Adverse Events (AE) are to be provided to BMS in aggregate via interim or
final study reports as specified in the agreement or, if a regulatory requirement [eg, IND
US trial] as part of an annual reporting requirement.

Non-serious AE information should also be collected from the start of a placebo lead-in
period or other observational period intended to establish a baseline status for the subjects.
8.2.2.1
Non-serious Adverse Event Collection and Reporting
The collection of non-serious AE information should begin at initiation of study drug. All
non-serious adverse events (not only those deemed to be treatment-related) should be collected
continuously during the treatment period and for a minimum of 100 days for nivolumab following
the last dose of study treatment.
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they
become serious. Follow-up is also required for non-serious AEs that cause interruption or
discontinuation of study drug and for those present at the end of study treatment as appropriate.
8.2.3
Laboratory Test Abnormalities
All laboratory test results captured as part of the study should be recorded following institutional
procedures. Test results that constitute SAEs should be documented and reported to BMS as such.
The following laboratory abnormalities should be documented and reported appropriately:

any laboratory test result that is clinically significant or meets the definition of an SAE

any laboratory abnormality that required the participant to have study drug discontinued or
interrupted

any laboratory abnormality that required the subject to receive specific corrective therapy.
It is expected that wherever possible, the clinical rather than laboratory term would be used by the
reporting investigator (eg, anemia versus low hemoglobin value).

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8.2.4
Reporting of Pregnancy and Lactation to the BMS
If, following initiation of the investigational product, it is subsequently discovered that a study
participant is pregnant or may have been pregnant at the time of investigational product exposure,
including during at least 5 half-lives after product administration, the investigational product will
be permanently discontinued in an appropriate manner (eg, dose tapering if necessary for
participant).
The investigator must immediately notify Worldwide.Safety@bms.com of this event and complete
one of the following forms within 24 hours of awareness of the event via either the CIOMS,
MedWatch or appropriate Pregnancy Surveillance Form in accordance with SAE reporting
procedures.
Protocol-required procedures for study discontinuation and follow-up must be performed on the
participant.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal
outcome and, where applicable, offspring information must be reported on the CIOMS,
MedWatch, BMS Pregnancy Surveillance Form, or approved site SAE form. A BMS Pregnancy
Surveillance Form may be provided upon request.
Any pregnancy that occurs in a female partner of a male study participant should be reported to
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. In
order for Sponsor or designee to collect any pregnancy surveillance information from the female
partner, the female partner must sign an informed consent form for disclosure of this information.
8.2.5
Other Safety Considerations
Any
significant
worsening
noted
during
interim
or
final
physical
examinations,
electrocardiograms, X-rays, and any other potential safety assessments, whether or not these
procedures are required by the protocol, should also be recorded as a non-serious or serious AE,
as appropriate, and reported accordingly.
8.3
Expedited Adverse Event Reporting
8.3.1
Expedited AE reporting for this study must be reported to the FDA/IRB per FDA and IRB
guidelines.These requirements are briefly outlined in the tables below (Section 8.3.2).
Written IND safety reports will be submitted to the FDA by the IND sponsor, for serious,
unexpected suspected adverse reactions within 15 calendar days of learning of its
occurrence. If the event is fatal or is deemed to be life threatening, the report will be made
within 7 calendar days. The IND sponsor will also make an assessment of whether the
event constitutes an unanticipated problem posing risks to subjects or others (UP). This
assessment will be provided to the Emory University IRB, which, in turn will make a final
determination. If the Emory IRB determines an event is a UP it will notify the appropriate
regulatory agencies and institutional officials.

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8.3.2
Table 6 Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization
indicated; disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of investigational product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This
does not include an adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of
stay, even if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat
a pre-existing condition that has not worsened is not a serious adverse event. A pre-existing condition is a clinical condition that is diagnosed
prior to the use of investigational products and is documented in the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours
and to BMS within 2 working days to meet certain local requirements); or
Is an overdose (whether accidental or intentional). Any adverse event associated with an overdose is considered a serious adverse event for
collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must
be reported within 24 hours to the Sponsor and to BMS within 2 working days.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a
serious adverse event when, based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or
surgical intervention to prevent one of the outcomes listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken
Did the adverse event cause investigational products to be discontinued?
Relationship
to
investigational
Product(s)
Did investigational product(s) cause the adverse event? The determination of the likelihood that investigational product(s) caused the adverse
event will be provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or
worksheet that supports the causality noted on the AE form, ensures that a medically qualified assessment of causality was done. This initialed
document must be retained for the required regulatory time frame. The criteria below are intended as reference guidelines to assist the
investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the available information.
The following components are to be used to assess the relationship between investigational
product and the AE; the greater the
correlation with the components and their respective elements (in number and/or intensity), the more likely BMS product caused the adverse
event (AE):
Exposure
Is there evidence that the subject was actually exposed to investigational product(s) such as: reliable history, acceptable
compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily
specimen?
Time
Course
Did
the
AE
follow
in
a
reasonable
temporal
sequence
from
administration
of
investigational
product(s)?
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely
Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or
environmental factors

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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to
investigational
(continued)
Dechallenge
Was investigational product(s) discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE
resolved/improved despite continuation of the BMS product; or (3) the trial is a single-dose drug trial); or (4)
BMS product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to investigational product(s) in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the
trial is a single-dose drug trial); or (3) BMS’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND
WHICH MAY HAVE BEEN CAUSED BY investigational PRODUCT, OR IF REEXPOSURE TO BMS
PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT, THEN THE
RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR AS PER DOSE
MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency
with
Trial
Treatment
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding
investigational product(s) or drug class pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according
to his/her best clinical judgment, including consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of
investigational product(s) relationship).
Yes, there is a reasonable
possibility of
investigational
product(s) relationship.
There is evidence of exposure to investigational product (s) . The temporal sequence of the AE onset relative
to the administration of investigational
product(s) is reasonable.
The AE is more likely explained by
investigational product(s) than by another cause.
No, there is not a reasonable
possibility
of
investigational
product(s) relationship
Subject did not receive the investigational
product OR temporal sequence of the AE onset relative to
administration of investigational product(s) is not reasonable OR the AE is more likely explained by another
cause than the BMS product. (Also entered for a subject with overdose without an associated AE.)
8.4
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions. ALL AEs are to be
reported through ONCORE.
8.5
Secondary Malignancy
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment
with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is
not considered a metastasis of the initial neoplasm.
All secondary malignancies that occur following treatment with an agent under an IND/IDE must
be reported through ONCORE. Three options are available to describe the event:

Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia
[AML])

Myelodysplastic syndrome (MDS)

Treatment-related secondary malignancy

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Any malignancy possibly related to cancer treatment (including AML/MDS) should also be
reported via the routine reporting mechanisms outlined in each protocol.
8.6
Second Malignancy
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a
metastasis from the initial malignancy).
A list of the adverse events and potential risks associated with the investigational or commercial
agents administered in this study can be found in investigator`s brochure.
9. LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES
9.1
Investigational Product
9.1.1
Nivolumab
The investigator shall take responsibility for and shall take all steps to maintain appropriate
records and ensure appropriate supply, storage, handling, distribution and usage of
investigational product in accordance with the protocol and any applicable laws and regulations.
Clinical Supplies will be provided by BMS as summarized in Table X.
Clinical Supplies will be provided by BMS.
9.1.2
Metformin ER
Metformin will be bought by the investigational pharmacy services at Winship Cancer Institute
and the funding will be provided by BMS.
The investigator shall take responsibility for and shall take all steps to maintain appropriate
records and ensure appropriate supply, storage, handling, distribution and usage of
investigational product in accordance with the protocol and any applicable laws and regulations.
9.1.3
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements.
9.1.4
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor-investigator
and/or designee are not blinded to treatment. Drug identity (name, strength) is included in the label
text; random code/disclosure envelopes or lists are not provided.
9.1.5
Storage and Handling Requirements

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Clinical supplies must be stored in a secure, limited-access location under the storage conditions
specified on the label.
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial
site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
9.1.6
Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received from
BMS or designee, the amount dispensed to and returned by the subjects and the amount remaining
at the conclusion of the trial. Upon completion or termination of the study, all unused and/or
partially used investigational product will be destroyed at the site per institutional policy. It is the
Investigator’s responsibility to arrange for disposal of all empty containers, provided that
procedures for proper disposal have been established according to applicable federal, state, local
and institutional guidelines and procedures, and provided that appropriate records of disposal are
kept.
10. STATISTICAL CONSIDERATIONS
10.1
Study Design/Endpoints/ Determination of Sample Size
This is a phase II trial. Primary objective is to determine the overall response rate. Historically
ORR with single agent Nivolumab in CRC is <5% and Metformin and Nivolumab combination
will have ORR of 15%. Simon’s MinMax two stage design is employed for the study with power
of 80% and alpha of 0.1. If there is 1 response in first 18 patients in the first stage of the study,
then it will proceed with second stage to enroll total of 28 patients. If there are 3 or more responders
out of the 28 patients then it would be positive study. This will enable us to evaluate clinical
endpoints (ORR, CEA, RFS, OS) as well as evaluate the impact on immune biomarkers.
10.2
Statistical and Analytical Plans
Summary statistics will be presented for all safety, efficacy and biomarker parameter analyses.
The purpose of these analyses is hypothesis generating. Various exploratory statistical tests may
be applied to data generated from this trial to generate hypotheses to be tested in subsequent trials.
In general, data for continuous parameters will be presented using descriptive statistics including
sample size, mean, and median; standard deviation; and minimum and maximum. Categorical
parameters be displayed using counts and percentages. Toxicities will be presented as worst
toxicity per patient and will be reported as percent toxicity.
Objective response rate will be calculated as proportion (Responders/Total patients) along with
95% confidence intervals using the Clopper-Pearson method. Chi-square test or Fisher’s exact test
will be used to compare the efficacy in term of response rate, biochemical response (CEA) between
the different groups stratified by biomarkers or other factors, respectively. Logistics regression

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model will be further employed to test the adjusted effect of biomarkers on the response rate after
adjusting for other clinical factors and demographic factors.
For progression free survival, progression or death from any cause will be defined as the event.
Patients will be censored at time of last follow-up. For overall survival, death from any cause will
be defined as the event. Patients will be censored at time of last follow-up. Overall survival (OS)
and progression free survival (PFS) rates of two patient groups stratified by response or other
factors will be estimated with the Kaplan-Meier method and compared between different groups
using the log-rank test, respectively. The PFS and OS of each patient group at specific time points,
such as 6 moths, 1 year, 3 year, and 5 year, etc. will be also estimated alone with 95% CI. Cox
proportional hazards models will be further used in the multivariable analyses to assess adjusted
effect of response on the patients’ OS and PFS after adjusting for other factors. Interaction terms
between these factors will also be tested for statistical significance. The proportional hazards
assumption will be evaluated graphically and analytically with regression diagnostics. Violations
of the proportional hazards assumptions will be addressed by use of time-dependent covariates or
extended Cox regression models.
For the biomarker study, descriptive statistics will be first used to summarize biomarker endpoints,
including analyses of tumor biopsies. Biomarker data will also be displayed graphically, where
appropriate. Depending on whether data is normally distributed, t-test or Wilcoxon rank sum test
will be used to compare each biomarker between any two groups stratified by response or other
factors, respectively. General linear model (GLM) will be used to compare each biomarker
between responders and nonresponders with and without adjusting for other factors. Logistics
regression model will be further employed to test the adjusted effect of biomarker on the response
rate after adjusting for other factors.
10.3
Evaluation of Response
All patients included in the study must be assessed for response to treatment, even if there are
major protocol treatment deviations or if they are ineligible. Each patient will be assigned one of
the following categories:
1) complete response, 2) partial response, 3) stable disease, 4)
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early
death because of other cause, or 9) unknown (not assessable, insufficient data).
[Note:
By
arbitrary convention, category 9 usually designates the “unknown” status of any type of data in a
clinical database.]
All of the patients who met the eligibility criteria (with the possible exception of those who
received no study medication) should be included in the main analysis of the response rate.
Patients in response categories 4-9 should be considered to have a treatment failure (disease
progression). Thus, an incorrect treatment schedule or drug administration does not result in
exclusion from the analysis of the response rate. Precise definitions for categories 4-9 will be
protocol specific.

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All conclusions should be based on all eligible patients. Subanalyses may then be performed on
the basis of a subset of patients, excluding those for whom major protocol deviations have been
identified (e.g., early death due to other reasons, early discontinuation of treatment, major protocol
violations, etc.). However, these subanalyses may not serve as the basis for drawing conclusions
concerning treatment efficacy, and the reasons for excluding patients from the analysis should be
clearly reported. The 95% confidence intervals should also be provided.
10.4
Analysis Sets
All subjects who receive any amount of study drug will be included in the evaluation of safety and
efficacy.
10.5
Subject Disposition and Baseline Characteristics
The number and percentage of subjects who enrolled, were treated, and who discontinued will be
tabulated. The reasons for treatment and study discontinuation will be presented. Demographic
and other baseline characteristics will be summarized using descriptive statistics or counts and
percentages, as appropriate.
10.6
Safety Analysis
10.6.1 Adverse Events
Adverse events will be classified using MedDRA System Organ Classes and Preferred Terms.
Furthermore, SAEs, AEs with a severity grade of 3 or above using NCI CTCAE version 4.0, AEs
deemed related to study drug, AEs leading to discontinuation of study drug, and AEs leading to
death will also be summarized in preferred term by system organ class and listed on an individual
subject basis.
10.6.2 Laboratory Data
Descriptive statistics for worst grade of each laboratory parameter by the NCI CTCAE scale
version 4.0 at baseline and follow-up will be presented along with change from Baseline.
Additionally, laboratory values ≥Grade 3 severity will be tabulated and listed on an individual
subject basis.
10.6.3 Dose Modifications and Reasons
The number of subjects with skipped doses, dose delays and dose reductions as well as major
reasons for dose modifications will be summarized.
11. ADMINISTRATIVE AND REGULATORY DETAILS

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11.1
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food
and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely responsible
for determining whether the trial and its results are subject to the requirements for submission to
the Clinical Trials Data Bank, http://www.clinicaltrials.gov.
Information posted will allow
subjects to identify potentially appropriate trials for their disease conditions and pursue
participation by calling a central contact number for further information on appropriate trial
locations and trial site contact information.
11.2
Pre-study Documentation
The Sponsor-Investigator must provide BMS with the following documents prior to the enrollment
of any subjects:

Copy of the IRB/IEC approval letter for protocol, informed consent, Investigator and site

Signed and dated current curricula vitae of the investigator

Copy of approved informed consent document

Copy of the FDA letter and IND receipt and number assignment

Signed Clinical Trial Agreement
11.3
Protocol Adherence
By signing the Form FDA 1572, the Investigator agrees to conduct the study according to the
protocol and the FDA regulations set forth in 21 CFR Parts 50, 54, 56, and 312.
11.4
Retention of Study Documents
All documentation of adverse events, records of study drug receipt and dispensation, and all IRB
correspondence will be maintained as required by FDA and Emory policy.
11.5
Data Management
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will provide
oversight for the conduct of this study. The DSMC functions independently within
Winship Cancer Institute to conduct internal monitoring functions to ensure that research being
conducted by Winship Cancer Institute Investigators produces high-quality scientific data in a
manner consistent with good clinical practice (GCP) and appropriate regulations that govern
clinical research.
Depending on the risk level of the protocol, the DSMC review may occur every
6 months or annually. For studies deemed High Risk, initial study monitoring will occur within 6
months from the date of the first subject accrued, with 2 of the first 5 subjects being reviewed. For
studies deemed Moderate Risk, initial study monitoring will occur within 1 year from the date of
the first subject accrued, with 2 of the first 5 subjects being reviewed. Subsequent monitoring will
occur in routine intervals per the Winship Data and Safety Monitoring Plan (DSMP).

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The DSMC will review pertinent aspects of the study to assess subject safety, compliance with the
protocol, data collection, and risk-benefit ratio. Specifically, the Winship Cancer Institute Internal
Monitors assigned to the DSMC may verify informed consent, eligibility, data entry, accuracy and
availability of source documents, AEs/SAEs, and essential regulatory documents. Following the
monitoring review, monitors will provide a preliminary report of monitoring findings to the PI and
other pertinent individuals involved in the conduct of the study. The PI is required to address and
respond to all the deficiencies noted in the preliminary report. Prior to the completion of the final
summary report, monitors will discuss the preliminary report responses with the PI and other team
members (when appropriate). A final monitoring summary report will then be prepared by the
monitor.
Final DSMC review will include the final monitoring summary report with
corresponding PI response, submitted CAPA (when applicable), PI Summary statement, and
available aggregate toxicity and safety data.
The DSMC will render a recommendation and rating based on the overall trial conduct. The PI is
responsible for ensuring that instances of egregious data insufficiencies are reported to the IRB.
Continuing Review submissions will include the DSMC recommendation letter.
Should any
revisions be made to the protocol-specific monitoring plan after initial DSMC approval, the PI will
be responsible for notifying the DSMC of such changes. The Committee reserves the right to
conduct additional audits if necessary.
Dr. Gbolahan and the investigators, the clinical research coordinator and the regulatory affairs
coordinator will meet to review and discuss study data to ensure subject safety weekly. During the
meetings the PI or co-I will review the eligibility criteria for each new patient. In addition, during
these meeting the group will review all the toxicity (AE/SAE) logs, random checks of case report
form completion and roadmap for each patient on the trial. All study personnel will be trained on
the protocol by the PI or co-I. Study personnel will sign training log prior to being included on
delegation of authority log. All AE and SAE will be handled according to Section 8.2 which
provides detailed instructions on reporting requirements.

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12. REFERENCES
Please provide the citations for all publications referenced in the text.
1.
Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2018. CA Cancer J Clin, 2018.
2.
Kawakami, H., A. Zaanan, and F.A. Sinicrope, Microsatellite instability testing and its
role in the management of colorectal cancer. Curr Treat Options Oncol, 2015. 16(7): p.
30.
3.
Mehrvarz Sarshekeh, A., M.J. Overman, and S. Kopetz, Nivolumab in the treatment of
microsatellite instability high metastatic colorectal cancer. Future Oncol, 2018.
4.
Guinney, J., et al., The consensus molecular subtypes of colorectal cancer. Nat Med,
2015. 21(11): p. 1350-6.
5.
Basile, D., et al., Immunotherapy for colorectal cancer: where are we heading? Expert
Opin Biol Ther, 2017. 17(6): p. 709-721.
6.
Le, D.T., et al., PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J
Med, 2015. 372(26): p. 2509-20.
7.
Bashir, B. and A.E. Snook, Immunotherapy regimens for metastatic colorectal
carcinomas. Hum Vaccin Immunother, 2017: p. 0.
8.
Bendell, J.C., et al., Clinical activity and safety of cobimetinib (cobi) and atezolizumab in
colorectal cancer (CRC). Journal of Clinical Oncology, 2016. 34(15_suppl): p. 3502-
3502.
9.
Buchbinder, E.I. and A. Desai, CTLA-4 and PD-1 Pathways: Similarities, Differences,
and Implications of Their Inhibition. Am J Clin Oncol, 2016. 39(1): p. 98-106.
10.
Brahmer, J.R., et al., Phase I study of single-agent anti-programmed death-1 (MDX-
1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and
immunologic correlates. J Clin Oncol, 2010. 28(19): p. 3167-75.
11.
Topalian, S.L., et al., Safety, activity, and immune correlates of anti-PD-1 antibody in
cancer. N Engl J Med, 2012. 366(26): p. 2443-54.
12.
Overman, M.J., et al., Nivolumab in patients with metastatic DNA mismatch repair-
deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-
label, multicentre, phase 2 study. Lancet Oncol, 2017. 18(9): p. 1182-1191.
13.
Overman, M.J., et al., Nivolumab in patients with DNA mismatch repair-
deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer
(mCRC): Long-term survival according to prior line of treatment from CheckMate-142.
Journal of Clinical Oncology, 2018. 36(4_suppl): p. 554-554.
14.
Jabbour, S. and B. Ziring, Advantages of extended-release metformin in patients with type
2 diabetes mellitus. Postgrad Med, 2011. 123(1): p. 15-23.
15.
Timmins, P., et al., Steady-state pharmacokinetics of a novel extended-release metformin
formulation. Clin Pharmacokinet, 2005. 44(7): p. 721-9.
16.
He, X.K., et al., Metformin Is Associated With Slightly Reduced Risk of Colorectal
Cancer and Moderate Survival Benefits in Diabetes Mellitus: A Meta-Analysis. Medicine
(Baltimore), 2016. 95(7): p. e2749.
17.
Mei, Z.B., et al., Survival benefits of metformin for colorectal cancer patients with
diabetes: a systematic review and meta-analysis. PLoS One, 2014. 9(3): p. e91818.

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18.
Meng, F., L. Song, and W. Wang, Metformin Improves Overall Survival of Colorectal
Cancer Patients with Diabetes: A Meta-Analysis. J Diabetes Res, 2017. 2017: p.
5063239.
19.
Joo, M.K., J.J. Park, and H.J. Chun, Additional Benefits of Routine Drugs on
Gastrointestinal Cancer: Statins, Metformin, and Proton Pump Inhibitors. Dig Dis, 2018.
36(1): p. 1-14.
20.
Henderson, D., et al., Metformin Has Positive Therapeutic Effects in Colon Cancer and
Lung Cancer. Am J Med Sci, 2017. 354(3): p. 246-251.
21.
Chang, Y.T., et al., Dose-Dependent Relationship Between Metformin and Colorectal
Cancer Occurrence Among Patients with Type 2 Diabetes-A Nationwide Cohort Study.
Transl Oncol, 2018. 11(2): p. 535-541.
22.
Eikawa, S., et al., Immune-mediated antitumor effect by type 2 diabetes drug, metformin.
Proc Natl Acad Sci U S A, 2015. 112(6): p. 1809-14.
23.
Scharping, N.E., et al., Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced
Reduction of Tumor Hypoxia. Cancer Immunol Res, 2017. 5(1): p. 9-16.
24.
Gang, W., et al., Strategy to targeting the immune resistance and novel therapy in
colorectal cancer. Cancer Med, 2018. 7(5): p. 1578-1603.
25.
Becht, E., et al., Immune and Stromal Classification of Colorectal Cancer Is Associated
with Molecular Subtypes and Relevant for Precision Immunotherapy. Clin Cancer Res,
2016. 22(16): p. 4057-66.
26.
Wirta, E.V., et al., Immunoscore in mismatch repair-proficient and -deficient colon
cancer. J Pathol Clin Res, 2017. 3(3): p. 203-213.

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13. APPENDICES
13.1
APPENDIX A
PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence
of disease.
0
Normal activity. Fully active, able
to
carry
on
all
pre-disease
performance without restriction.
90
Able to carry on normal activity;
minor signs or symptoms of disease.
80
Normal activity with effort; some
signs or symptoms of disease.
1
Symptoms,
but
ambulatory.
Restricted in physically strenuous
activity, but ambulatory and able to
carry
out work
of
a light
or
sedentary
nature
(e.g.,
light
housework, office work).
70
Cares for self, unable to carry on
normal activity or to do active work.
60
Requires occasional assistance, but is
able to care for most of his/her needs.
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.
50
Requires considerable assistance and
frequent medical care.
40
Disabled, requires special care and
assistance.
3
In bed >50% of the time. Capable
of only limited self-care, confined
to bed or chair more than 50% of
waking hours.
30
Severely
disabled,
hospitalization
indicated. Death not imminent.
20
Very sick, hospitalization indicated.
Death not imminent.
4
100%
bedridden.
Completely
disabled. Cannot carry on any self-
care.
Totally confined to bed or
chair.
10
Moribund,
fatal
processes
progressing rapidly.
5
Dead.
0
Dead.

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13.2
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for
Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting.
(http://ctep.cancer.gov/reporting/ctc.html)
13.3
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for
Evaluating Response in Solid Tumors
RECIST version 1.1* will be used in this study for assessment of tumor response. While either
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this
study.
* As published in the European Journal of Cancer:
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J.
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan,
D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.
In addition, volumetric analysis will be explored by central review for response assessment.

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13.4
APPENDIX B-E
Appendix B
Pill Diary for Cycle 1 Lead in phase (Day -14 to -1)
Protocol
Subject
Number
Subject
Initials
Visit
WCI
Cycle
1
Patient Diary
Please use this diary to record your daily protocol medication.
Metformin Dose
Please take _1_ capsule of __500___ mg twice daily for 3 days
Date:
Time:
Time:
Record date and time taken for each day
Day -14
Day -13
Day -12
Please use this diary to record your daily protocol medication.
Metformin Dose
Please take _1_ capsule of __500___ mg AM and 2 capsules of 500 mg PM for 4 days
Date:
Time:
Time:
Record date and time taken for each day
Day -11

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Day -10
Day -9
Day -8
Please use this diary to record your daily protocol medication.
Metformin Dose
Please take _2_ capsules of __500___ mg AM and 2 capsules of 500 mg PM for 7 days
Date:
Time:
Time:
Record date and time taken for each day
Day -7
Day -6
Day -5
Day -4
Day -3
Day -2
Day -1
Please sign at the completion of this cycle and return with pill bottle to the study team.
Patient’s
Signature ____________________________________ Date______________________________

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Please use this diary to record your daily protocol medication.
Pill Diary for Cycle 1 (Day 1 to 28) and further cycles
Protocol
Subject
Number
Subject
Initials
Visit
WCI
Cycle
1
Metformin Dose
Please take _____ mg AM and _____ mg PM
Date:
Time:
Time:
Record date and time taken for each day
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9

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Day 10
Day 11
Day 12
Day 13
Day 14
Day 15
Day 16
Day 17
Day 18
Day 19
Day 20
Day 21
Day 22
Day 23
Day 24
Day 25

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Day 26
Day 27
Day 28
Please sign at the completion of this cycle and return with pill bottle to the study team.
Patient’s
Signature ____________________________________ Date______________________________
Appendix C
Blood glucose log
Please check your blood glucose level and record the date and time
Date:
Time and glucose level
Time and glucose level
Record date and time taken for each day
Day -14
Day -13
Day -12
Day -11
Day -10
Day -9
Day -8

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Day -7
Day -6
Day -5
Day -4
Day -3
Day -2
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9

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Day 10
Day 11
Day 12
Day 13
Day 14
Please sign at the completion and return with pill bottle to the study team.
Patient’s
Signature ____________________________________ Date______________________________
Appendix D
Health/Medical Complaints
Please record all health/medical complaints you may have experienced
below.
Please describe what you experienced
Date Started
Date Stopped

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Appendix E
Other Medications
Record all medications taken during this cycle for example prescriptions
and over the counter including vitamins.
Name
of
Medication
Why did you take the medication?
Date
Medication
Started
Date
Medication
Stopped
If you have any questions, please call: ________________________

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Protocol Review Checklist
(Please delete after review)
□Phase of Study Clear in Title
□Clear Follow-up
and throughout protocol
□References
□Correct Contact Information
□Appendicies (QOL, Response Criteria,
□IND/IDE # (if Applicable) or IND/IDE
Staging Criteria, etc)
Exempt Clearly stated on cover page
□Conmed
clearly stated
□Supportive meds
□Version # & Version Date correct throughout
□Prohibited meds
(cover page & header)
□Calendar of Events
□Study Schema / Synopsis
□Statistician Review / Consultation
□Table of Contents
□DSMP plan identified
□Designated pg # match section
□Investigator Signature Page
□Objectives
□Data Capture
□Background
□eCRF system
□Science
□Data Collection timeline
□Reasoning for this study
□Correlatives/correlative science
treatment/device (combination)
□Correlative specimens?
□Eligibility
□Lab utilized for correlatives?
□Inclusion Criteria
□QOL
□Exclusion Criteria
□Collection procedures
□Do parameters match remainder
□Shipping/storage procedures
of protocol?
□Processing procedures
□Procedures Match throughout Protocol?
□Definition of SAE
□Have visit windows been designated?
□SAE reporting
□Font Type & Size Consistent
□Deviations / reporting requirements
□Have procedures been spelled out?
□Does Budget match Protocol
(i.e. vitals, chemistry)
expectations
□Registration Process clearly designated
□IRB/Regulatory expectations
□Treatment Clearly Specified
□Treatment
□DLT clearly specified
□Drug shipment
□Dose Modifications
□Commercial or through
□Stopping Rules
IDS
□Accrual goal # and timeline clearly stated
□Storage/destruction
□Accrual population?
□Side effects
□Is this a Multi-Site study?
□Study Termination
□Multi-Site Monitoring Plan inserted
□Registration procedures detailed
□Eligibility confirmation process
□Randomization/dose assignment
□SAE/DLT reporting requirements for
sub-sites
□Data reporting for sub-sites
□Does anything have to be sent to Emory?

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1