A Phase II Study of Metformin Plus Modified FOLFOX 6 in Patients With Metastatic Pancreatic Cancer
Phase: PHASE2
Conditions: Acinar Cell Adenocarcinoma of the Pancreas, Duct Cell Adenocarcinoma of the Pancreas, Recurrent Pancreatic Cancer, Stage IV Pancreatic Cancer
Sponsor: Case Comprehensive Cancer Center

 
Protocol Version 8, dated 4/23/2015 
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CASE COMPREHENSIVE CANCER CENTER 
__________________________________________________________________ 
 
 
STUDY NUMBER: CASE 1212 
 
 
STUDY TITLE:  A Phase II Study of Metformin plus modified FOLFOX 6 in Patients with 
Metastatic Pancreatic Cancer 
 
 
 
 
PRINCIPAL INVESTIGATOR: 
 
 
 
 
Smitha Krishnamurthi, MD 
 
 
 
 
Case Comprehensive Cancer Center 
University Hospitals Case Medical Center 
 
 
 
 
Seidman Cancer Center 
 
 
 
 
11100 Euclid Avenue, Cleveland, OH   44106 
 
CO-PRINICPAL INVESTIGATORS: 
 
 
 
 
 
Robert Pelley, MD 
Staff Oncologist 
Cleveland Clinic Foundation 
9500 Euclid Avenue, Cleveland, OH 44195 
 
CO- INVESTIGATORS:  
Nathan A. Berger, M.D. 
Case Western Reserve University School of Medicine 
Health Sciences Library 
10900 Euclid Avenue, Cleveland, OH 44106 
 
 
 
 
 
Dimitrios Iliopoulos, Ph.D ( Correlative studies) 
Institute of Molecular Medicine (IMED) 
David Geffen School of Medicine 
UCLA 
650 Charles E.Young Drive South 
Los Angeles, CA 90025-7278 
 
 
 
 
 
Neal Meropol, MD 
 
 
 
 
Case Comprehensive Cancer Center 
University Hospitals Case Medical Center 
 
 
 
 
Seidman Cancer Center 
11100 Euclid Avenue, Cleveland, OH   44106 
 
John J. Pink, PhD 
Case Western Reserve University Medical School 
WolsteinRsearch Building-3529 
Cleveland, OH 44106 

 
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Richard Chang, MD 
 
 
 
 
Case Comprehensive Cancer Center 
University Hospitals Case Medical Center 
 
 
 
 
Seidman Cancer Center 
11100 Euclid Avenue, Cleveland, OH   44106 
 
Joseph Gibbons, MD 
 
 
 
 
Case Comprehensive Cancer Center 
University Hospitals Case Medical Center 
 
 
 
 
Seidman Cancer Center 
11100 Euclid Avenue, Cleveland, OH   44106 
 
Yan Feng, MD 
Case Comprehensive Cancer Center 
University Hospitals Case Medical Center 
Seidman Cancer Center 
11100 Euclid Avenue, Cleveland, OH 44106 
 
Christopher Hoimes, MD 
Case Comprehensive Cancer Center 
University Hospitals Case Medical Center 
Seidman Cancer Center 
11100 Euclid Avenue, Cleveland, OH 44106 
 
Joel Saltzman, MD 
Lake University – Seidman Cancer Center (LUSCC) 
9485 Mentor Avenue, Suite #3 
Mentor, OH  44060 
 
Mark Bergman, MD 
Lake University – Seidman Cancer Center (LUSCC) 
9485 Mentor Avenue, Suite #3 
Mentor, OH  44060 
 
 
 
 
 
Willem van Heeckeren, MD  
 
 
 
 
Lake University – Seidman Cancer Center (LUSCC) 
9485 Mentor Avenue, Suite #3 
 
 
 
 
Mentor, OH  44060 
 
 
 
 
 
Maria Espinosa, MD 
Lake University – Seidman Cancer Center (LUSCC) 
9485 Mentor Avenue, Suite #3 
 
 
 
 
Mentor, OH  44060 
 
 
 
 
 
Raymond Lobins, MD 
Lake University – Seidman Cancer Center (LUSCC) 
9485 Mentor Avenue, Suite #3 
 
 
 
 
Mentor, OH  44060 

 
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Lois Teston, MD 
 
 
 
 
UHHS Chagrin Highlands – Seidman Cancer Center 
 
 
 
 
3909 Orange Place 
 
 
 
 
Orange Village, OH  44122 
 
                                                      Suresh Mendpara, MD 
 
 
 
 
University Hospitals Seidman Cancer Center at Sharon Health 
 
 
 
 
5133 Ridge Road 
 
 
 
 
Wadsworth, Ohio 44281 
 
 
 
 
 
 
 
 
 
Mukesh Bhatt, MD 
 
 
 
 
University Hospitals Seidman Cancer Center at Sharon Health 
 
 
 
 
5133 Ridge Road 
 
 
 
 
Wadsworth, Ohio 44281 
 
 
 
 
 
Elliot Dickman, MD 
 
 
 
 
Monarch 
 
 
 
 
5855 Landerbrook Drive, Suite 100 
 
 
 
 
Mayfield Heights, OH  44124 
 
 
 
 
 
Jason Stern, MD 
 
 
 
 
Monarch 
 
 
 
 
5855 Landerbrook Drive, Suite 100 
 
 
 
 
Mayfield Heights, OH 44124 
 
 
 
 
 
Judah Friedman, MD 
 
 
 
 
University Hospitals Geauga Medical Center 
 
 
 
 
13207 Ravenna Road 
 
 
 
 
Chardon, OH  44024 
 
 
 
 
 
Xuan Huang, MD 
 
 
 
 
Monarch 
 
 
 
 
5855 Landerbrook Drive, Suite 100 
 
 
 
 
Mayfield Heights, OH 44124 
 
 
 
 
 
Neeraj Mahajan, MD 
 
 
 
 
University Hospitals Seidman Cancer Center at Sharon Health 
 
 
 
 
5133 Ridge Road 
 
 
 
 
Wadsworth, Ohio  44281 
 
 
 
 
 
Gregory Warren, MD 
 
 
 
 
Southwest General Health Center 
 
 
 
 
18697 Bagley Road 
 
 
 
 
Middleburg Heights, OH  44130 
 
 
 
 
 
Gil Peleg, MD 
 
 
 
 
Southwest General Health Center 
 
 
 
 
18697 Bagley Rd.  
 
 
 
 
Middleburg Heights, Oh 44130 
 

 
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Jill Vollweiler, MD 
 
 
 
 
Southwest General Health Center 
 
 
 
 
18697 Bagley Road 
 
 
 
 
Middleburg Heights, OH  44130 
 
 
 
 
 
Wenhui Zhu, MD 
 
 
 
 
Southwest General Health Center 
 
 
 
 
18697 Bagley Road 
 
 
 
 
Middleburg Heights, OH  44130 
 
 
 
 
 
Vinay Gudena, MD 
 
 
 
 
Firelands Regional medical Center 
 
 
 
 
701 Tyler Street 
 
 
 
 
Sandusky, OH  44870 
 
 
 
 
 
Amy Reese, MD 
 
 
 
 
Firelands Regional medical Center 
 
 
 
 
701 Tyler Street 
 
 
 
 
Sandusky, OH  44870 
 
 
 
 
 
Patrick Litam, MD 
 
 
 
 
SCC at Mercy Cancer Center 
 
 
 
 
41201 Schaden Road 
 
 
 
 
Elyria, OH  44035 
 
 
 
 
 
Ruben Escuro, MD 
 
 
 
 
SCC at Mercy Cancer Center 
 
 
 
 
41201 Schaden Road 
 
 
 
 
Elyria, OH  44035 
 
 
 
 
 
Belagodu Kantharaj, MD 
 
 
 
 
SCC at Mercy Cancer Center 
 
 
 
 
41201 Schaden Road 
 
 
 
 
Elyria, OH  44035 
 
 
 
 
 
Jay Sidloski, MD 
 
 
 
 
SCC at Mercy Cancer Center 
 
 
 
 
41201 Schaden Road 
 
 
 
 
Elyria, OH  44035 
 
 
 
 
 
Michael Gibson, MD 
 
 
 
 
University Hospitals Case Medical Center 
 
 
 
 
Seidman Cancer Center 
 
 
 
 
11100 Euclid Avenue 
 
 
 
 
Cleveland, OH  44106 
 
 
 
 
 
 
 

 
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Jennifer Eads, MD 
 
 
 
 
University Hospitals Case Medical Center 
 
 
 
 
Seidman Cancer Center 
 
 
 
 
11100 Euclid Avenue 
 
 
 
 
Cleveland, OH  44106 
 
 
]STATISTICIAN:  
 
Marc Schluchter, Ph.D 
 
 
 
 
Case Comprehensive Cancer Center 
University Hospitals Case Medical Center 
 
 
 
 
Seidman Cancer Center 
11100 Euclid Avenue  
 
 
 
Cleveland, OH   44106 
 
 
 
 
 
 
SPONSOR: 
 
 
Case Comprehensive Cancer Center  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
R
E
G
I
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T
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• Baseline assessment of tumor 
burden with radiographic 
imaging. 
• If available, examine, in 
archived formalin fixed, 
paraffin embedded pancreatic 
cancer tissue, the following: 
o Expression of Insulin 
Receptors (IR) and 
LKB1 
o Activation markers     
(P-IRS-1, P-AKT,     
4E-BP1) 
o mRNA expression 
levels of IL 6, STAT3 
transcription factor 
and SREBP1c, 
ACC1, FAS) by real-
time PCR analysis. 
• Examine in the blood the 
following correlatives: 
CA19-9, glucose and insulin 
levels in addition to 
Interleukin 6, STAT3, 
LEPTIN, IGF1, SREBP1c, 
ACC1, FAS mRNA levels 
and the expression levels of 
the microRNA 
panel(assessed by real-time 
PCR analysis). 
 
2-week treatment cycles 
• Metformin 1000 mg orally twice daily. 
• Modified FOLFOX 6 intravenously once 
every 2 weeks as follows:  
- 
Oxaliplatin 85 mg/m2 
- 
Leucovorin 400 mg/m2, followed by: 
- 
5-FU 400 mg/m2 bolus then 2400 mg/m2 a 
continuous infusion over 46 hours.  
• Reexamine the blood levels of the 
correlatives (that were done at the beginning 
of the study) after the first 4 cycles of 
treatment. 
• Repeat radiographic imaging every 4 
cycles to assess treatment response 
 
Continue treatment until disease 
progression or unacceptable 
toxicity develops 
 
Metformin introductory period 
 
• Day 1-->4    500 mg (extended release 
form) orally twice daily  
•  Day 5 -->7   1000 mg (extended release 
form) orally twice daily 

 
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TABLE OF CONTENTS 
                                                                         Page 
 
 STUDY SCHEMA………………………………………………………………………………6 
 
 
1.0       INTRODUCTION/BACKGROUND…………………………………………………...9 
 
 
 
2.0 
OBJECTIVES…………………………………………………………………………..11 
 
 
3.0 
STUDY DESIGN……………………………………………………………………….12 
 
4.0  
PATIENT SELECTION……………………………………………………………….13 
 
 
5.0 
REGISTRATION…………………………………………………………………........16 
 
 
 
6.0  
TREATMENT PLAN…………………………………………………………………..16 
 
 
7.0 
DOSING DELAYS / DOSE MODIFICATIONS………………...…………………...20 
 
 
 
8.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS.......................24 
 
 
 
 
9.0 
PHARMACEUTICAL INFORMATION………………………..……………………30 
 
 
10.0 
CORRELATIVE / SPECIAL STUDIES…………………………………………..….35 
 
 
 11.0 
STUDY PARAMETERS AND CALENDAR…………………..……………………..37 
 
 
 12.0 
MEASUREMENT OF EFFECT………………………………………………..……..42 
 
 
 13.0 
RECORDS TO BE KEPT/REGULATORY CONSIDERATIONS……………..…..47 
 
 
 14.0 
STATISTICAL CONSIDERATIONS……………………………………………..….49 
 
 

 
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REFERENCES…………………………………………………………………………...…….51 
 
 
APPENDICES 
 
 
APPENDIX A……………………………………………………………………..……54 
 
ECOG Performance Status Criteria  
 
 
 
APPENDIX B…………………………………………………………………………..55 
 
Patient Pill Diary 
 
 
 
Figure 1…....................................................................................................................................56 
 

 
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1.0 
INTRODUCTION/BACKGROUND 
 
1.1 
Pancreatic Cancer 
 
Pancreatic adenocarcinoma is an aggressive gastrointestinal cancer with an estimated annual 
incidence of 44,030 cases in the United States, and is also expected to account for 
approximately 37,600 deaths in the United States in 2011 making it the fourth leading cause 
of cancer death for both men and women. Five-year survival rate is around 6 %. The 
incidence of diagnosis peaks in the seventh and eighth decade of life (1). Pancreatic 
adenocarcinoma is characterized by extensive local growth and early metastasis, making 
surgical control of disease uncommon.As a result, chemotherapeutic agents are often 
employed in an effort to control growth and spread of the cancer, as well as to prolong life 
and maximize function for patients with pancreatic cancer.  
Currently, the most widely used first line regimens for metastatic pancreatic cancer in the US 
involves gemcitabine, which is a nucleoside analog, either alone or in combination with 
erlotinib, an inhibitor of epidermal growth factor receptor-associated tyrosine kinase. Median 
survival with gemcitabine based regimen ranges approximately between 5.2-7.2 months 
(2,3,4). 
Recently, a new combination therapy consisting of 5-FU/LV plus oxaliplatin and irinotecan 
(FOLFIRINOX) was approved as a first line treatment for metastatic pancreatic cancerafter a 
large randomized phase 3 trial showed significant improvement in overall survival compared 
to gemcitabine monotherapy (11.1 vs 6.8 months, p < 0.001). There are, however, many 
concerns about the toxicity of the FOLFIRINOX regimen. The grade 3/4 toxicity rates were 
12.3% for diarrhea, 15.6% for nausea, 17.2% for vomiting, 24% for fatigue, 47.9% for 
neutropenia, and 5.7% for febrile neutropenia. Patients who were enrolled in the study had an 
ECOG performance status of 0-1 (3). Therefore, this regimen has not been completely 
adapted by the medical oncology community. 
Clearly, new therapies that could improve survival in patients with pancreatic 
adenocarcinoma and has an acceptable toxicity profileare urgently needed. 
 
1.2Metformin 
 
Metformin belongs to the biguanide class of oral hypoglycemic agents. It is the drug of 
choice forpatients with type 2 diabetes and is the most widely prescribed anti-diabetic 
drug (5). Recent evidence suggests that metformin may be active in the prevention and 
treatment of cancer. In a case control study of over 11,000 diabetic patients, metformin 
usage was associated with a 21% lower risk of developing cancers (6). In another study 
that included about 63000 diabetic patients, patients who used insulin or sulfonylureas 
had an increased risk of cancer (HR 1.36 and 1.42 respectively with p < 0.001) compared 
to those who used metformin monotherapy(7). A hospital-based case control study found 
that diabetic patients who used metformin had a significantly lower risk of developing 
pancreatic cancer with odds ratio of 0.38, 95% CI 0.22-0.69, p= 0.001 (8). Another 
retrospective study found that among diabetic patients with breast cancer receiving 

 
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neoadjuvant therapy, those on metformin were more likely to have a pathologic complete 
response rate (24% compared to 8% for diabetic patients not using metformin) (9). 
 
Most recently, at ASCO 2011, several retrospective studies were presented that showed 
improved outcomes in cancer patients who were taking metformin (10, 11, 12). One 
study showed that the use of Metformin in type II noninsulin-dependent diabetes patients 
with colorectal cancer was associated with improved overall survival compared to 
patients not treated with metformin (76.9 months vs 56.9 months, p = 0.048) (10). A 
similar study showed that metformin appears to improve the overall survival rate of 
patients with colorectal cancer treated with chemotherapy compared to patients not 
treated with metformin with HR of 0.61(0.41-0.91;p=0.017) (11). A third study, 
suggested that metformin may improve the overall survival in diabetic patients with 
pancreatic cancer with HR of 0.67 (95% CI: 0.51-0.88, p=0.005) (12). 
 
The mechanism by which metformin may act as an antineoplastic agent is not well 
defined. Metformin may exert its cell growth-inhibitory effects through two distinct 
mechanisms: a direct mechanism (insulin independent) through activation of adenosine 
monophosphate-activated protein kinase (AMPK) and an indirect mechanism depending 
on insulin/insulin-like growth factor 1(IGF-1) signaling. Both direct and indirect pathways 
lead to inhibition of mammalian target of rapamycin (mTOR) complex that plays a central 
role in cancer cell growth (13, 14). Of note, as an anti-diabetic agent it is believed that 
metformin inhibits the gluconeogenesis through activation of AMPK as well (15). 
 
Two studies (16,17) demonstrated that metformin inhibits the growth of breast cancer 
cells through AMPK activation resulting in inhibition of mTOR. Another study (18) 
showed that metformin inhibits the cross-talk between insulin and G-protein coupled 
receptor signaling systems in pancreatic cancer cells by induction of AMPK, leading to 
inhibition of DNA synthesis and proliferation. In the same study metformin inhibited the 
growth of human pancreatic cancer cell xenografts. Similar studies reported inhibitory 
effects of metformin on growth of colon, lung, prostate and ovarian cancer cells (5). 
 
Dr. Iliopoulos (a collaborator on this study) and colleagues conducted preclinical studies 
of metformin in combination with chemotherapy. They reported that the combination of 
doxorubicin with metformin suppressed tumor growth and prolonged remission in breast 
cancer mouse models, through inhibition of breast cancer stem cells (19). They have also 
reported in a separate study that inhibition of breast cancer stem cells is mediated via 
suppressing IL6 expression (20). Additional data (personal communication) showed that 
the combination of metformin and FOLFOX (5-FU, leucovorin and oxaliplatin) in two 
pancreatic cancer mouse models suppressed >90% tumor growth and inhibited 
metastasis. Antitumor activity was associated with reduced nuclear factor-kappa B (NF-
κB) and IL6 expression. Metformin may reduce cardiovascular complications through 
suppression of NF-κBand IL6 in endothelial cells (21). Serum interleukin-6 levels were 
found to decrease following metformin treatment in women with polycystic ovary 
syndrome (22). Finally, the team also identified a panel of micro-RNAs (miR-200b, miR-
145, miR-21, miR-210, let-7a, miR-20a, miR-34, miR-204, miR-214) that were highly 
associated with the survival of pancreatic cancer cells. 
 

 
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Metformin is a very safe and well-tolerated drug (5). Many cancer patients who have 
diabetes continue to use it while they are receiving chemotherapy. The most common 
side effects are gastrointestinal, such as diarrhea, nausea/vomiting and flatulence, which 
are reported to occur in less than 10 % of patients taking the extended-release form of 
metformin (23). Metformin rarely causes hypoglycemia and is associated with very low 
incidence of lactic acidosis (<1/10,000), predominantly in patients with poor renal 
function. 
 
Currently, there are several phase 2 and 3 clinical trials exploring the effect of metformin 
on cancer outcome in different types of cancer (24). 
 
 
1.3 
Modified FOLFOX 6 
 
FOLFOX (5-FU and oxaliplatin) is an approved second line regimen in metastatic 
pancreatic cancer. A study showed that it improves survival compared to 5-
FU/Leucovorin when used as second line treatment (25). Also, there is some but limited 
data about its efficacy in first line regime with similar outcome to gemcitabine (26). The 
combination of FOLFOX plus irinotecan (FOLFIRINOX) also improves survival 
compared to gemcitabine as first-line treatment of metastatic pancreatic cancer (3). 
 
1.4 
Rationale  
 
Based on the growing volume of preclinical and clinical evidences that metformin may 
have antineoplastic effect in different types of cancer, in particular, our disease of interest 
(pancreatic cancer), and based on the potential data that showed in vivo synergy between 
metformin and FOLFOX which is a known active regimen in pancreatic cancer, we 
propose a phase 2 clinical study to evaluate the effectiveness of metformin plus FOLFOX 
as first line therapy in patients with metastatic pancreatic cancer.  
 
2.0  
OBJECTIVES 
 
 
2.1 
Primary Objective 
 
To determine if metformin when added to FOLFOX improves overall survival in patients 
with metastatic pancreatic cancer. 
 
2.2 
Secondary Objective(s) 
 
1. To assess response rate (RR), 
2. To assess progression free survival (PFS) 
3. To assess toxicity in patients with metastatic pancreatic cancer receiving FOLFOX and 
metformin. 
4. To identify tumor/serum correlative markers (see section 10.0) 
 
 
 

 
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3.0 
 
STUDY DESIGN 
 
 
3.1 Study design including dose escalation / cohorts 
 
Patients with previously untreated histologically confirmed metastatic pancreatic cancer 
will be enrolled in this study.  
Metformin will be administered alone for a one-week introductory period before the 
addition of FOLFOX according to the following schedule: 
- Day 1-->4               500 mg twice daily  
- Day 5 -->7              1000 mg twice daily 
- Day 8 and beyond  1000 mg twice daily with chemotherapy 
 
“ Starting with a low dose metformin and increasing it gradually is a common practice      when 
using metformin. It is believed to minimize the odds of gastroenterology side effects. Therefore, 
we have implemented this short introductory period”. 
 
FOLFOX will be administered intravenously once every 2 weeks as follows: Oxaliplatin 
85 mg/m2, leucovorin 400 mg/m2, followed by 5-FU 400 mg/m2 bolus then 2400 mg/m2 a 
continuous infusion over 46 hours.  
Radiographic imaging will be performed at baseline and after every 4 cycles. RECIST 
version 1.1 will be used to assess response to treatment.  
Treatment will continue until disease progression, unacceptable toxicity or decision of 
patient/physician. 
 
 
3.2  
Number of Subjects 
 
Estimated sample size is 43 patients(see section 14.0) 
 
 
3.3  
Replacement of Subjects 
 
Subjects who receive less than 2 cycles of treatment and have to be withdrawn from the study 
will be replaced unless the withdrawal is secondary to progression or unacceptable 
toxicity. 
 
3.4Expected Duration of Subject Participation 
 
3.4.1 Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment may continue until one 
of the following criteria applies: 
 
• 
Disease progression 
 
• 
Intercurrent illness that prevents further administration of treatment 
 

 
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• 
The investigator considers it, for safety reasons, to be in the best interest of the patient.  
 
• 
Unacceptable adverse event(s) such as: 
 
-Unacceptable treatment related toxicity, NCI CTC AE version 4.0. Grade 3 or 4 that fails 
to recover to baseline or < Grade 3 in the absence of treatment within 4 weeks. 
 
-Any toxicity or other issue that causes a delay of study drug administration by more than 
4 weeks. 
 
• 
General or specific changes in the patient’s condition rendering the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
• 
Patient decision to withdraw from treatment (partial consent) or from the study (full 
consent). 
 
• 
Pregnancy during the course of the study for a child-bearing participant. 
 
• 
Initiation of other anticancer therapy. 
 
• 
Death 
 
 
3.4.2 Duration of Follow Up 
 
Patients will be followed until death. Patients who are removed from study will be followed 
every 6 months until death. Patients removed from study for unacceptable adverse events will 
be followed until resolution or stabilization of the adverse event, then every 6 months until 
death. 
 
4.0 
PATIENT SELECTION 
 
 
4.1 
Inclusion Criteria 
 
 
Patients must meet all of the following inclusion criteria to be eligible for enrollment:  
 
 
4.1.1 Patients must have histologically or cytologically confirmed metastatic pancreatic 
adenocarcinoma(or any mixed pathology if adenocarcinoma is predominant). 
 
4.1.2 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) as >20 
mm with conventional techniques or as >10 mm with spiral CT scan.  
 
4.1.3 
Patients must have not received systemic chemotherapy for metastatic disease. 

 
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Prior chemotherapy, radiation therapy, concurrent chemoradiation are allowed if used for treatment of 
non-metastatic disease. 
 
Prior palliative radiation for symptom management is allowed.  
Any Chemotherapy must have been completed 4 weeks prior to enrollment. 
Any Radiotherapy must have been completed 2 weeks prior to enrollment. 
 
4.1.4 Age >18 years.  
 
Because no dosing or adverse event data are currently available on the use of 
modified FOLFOX 6 in patients <18 years of age, children are excluded from this 
study. 
 
4.1.5 ECOG performance status 0-2 (see Appendix A). 
 
 
4.1.6 Patients must have adequate organs and marrow function as defined below.  
Pre- study labs must be done within 1 week before starting treatment.  
 
Absolute neutrophil count ≥1,500/dL 
• Platelets ≥100,000/dL 
• Hemoglobin ≥9g/dL 
• Total bilirubin ≤ 2 mg/dL 
• AST(SGOT)/ALT (SGPT) ≤ 2.5 × institutional upper limit of normal 
• Creatinine ≤  1.5 
 
4.1.7 5-FU and/or oxaliplatin chemotherapy could cause fetal risk. Therefore, women of 
childbearing potential and men must agree to use adequate contraception (double 
barrier method of birth control or abstinence)prior to study entry and for the duration 
of study participation. 
 
Should a woman become pregnant or suspect that she is pregnant while she or her 
partner is participating in this study, she should inform the treating physician 
immediately. 
 
 
4.1.8 Subjects must have the ability to understand and the willingness to sign a written 
informed consent document. 
 
4.1.9   Patients with diabetes are eligible for this trial  All diabetic patients who are enrolled on this study 
should discuss the need to change their diabetes management regimen with their primary care physician 

 
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15 
or endocrinologist prior to enrollment. 
 
4.1.10  Diabetic patients who are on metformin are eligible as long as they have been on metformin for 
less than 6 months (estimated 6 months or less duration of metformin therapy from start of metformin to 
enrollment on study) 
4.2 
Exclusion Criteria 
 
 
The presence of any of the following will exclude a patient from study enrollment. 
 
4.2.1Chemotherapy within 4 weeks prior to entering the study, radiotherapy within 2 weeks 
priorto entering the study or failure to recover from adverse events due to agents 
administered more than 4 weeks earlier. 
4.2.2Prior treatment toxicities must be resolved to < Grade 1 according to NCI CTCAE Version 
4.0. 
 
4.2.3 Current use of metformin for more than 6 months prior to enrollment on study. 
 
4.2.4Use of any other investigational agents. 
 
4.2.5 Patients with untreated brain metastases should be excluded from this clinical trial 
because of their poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other adverse 
events. 
 
4.2.6History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to metformin or oxaliplatin or 5-FU. 
 
4.2.7 Active second primary malignancy or history of second primary malignancy within the 
last 3 years, with the exception of basal cell skin cancers or carcinoma in situ that have 
been adequately treated. 
 
4.2.8Patients with uncontrolled intercurrent illness including, but not limited to ongoing or 
active infection, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements.  
 
4.2.9Pregnant or nursing women. 
Note: Ineligibility is because 5-FU and or Oxaliplatinhave the potential for teratogenic or 
abortifacient effects. As for metformin, the potential for teratogenic or abortifacient 
effects is unknown. 
 
4.2.10 HIV-positive patients. Note:  Ineligibility is because of increased risk of lethal 
infections when treated with marrow suppressive therapy.  
 

 
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4.2.Chronic or planned acute alcohol use of 3 or more drinks per day. 
4.2.12Metabolic acidosis, acute or chronic, including ketoacidosis. 
4.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
 
 
5.0 
REGISTRATION  
 
5.1  
Registration 
 
All subjects who have been consented are to be registered in the OnCore Database. For those 
subjects who are consented, but not enrolled, the reason for exclusion must be recorded. 
 
All subjects will be registered through Name of Lead site and will be provided a study 
number by calling telephone number of study coordinator. 
 
 
6.0  
TREATMENT PLAN 
 
6.1 
MetforminAdministration 
 
Metformin will be administered alone for a 1-week introductory period before the addition of 
FOLFOX according to the following schedule: 
- Day 1-->4               500 mg twice daily  
- Day 5 -->7              1000 mg twice daily 
After the introductory period, patient will be continued on metformin 1000 mg twice daily in 
2-week (14 day) cycles. 
“All patients will be taking an extended release form of metformin and will be instructed     
to take it with meals. This will minimize the odds of gastroenterology side effects” 
 
Patients will be provided with a Patient Pill Diary (Appendix B) and instructed in its use to 
record each dose of oral medication.  Patients will be asked to bring the diary with them to 
each appointment. 
 
 
6.2FOLFOX6 Administration:  
 
Patients will receive modified FOLFOX6 (mFOLFOX6) on an outpatient basis on Day 1 of 
each 2-week (14 day) cycle.  First cycle to begin as soon as the metformin introductory 
period is over. This regimen consists of concurrent IV administration of 85 mg/m2oxaliplatin 
and 400 mg/m2leucovorin over 120 minutes, followed by 400 mg/m2 5-fluorouracil (FU) 
bolus, then 2400 mg/m2 5-FU as a 46 hour infusion. An ambulatory infusion pump may be 
used for the 5-FU infusion.  All patients must have central intravenous access (e.g., mediport, 
PICC line) for the continuous infusion of 5-FU. 
 

 
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17 
 
 
6.3General Concomitant Medications and Supportive Care Guidelines 
 
Patients should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, antiemetics, etc when appropriate. 
6.3.1Antiemetics 
5-FU and oxaliplatin may be emetogenic. Antiemetics such as ondansetron, dolasetron, or 
granisetron should be used prior to each cycle of therapy. 
A recommended anti-emetic regimen is provided below: 
Pre medications: Dexamethasone 16 mg IV 30 min prior to oxaliplatinandondansetron 16 mg IV 
30 min prior to oxaliplatin 
Take home medications: Dexamethasone 4 mg PO bid X 4 doses starting the day after oxaliplatin 
administration 
Ondansetron 8mg orally q 8 hours prn nausea and Prochloroperazine (Compazine) 10mg orally q 
8 hours prn nausea 
6.3.2 Growth Factors 
The American Association of Clinical Oncology (ASCO) guidelines will be followed for the 
prophylactic use of G-CSF. 
6.3.3 Oxaliplatin-Related Issues 
• Peripheralneuropathy:Oxaliplatin is consistently associated with 2 types of peripheral 
neuropathy, which includes paresthesias and dysesthesias of the hands, feet, and perioral 
region. Patients treated in this study will be counseled to avoid cold drinks and exposure 
to cold.  
• Hypersensitivity:Oxaliplatin, as is the case with all platinum-containing compounds, is 
associated with a measurable (approximately 11%) incidence of hypersensitivity 
reactions, usually after multiple doses of treatment. This may present as bronchospasm, 
hypotension, and even hemolytic anemia. Pretreatment with glucocorticoids and 
antihistamines may be useful for some patients, but may not always prevent the 
development of anaphylactoid reactions, especially in patients with a prior history of 
hypersensitivity to this agent. For patients who have experienced a Grade 1 or 2 acute 
hypersensitivity reaction that is assessed as related to oxliplatinadministration, the 
following premedication is recommended prior to each subsequent dose of oxaliplatin 
(patients who have grade 3 or 4 acute hypersensitivity reactions should discontinue 
oxaliplatin therapy): Dexamethasone 20 mg PO or IV, 12 and 6 hours prior to the 
oxaliplatindose; Dexamethasone 20 mg PO or IV, as well as diphenhydramine 50 mg IV, 
and one of the following: cimetidine 300 mg IV, ranitidine 50 mg IV, or famotidine 20 
mg IV 30-60 minutes prior to oxaliplatin administration. If these prophylactic measures 

 
Protocol Version 8, dated 4/23/2015 
18 
fail to prevent oxaliplatin-related hypersensitivity, therapy with oxaliplatinshould be 
discontinued.  
• LaryngopharyngealDysesthesia: An unusual laryngopharyngealdysesthesia (LPD), a loss 
of sensation of breathing without any objective evidence of respiratory distress 
(laryngospasm, bronchospasm or hypoxia) has also been observed. This neurotoxicity 
may be induced or exacerbated upon exposure to cold and should be distinguished from a 
hypersensitivity reaction. If a patient develops LPD, the patient’s oxygen saturation 
should be evaluated via a pulse oximeter and, if normal, reassurance, a benzodiazepine or 
other anxiolytic agent should be considered and the patient should be observed in the 
clinic until the episode has resolved. The oxaliplatin infusion may then be continued at a 
reduced rate, 33% of the original rate. Because this syndrome may be associated with the 
rapidity of oxaliplatin infusion, subsequent doses of oxaliplatin should be administered as 
6-hour infusions. To minimize the risk of LPD, patients will be instructed to avoid ice 
and cold drinks the day of treatment.  
• Oral cryotherapy: Patients on oxaliplatin should not receive oral cryotherapy on day 1 
and 2 of each cycle as this may exacerbate laryngopharyngealdysesthesia caused by 
oxaliplatin.  
• Pulmonary fibrosis: In the case of unexplained respiratory symptoms such as 
nonproductive cough, dyspnea or radiological pulmonary infiltrates, oxaliplatin should be 
discontinued until further investigation excludes interstitial pulmonary fibrosis. If 
interstitial pulmonary fibrosis is confirmed, oxaliplatin therapy should be terminated. 
• Veno-occlusive disease (VOD) is estimated to occur in 1 in 5000 patients treated with 
oxaliplatin and 5-FU. All patients on and off therapy who develop signs and symptoms of 
VOD should be thoroughly evaluated, closely monitored, and supported as clinically 
indicated. Evaluation of VOD should include observation of liver and spleen size, 
assessment for ascites and jaundice, inquiry into and evaluation of any gastrointestinal 
bleeding, and ultrasound to evaluate for reversal of portal blood flow. Consider 
measuring serum procollagen type III, which can rise early in the course of VOD. 
 
6.3.4Metformin-Related Issues 
• Use of iodinated contrast:Concurrent use of metformin is contraindicated in participants 
receiving intravascular iodinated contrast media due to an association with lactic acidosis 
and acute renal failure. If/when participants on study will be exposed to iodinated 
contrast (such as when they are getting a scan) the metformin must be temporarily 
discontinued at the time of or prior to the procedure, and withheld for 48 hours 
subsequent to the procedure. 
• Hypoglycemia:Although it is very rare, hypoglycemia could occur. Some of the factors 
that could increase the risk of hypoglycemia are: 
- 
Diabetic patients who are taking other glucose lowering-agents (eg, sulfonylureas, 
insulin). 

 
Protocol Version 8, dated 4/23/2015 
19 
- 
Concomitant use of fluoroquinolones. 
- 
Concomitant use of beta blocking agents. 
- 
Diabetics patients will be asked to monitor their glucose at home through a 
glucometer twice weekly at least.  Also, all diabetic patients should discuss the need 
to change their diabetes management regimen with their Primary care physician or 
endocrinologist.   
If patients are on fluoroquinolones and/or beta blocking agents, it will be left at the discretion of 
their primary providerto decide on how often their glucose level needs to be checked, whether at 
home through a glucometer or throughlaboratory blood draw. 
Vitamin B12: In controlled clinical trials of metformin hydrochloride tablets, a decrease to 
subnormal levels of previously normal serum Vitamin B12 levels, without clinical 
manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to 
interference with B12 absorption from the B12 -intrinsic factor complex, is, however, very rarely 
associated with anemia and appears to be rapidly reversible with discontinuation of metformin 
hydrochloride tablets or Vitamin B12 supple- mentation. Vitamin B12 levels need only to be 
checked in the case of unexplained/irreversible anemia. If Vitamin B12 level was found to be 
low, Vitamin B12 supplementation could be given orally.  
6.4  
Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment may continue until one of 
the following criteria applies: 
 
• Disease progression 
 
• Intercurrent illness that prevents further administration of treatment 
 
• The investigator considers it, for safety reasons, to be in the best interest of the patient.  
 
• Unacceptable adverse event(s) such as: 
 
-Unacceptable treatment related toxicity, NCI CTC AE version 4.0.Grade 3 or 4 that fails to    
recover to baseline or < Grade 3 in the absence of treatment within 4 weeks 
 
-Any toxicity or other issue that causes a delay of study drug administration by more than 4 
weeks.  
 
• General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
 
• Patient decision to withdraw from treatment (partial consent) or from the study (full 
consent) 
 
• Pregnancy during the course of the study for a child-bearing participant 

 
Protocol Version 8, dated 4/23/2015 
20 
 
• Initiation of other anticancer therapy 
 
• Death 
 
 
6.5 
Duration of Follow Up 
 
Patients will be followed for survival until death. Patients who are removed from study will be 
followed every 6 months until death.  Patients removed from study for unacceptable adverse 
events will be followed every 6 months until resolution or stabilization of the adverse event, then 
until death. 
Patients will be followed for toxicity for 30 days after treatment has been discontinued or 
until death, whichever occurs first.  
 
The clinical course of each event will be followed until resolution, stabilization, or until it 
has been determined that the study treatment or participation is not the cause.  
 
Serious adverse events that are still ongoing at the end of the study period will necessitate 
follow-up to determine the final outcome. Any serious adverse event that occurs after the 
study period and is considered to be possibly related to the study treatment or study 
participation will be recorded and reported immediately. 
 
6.6        Leucovorin shortage: 
 
There is currently (as per April 2012) a shortage of leucovorin in the United States. 
If this shortage continues when this study is open, patients may be treated with IV levo-
leucovorin at 200mg/m2 instead of leucovorin at 400 mg/m2 . If levo-leucovorin is not an 
option, patients may be treated with low-dose leucovorin at 20mg/m2 or may be treated 
without leucovorin.  
 
 
7.0   DOSING DELAYS / DOSE MODIFICATIONS 
 
7.1  Metformin dose modifications 
 
Metformin will be administered alone for a 1 week introductory period before the 
addition of the " Folfox chemotherapy" according to the following schedule: 
- Day 1-->4               500 mg twice daily  
- Day 5 -->7              1000 mg twice daily 
- Day 8 and beyond  1000 mg twice daily with chemotherapy 
 
7.1.1 Gastrointestinaladverse events (except hepatic dysfunction) 
  
Through the above titrating schedule, the use of the extended release form of metformin 
and the administration of metformin with meals, the odds of metformin related GI side 
effects will be much minimized. 

 
Protocol Version 8, dated 4/23/2015 
21 
Considering that most metformin related GI toxicity are transient, self-resolved with 
continuous use and usually managed individually with no universally adopted 
guidelines, GI side effects which are expected to be less than 10 %, will be managed on a 
case by case basis by the investigator. 
  
The following points will be taken into consideration; 
  
During the introductory period (before chemotherapy is started): 
1) When/if GI side effects develop; patient should be encouraged to continue the 
medication since symptoms could very well self-resolve.  
2) The investigator may delay the dose increase to 1000 mg twice daily for grade 3 or 
above GI toxicity that persist and doesn't respond to symptomatic management) until 
symptoms improve/resolve. 
3) If GI symptoms occur and persist upon increasing the dose to 1000 mg twice daily, 
dose could be reduced again to 500 mg twice daily (if grade 3 or above GI toxicity 
persist) and chemotherapy will be initiated while on this dose.  
  
After the introductory period (after chemotherapy is started): 
  
1) When/if new onset GI side effects occur; it will be, most likely, due to chemotherapy 
(FOLFOX) rather than due to metformin. Therefore, the investigator will follow the 
FOLFOX dose modifications schedule. 
2) In the rare events where GI symptoms are felt to be related to metformin, the case will 
be discussed among the investigators to decide on whether the metformin dose should be 
reduced or modified. 
3) If patient is started on chemotherapy while taking 500 mg twice daily dose (rather than 
the 1000 mg twice daily), the investigators will continue to assess the symptoms and 
potentially consider increasing the dose to 1000 mg twice daily with cycle # 2 of chemo. 
 
7.1.2Hepatic dysfunction: 
- Metformin must be stopped If bilirubin increases to >2.  Bilirubin levels will be 
checked weekly and metformin can be resumed once bili is <2. 
- Metformin must be stopped if AST or ALT increase to > 2.5 ULN. AST/ALT levels 
will be checked weekly and metformin can be resumed only if levels go below 2.5 ULN. 
 
7.1.3 
Renal dysfunction: 
- Metformin must be stopped if creatinine increases to > 1.5. Creatinine level will be 
checked weekly and metformin can be resumed once creatincine is < 1.5 
 
7.1.4 Others: 
- If any other toxicity develop and felt that it is related to metformin, further treatment 
will be at the discretion of the investigator. 
 
 
 
 
 

 
Protocol Version 8, dated 4/23/2015 
22 
 
 
7.2 mFOLFOX 6 modifications 
 
mFOLFOX dose levels 
 
 
 
mFOLFOX dose modifications: 
 
Dose modifications will be required for AEs observed during the cycle and on day 1 of a cycle.  
Dose modifications will be based on the AE requiring the greater modification.  
NCI CTC v 4.0 
Category/Grade  
Modifications for AEs that 
occurred DURING A CYCLE 
but did not require a treatment 
delay  
Modifications for AEs that 
required a TREATMENT 
DELAY (observed on day 1 
of cycle) a. Hold 
mFOLFOX6 for treatment-
related toxicities listed in 
this table that are > grade 1 
on day 1 of a cycle (except 
ANC).  
Blood/Bone Marrow  
Neutrophils/ Granulocytes b 
Grade 2  
Maintain dose  
Maintain dose 
Grade 3  
Maintain dose  
5FU and oxaliplatin 1 dose 
level  
Grade 4  
↓ 5FU and oxaliplatin 1 dose 
level  
↓ 5FU and oxaliplatin 2 dose 
levels  
Platelets c 
Grade 2  
Maintain dose  
↓5FU and oxaliplatin 1 dose 
level  
Grade 3  
↓ 5FU and oxaliplatin 1 dose 
level  
↓5FU and oxaliplatin 1 dose 
level  
Grade 4  
↓ 5FU and oxaliplatin 2 dose 
levels  
↓ 5FU and oxaliplatin 2 dose 
levels  
Diarrhead 
Grade 2  
Maintain dose  
↓5FU by one dose level.  
Grade 3  
↓5FU 1 dose level  
↓5FU 1 dose level  
 
Dose Level 
Oxaliplatin 
mg/m2 
Leucovorin 
mg/m2 
5-FU Bolus 
mg/m2 
5-FU Infusion 
mg/m2 
 
Starting dose 
85 
400 
400 
2400 
 
Dose Level -1 
71 
400 
334 
2000 
 
Dose Level -2 
57 
400 
267 
1600 

 
Protocol Version 8, dated 4/23/2015 
23 
Grade 4  
↓5FU by 2 dose levels and 
oxaliplatin by 1 dose level  
↓5FU by 2 dose levels and  
oxaliplatin by 1 dose level  
Hepatic Function e 
Total bilirubin, AST  
Hold all study therapy until bilirubin returns 
to baseline grade and AST is ≤ grade 1.  
Grade 2  
oxaliplatin one dose level  
↓oxaliplatin 1 dose level  
Grade 3  
↓5FU and oxaliplatin one 
dose level.  
↓5FU and oxaliplatin 2 dose 
levels  
Grade 4  
Stop all study therapy  
Stop all study therapy  
 
Infection  
Febrile Neutropenia  
Grade 3  
↓5FU and oxaliplatin 1 dose 
level f 
↓5FU and oxaliplatin 1 dose 
level f 
Grade 4  
↓5FU and oxaliplatin 2 dose 
levels f 
↓5FU and oxaliplatin 2 dose 
levels f 
Infection with Grade 3 or 4 ANC  
Grade 3  
↓5FU and oxaliplatin 1 dose 
level f 
↓5FU and oxaliplatin 1 dose 
level f 
Grade 4  
↓5FU and oxaliplatin 2 dose 
levels f 
↓ 5FU and oxaliplatin 2 dose 
levels f 
Infection with normal ANC  
Grade 3  
Maintain dose  
Maintain dose  
Grade 4  
↓5FU and oxaliplatin 1 dose 
level  
↓5FU and oxaliplatin 1 dose 
level  
Pulmonary Toxicity  
Cough ≥ grade 3  
Hold all study therapy until interstitial lung disease is ruled 
out.  
If non-infectious interstitial lung disease is confirmed, 
discontinue all study therapy.  
If non-infectious interstitial lung disease is ruled-out and 
infection (if any) has resolved, patients with persistent grade 2 
dyspnea or hypoxia may resume treatment at the discretion of 
the P.I.  
Dyspnea ≥ grade 2  
Hypoxia ≥ grade 2  
Pneumonitis/pulmonary infiltrates  
≥ grade 2  
Pulmonary fibrosis ≥ grade 2  
Other clinically significant AEsg 
Except oxaliplatin-Related Neurologic toxicity  
Grade 2  
Maintain dose  
↓5FU and oxaliplatin 1 dose 
level  
Grade 3  
↓5FU and oxaliplatin1 dose 
level  
↓5FU and oxaliplatin 2 dose 
levels  
Grade 4  
↓5FU and oxaliplatin2 dose 
levels  
↓ 5FU and oxaliplatin 2 dose 
levels  
Oxaliplatin-Related Neurologic Toxicity  
Paresthesias/Dysesthesias 
(may be cold-induced)  
Resolved During the Cycle  
Persistent Between Doses  
Grade 1  
Maintain dose  
Maintain dose   

 
Protocol Version 8, dated 4/23/2015 
24 
Grade 2  
Maintain dose 
↓oxaliplatin 1 dose level 
Grade 3  
↓oxaliplatin 1 dose level  
Discontinue oxaliplatin 
Grade 4  
Discontinue oxaliplatin 
Discontinue oxaliplatin 
Laryngeal Dysesthesias 
See section 6.3.2  
 
 
a)Treatment may not proceed until treatment-related toxicity has resolved to ≤ grade 1, except for neutrophils which 
must be ≥ 1200/mm3 in order to treat. Hold study drugs and recheck weekly.  
b)Neutrophils must be ≥ 1200/mm3 in order to treat.  
c)Treat if platelets are ≥ 75,000/mm3. Consider hemolytic uremic syndrome/ thrombotic thrombocytopenic purpura 
for ≥ grade 2 thrombocytopenia. If confirmed, discontinue oxaliplatin.  
d)Hold mFOLFOX6 for grade 3 or 4 diarrhea at any time during a cycle or for grade 2 diarrhea on day 1 of a cycle. 
Resume treatment as per table when diarrhea has resolved to ≤ grade 1.  
e)Elevation of bilirubin or AST to ≥ grade 3 will require bilirubin and transaminases to be monitored weekly. If all 
elevations do not resolve to ≤ grade 1 after 4 weeks, discontinue study therapy. Then monitor bilirubin and 
transaminases q 2 weeks for 2 months, then q 4 weeks until 1 year from study entry or until all elevations resolve to 
≤ grade 1. Hold all study therapy for suspected veno-occlusive disease (VOD) of the liver (manifestations include 
hyperbilirubinemia, ascites, weight gain due to fluid retention, hepatomegaly, splenomegaly, or other signs of portal 
hypertension). If VOD is diagnosed, discontinue all study therapy.  
f) Administer G-CSF with subsequent cycles.  
g)The determination of clinically significant is at the discretion of the treating physician.  
 
 
8.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
The following is a list of AEs (Section 8.1) and the reporting requirements associated with 
observed AEs (Sections 8.3 and 8.4).  
 
The clinical course of each event will be followed until resolution, stabilization, or until it has 
been determined that the study treatment or participation is not the cause.  
 
Serious adverse events that are still ongoing at the end of the study period will necessitate 
follow-up to determine the final outcome. Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study treatment or study participation will 
be recorded and reported immediately. 
 
8.1 
Adverse Events and Potential Risks 
 
8.1.1 Metformin 
 
>10%: 
Gastrointestinal: Diarrhea, nausea/vomiting, flatulence (Note: With the extended release 
form, these symptoms are reported to occur in less than 10 % of patients). 
Neuromuscular & skeletal: Weakness  
1% to 10%: 
Cardiovascular: Chest discomfort, flushing, palpitation 

 
Protocol Version 8, dated 4/23/2015 
25 
Central nervous system: Headache , chills, dizziness, lightheadedness 
Dermatologic: Rash 
Endocrine & metabolic: Hypoglycemia 
Gastrointestinal: Indigestion , abdominal discomfort , abdominal distention, abnormal 
stools, constipation, dyspepsia/ heartburn, taste disorder 
Neuromuscular & skeletal: Myalgia 
Respiratory: Dyspnea, upper respiratory tract infection 
Miscellaneous: Decreased vitamin B12levels , increased diaphoresis, flu-like syndrome, 
nail disorder 
<1% (Limited to important or life-threatening):  
Lactic acidosis, leukocytoclasticvasculitis, megaloblastic anemia, pneumonitis 
8.1.2  Oxaliplatin 
> 10% 
Central nervous system: Fatigue (61%), fever (25%), pain (14%), headache (13%), 
insomnia (11%) 
Gastrointestinal: Nausea (64%), diarrhea (46%), vomiting (37%), abdominal pain (31%), 
constipation (31%), anorexia (20%), stomatitis (14%) 
Hematologic: Anemia (64%; grades 3/4: 1%), thrombocytopenia (30%; grades 3/4: 3%), 
leukopenia (13%) 
Hepatic: AST increased (54%; grades 3/4: 4%), ALT increased (36%; grades 3/4: 1%), 
total bilirubin increased (13%; grades 3/4: 5%) 
Neuromuscular & skeletal: Peripheral neuropathy (may be dose limiting; 76%; acute 65%; 
grades 3/4: 5%; persistent 43%; grades 3/4: 3%), back pain (11%) 
Respiratory: Dyspnea (13%), cough (11%) 
1% to 10%: 
Cardiovascular: Edema (10%), chest pain (5%), peripheral edema (5%), flushing (3%), 
thromboembolism (2%) 
Central nervous system: Dizziness (7%) 
Dermatologic: Rash (5%), alopecia (3%), hand-foot syndrome (1%) 
Endocrine & metabolic: Dehydration (5%), hypokalemia (3%) 
Gastrointestinal: Dyspepsia (7%), taste perversion (5%), flatulence (3%), mucositis (2%), 
gastroesophageal reflux (1%), dysphagia (acute 1% to 2%) 

 
Protocol Version 8, dated 4/23/2015 
26 
Genitourinary: Dysuria (1%) 
Hematologic: Neutropenia (7%) 
Local: Injection site reaction (9%; redness/swelling/pain) 
Neuromuscular & skeletal: Rigors (9%), arthralgia (7%) 
Ocular: Abnormal lacrimation (1%) 
Renal: Serum creatinine increased (5% to 10%) 
Respiratory: 
URI 
(7%), 
rhinitis 
(6%), 
epistaxis 
(2%), 
pharyngitis 
(2%), 
pharyngolaryngealdysesthesia (grades 3/4: 1% to 2%) 
Miscellaneous: Allergic reactions (3%); hypersensitivity (includes urticaria, pruritus, facial 
flushing, shortness of breath, bronchospasm, diaphoresis, hypotension, syncope: grades 
3/4: 2% to 3%); hiccup (2%). 
For more information on toxicities associated with oxaliplatin, please see the package 
insert. 
8.1.3 5-FU 
Hematologic: Leukopenia, thrombocytopenia, anemia, pancytopenia, thrombocytopenia, 
agranulocytosis; can also be dose limiting; less common with continuous infusion.  
Dermatologic: Dermatitis, nail changes, hyperpigmentation, hand-foot syndrome with 
protracted infusions, alopecia, fissuring, photosensitivity as manifested by erytema or 
increased pigmentation of the skin, nail changes (including loss of nails).  
Gastrointestinal: Nausea, vomiting, anorexia; diarrhea, can be dose limiting; mucositis, 
more common with 5-day infusion, occasionally dose limiting; severe, cholera-like 
diarrhea which can be fatal given with leucovorin; gastro- intestinal ulceration, bleeding, 
stomatitis, esophagopharyngitis.  
Neurologic: Cerebellar syndrome (headache and cerebellar ataxia).  
Cardiac: myocardial ischemia, angina, noted with continuous infusion,  thrombophlebitis.  
Ophthalmic: Eye irritation, nasal discharge, watering eyes, blurred vision.  
Hepatic: Hepatitis with hepatic infusion.  
Allergic reaction: anaphylaxis, generalized allergic reactions.  
Psychiatric: disorientation, confusion, euphoria 
Other: nose bleeds  
For more information about 5-FU toxicity please see package insert. 

 
Protocol Version 8, dated 4/23/2015 
27 
8.1.4  Leucovorin 
Hematologic: Thrombocytopenia, leukopenia.  
Dermatologic: Skin rash, alopecia.  
Gastrointestinal: Nausea, vomiting, diarrhea, stomatitis, constipation.  
Allergic: Skin rash, hives, pruritis.  
Pulmonary: Wheezing (possibly allergic origin).  
Other: infection, lethargy, fatigue, anorexia, headache; may potentiate the  toxic effects of 
fluoropyrimidine therapy, resulting in increased hematologic and gastrointestinal (diarrhea, 
stomatitis) adverse effects.   
See Package Insert for additional information on leucovorin.  
8.2 
Definitions  
 
8.2.1 
Adverse Events   
 
An adverse event (AE) is any unfavorable or unintended event, physical or psychological, 
associated with a research study, which causes harm or injury to a research participant as a result 
of the participant’s involvement in a research study. The event can include abnormal laboratory 
findings, symptoms, or disease associated with the research study. The event does not necessarily 
have to have a causal relationship with the research, any risk associated with the research, the 
research intervention, or the research assessments.  
 
Adverse events may be the result of the interventions and interactions used in the research; 
the collection of identifiable private information in the research; an underlying disease, 
disorder, or condition of the subject; and/or other circumstances unrelated to the research or 
any underlying disease, disorder, or condition of the subject. In general, adverse events that 
are at least partially the result of (a) or (b) would be considered related to the research, 
whereas adverse events solely related to (c) or (d) would be considered unrelated to the 
research.  
External adverse events are adverse events experienced by subjects enrolled in multicenter 
clinical trials at sites other than the site(s) over which the Institutional Review Board has 
jurisdiction.  
Internal adverse events are adverse events experienced by subjects enrolled at the site(s) 
under the IRB’s jurisdiction for either multicenter or single-center research projects.  
 
8.2.2 The significance of an adverse event is used to describe the patient/event outcome or 
action criteria associated with events that pose a threat to a patient’s life or functioning (i.e., 
moderate, severe or life threatening).  Based on the National Cancer Institute Guidelines for 
the Cancer Therapy Evaluation Program, severity can be defined by the following grades of 
events: 

 
Protocol Version 8, dated 4/23/2015 
28 
 
 
Grades 1 are mild adverse events. (e.g., minor event requiring no specific medical 
intervention; asymptomatic laboratory findings only; marginal clinical relevance) 
 
Grades 2 are moderate adverse events (e.g., minimal intervention; local intervention; non-
invasive intervention; transfusion; elective interventional radiological procedure; therapeutic 
endoscopy or operation). 
 
Grades 3 are severe and undesirable adverse events (e.g., significant symptoms requiring 
hospitalization or invasive intervention; transfusion; elective interventional radiological 
procedure; therapeutic endoscopy or operation). 
 
Grades 4 are life threatening or disabling adverse events (e.g., complicated by acute, life-
threatening metabolic or cardiovascular complications such as circulatory failure, 
hemorrhage, sepsis; life–threatening physiologic consequences; need for intensive care or 
emergent invasive procedure; emergent interventional radiological procedure, therapeutic 
endoscopy or operation). 
 
Grades 5 are fatal adverse event resulting in death.     
 
8.2.3 Serious Adverse Events 
A serious adverse event (SAE) is any adverse experience occurring at any dose that results 
in any of the following outcomes:  
• Results in death. 
• Is a life-threatening adverse experience.  The term life-threatening in the definition 
of serious refers to an adverse event in which the subject was at risk of death at the 
time of the event.  It does not refer to an adverse event which hypothetically might 
have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization.  
Any adverse event leading to hospitalization or prolongation of hospitalization will be 
considered as Serious, UNLESS at least one of the following expectations is met: 
o The admission results in a hospital stay of less than 12 hours OR 
o The admission is pre-planned (i.e., elective or scheduled surgery arranged 
prior to the start of the study) OR 
o The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care. 
However it should be noted that invasive treatment during any hospitalization may 
fulfill the criteria of “medically important” and as such may be reportable as a serious 
adverse event dependent on clinical judgment.  In addition where local regulatory 
authorities specifically require a more stringent definition, the local regulation takes 
precedent.  
• Results in persistent or significant disability/incapacity.  The definition of 
disability is a substantial disruption of a person’s ability to conduct normal life’s 
functions. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event.  Important medical events that may not result death, 
be life-threatening, or require hospitalization may be considered a serious adverse 

 
Protocol Version 8, dated 4/23/2015 
29 
experience when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood disease or disorders, or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
8.2.4 Expectedness 
Adverse Events can be Expected or Unexpected. 
 
An expected adverse event is an event previously known or anticipated to result from 
participation in the research study or any underlying disease, disorder, or condition of the 
subject. The event is usually listed in the Investigator Brochure, consent form or research 
protocol.  
 
An unexpected adverse event is an adverse event not previously known or anticipated to result 
from the research study or any underlying disease, disorder, or condition of the subject.  
 
8.2.5 Attribution 
Attribution is the relationship between an adverse event or serious adverse event and the study 
drug.  Attribution will be assigned as follows: 
 
• Definite – The AE is clearly related to the study drug. 
• Probable – The AE is likely related to the study drug. 
• Possible – The AE may be related to the study drug. 
• Unlikely – The AE is doubtfully related to the study drug. 
• Unrelated – The AE is clearly NOT related to the study drug. 
 
8.3  
Reporting Procedures for All Adverse Events 
 
All participating investigators will assess the occurrence of AEs throughout the subject’s 
participation in the study.  Subjects will be followed for toxicity for 30 days after treatment has 
been discontinued or until death, whichever occurs first.  The clinical course of each event will 
be followed until resolution, stabilization, or until it has been determined that the study treatment 
or participation is not the cause.   
 
The investigator is responsible for ensuring that all adverse events observed by the investigator 
or reported by the subject which occur after the subject has signed the informed consent are fully 
recorded in the subject’s case report form, subject’s medical records, and/or any other 
institutional requirement. Source documentation must be available to support all adverse events. 
 
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to 
withdraw from the study), requiring treatment or causing apparent clinical manifestations, or 
judged relevant by the investigator, should be reported as an adverse event.   
 
The investigator will provide the following for all adverse events: 
• Description of the event 
• Date of onset and resolution 
• Grade of toxicity  

 
Protocol Version 8, dated 4/23/2015 
30 
• Attribution of relatedness to the investigational agent 
• Action taken as a result of the event 
• Outcome of event 
 
In this study, descriptions and grading scales found in the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 available at http://ctep.cancer.govwill be utilized for 
AEreporting.  
 
Investigative sites will report adverse events to their respective IRB according to the local IRB’s 
policies and procedures in reporting adverse events. 
 
8.4  
Serious Adverse Event Reporting Procedures 
 
Serious adverse events that occur beginning with the signing of the informed consent form, 
during treatment, or within 30 days of the last dose of treatment must be reported to the Principal 
Investigator. 
 
Investigative sites will report serious adverse events to their respective IRB according to the 
local IRB’s policies and procedures in reporting serious adverse events. 
 
8.4.1 FDA Reporting 
 
The principal investigator will be responsible for all communication with the FDA.  In 
accordance with 21 CFR 312.32, the Principal Investigator is responsible for notifying the FDA 
of SAEs that are serious, unexpected (not listed in the Investigator Brochure) and judged to be 
related (i.e., possible, probable, definite) to the study drug. 
 
8.5  
Data Safety Toxicity Committee 
 
It is the Case Comprehensive Cancer Center’s Principal Investigator’s responsibility to ensure 
that ALL serious adverse events are reported to the Case Comprehensive Cancer Center’s Data 
Safety Toxicity Committee. This submission is simultaneous with their submission to the 
Sponsor or other Regulatory body.  
 
 
 
9.0 
PHARMACEUTICAL INFORMATION 
 
9.1 
Metformin 
 
Chemical Name:N,N-dimethylimidodicarbonimidicdiamide hydrochloride 
 
Classification:Biguanides 
 
Molecular Formula:C4H11N5 
 
Mode of Action:  
As a diabetic mediation, decreases hepatic glucose production and increases insulin 
sensitivity. 
Refer to background for mechanism of potential antineoplastic effects. 

 
Protocol Version 8, dated 4/23/2015 
31 
Metabolism:Metformin is excretedunchanged in the urine and does not undergo hepatic 
metabolism (no metabolites have beenidentified in humans) nor biliary excretion. Renal 
clearance is approximately 3.5 timesgreater than creatinine clearance, which indicates that 
tubular secretion is the major route ofmetformin elimination.  
Following oral administration, approximately 90% of the absorbed drug is eliminated via the 
renal route within the first 24 hours, with a plasma elimination half-life ofapproximately 6.2 
hours. In blood, the elimination half-life is approximately 17.6 hours, suggestingthat the 
erythrocyte mass may be a compartment of distribution. 
 
Route of administration: This is an oral drug that should be taken with food. 
 
Availability: 
 
Metformin is commercially available at the following doses: 
500 mg, 850 mg, 1000 mg (fast release) tablets. 
500 mg, 750 mg ( extended release ) tablets. 
100 mg/ml (118 ml, 473 ml) oral solutions. 
 
Storage:Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP 
Controlled Room Temperature. 
Metformin Ordering: 
Metformin Hydrochloride 500 mg (extended-release) tablets will be prescribed for each patient 
enrolled on this study using a special clinical trial prescription. The prescription will be filled 
through the institutions investigational pharmacy. 
9.2 Oxaliplatin 
Chemical name:  cis-[(1 R,2R)-1,2-cyclohexanediamine-N,N’] [oxalato(2- )-O,O’] platinum. 
Classification: Platinum Derivative  
Molecular Formula: C8H14N2O 
Approximate Solubility: 
Slightly soluble in water (solubility in water at 20° C is 6 mg/mL). Very slightly soluble in 
methanol (solubility in methanol at 20° C is 0.125 mg/mL). Practically insoluble in ethanol and 
acetone The pH of an aqueous solution of 2 mg/mL is between 4.8 and 5.7. 
Mode of Action 
Oxaliplatin is biotransformed to a reactive species which complex with (crosslink) DNA, amino 
acids, proteins, and other macromolecules and cause tumor cell death by preventing cellular 
replication and transcription and stimulating cells to undergo apoptosis. 
How Supplied 
Oxaliplatin is supplied in clear, glass, single-use vials with gray elastomeric stoppers and 
aluminum flip-off seals containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free 

 
Protocol Version 8, dated 4/23/2015 
32 
lyophilized powder for reconstitution. Lactose monohydrate is also present as an inactive 
ingredient. 
NDC 0024-0596-02: 50 mg single-use vial with green flip-off seal individually packaged in a 
carton. 
NDC 0024-0597-04: 100 mg single-use vial with dark blue flip-off seal individually packaged in 
a carton. 
RECONSTITUTION OR FINAL DILUTION MUST NEVER BE PERFORMED WITH A 
SODIUM CHLORIDE SOLUTION OR OTHER CHLORIDE- CONTAINING 
SOLUTIONS. 
The lyophilized powder is reconstituted by adding 10 mL (for the 50 mg vial) or 20 mL (for the 
100 mg vial) of Water for Injection, USP or 5% Dextrose Injection, USP. Do not administer the 
reconstituted solution without further dilution. The reconstituted solution must be further 
diluted in an infusion solution of 250-500 mL of 5% Dextrose Injection, USP. 
After reconstitution in the original vial, the solution may be stored up to 24 hours under 
refrigeration (2-8°C [36-46°F]). After final dilution with 250-500 mL of 5% Dextrose Injection, 
USP, the shelf life is 6 hours at room temperature (20-25°C [68-77°F]) or up to 24 hours 
under refrigeration (2-8°C [36-46°F]). ELOXATIN is not light sensitive. 
Incompatibilities 
Oxaliplatinis incompatible in solution with alkaline medications or media (such as basic 
solutions of 5-FU) and must not be mixed with these or administered simultaneously through the 
same infusion line. The infusion line should be flushed with D5W prior to administration of any 
concomitant medication. 
Do not use for the preparation or administration needles or intravenous infusion sets containing 
aluminum items (risk of degradation of oxaliplatin upon contact with aluminum). Handling 
and Disposal 
As with other potentially toxic anticancer agents, care should be exercised in the handlingand 
preparation of infusion solutions prepared fromOxaliplatin. The use of gloves is recommended. 
If a solution of Oxaliplatin contacts the skin, wash the skin immediately and thoroughly with 
soap and water. If Oxaliplatincontacts the mucous membranes, flush thoroughly with water. 
Procedures for the handling and disposal of anticancer drugs should be considered. Several 
guidelines on the subject have been published. There is no general agreement that all of the 
procedures recommended in the guidelines are necessary or appropriate. 
Storage 
Store the intact vials at controlled room temperature. Excursions permitted to 15°C to 30°C 
(59°F to 86°F), not exceeding 30°C. 
 

 
Protocol Version 8, dated 4/23/2015 
33 
Stability 
The freeze-dried powder is stable for 3 years at room temperature protected from light. 
Reconstituted solution: in 5% Dextrose or Water for Injection in the original vial, the solution 
may be stored for up to 24 hours between 2C to 8 C (36F-46F). Infusion solution: after 
dilution in 250-500 ml 5% Dextrose in Water, the shelf life is 24 hours at 2C to 8C (36F-
46F) or 6 hours at room temperature (20-25 degrees Celsius). 
Route of Administration 
Intravenous. 
Availability 
Commercially available. 
9.3 5-Fluorouricil (5-FU) 
Classification: Antimetabolite  
Molecular Formula: C4H3FN2O2 
Mode Of Action 
Fluorouracil is a pyrimidine antagonist that interferes with nucleic acid biosynthesis. The 
deoxyribonucleic acid of the drug inhibits thymidylatesynthetase, thus inhibiting the formation of 
the thymidylic acid form deoxyridylic acid, thus interfering in the synthesis in the synthesis of 
DNA. It also interferes with RNA synthesis. 
Storage and Stability 
Stable for prolonged periods of time (7 days at 37 °C, several weeks at 25 °C, at least 4 months 
at 0-4 °C) if protected from light. Inspect for precipitate; if apparent, agitate vial vigorously or 
gently heat to not greater than 140 F in a water bath. Do not allow to freeze. 
Handling and Disposal 
Procedures for the handling and disposal of anticancer drugs should be considered. Several 
guidelines on the subject have been published. There is no general agreement that all of the 
procedures recommended in the guidelines are necessary or appropriate. 
Route of Administration 
Intravenous. 
Warnings 
The daily dose of fluorouracil is not to exceed 800 mg. 
Fluorouracil should be used with extreme caution in poor risk patients with history of high-dose 

 
Protocol Version 8, dated 4/23/2015 
34 
pelvic irradiation or previous use of alkylating agents, those who have a widespread involvement 
of bone marrow by metastatic tumors or those with impaired hepatic or renal function. 
Rarely, unexpected, severe toxicity (e.g., stomatitis, diarrhea, neutropenia and neurotoxicity) 
associated with 5-fluorouracil and despite 5-fluorouracil dose lowering, toxicity recurred and 
progressed with worse morbidity. Absence of the dihydropyrimidine dehydrogenase enzyme 
appears to result in prolonged clearance of 5-fluorouracil. 
Availability 
Commercially available in 500 mg/10 ml ampules and vials, and 1 gm/20 ml, 2.5 gm/50 ml, and 
5 gm/100 ml vials. 
9.4 Leucovorin 
Classification 
Tetrahydrofolic acid derivative 
Molecular Formula: C20H23N7O7 
Mode of Action 
Leucovorin acts as a biochemical cofactor for 1-carbon transfer reactions in the synthesis of 
purines and pyrimidines. Leucovorin does not require the enzyme dihydrofolatereluctase 
(DHFR) for conversion to tetrahydrofolic acid. The effects of methotrexate and other DHFR-
antagonists are inhibited by leucovorin. 
Leucovorin can potentiate the cytotoxic effects of fluorinated polymerades (i.e., fluorouracil and 
floxuridine). After 5-FU is activated within the cell, it is accompanied by a folateconfactor, and 
inhibits the enzyme thymadylatesynthetase, thus inhibiting pyrimidine synthesis. Leucovorin 
increases the folste pool, thereby increasing the binding of folate cofactor and active 5-FU with 
thymidylatesynthetase. 
Storage and Stability 
All dosage forms are stored at room temperature. The reconstituted parenteral solution, 10 
mg/ml, is stable for at least 7 days at room temperature. At concentrations of 0.5-0.9 mg/ml the 
drug is chemically stable for at least 24 hours at room temperature under normal laboratory light. 
Preparation 
The 50 and 100-mg vials for injection are reconstituted with 5 and 10 ml of sterile water or 
bacteriostatic water, respectively, resulting in a 10-mg/ml solution. The 350-mg vial is 
reconstituted with 17-ml sterile water resulting in a 20-mg/ml solution. 
Administration 
Intravenous 

 
Protocol Version 8, dated 4/23/2015 
35 
Compatibilities 
Leucovorin (0.5-0.9 mg/ml) is chemically stable for at least 24 hours in normal saline, 5% 
dextrose, 10% dextrose, Ringer’s injection or lactated Ringer’s injection. Leucovorin (0.03, 0.24, 
and 0.96 mg/ml) is stable for 48 hours at room and refrigeration temperatures when admixed 
with floxuridine (FUDR, 1, 2 and 4 mg/ml) in normal saline. Leucovorin is also compatible with 
fluorouracil. 
Availability 
Commercially available as a tablet (5, 10, 15, 25 mg), cryodessicated powder for oral solution, 
and in parenteral formulations (3 and 5 mg ampule; 50 mg, 100 mg and 350 mg vial). 
 
10.0 
CORRELATIVE / SPECIAL STUDIES 
 
10.1 Use of tumor blocks 
Blocks of archived formalin fixed paraffin embedded pancreatic cancer tissues of each 
patient (if available) will be sent to Dr. Dimitrios Iliopoulos’ Laboratory at the following 
address: 
Dimitrios Iliopoulos Ph.D 
Institute of Molecular Medicine (IMED) 
David Geffen School of Medicine 
UCLA 
650 Charles E.Young Drive South 
Los Angeles, CA 90025-7278 
 
If paraffin block embedded is not available, unstained slides could be sent (preferably about 
25 slides). 
The following markers will be examined: 
 
Insulin Receptor (IR): 
We will examine expression of Insulin receptor(IR)by Immunohistochemistry (IHC) in 
archived formalin fixed, paraffin embedded pancreatic cancer tissue. IR is believed to 
mediate insulin action on pancreatic tissue. The expression of IR will be indicative of the 
capacity of tumor cells to respond to indirect (insulin dependent) effects of metformin  
(Figure 1, page 55). 
 
LKB1: 
We will examine expression of LKB1 by IHC in archived formalin fixed, paraffin embedded 
pancreatic cancer tissue. LKB1 is a primary upstream kinase of AMPK. LKB1 expression is 
key to the ability of metformin to affect AMPK activity within tumors and to suppress the 
growth-promoting outputs of this signaling pathway. LKB1expression will be indicative of 
the capacity of tumor cells to respond to direct effects of metformin (Figure 1, page 55). 
 
Phosphoantibody Markers of Activation of Key Signaling Pathways: 
The expression of IR and LKB1willbe indicative of the capacity of tumor cells to respond to 
indirect and direct effects of metformin respectively. However, the expression of these 
factors cannot distinguish whether the downstream pathways are actually activated. 

 
Protocol Version 8, dated 4/23/2015 
36 
Therefore, we will also evaluate by IHC activation markers of these pathways (P-IRS-1, P-
AKT, 4E-BP1) in the archived formalin fixed, paraffin embedded pancreatic cancer tissue as 
predictors of metformin benefit (Figure 1, page 55).  
 
mRNA expression levels of inflammatory markers and lipid metabolism markers 
 RNA will be extracted from the archived formalin pancreatic cancer tissues and we will 
examine the mRNA expression levels of inflammatory markers (interleukin 6 and STAT3)by real-
time PCR analysis, in order to evaluate the activation of inflammatory signaling pathway. 
Furthermore, in the same tissues we will examine STAT3 phosphorylation status (Tyr705) by 
Immunohistochemistry. 
 
Also,mRNA expression levels of Lipid metabolism markers (SREBP1c, ACC1, FAS) will be 
examined by real-time PCR analysis, in order to evaluate the activation of lipid metabolism signaling 
pathways (metformin was shown to inhibit some lipid metabolism factors that are implicated in the 
pathogenesis of insulin resistance, dyslipidemia and diabetes) (15). 
 
10.2 Use of Blood Samples 
The following blood samples will be drawn from patients on day 1 of treatment (or within 1 week 
prior to the metformin introductory period) and after the first 4 cycles of treatment (except for fasting 
glucose and CA 19-9 levels which will be drawn after every 4 cycles). 
 
- 
1 red yellow tube (4 ml) for fasting Glucose 
- 
1 red yellow tube (4 ml) for CA 19-9 
- 
1 lavender (EDTA) tube (4ml) for insulin and IGF-1 
- 
1 lavender (EDTA) tube (4ml) for inflammatory markers 
- 
1 lavender (EDTA) tube (4ml) for lipid metabolism markers 
- 
1 lavender (EDTA) tube (4 ml) for micro RNA panel 
 
Blood from all lavender tubes will spun and the plasma will be stored in a freezer 
maintained at -80°C. Subsequently, the samples will be shipped frozen (in batches) 
on dry ice to Dr. Dimitrios Iliopoulos laboratory at the address mentioned in section 
10.1. 
 
The red yellow tubes (fasting glucose and CA 19-9) will be sent directly to the labs at 
University Hospitals or CCF. 
 
Glucose, Insulin and IGF1: 
 
Levels of glucose, insulin and IGF1 will be measured in blood on day 1 of treatment (or 
within 1 week prior to the metformin introductory period) and afterthe first 4 cycles of 
treatment (fasting glucose will be measured every 4 cycles). 
 
The purpose of these tests is to assess if baseline glucose, insulin and IGF1 levels predict metformin 
benefit and if the change in these levels after treatment correlate with any metformin benefit. 
 
Inflammatory markers and lipid metabolism markers: 
 
Levels of Interleukin 6, STAT3, LEPTIN, SREBP1c, ACC1 and FAS mRNA levelswill be 
assessed by real-time PCR analysis in blood samples derived from day 1 of treatment (or 
within 1 week prior to the metformin introductory period) and after the first 4 cycles of 
mFOLFOX6. 

 
Protocol Version 8, dated 4/23/2015 
37 
The purpose of these tests is to assess if baseline levels predict metformin benefit and if the change in 
these levels after treatment correlate with any metformin benefit. 
 
microRNA panel 
As mentioned in section 1.2, Dr. Iliopoulos and his team identified a microRNA panel that was highly 
associated with pancreatic cancel cells survival. Therefore, we are planning to assess the expression 
levels of the microRNA panel by real-time PCR analysis in blood samples derived from day 1 of 
treatment (or within 1 week prior to the metformin introductory period) and after the first 4 cycles of 
treatment. 
 
CA 19-9 
CA 19-9 Level will be measured in blood on day 1 of treatment (or within 1 week prior to the 
metformin introductory period) and then every 4 cycles of treatment. 
CA 19-9 is a tumor marker that is usually elevated in patients with pancreatic cancer. 
The purpose of this test is to assess if CA 19-9 levels at baseline and after treatment correlate 
with metformin benefit. 
 
 
10.3 All specimens’ information will be logged into the OnCore database, then de-identified 
using a code specific for this trial. 
 
10.4 The above biomarkers will be compared between patients who respond and do not 
respond using an exact Wilcoxon rank-sum test. Their relationship to time to-event outcomes 
(OS and PFS) will be examined using the Cox proportional hazards model.  Due to small 
sample sizes, these analyses will be exploratory. 
 
11.0  STUDY PARAMETERS AND CALENDAR 
 
11.1 
Study Parameters 
 
11.1.1 Screening(baseline) Evaluation 
 
Screening studies and evaluations will be used to determine the eligibility of each subject for 
study inclusion.Screening evaluations are to be conducted within 1 week prior to administration 
of protocol therapy. Scans, x-rays, EKG and echo must be done within 4 weeks prior to the start 
of therapy. In the event that the patient’s condition is deteriorating, laboratory evaluations should 
be repeated within 48 hours prior to initiation of the next cycle of therapy. 
The followings should be obtained at baseline: 
 
• Informed Consent 
• Demographics 
• Medical History  
• Complete physical examination  
• Height 
• Weight 
• Vital signs  
• Concomitant Medications Assessment  

 
Protocol Version 8, dated 4/23/2015 
38 
• ECOG Performance Status 
• Baseline Symptoms Assessment 
• Laboratory Studies: 
• Complete Blood Count (CBC) with differentialand platelets 
• Comprehensive metabolic panel 
• Calculated creatinine clearance will be done if creatinine and/or BUN are 
abnormal.    
• ß-HCG for women of childbearing potential  
• ECG 
• Radiographic tumor assessment. 
 
11.1.2 Treatment Period 
 
Within 1 week prior to “metformin introductory period” or on day 1 of this period: 
 
• Correlative Studies: 
CA19-9, fasting glucose and insulin levels in addition to Interleukin 6, STAT3, 
LEPTIN, IGF1, SREBP1c, ACC1, FAS mRNA levels and the expression levels of the 
microRNA panel (in blood). 
 
The followings need to be repeated only if screening evaluations were conducted > 1 week 
prior to administration of protocol therapy (prior to the metformin introductory period).   
 
• Physical Examination (may be performed up to 6 days prior to day 1) 
• Weight 
• Vital signs  
• Concomitant Medications Assessment 
• ECOG Performance Status   
• Baseline Symptoms Assessment  
• Complete Blood Count (CBC) with differential and platelets 
• Comprehensive metabolic panel 
• Calculated creatinine clearance will be done if creatinine and/or BUN are abnormal.    
 
After the “ metformin introductory period" (see section 6.1), treatment will begin in 2-week 
cycles. 
 
Cycle 1, Day 1 
 
• mFOLFOX 6 administration 
• Continue metformin administration 
 
Cycle 1, Day 2-14 
 
• 
Metformin administration 
 

 
Protocol Version 8, dated 4/23/2015 
39 
 
Day 1 of every following cycle 
 
• Physical Examination 
• Weight 
• Vital signs 
• Concomitant medications assessment 
• Toxicity assessment 
• Laboratory Studies (could be done one day prior to treatment): 
• Complete Blood Count (CBC) with differential and platelets 
• Comprehensive metabolic panel 
• Calculated creatinine clearance will be done if creatinine and/or BUN are 
abnormal.    
• mFOLFOX 6 administration 
• Metformin administration 
 
Day 2-14 of every following cycle 
 
• Metformin administration 
 
Every 4 cycles: 
 
• Radiographic tumor assessment. 
• Correlatives (Insluin, Interleukin 6, STAT3, LEPTIN, IGF1, SREBP1c, ACC1, 
FAS mRNA levels and the expression levels of the microRNA panel) will be sent 
once after the first 4 cycles (day 1 of cycle 5). 
• Fasting glucose levels and CA 19-9 levels will be sent every 4 cycles. 
 
End of treatment: 
 
• Physical exam.  
• Weight and vital signs including blood pressure, pulse, respiratory rate, and 
temperature.  
• ECOG Performance Status  
• Toxicity Evaluation. Treatment-related AEs will be followed until resolved.  
• Documentation of all concomitant medications and procedures.  
• CBC and comprehensive metabolic panel  
• Radiographic tumor assessment (if not done within the last 4 weeks)  
• If patient went off study before 4 cycles of mFOLFOX6 but received at least 2 
cycles, the following correlatives (CA19-9, glucose and insulin levels in addition 
to Interleukin 6, STAT3, LEPTIN, IGF1, SREBP1c, ACC1, FAS mRNA levels 
and the expression levels of the microRNA panel) will be sent . 
 
 
 
 
 

 
Protocol Version 8, dated 4/23/2015 
40 
11.2 
Calendar 
 
 
Study Days 
 
Pre-
Study 
Metformin 
introductory 
period 
Cycle 
1 
Day 1 
Cycle 
1 
Day 
2-14 
Cycle  
2 + 
ongoing 
Cycles,  
Day 1 
Cycle  
2 + 
ongoing 
cycles 
Day 2-
14 
 
End of 
treatment  
REQUIRED ASSESSMENTS 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Height  
X 
 
 
 
 
 
 
Weight  
X1 
X 
 
X 
 
X 
Vitals  
X1 
X 
 
X 
 
X 
Physical Examination 
X1 
X  
 
X 
 
X 
Concomitant Med Assessment 
X1 
X  
 
X 
 
X 
ECOG PS 
X1 
X  
 
X 
 
X 
Baseline Symptoms 
X1 
X  
 
 
 
 
Adverse Event Assessment 
X1 
X 
X 
X 
X 
X 
ECG  
X2 
 
 
 
 
 
 
CBC / diff / platelets  
X1 
 
 
X 
 
X 
Serum CMP3 
X1 
 
 
X 
 
X 
ß-HCG (women of childbearing 
potential) 
X2 
 
 
 
 
 
 
DISEASE ASSESSMENT 
 
 
 
 
 
 
 
Tumor Measurements by radiologic 
evaluation (metformin must be 
discontinued at the time of or prior to 
any contrast scan and withheld for 48 
hours subsequent to the scan. 
 
X2 
 
 
 
 
Tumor measurements are repeated every 4 cycles. 
Documentation (radiologic) must be provided for 
patient removed from study for progressive disease.  
 
 
TREATMENT 
 
 
 
 
 
 
 
mFOLFOX6 administration 
 
 
X 
 
X 
 
 
Metformin 
 
X 
X 
X 
X 
X 
 
CORRELATIVES 
 
 
 
 
 
 
 
 
 
Correlative studies on archived 
formalin fixed, paraffin embedded 
pancreatic cancer tissue: 
1) Examine the expression of 
(IR)and LKB1  
2) Evaluate the expression of (P-
IRS-1, P-AKT, 4E-BP1) 
3) Examine the mRNA expression 
levels of interleukin 6 and 
STAT3 transcription factor by 
real-time PCR analysis. 
 
 
 
 
X4 
 
 
 
 
 
 
Correlative studies from the blood: 
CA19-9, fasting glucose and insulin 
levels in addition to Interleukin 6, 
 
 
 
 
 
Day 
1 
of 
cycle 5 and 
 
 

 
Protocol Version 8, dated 4/23/2015 
41 
 
 
 
 
1 
Within 1 week of starting treatment (if done prior to 1 week of starting treatment, they need to be repeated within 1 week of or day 1 of 
metformin introductory period). 
2 
Within4 weeks prior to first treatment 
3 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, 
SGOT[AST], SGPT[ALT], sodium. 
4 
These should be done on day 1 of metformin introductory period or before starting treatment once patient is deemed eligible for the study and 
officially enrolled. 
5 
Diabetics patients will be asked to monitor their glucose at home through a glucometer twice weekly at least. 
6 
Physical examination may be performed up to 6 days before day 1 of each cycle.   
 
STAT3, LEPTIN, IGF1, SREBP1c, 
ACC1, FAS mRNA levels and the 
expression levels of the microRNA 
panel 
 
X4,5 
then 
for 
CA19-9 and 
glucose only 
every 
4 
cycles. 
MISC ITEMS 
 
 
 
 
 
 
 
Pill diary 
 
X 
X 
X 
X 
X 
 

 
Protocol Version 8, dated 4/23/2015 
42 
12.0  MEASUREMENT OF EFFECT  
 
 
12.1 
Antitumor Effect  
 
For the purposes of this study, patients should be re-evaluated for response every4 cycles of 
treatment.. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. For primary brain tumors, response and progression 
will be evaluated using the RANO criteria [J ClinOncol 28: 1963-1972.2010]. 
 
12.1.1   Definitions 
 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
treatment. 
 
Evaluable for objective response:Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for response. These patients will have their response classified 
according to the definitions stated below.  (Note: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that 
are evaluable, but do not meet the definitions of measurable disease, have received at least 
one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for 
non-target disease. The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions.  
 
 
12.1.2  Disease Parameters 
 
Measurable Disease: Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter for non-nodal lesions and short axis for nodal 
lesions to be recorded) as > 20 mm by chest x-ray, as > 10 mm with CT scan, or > 10 mm 
with calipers by clinical exam.  All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be > 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no grater than 5 mm).  At baseline and in follow-up, only the short axis 
will be measured and followed.  
 

 
Protocol Version 8, dated 4/23/2015 
43 
Non-measurable disease: All other lesions (or sites of disease), including small lesions 
(longest diameter < 10 mm or pathological lymph nodes with > 10 to < 15 mm short axis) are 
considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI) are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline.  Target lesions should be selected on the basis of their 
size (lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements. It may 
be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance; the next largest lesion, which can be measured 
reproducible, should be selected. A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the baseline 
sum diameters. If lymph nodes are to be included in the sum, then only the short axis is 
added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions: All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should also 
be recorded at baseline.  Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout follow-
up. 
 
12.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged, but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and > 10 mm diameter as assessed 
using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is recommended. 

 
Protocol Version 8, dated 4/23/2015 
44 
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI:These techniques should be performed with cuts of 10 mm or less in 
slice thickness contiguously. Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm. This applies to tumors of the chest, abdomen, and pelvis. Head and 
neck tumors and those of extremities usually require specific protocols. 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease. Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be measured/assessed on the same 
pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type 
of scanner should be used and the image acquisition protocol should be followed as closely 
as possible to prior scans. Body scans should be performed with breath-holding techniques, if 
possible.  
 
UltrasoundUltrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next.  If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be 
used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 
96:487-488, 2004; J ClinOncol 17, 3461-3467, 1999; J ClinOncol 26: 1148-1159, 2008].  In 
addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria 
which are to be integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
 
 
 

 
Protocol Version 8, dated 4/23/2015 
45 
Cytology, Histology These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side 
effect of the treatment) and progressive disease. 
 
12.1.4 Response Criteria 
 
 
12.1.4.1 
Evaluation of Target lesions 
 
 
Response 
Evaluation of Target Lesions 
Complete Response 
(CR) 
Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have 
reduction in short axis to < 10 mm. 
Partial Response  
         (PR) 
At least a 30% decrease in the sum of diameters of 
target lesions, taking as reference the baseline sum of 
diameters. 
Progressive Disease 
(PD) 
At least a 20% increase in the sum of diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.   
Note: the appearance of one or more new lesions is 
also considered progression. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on study. 
 
12.1.4.2 
Evaluation of Non-Target lesions 
 
Response 
Evaluation of Non-Target Lesions 
Complete Response 
(CR) 
Disappearance 
of 
all 
non-target 
lesions 
and 
normalization of tumor marker level. All lymph nodes 
must be non-pathological in size (< 10 mm short axis). 
Note: If tumor markers are initially above the upper 
normal limit, they must normalize for a patient to be 
considered in complete clinical response.  
 
 
 
Non-CR/ Non-PD 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits. 

 
Protocol Version 8, dated 4/23/2015 
46 
 
[Incompleteresponse/ 
StableDisease (SD)] 
 
Progressive 
Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status. It must be 
representative of overall disease status change, not a 
single lesion increase. 
 
Although a clear progression of ‘non-target’ lesions 
only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and 
the progression status should be confirmed at a later 
time by the review panel (or Principal Investigator).  
 
12.1.4.2 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started). The patient’s best response assignment will depend on the achievement 
of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best 
Overall 
Response 
when 
Confirmation 
is 
Required* 
CR 
CR 
No 
CR 
> 4 wks. Confirmation ** 
 
CR 
 
Non-CR/Non-PD 
 
No 
 
 
PR 
 
 
> 4 wks. Confirmation ** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
Documented at least once 
> 4 wks from baseline ** 
PD 
Any 
Yes or No 
PD 
 
No prior SD, PR or CR 
 
Any 
PD *** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*         See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**       Only for non-randomized trials with response as primary endpoint. 
***     In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration.”  Every 
effort should be made to document the objective progression even after discontinuation of treatment.  
 

 
Protocol Version 8, dated 4/23/2015 
47 
 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesion 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD * 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any  
Yes 
PD 
*        ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used 
as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can 
be measured is not advised. 
 
 
12.1.5  Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started) 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that progressive disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started, including the baseline measurements. 
 
13.0 RECORDS TO BE KEPT /REGULATORY CONSIDERATIONS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 8.0 
(Adverse Events: List and Reporting Requirements). 
 
13.1 
Data Reporting 
 
The OnCore Database will be utilized, as required by the Case Comprehensive Cancer 
Center, to provide data collection for both accrual entry and trial data management.  OnCore 
is a Clinical Trials Management System housed on secure servers maintained at Case 
Western Reserve University.  OnCore properly used is compliant with Title 21 CFR Part 11.  
Access to data through OnCoreis restricted by user accounts and assigned roles.  Once 
logged into the OnCore system with a user ID and password, OnCore defines roles for each 
user, which limits access to appropriate data. User information and password can be obtained 
by contacting the OnCore Administrator at oncore-registration@case.edu. 
 
OnCore is designed with the capability for study setup, activation, tracking, reporting, data 
monitoring and review, and eligibility verification. This study will utilize electronic Case 
Report Form completion in the OnCore database.  A calendar of events and required forms 
are available in OnCore. 
 

 
Protocol Version 8, dated 4/23/2015 
48 
 
13.2 
Regulatory Considerations 
The study will be conducted in compliance with ICH guidelines and with all applicable federal 
(including 21 CFR parts 56 & 50), state or local laws.  
13.2.1 Written Informed consent 
Provision of written informed consent must be obtained prior to any study-related procedures.  
The Principal Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study as well as the 
subject’s financial responsibility.  Subjects must also be notified that they are free to discontinue 
from the study at any time.  The subject should be given the opportunity to ask questions and 
allowed time to consider the information provided. 
The original, signed written Informed Consent Form must be kept with the Research Chart in 
conformance with the institution’s standard operating procedures. A copy of the signed written 
Informed Consent Form must be given to the subject. 
13.2.2 Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a 
subject must sign an authorization to release medical information to the sponsor and/or allow the 
sponsor, a regulatory authority, or Institutional Review Board access to subject’s medical 
information that includes all hospital records relevant to the study, including subjects’ medical 
history. 
 
13.2.3 Accessing Electronic Medical Records for University Hospitals Health System  and 
Cleveland Clinic Foundation 
 
This study will access electronic medical records systems to obtain medical information for 
the subjects enrolled to this study.  
 
In order to insure patient safety, investigators and study personnel must have up-to-the-
minute health information for subjects enrolled to this study.  Therefore, electronic medical 
records must be utilized to obtain medical information in a timely manner.   
 
The following electronic systems will be used:  IDX program to access scheduling 
information; UH Physician Portal to access lab results and physician notes;; COPATH to 
locate archived pathology records; PACS to access radiological imaging results; and 
MySecureCare (Sunrise Clinical Manager) to access some or all of the above information 
when this application is fully functional.   
At the Cleveland Clinic Foundation, the EPIC EMR system will be used to access all 
required information. 
 
Access to these systems is required for the life of this research study.   
 

 
Protocol Version 8, dated 4/23/2015 
49 
Information obtained from electronic systems will be copied into the SeidmanCancer Center 
Clinical Trials Unit research chart and/or printed (lab results, physician notes, etc.) and stored 
in the research chart.  Research charts are kept secure and destroyed according to UH policy.   
 
 
Study data will be obtained by the PI, co-investigators, study coordinator, and/or data 
manager for this study via password-protected login.  The PI,Rami Manochakian, MD is a 
Case Western Reserve University employee with a University Hospitals email address and 
IT&S log on ID and Password. All study personnel involved in this research will adhere to 
the UH policies regarding confidentiality and Protected Health Information.   
 
13.2.4 Retention of records 
 
The Principal Investigator of The Case Comprehensive Cancer Center supervises the retention of 
all documentation of adverse events, records of study drug receipt and dispensation, and all IRB 
correspondence for as long as needed to comply with national and international regulations. No 
records will be destroyed until the Principal Investigator confirms destruction is permitted.  
 
13.2.5 Audits and inspections 
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the Center to perform audits 
or inspections, including source data verification.  The purpose of an audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analysed, and 
accurately reported according to the protocol, Good Clinical Practice (GCP), guidelines of the 
International Conference on Harmonization (ICH), and any applicable regulatory requirements.   
13.2.6 Data Safety and Monitoring Plan 
 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data and 
Safety Monitoring Plan in accordance with NCI regulations.  
 
14.0     STATISTICAL CONSIDERATIONS 
 
14.1     Study design/Endpoints: 
 
Primary endpoint: is the median overall survival (OS) defined by the time from first day 
of treatment to death from any cause. We hypothesize that metformin plus FOLFOX will 
result in a median overall survival of 10.2 months which is a 50% improvement 
compared to 6.8 months which is the median overall survival of patients with metastatic 
pancreatic cancer treated with gemcitabine (3).   
 
Secondary endpoints: 
1. Response rate (RR) Objective tumor response (partial response, complete response,  
stable disease or progressive disease) based on CT scans or MRI scans if patient is 
allergic to contrast agent or has some other contraindication to a CT scan. These will 
be evaluated according to RECIST criteria. 

 
Protocol Version 8, dated 4/23/2015 
50 
2. Progression free survival (PFS) defined by the time from first day of treatment 
received to the earlier documented disease progression or death from any cause. PFS 
will be determined by the investigator using RECIST 1.1 criteria 
3. Toxicity evaluated through number of grade 3 and 4 toxicities according to National 
Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE; 
Version 4.0) that occur after Cycle 1, day 1 in addition to the incidence, nature and 
severity of all adverse events that occur on or after Cycle 1, Day 1 
4. Correlative studies (mentioned above)which will be exploratory.  
 
14.2     Sample size/Accrual rate: 
For a 1-sided test with type I error 0.10 assuming exponential distribution of survival to 
have 85% power to detect a difference of 6.8 vs. 10.2 months in median survival, 43 
patients are required (27). Based on a projected accrual rate of 3-4 patients per month, we 
expect a 12-month accrual period.  
 
 
14.3    Stratification factors: 
           N/A 
 
14.4Statistical analysis of endpoints: 
Overall survival (OS) will be calculated using Kaplan Meier methods and the median will be 
estimated assuming an exponential distribution (28).  
Progression free survival (PFS) will also be calculated using Kaplan Meier methods and the 
median will be estimated assuming an exponential distribution (28).  
The true response rate of the combination therapy for this patient population will be estimated 
based on the number of responses using a binomial distribution and its confidence intervals will 
be estimated using Wilson’s method. 
The toxicity profile of the combination therapy will be tabulated. 
The correlative studies will be compared between patients who respond and do not respond using 
an exact Wilcoxon rank-sum test. Their relationship to time to-event outcomes (OS and PFS) 
will be examined using the Cox proportional hazards model.  Due to small sample sizes, these 
analyses will be exploratory. 
14.5    Reporting and exclusion: 
 
14.5.1 Evaluation of toxicity. 
All patients will be evaluable for toxicity from the time of their first treatment. 
14.5.2 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 

 
Protocol Version 8, dated 4/23/2015 
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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.   
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.  
REFERENCES 
1. Siegel R, Ward E, Brawley O, Jemal A, Cancer Statistics 2011, CA Cancer J Clin 
2011;61:212–236 
2. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with 
gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the 
National Cancer Institute of Canada. Clinical Trials Group. J ClinOncol 2007;25:1960-
1966 
3. Conroy et al, Folfirinoxvs Gemcitabine in metastatic pancreatic cancer, N Engl J Med 
2011;364:1817-25. 
4. Di Marco M, Di Cicilia R, Macchini M, et al. Metastatic pancreatic cancer: is 
gemcitabine still the best standard treatment? Oncol Rep 2010;23:1183-92. 
5. Ben Sahra, et al. Metformin in Cancer Therapy: A New Perspective for an Old 
Antidiabetic Drug? Mol Cancer Ther2010; 9:1092-1099. 
6. Evans et al, Metformin and reduced risk of cancer in diabetic patients, BMJ 2005; 
330:1304-5 
7. Currie CJ et al, The influence of glucose-lowering therapies on cancer risk in type 2 
diabetes, Diabetologia 2009;52:1766-77 
8. Li D et al, Antidiabetic Therapies Affect Risk of Pancreatic Cancer,Gastroenterology 
2009; 137:482-488 
9. Jiralerspong et al, Metformin and Pathologic Complete Responses to Neoadjuvant 
Chemotherapy in Diabetic Patients With Breast Cancer,ClinOncol 2009; 27:3297-3302. 

 
Protocol Version 8, dated 4/23/2015 
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10. Hassabo et al, Survival advantage associated with metformin usage in patients with 
colorectal cancer and type II noninsulin-dependent diabetes, J ClinOncol 2011; 29 (suppl; 
abstr 3618) 
11. Bansal et al, The effect of metformin on overall survival of patients with colorectal 
cancer treated with chemotherapy, J ClinOncol 2011; 29 ( suppl; abst 2608) 
12. Sadeghi et al, Effect of metformin on survival of diabetic patients with pancreatic 
adenocarcinoma, J ClinOncol 2011; 29 ( suppl; abstr 4063) 
13. Engelman et al, Chemoprevention Meets Glucose ControlCancer Prev Res 2010; 3:1049-
1052 
14. Gonzalez-Angulo et al, Metformin: A Therapeutic Opportunity in Breast Cancer, Clin 
Cancer Res 2010;16:1695-1700 
15. Zhou et al, Role of AMP-activated protein kinase in mechanism of metformin action, J 
clin Invest 2001; 108: 1167-74 
16. Dowling RJO et al, Metformin Inhibits Mammalian Target of Rapamycin–Dependent 
Translation Initiation in Breast Cancer Cells Ca Res 2007;67:10804-12 
17. Alimova IN et al, Metformin inhibits breast cancer cell growth, colony formation and 
induces cell cycle arrest in vitro, Cell Cycle 2009;6:909-15 
18. Kisfalvi K et al, Metformin Disrupts Crosstalk between G Protein–Coupled Receptor and 
Insulin Receptor Signaling Systems and Inhibits Pancreatic Cancer Growth, Ca Res 
2009; 69:6539-6545 
19. Hirsch, Ilopoulos et Al, Metformin Selectively Targets Cancer Stem Cells, and Acts 
Together with Chemotherapy to Block Tumor Growth and Prolong Remission, Cancer 
Res 2009; 69: 7505-7511 
20. Iliopoulos D et al., Inducible formation of breastcancer stem cells and their dynamic 
equilibrium with non-stem cancer cells viaIL6 secretion. PNAS,2011, 108(4):1397-402 
21. Huang et al, Metformin inhibits TNF-alpha-induced IkappaB kinase phosphorylation, 
IkappaB-alpha degradation and IL-6 production in endothelial cells through PI3K-
dependent AMPK phosphorylation,Int J Cardiol. 2009 May 15;134(2):169-75 
22. Luque-Ramirez et al, Treatment of polycystic ovary syndrome (PCOS) with metformin 
ameliorates insulin resistance in parallel with the decrease of serum interleukin-6 
concentrationHormMetab Res. 2010 Oct;42(11):815-20 
23. Watson Pharma , Metformin Hydrochloride tablets and Metformin Hydrochloride 
extended-release tablets, US Prescribing Information. 
24. WWW.Clinicaltrials.gov 
25. Pelzer et al, A randomized trial in patients with gemcitabine refractory pancreatic cancer. 

 
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Final results of the CONKO 003 study, J ClinOncol 26: 2008 (May 20 suppl; abstr 4508) 
26. Ghosn et al, FOLFOX-6 combination as the first-line treatment of locally advanced 
and/or metastatic pancreatic cancer. Am J ClinOncol. 2007 Feb;30(1):15-20 
27. http://www.swogstat.org/stat/public/one_survival.htm 
28. Kaplan EL, and Meier P. (1958). Nonparametric estimation from incomplete 
observations. Journal of the American Statistical Association. 53:457-481. 
 
 
 
 
 

 
Protocol Version 8, dated 4/23/2015 
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APPENDIX A 
 
PERFORMANCE STATUS CRITERIA 
 
 
 
ECOG Performance Status Scale 
 
Grade 
Descriptions 
 
 
0 
 
Normal activity. Fully active, able to carry on all 
pre-disease performance without restriction. 
 
 
 
1 
 
Symptoms, but ambulatory.  Restricted in 
physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary 
nature (e.g., light housework, office work). 
 
 
 
2 
 
In bed < 50% of the time. Ambulatory and capable 
of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking 
hours. 
 
 
 
3 
 
In bed > 50% of the time. Capable of only limited 
self-care, confined to bed or chair more than 50% 
of waking hours. 
 
 
 
4 
 
100% bedridden. Completely disabled. Cannot 
carry on any self-care. Totally confined to bed or 
chair.  
 
 
5 
 
 
Dead. 
 
 
 
 

 
Protocol Version 8, dated 4/23/2015 
55 
 
APPENDIX B 
PATIENT PILL DIARY 
 
Patient Name ______________________Patient Study ID __________Date ___/___/___ 
Drug ____Metformin_________________________Cycle #:_______________________________ 
 
INSTRUCTIONS FOR THE PATIENT: 
   1.  Days 1-4, take one 500 mg tablet twice daily, 12 hours apart 
   2.  Days 5 – 7, take two 500 mg tablet twice daily, 12 hours apart. 
3. From day 7 and forward take _____ tablet(s) twice daily with food, 12 hours apart.  
   4.  Record the date, he time and the number of tablets that were taken. 
   5.  Record any comments or side effects experienced in the comment column. 
   6.  Bring medication and this pill diary to each appointment. 
Day 
Date 
Time of AM 
dose 
# of tablets  
 
 
500 
mg 
tablets 
Time of PM 
dose 
# of tablets  
500 
mg tablets 
 
 
Comments 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
Patient signature____________________________Printed name___________________________ 
RN signature_______________________________ 
 
Date_____________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 

 
Protocol Version 8, dated 4/23/2015 
56 
 
 
 
Figure 1 
 
 
 
Gonzalez Angulo et al Clin Cancer Res; 16(6) March 15, 2010