A Randomized Placebo Controlled Phase II Trial of Metformin in Conjunction With Chemotherapy Followed by Metformin Maintenance Therapy in Advanced Stage Ovarian, Fallopian Tube and Primary Peritoneal Cancer
Phase: PHASE2
Conditions: Brenner Tumor, Malignant Ascites, Malignant Pleural Effusion, Ovarian Clear Cell Cystadenocarcinoma, Ovarian Endometrioid Adenocarcinoma, Ovarian Mixed Epithelial Carcinoma, Ovarian Serous Cystadenocarcinoma, Ovarian Undifferentiated Adenocarcinoma, Recurrent Fallopian Tube Cancer, Recurrent Ovarian Epithelial Cancer, Recurrent Ovarian Germ Cell Tumor, Recurrent Primary Peritoneal Cavity Cancer, Stage IIIA Fallopian Tube Cancer, Stage IIIA Ovarian Epithelial Cancer, Stage IIIA Ovarian Germ Cell Tumor, Stage IIIA Primary Peritoneal Cavity Cancer, Stage IIIB Fallopian Tube Cancer, Stage IIIB Ovarian Epithelial Cancer, Stage IIIB Ovarian Germ Cell Tumor, Stage IIIB Primary Peritoneal Cavity Cancer, Stage IIIC Fallopian Tube Cancer, Stage IIIC Ovarian Epithelial Cancer, Stage IIIC Ovarian Germ Cell Tumor, Stage IIIC Primary Peritoneal Cavity Cancer, Stage IV Fallopian Tube Cancer, Stage IV Ovarian Epithelial Cancer, Stage IV Ovarian Germ Cell Tumor, Stage IV Primary Peritoneal Cavity Cancer
Sponsor: University of Chicago

1 
Local Protocol #:  UC IRB13-1235 
 
 
A RANDOMIZED PLACEBO CONTROLLED PHASE II TRIAL OF METFORMIN IN 
CONJUNCTION WITH CHEMOTHERAPY FOLLOWED BY METFORMIN 
MAINTENANCE THERAPY IN ADVANCED STAGE OVARIAN, FALLOPIAN TUBE 
AND PRIMARY PERITONEAL CANCER 
 
 
Coordinating Center: 
 
 
The University of Chicago 
 
Principal Investigator: 
S. Diane Yamada, M.D. 
 
University of Chicago Medicine 
 
5841 S. Maryland Avenue, MC 2050 
 
Chicago, Il 60637 
 
773-702-6721 
 
Fax: 773-702-5411 
 
sdyamada@uchicago.edu 
 
 
Co-Investigators: 
Gini Fleming, M.D. 
 
University of Chicago Medicine 
 
5841 S. Maryland Avenue, MC 2115 
 
Chicago, IL 60637 
 
773-702-6712 
 
Fax: 773-702-3163 
 
gfleming@medicine.bsd.uchicago.edu 
 
 
 
Iris Romero, M.D. 
 
University of Chicago Medicine 
 
5841 S. Maryland Avenue, MC 2050 
 
Chicago, IL 60637 
 
773-702-6722 
 
773-702-5411 
 
iromero@babies.bsd.uchicago.edu 
 
 
 
Ernst Lengyel, M.D., Ph.D. 
 
University of Chicago Medicine 
 
5841 S. Maryland Avenue, MC 2050 
 
Chicago, IL 60637 
 
773-702-6722 
 
Fax: 773-702-5411 
 
elengyel@uchicago.edu 
 

Protocol #:UC IRB13-1235 
Version Date:11-15-19 
 
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Statisticians: 
 
 
 
Theodore Karrison, PhD 
 
Department of Health Studies 
 
 
University of Chicago Medicine 
 
5841 S. Maryland Avenue, MC 2007 
 
Chicago, IL 60637 
 
Ph. 773-702-9326 
 
Fax. 773-702-1979 
 
karr@uchicago.edu 
 
 
Matthew J. Maurer 
Division of Biomedical Statistics and Informatics 
Mayo Clinic 
200 First Street  
Rochester, MN 55905 
Ph. 507-266-2064 
maurer.matthew@mayo.edu 
 
 
 
Principal Investigators at Participating Sites: 
 
Sean C. Dowdy, M.D. 
Mayo Clinic 
200 First Street SW 
Rochester, MN  
Ph. 507-266-0225 
dowdy.sean@mayo.edu 
 
 
Gustavo C. Rodriguez, M.D. 
NorthShore University Health System  
2650 Ridge Avenue 
Walgreen Building #1507 
Evanston, IL 60201 
Ph. 847-570-2639 
grodriguez@northshore.org 
 
 
James A. Wallace, M.D. 
Ingalls Memorial Hospital 
1 Ingalls Drive  
Harvey, IL 60426 
Ph. 708-339-4800 
james.wallace@uchospitals.edu 

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Charles Leath III, M.D. 
University of Alabama 
1700 6th Ave South  
10th Floor Women and Infants Center, Suite 10250 
Birmingham, AL 35233 
Ph. 205-934-4986 
cleath@uabmc.edu 
 
 
Rodney Rocconi, M.D. 
University of South Alabama 
1660 Springhill Avenue 
Mobile, AL 36604 
Ph. 251-665-8000 
rocconi@health.southalabama.edu 
 
 
Michael Goodheart, M.D. 
University of Iowa 
200 Hawkins Drive 
31506 PFP 
Iowa City, IA 52242 
Ph. 319-356-2015 
michael-goodheart@uiowa.edu 
 
 
James L Wade, III, M.D. 
Decatur Memorial Hospital 
Clinical Research Department 
2300 N. Edward Street 
Decatur, IL 62526 
Ph. 217-876-6600 
jlwade3@sbcglobal.net 
 
 
Other Participating Sites: 
 
Northwest Community Hospital 
Arlington Heights, IL 
Ph. 847-618-1000 
 
 
 
 

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Protocol History 
 
Version Date 
Description of Action 
1/28/14 
Original Submission 
4/29/14 
Amendment #1 
12/15/14 
Amendment #2 
5/11/15 
Amendment #3 
9/18/15 
Amendment #4 
6/29/16 
Amendment #5 
10/11/16 
Amendment #6 
04/12/17 
Amendment #7 
01/16/18 
Amendment #8 
12/04/18 
Amendment #9 
11/15/19 
Amendment #10 
 
 
This study is being conducted by institutional members of the Personalized Cancer Care 
Consortium (PCCC), as well as additional sites.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol #:UC IRB13-1235 
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SCHEMA 
 
Target population: 
-Primary epithelial ovarian, fallopian tube or primary peritoneal cancer, stage III or IV 
-Primary cytoreductive surgery with macroscopic residual disease (optimally debulked < 1 cm 
with visible residual disease) OR suboptimally debulked OR  
-Planned for neoadjuvant chemotherapy 
 
 
 
 
 
 
 
 
 
Primary cytoreductive surgery followed by adjuvant therapy  
 
 
 
-Stage III or IV 
R 
-Histologically confirmed 
A 
 ovarian, fallopian tube or 
N 
 primary peritoneal cancer 
D 
-Optimally debulked < 1 cm 
O 
with macroscopic visible 
M 
disease OR 
I 
-Sub optimally debulked  
 
Z 
 
 
 
 
 
 
 
 
      E 
 
 
 
 
 
 
 
Registration 
 
*Olaparib maintenance therapy allowed 
 
Neoadjuvant chemotherapy followed by interval debulking surgery (IDS)— 
PARTICIPATING in correlative tissue collection substudy 
 
-Investigator suspects stage III or IV ovarian, fallopian tube, or primary peritoneal cancer: 
 
-CA125>250 OR CA125:CEA ratio > 25 OR CA125 < 250 with no evidence of GI cancer 
 
AND 
 
-Ascites OR 
 
-Carcinomatosis OR 
 
-Omental caking OR 
 
-Pleural effusions  
 
 
 
 
 
 
 
 
 
   R 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   A 
 
 
 
 
 
 
   N 
 
 
 
 
 
 
 
 
 
   D 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   O 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   M 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    I 
 
 
 
                      Z 
 
 
 
 
 
 
    E 
 
 
 
Taxane/platinum based 
chemotherapy/metformin x 6 
cycles (up to 8 cycles allowed) 
followed by metformin 
maintenance therapy* 
Taxane/platinum based 
chemotherapy/placebo x 6 cycles 
(up to 8 cycles allowed) followed 
by placebo maintenance* 
 
Laparoscopically  
directed biopsies 
or core biopsies 
Taxane/platinum 
based            
chemotherapy/ 
metformin x 3 or 4  
cycles  
Taxane/platinum 
based 
chemotherapy/ 
placebo x 3 or 4 
cycles  
Taxane/platinum 
based chemotherapy/ 
metformin x 3 or 4 cycles 
(total of up to 8 cycles 
allowed) 
followed by metformin 
maintenance* 
Taxane/platinum based 
chemotherapy/placebo x 3 
or 4 cycles (total of up to 8 
cycles allowed)  
followed by placebo 
maintenance*  
Interval 
debulking 
surgery 
Pre-registration 
Registration 
Interval 
debulking 
surgery 

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*Olaparib maintenance therapy allowed 
 
 
Neoadjuvant chemotherapy followed by interval debulking surgery (IDS)- 
NOT PARTICIPATING in correlative tissue collection substudy 
 
-Presumed stage III or IV based on ascites, peritoneal carcinomatosis, omental caking 
-Histologically confirmed carcinoma consistent with ovarian, fallopian tube or primary 
peritoneal cancer: 
 
-Cytology OR FNA OR core biopsies OR surgically directed biopsies showing 
 
adenocarcinoma 
-CA125 >250 OR CA125:CEA ratio > 25 OR CA125 < 250 with no evidence of GI cancer 
 
 
 
 
 
 
 
 
 R 
 
 
 
 
 
 A 
 
 
 
 
 
 N  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 D  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 O  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 M 
 
 
 
              I 
 
 
 
 
 
  Z 
 
 
 
 
 
  E 
 
 
 
 
*Olaparib maintenance therapy allowed 
 
Acceptable chemotherapy regimens will include: 
1. R1: IV paclitaxel 175 mg/m2 plus IV carboplatin AUC 5-6 every 21 days  
2. R2: IV docetaxel 75 mg/m2 plus IV carboplatin AUC 5-6  every 21 days 
3. R3: IV paclitaxel 80 mg/ m2 day 1, 8, and 15 plus IV carboplatin AUC 5-6 day 1 every 
21 days 
 
Acceptable alternative chemotherapy regimens for elderly patients ≥ 70 will include: 
 
1.   R4: IV paclitaxel 135 mg/m2 plus IV carboplatin AUC 5* plus optional G-CSF every 21 
days 
2. R5: IV paclitaxel 60 mg/m2 day 1, 8, and 15 plus IV carboplatin AUC 5* day 1 every 21 
days (day 15 paclitaxel optional) 
3. R6: IV paclitaxel 60 mg/m2 plus IV carboplatin AUC 2 day 1, 8, and 15 every 21 days 
 
*Patients for whom the physician deems carboplatin AUC 5 to be unsafe may be treated with 
AUC 4. 
Histologic  
OR  
cytologic 
diagnosis 
Taxane/platinum based 
chemotherapy/placebo  
x 3 or 4 cycles  
Taxane/platinum 
based chemotherapy/ 
metformin x 3 or 4 
cycles (total of up to 8 
cycles allowed) 
followed by metformin 
maintenance* 
Taxane/platinum 
based chemotherapy/ 
placebo x 3  or 4 
cycles (total of up to 
8 cycles allowed) 
followed by placebo 
maintenance*  
Interval 
debulking 
surgery 
Interval 
debulking 
surgery 
Taxane/platinum based 
chemotherapy/metformin  
x 3 or 4 cycles  
Registration 

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Subjects can receive a total of 8 cycles of chemotherapy 
 
Metformin dose will be 850 mg po q day starting on day 1 of chemotherapy then increased to 
850 mg po BID as tolerated.  
 
Total duration of metformin/placebo is for 2 years from date of randomization or until radiologic 
progression of disease or intolerance to metformin.  
 
Olaparib maintenance therapy allowable for BRCA germline mutation carriers. Total duration is 
for 2 years from completion of chemotherapy or progression of disease, whichever comes first. 
 
Planned total sample size: 160 (80% power to detect 5 months improvement in median 
progression free survival (PFS) with D=0.15, allowing for 10% dropout. 
 
Primary endpoint: Progression free survival 
 
Secondary endpoints: 
 
 
-Biochemical response rate 
 
-Overall survival 
 
-Time to biochemical progression 
 
-Toxicity 
 
Ancillary endpoints: 
 
-Correlative biomarkers 

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TABLE OF CONTENTS 
 
1. 
OBJECTIVES ....................................................................................................................10 
1.1 
Primary Objective ..................................................................................................10 
1.2 
Secondary Objectives .............................................................................................10 
1.3 
Exploratory Objectives ..........................................................................................10 
2. 
BACKGROUND ...............................................................................................................10 
2.1 
Standard management  ...........................................................................................10 
2.2 
Metformin ..............................................................................................................12 
2.3 
Rationale for combination therapy and maintenance therapy ................................14 
2.4 
Correlative Studies Background ............................................................................15 
3. 
PATIENT SELECTION ....................................................................................................16 
3.1 
Eligibility Criteria for Pre-Registration  ................................................................16 
3.2 
Exclusion Criteria For Pre-Registration .................................................................16 
3.3 
Eligibility Criteria for Registration ........................................................................17 
3.4 
Exclusion Criteria for Registration ........................................................................19 
4. 
REGISTRATION PROCEDURES ...................................................................................20 
4.1 
General Guidelines .................................................................................................20 
4.2 
Registration Process ...............................................................................................20 
5. 
TREATMENT PLAN ........................................................................................................21 
5.1 
Agent Administration .............................................................................................21 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................26 
5.3 
Duration of Therapy ...............................................................................................26 
5.4 
Duration of Follow Up ...........................................................................................27 
5.5 
Criteria for Unblinding of Study Medication .........................................................27 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................27 
6.1 
General guidelines  ................................................................................................27 
6.2 
Suggested modifications  .......................................................................................28 
6.3 
Metformin Toxicity ................................................................................................30 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................33 
7.1 
Adverse Event Characteristics ...............................................................................33 
7.2 
Adverse Event Definitions .....................................................................................33 
7.3 
Adverse Event Reporting Requirements ................................................................34 
8. 
PHARMACEUTICAL  INFORMATION .........................................................................35 
8.1 
Metformin ..............................................................................................................35 
8.2 
Study Drug Compliance .........................................................................................36 
8.3 
Return and Retention of Study Drug .....................................................................36 
8.4 
Paclitaxel ................................................................................................................37 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................39 

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9.1 
Biomarker Studies ..................................................................................................39 
Laboratory Manual (attachment) ...................................................................................................42 
10. 
STUDY CALENDAR ....................................................... Error! Bookmark not defined. 
11. 
MEASUREMENT OF EFFECT........................................................................................46 
11.2 
Response Parameters .............................................................................................49 
12. 
DATA REPORTING .........................................................................................................52 
13. 
STATISTICAL CONSIDERATIONS...............................................................................52 
13.1 
Study Design/Primary Endpoints and Analysis .....................................................53 
13.2 
Sample Size/Accrual Rate ......................................................................................53 
13.3 
Stratification Factors and Randomization ..............................................................53 
13.4 
Analysis of Secondary Endpoints ..........................................................................54 
13.5 
Reporting and Exclusions ......................................................................................55 
14. 
STUDY MANAGEMENT and regulatory affairs .............................................................55 
14.1 
Multicenter Guidelines ...........................................................................................55 
14.2 
Institutional Review Board (IRB) Approval and Consent .....................................56 
14.3 
Required Documentation .......................................................................................56 
14.4 
Data and Safety Monitoring ...................................................................................56 
14.5 
Auditing .................................................................................................................58 
14.6 
Amendments to the Protocol ..................................................................................59 
14.7 
Annual IRB Renewals, Continuing Review and Final Reports .............................60 
14.8 
Record Retention ...................................................................................................60 
14.9 
Obligations of Study Site Investigators .................................................................60 
REFERENCES ..............................................................................................................................60 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................66 
APPENDIX B 
MULTICENTER GUIDELINES...............................................................67 
 
APPENDIX C 
PILL CALENDAR…………………………………………………........69 
 
 

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1. OBJECTIVES 
 
1.1 
Primary Objective 
 
To determine if the addition of metformin to standard adjuvant or neoadjuvant 
chemotherapy plus extended metformin beyond standard chemotherapy increases 
progression free survival when compared to 6 cycles of standard chemotherapy alone in 
non-diabetic subjects with stage III (with any gross residual disease) or stage IV ovarian, 
primary peritoneal, or fallopian tube carcinoma. 
 
1.2 
Secondary Objectives 
 
To determine whether the addition of metformin to standard chemotherapy plus extended 
metformin beyond standard chemotherapy increases the time to biochemical progression 
when compared to chemotherapy alone 
 
To compare biochemical (CA-125) response rates in the two arms 
 
To describe and compare toxicities in the two arms 
 
To compare overall survival in both arms 
 
1.3 
Exploratory Objectives 
 
To elucidate metformin’s molecular mechanism of action in ovarian, fallopian tube or 
primary peritoneal cancer by: (i) determining whether metformin’s anti-cancer effects are 
mediated by systemic metabolic changes, a direct effect on tumor cells, or both, and (ii) 
testing the metabolic and proteomic alterations induced in biospecimens from non-diabetic 
patients prospectively treated with standard chemotherapy in conjunction with metformin 
compared to placebo. 
 
2. BACKGROUND 
 
2.1 
Standard management of ovarian, fallopian tube and primary 
peritoneal cancer 
 
Currently, the standard treatment for ovarian, fallopian tube and primary peritoneal cancer, 
hereafter referred to as OvCa, consists of aggressive surgery to remove all visible tumor and six 
cycles of a platinum and taxane containing chemotherapy regimen followed by close 
surveillance. Despite initial response rates of over 80%, the majority of women with advanced 
stage disease will suffer a recurrence (1,2). Ultimately, OvCa has the highest fatality to case ratio 
of all the gynecologic malignancies which has stimulated a range of approaches to improve 
outcome. For those patients with stage III disease who have been optimally debulked (surgically 
cytoreduced) to less than 1 cm of residual disease, intraperitoneal chemotherapy has 
demonstrated a significant survival benefit over intravenous chemotherapy with median 

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progression free survival (PFS) of 23.8 months compared to 18.3 months with IV therapy and 
median overall survival (OS) of 65.6 months vs 49.7 months with IV therapy (3). In the 
suboptimally debulked patient population, however, PFS and OS have remained relatively 
constant with the last significant improvement occurring with the addition of paclitaxel to 
platinum based chemotherapy. GOG 111, which incorporated paclitaxel into frontline therapy 
with cisplatin, improved median PFS to 18 months from 12 months and OS to 38 months from 
24 months over a non-paclitaxel containing regimen (4). Despite the investment of significant 
resources, new drug development in OvCa has been slow. Introduction of the last new drug, 
liposomal doxorubicin (Doxil®), occurred 14 years ago. GOG 182/ICON 5 was a randomized 
phase III multi-institutional trial that incorporated liposomal doxorubicin, or gemcitabine as a 
triplet regimen with paclitaxel and carboplatin or topotecan, or gemcitabine as a sequential 
doublet regimen with paclitaxel and carboplatin. This strategy of adding a third cytotoxic agent 
to the backbone of paclitaxel and carboplatin intravenously did not yield an improvement in PFS 
(15.4-16.4 months) or OS (39.6-44.2 months) over paclitaxel and carboplatin alone (5, 6).  In 
addition to adding cytotoxic agents (GOG 182/ICON5), other strategies to augment PFS in 
suboptimally debulked patients have included the use of molecularly targeted agents (GOG 218, 
ICON7)  to frontline therapy.  The addition of bevacizumab, an anti-angiogenic agent, to 
paclitaxel and carboplatin and as maintenance therapy did improve PFS by nearly 3 months in 
GOG 218 but did not change OS (7). Similar results were obtained in the ICON7 study (8).  
Given the cost of bevacizumab, its use in the upfront setting has not been deemed cost effective 
(9). Other strategies in this patient population have included using a dose dense chemotherapy 
approach. The Japanese GOG performed a randomized phase III study in patients with stage II to 
IV disease utilizing weekly paclitaxel at 80 mg/m2 on days 1, 8, and 15 of a 21 day regimen in 
conjunction with carboplatin AUC 6 on day 1 as compared to intravenous paclitaxel and 
carboplatin on day 1 of a 21 day regimen. The long term results for those patients with 1 cm of 
residual disease showed a significant improvement in PFS: 17.6 months with the weekly dose 
dense regimen as compared to 12.1 months with the q 21 day regimen. OS also increased to 51.2 
months from 33.5 months with the dose dense regimen (10). 
 
Standard chemotherapy regimens for OvCa patients include adjuvant paclitaxel and carboplatin 
IV q 21 days and dose dense paclitaxel day 1, 8 and 15 with carboplatin day 1 IV q 21 days. In 
patients with large volume disease, a neoadjuvant chemotherapy approach with 3 cycles of 
paclitaxel and carboplatin IV followed by an interval debulking procedure and another 3 cycles 
has also been deemed equivalent to primary cytoreduction followed by paclitaxel and carboplatin 
IV q 21 days (11).  Elderly patients may experience increased toxicity with standard doses of 
chemotherapy. In a retrospective analysis, reduced doses of chemotherapy appeared to be better 
tolerated in patients over the age of 70 (12). These reduced doses of chemotherapy are currently 
being evaluated for toxicity in GOG 273. Despite an increase in the percentage of patients who 
attain 5 year survivals, patients with stage III and IV disease, particularly those with a large 
initial tumor burden, those with poorer performance status and those who are suboptimally 
debulked, continue to have the worst outcome and new approaches to therapy, that are cost 
effective, warrant investigation.  
 
 
 

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2.2
Metformin
A protective effect of metformin against cancer was initially suggested by observational studies 
describing decreased cancer risk and increased survival among diabetic patients using metformin 
compared to individuals not using metformin (13-15). In a meta-analysis of these studies 
metformin use was associated with a 31% decrease in cancer risk (17). While provocative, these 
retrospective observational studies have inherent limitations (i.e. recall and allocation bias, 
confounding) and the metformin literature has been criticized for time related biases (18). A 
study using Women’s Health Initiative data was able to partly overcome these limitations.  The 
study prospectively collected data on metformin use and using a time-dependent exposure 
analysis, found that diabetic women on metformin had a lower incidence of breast cancer (19). 
Building on the observational studies, several pre-clinical studies have now been published 
indicating that metformin inhibits growth of cancer cell lines (20-22), decreases tumor growth in 
pre-clinical models (23-25), and may increase chemosensitivity when added to chemotherapy in 
breast (25), endometrial (23, 26), and OvCa (22,27-29). Retrospective studies in breast (30) and 
lung cancer (31) have found higher rates of response to neoadjuvant chemotherapy among 
metformin users.  
The University of Chicago and the Mayo Clinic have independently shown in retrospective 
studies that patients with diabetes who use metformin have a significantly better prognosis and 
their tumors are more sensitive to chemotherapy than those who have not used metformin (32, 
33). Moreover, our pre-clinical studies, using OvCa cell lines and mouse models, suggest that 
metformin inhibits tumor growth, alters the interaction between cancer cells and stromal cells in 
the tumor microenvironment, and sensitizes tumor cells to platinum/paclitaxel chemotherapy by 
modifying OvCa cell metabolism (Figure 1). 

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In addition to the retrospective studies that correlate metformin use with improved survival, one 
prospective study is also suggestive of an association with improved recurrence free survival. 
Among diabetic patients on the MIMOSA trial of abagovomab, a murine monoclonal antibody 
directed against CA125, those patients who received metformin had a HR for recurrence free 
survival (RFS) of 0.42 [CI: 0.175-1.002], p=0.05. Median OS had not been met in the metformin 
patients with a HR = 0.295 [CI: 0.109-0.803], p=0.02 compared to diabetic patients not receiving 
metformin (34, 35).   Therefore, the existing body of literature supports the theory that 
metformin has both a protective and therapeutic effect in cancer. 
The mechanisms mediating metformin’s effects are unclear. The vast majority of the pre-clinical 
work has been completed using supra-physiologic doses (mM range) of metformin, leaving the 
true in vivo cancer targets of the diabetes drug largely unknown. The need for higher 
concentrations of metformin to elicit a response in vitro may be partially explained by the 
artificial metabolic environment of mammalian cell culture (high levels of insulin, glucose and 
growth factors). However, a recent study has shown that that when combined with 
chemotherapy, physiologically attainable concentrations (μM range) of metformin reduced 
proliferation and apoptosis) in OvCa cell lines (36).
Our group at the University of Chicago has performed in vitro studies to examine the effect of 
the combination of chemotherapy and metformin on cellular proliferation.  In the resistant cell 
line (IGROV-CP) the addition of metformin to carboplatin increased the cytotoxic effect of 
carboplatin (Fig. 1B). In addition, treatment with paclitaxel plus metformin increased 
cytotoxicity versus paclitaxel alone (data not shown).  These findings were corroborated in vivo 
using the LSL-K-rasG12D/+PtenloxP/loxP genetic mouse model (37) where Kras is activated and Pten 
is deleted in ovarian surface epithelial cells, leading to OvCa (38). Mice treated with carboplatin 
or paclitaxel plus metformin and metformin alone had significantly lower tumor volume than 
control treated mice (Fig. 1C). These preliminary results are consistent with other pre-clinical 
reports in OvCa (27, 28) and breast cancer (25) which demonstrated that metformin increased 
cytotoxicity when added to chemotherapy in vitro and decreased tumor burden in mouse models 
when added to chemotherapy. 
Mechanistic studies of metformin in cancer have focused on the activation of AMPK by the 
tumor suppressor liver kinase b1 (LKB1) and the subsequent inhibition of mTOR (39, 40). 
However, the metabolic effects of metformin are far-reaching and include modifications in 
insulin, glucose, and lipid metabolism through inhibition of the canonical AMPK pathway (41), 
as well as an increasing number of newly recognized unique targets. For example, metformin has 
increased activity in the setting of p53 loss of function (23). Since p53 is involved in mediating 

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14 
the energy-conserving response to AMPK activation, its loss probably heightens metformin-
induced energy stress on cancer cells. Most serous OvCa have mutations in p53 (42) and it 
would seem plausible that metformin might be more active against p53-deficient cells. Another 
unique aspect of cancer cell energetics is that normal cells generate ATP through oxidative 
phosphorylation, while tumors rely on aerobic glycolysis to generate energy (43). In addition, the 
metabolic stress induced by metformin on cells may make them particularly vulnerable to 
chemotherapy. In OvCa, we have found that one reason why OvCa cells metastasize to the 
omentum is the availability of high-energy lipids in omental adipocytes. OvCa cells induce 
lipolysis in adipocytes which then transfer lipids to cancer cells, leading to increased utilization 
of lipids through fatty acid oxidation (44). Given the bioenergetic changes found in cancer cells, 
the fact that almost all serous OvCa have p53 mutations, and the significant metabolic effects of 
metformin, there is a solid biologic rationale to support the possibility that metformin could 
serve as a metabolic therapeutic for the treatment of OvCa.  
 
2.3 
Rationale for combination therapy and maintenance therapy 
 
The observational and retrospective studies in OvCa subjects suggest that those who received 
metformin in conjunction with chemotherapy have an improvement in survival. Presumably, the 
diabetic patients in these retrospective studies also continued metformin after the completion of 
their chemotherapy as well, in essence, receiving “maintenance” metformin. Our in vitro and in 
vivo studies would support the synergistic effect of metformin when administered with 
chemotherapy. This supports the rationale for the use of metformin in conjunction with adjuvant 
or neoadjuvant chemotherapy.  
 
In xenograft models of breast cancer, metformin has been shown to kill cancer stem cells and 
prolong remission (45). More specifically, in OvCa, metformin has been shown to reduce the 
percentage of ALDH+ ovarian cancer stem cells (CSC) both in vitro and in vivo. Metformin, 
even as a single agent, slowed the growth of OvCa CSC in vivo (46). Preliminary results of an 
ongoing randomized phase III trial of maintenance metformin in non-diabetic patients with early 
stage breast cancer have demonstrated expected metabolic effects in the metformin group with 
acceptable tolerance and no adverse metabolic events (47).   In addition to the systemic 
metabolic effects that metformin may have on the OvCa environment, a maintenance strategy 
will address the potential role metformin may play in eradication of CSC and suppression of 
CSC growth. In sum, this clinical trial will lay the groundwork to determine whether metformin 
is an effective cancer therapeutic in patients with OvCa.  
 
In 2018, the SOLO1 study was published, a randomized phase III trial analyzing the use of 
PARP maintenance therapy with olaparib vs placebo as maintenance therapy after completion of 
chemotherapy in those with BRCA germline or somatic mutation carriers. The vast majority of 
patients had germline BRCA mutations. The study showed a significant difference in PFS for 
those who received olaparib. At 41 months median follow-up, the hazard ratio for disease 
progression or death at 3 years was 60% vs 27% (HR 0.30, 95% CI 0.23-0.41, p<0.001). The 
median PFS in the olaparib group was 49.9 months vs 13.8 months in the placebo group (67). 
Use of olaparib maintenance therapy in stage II-IV ovarian, fallopian tube, and primary 

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15 
peritoneal cancer patients who have experienced a complete clinical or partial remission is listed 
as acceptable standard maintenance therapy in the NCCN guidelines version 1.2019 (68).  
 
2.4 
Correlative Studies Background 
 
The goal of the correlative studies in this clinical trial is to begin identifying novel biomarkers 
and molecular mechanisms of metformin in OvCa. Given a patient population that is newly 
diagnosed with advanced stage OvCa, administration of chemotherapy is considered a vital 
component of initial treatment. Metformin/placebo administration in conjunction with 
chemotherapy for primary treatment is a unique approach and will allow for an analysis of 
metformin effect.  Towards this end, biospecimens (tumor sample and fasting serum) will be 
collected during the clinical trial for exploratory biomarker studies. Currently, the precise 
molecular mechanism of action by which metformin exerts its anticancer effects is unclear. It is 
hypothesized that metformin may act directly on cancer cells or its beneficial effects may be a 
result of reduction of systemic insulin and glucose levels.  Mirroring clinical trials of metformin 
in breast cancer (48), the clinical trial correlative studies will focus in these two areas as outlined 
in detail below: 
 
Systemic effects: In diabetes, metformin’s primary effect is reducing gluconeogenesis in 
hepatocytes resulting in reduced systemic glucose levels and ultimately reduction of systemic 
insulin levels.  It is plausible that the systemic effects of metformin mediate its anticancer effects 
since insulin has been shown to be mitogenic and elevated insulin levels are associated with 
worse prognosis (49).  In addition, elevated glucose levels have been associated with increased 
risk and mortality in cancer in general (50) and ovarian cancer specifically (51, 52).   
 
Tumor effects: Novel biomarkers and molecular mechanisms will be discovered using paired pre 
and post-Rx specimens from a prospective clinical trial. In addition to reducing systemic insulin 
and glucose, metformin alters lipid metabolism through the canonical AMPK pathway (53). In 
preliminary studies, we have found that almost all OvCa cell lines tested (8/10) expressed the 
metformin transporter OCT1 and LKB1, and that metformin activates AMPK, a finding also 
reported by others (29). When activated, AMPK inactivates the key regulatory enzyme in lipid 
metabolism, acetyl CoA carboxylase (ACC), leading to decreased fatty acid synthesis (regulated 
by fatty acid synthase, FASN). To determine whether these metformin effects are present in 
OvCa, we completed several experiments with SKOV3ip1 OvCa cells, which express OCT-1. 
Metformin increased inactivated ACC and decreased FASN levels.  To further understand the 
effect of metformin in OVCA, tumor microarrays (TMA) will be constructed using 5x5mm cores 
of tumor samples from participants in the clinical trial.  The TMAs will be stained for metformin 
targets and the level of expression will be compared between treatment arms and correlated with 
clinical outcome. .  In the candidate driven approach described above, we expect that metformin 
targets will be differentially expressed in biospecimens collected before and after metformin 
treatment, and that the primary biological effect of metformin in this setting will be a direct 
effect on signaling pathways in tumors. For an unbiased approach, the OvCa proteome before 
and after chemotherapy/metformin will be quantified in the paired tumor samples using 
quantitative proteomics. This validated and reproducible  proteomic approach will allow us to 
identify novel proteins and pathways that change with chemotherapy alone versus chemotherapy 

Protocol #:UC IRB13-1235 
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with metformin. 
 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria for Pre-Registration (subjects  undergoing neoadjuvant 
chemotherapy who might be candidates for correlative tissue collection substudy 
and are being registered prior to histologic confirmation) 
 
3.1.1 A reasonable suspicion of ovarian cancer by the treating oncologist is required, 
evidenced by abdominal carcinomatosis, omental caking, pleural effusions or ascites 
AND an elevated CA125 > 250 OR CA125:CEA ratio > 25 OR CA125 < 250 with no 
evidence of GI cancer.  
 
3.1.2 Age ≥18 years  
 
3.1.3 ECOG performance status ≤2  
 
3.1.4 Patients must have normal organ and marrow function as defined below (labs within 4 
weeks of preregistration): 
 
 
leukocytes 
≥3,000/mcL 
 
absolute neutrophil count 
≥1,500/mcL 
 
platelets 
≥100,000/mcL 
 
total bilirubin 
≤ upper normal institutional limits (except for patients 
with Gilbert’s Disease who are eligible despite elevated serum bilirubin level) 
 
AST(SGOT)/ALT(SGPT) 
≤2.0 × institutional upper limit of normal 
 
creatinine 
< institutional upper limit of normal (ULN)  
OR 
 
creatinine clearance 
≥60 mL/min/1.73 m2 for patients with creatinine levels 
above institutional normal. 
 
blood glucose  
 
≤ 126 mg/dL fasting or <140 mg/dL nonfasting 
 
3.1.5 Signed written pre-registration informed consent document 
 
 
3.2 
Exclusion Criteria For Pre-Registration 
 
3.2.1 Subjects with known diabetes and those taking metformin, sulfonylureas, 
thiazolidenediones or insulin for any reason. 
 
3.2.2 Patients who are receiving any other investigational agents.  
 
3.2.3 Subjects with comorbidities that would limit their two year survival for reasons other 
than ovarian cancer.  
 

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3.2.4 Concurrent active invasive malignancy or one previously diagnosed with a greater 
than 30% chance of recurrence in the next two years. 
 
3.2.5 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to metformin.  
 
3.2.6 Subjects must not have conditions associated with increased risk of metformin-
associated lactic acidosis, including New York Heart Association Class III or IV 
congestive heart failure, history of acidosis of any type, alcoholic liver disease, or 
habitual intake of 3 or more alcoholic beverages per day. 
 
3.2.7 Uncontrolled intercurrent illness including, but not limited to, ongoing or active major 
infection, unstable angina pectoris, or psychiatric illness/social situations that would 
limit compliance with study requirements. 
 
3.2.8 Pregnant or nursing women are excluded from this study because the safety of 
metformin in pregnancy has not been established. 
 
3.3 
Eligibility Criteria for Registration 
 
    3.3.1    Subjects must have histologically confirmed carcinoma consistent with ovarian,    
fallopian tube, or primary peritoneal carcinoma (any of these three are referred to in 
this protocol as “ovarian cancer (OvCA)” OR a cytological diagnosis of carcinoma. 
The following histologic subtypes are included: serous, endometrioid, undifferentiated, 
clear cell, mixed, transitional, malignant Brenner tumor or adenocarcinoma NOS. 
Subjects eligible for this study may be in one of three surgical categories: 1) status 
post primary debulking surgery 2) undergoing neoadjuvant chemotherapy at a site not 
participating in correlative tissue collection sub study OR 3) undergoing neoadjuvant 
chemotherapy at a site participating in correlative tissue collection sub study.  
 
3.3.2 Subjects undergoing primary debulking surgery must have stage III or IV disease and 
have undergone surgery to include, at a minimum, removal of the uterus, ovaries and 
fallopian tubes. These patients may be optimally debulked (less than 1 cm residual 
disease) but must have grossly visible macroscopic residual disease OR be 
suboptimally debulked.  
 
3.3.3 Subjects for whom neoadjuvant chemotherapy followed by interval cytoreductive 
surgery is planned must have fine needle aspirate (FNA) or other cytology showing 
adenocarcinoma OR core biopsies OR surgically directed biopsies showing 
adenocarcinoma AND CA125 over 250 OR CA125:CEA ratio > 25 OR CA< 250 with 
no evidence of GI cancer. They should have presumed stage III or IV disease, 
generally based on abdominal carcinomatosis, omental caking, pleural effusions or 
ascites.  
 

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18 
3.3.4 The subject and her physician must agree to 6 cycles (a total of up to 8 cycles will be 
allowed) of one of the standard of care regimens allowed on this protocol. These 
regimens (starting dosage) include: 
 
 
< 70 years of age: 
 
 
-R1: IV paclitaxel 175 mg/m2 and carboplatin AUC 5-6 every 21 days  
 
-R2: IV docetaxel 75 mg/m2 and carboplatin AUC 5-6 every 21 days 
-R3: IV paclitaxel 80 mg/m2 day 1, 8, and 15 and carboplatin AUC 5-6 day 1 every 
21 days.  
 
≥70 years of age may (but not required to) choose one of the following alternative regimens: 
 
-R4: IV paclitaxel 135 mg/m2 plus IV carboplatin AUC 5 plus optional G-CSF every 
21 days 
 
-R5: IV paclitaxel 60 mg/m2 day 1, 8, and 15 plus IV carboplatin AUC 5 day 1 every 
21 days (day 15 paclitaxel optional) 
 
-R6: IV paclitaxel 60 mg/m2 plus IV carboplatin AUC 2 day 1, 8, and 15 every 21 
days 
 
Use of granulocyte colony stimulating factor is  permitted, but additional 
chemotherapy agents (e.g. gemcitabine) or biologic agents (e.g. bevacizumab) are not. 
Dose modifications for patients > age 70 are allowable as indicated above.  Patients  
≥ age 70 for whom the physician deems carboplatin AUC 5 to be unsafe may be 
treated with AUC 4. 
 
3.3.5 Age ≥18 years 
 
3.3.6 ECOG performance status ≤2  
 
3.3.7 Patients must have normal organ and marrow function as defined below (labs within 
one week of registration if patient postop, otherwise within two weeks of registration): 
 
 
leukocytes 
≥3,000/mcL 
 
absolute neutrophil count 
≥1,500/mcL 
 
platelets 
≥100,000/mcL 
 
total bilirubin 
≤ upper normal institutional limits (except for patients 
with Gilbert’s Disease who are eligible despite elevated serum bilirubin level) 
 
AST(SGOT)/ALT(SGPT) 
≤2.0 × institutional upper limit of normal 
 
creatinine 
< institutional upper limit of normal (ULN)  
OR 
 
creatinine clearance 
≥60 mL/min/1.73 m2 for patients with creatinine levels 
above institutional normal. 
 
blood glucose  
 
< 126 mg/dL fasting or ≤ 140 mg/dL nonfasting 
 

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19 
 
3.3.8  Women of child-bearing potential must agree to use an effective method of birth control 
on trial, as the safety of metformin in pregnancy has not been established. An effective 
method of birth control includes surgical sterilization of woman or her partner, 
abstinence, or two barrier methods (e.g. condom plus diaphragm); or hormonal methods 
of birth control (oral contraceptives or intrauterine device). 
 
3.3.9   Ability to understand and the willingness to sign a written informed consent document 
 
3.4 
Exclusion Criteria for Registration 
 
3.4.1    Mucinous adenocarcinoma, borderline tumors. 
 
3.4.2    Subjects who will undergo intraperitoneal chemotherapy 
  
3.4.3.   Subjects receiving neoadjuvant chemotherapy for whom interval debulking surgery                    
(assuming adequate response to therapy) is not planned. 
 
3.4.4 Subjects receiving chemotherapy regimens not specified in the inclusion criteria 
 
3.4.5 Subjects should not be participating in other clinical trials of interventions designed to 
reduce risk of ovarian  cancer recurrence or plan to receive off –protocol maintenance 
therapy (e.g. paclitaxel or bevacizumab). Use of olaparib in BRCA genetic mutation 
carriers per FDA approval is allowable. 
 
3.4.6 Subjects with known diabetes, fasting glucose over 126 mg/dL or random glucose over 
140 mg/dL and those taking metformin, sulfonylureas, thiazolidenediones or insulin 
for any reason. Either fasting OR random glucose may be used to determine eligibility. 
 
3.4.7 Patients who are receiving any other investigational agents.  
 
3.4.8 Subjects with comorbidities which would lead to a clinical expectation that they will 
not survive two years for reasons other than ovarian cancer.  
 
3.4.9 Concurrent active invasive malignancy or one previously diagnosed with a greater 
than 30% chance of recurrence in the next two years. 
 
3.4.10 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to metformin.  
 
3.4.11 Subjects must not have conditions associated with increased risk of metformin-
associated lactic acidosis, including New York Heart Association Class III or IV 
congestive heart failure, history of acidosis of any type, alcoholic liver disease, or 
habitual intake of 3 or more alcoholic beverages per day. 
 

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3.4.12 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. 
 
3.4.13 Pregnant or nursing women are excluded from this study because the safety of 
metformin in pregnancy has not been established. 
 
 
4. REGISTRATION PROCEDURES 
 
 
4.1 
General Guidelines 
 
Eligible subjects will be entered on study centrally by the University of Chicago study 
coordinator.  All sites should call the study coordinator at (773) 834-1746 or 
PhaseIICRA@medicine.bsd.uchicago.edu to verify availability of a slot.    
 
For subjects who undergo primary debulking surgery or neoadjuvant chemotherapy not 
on the tissue collection substudy, registration will take place after histologic confirmation 
consistent with OvCa. For subjects undergoing neoadjuvant chemotherapy and the tissue 
collection substudy, pre-registration will be required prior to obtaining baseline research 
samples. Registration will then take place after histologic confirmation of OvCA. 
Following registration, patients should begin randomized protocol treatment within 14 
business days. Study medication does not need to commence exactly on day 1 of 
chemotherapy.  The specific chemotherapy regimen, dosing schedule, and number of 
cycles of chemotherapy will be declared at the time of registration. Issues that would 
cause treatment delays should be discussed with the Principal Investigator.  If a patient 
does not receive protocol therapy following registration but prior to randomization, the 
patient’s registration on the study will be cancelled.  The study coordinator/CRA should 
be notified of cancellations as soon as possible. 
 
4.2 
Registration Process 
 
When a potential patient has been identified, notify the CRA via phone or email to ensure 
registration on the study (773) 834-1746 or PhaseIICRA@medicine.bsd.uchicago.edu. 
Reservations for potential subjects will only be held for subjects who have signed consent 
for that particular study. 
  
When registering a subject, the following must occur:  
 
x Confirm that the institution has current IRB approval of the correct version of 
protocol/consent and has an annual update on file.  
x Submit all required materials (Eligibility Checklist, Source documentation, & signed 
consent form) to confirm eligibility and required pre-study procedures to the CRA a 

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21 
minimum of 48 hours prior to the subject’s scheduled therapy start date or a minimum 
of 24 hours prior to planned biopsy or procedure in the case of pre-registration. 
x Source documentation includes copies of all original documents that support each 
inclusion/exclusion criteria.  The eligibility checklist does not serve as source 
documentation but rather as a checklist that original source documentation exists. 
x Communicate with the above CRA to ensure all necessary supporting source 
documents are received and the potential subject is eligible to start treatment on 
schedule. If there are questions about eligibility, the CRA will discuss it with the PI. 
The PI may clarify, but not overturn, eligibility criteria.  
x Submit specific chemotherapy regimen, dosing schedule, and number of cycles of 
chemotherapy to be administered for the subject 
x Confirm registration of subjects by obtaining a subject study ID number from the 
CRA via phone, fax or email.  
x The date the patient is randomized will be considered the patient’s “OnStudy Date.” 
The patient’s subject ID will be assigned and a confirmation of registration will be 
issued by the CRA on this date. Subjects that sign consent and do not go “OnStudy” 
will be recorded in the database with the date they signed consent and the reason for 
not going “OnStudy” (e.g., Ineligible, Screen Failure or Withdrawn Consent).  
 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
This is a randomized placebo-controlled study. Metformin HCl tablets 850 mg, and placebo 
tablets will be purchased by the Mayo Clinic or the University of Chicago. The University of 
Chicago will coordinate distribution to the site pharmacies. Each bottle provided to subjects by 
the site will be labeled with a protocol number, dosing and storage instructions, and the 
expiration date, when required. The contents of the label will be in accordance with all 
applicable regulatory requirements. 
 
Treatment is expected to be administered on an outpatient basis.  Reported adverse events and 
potential risks are described in Section 7.  Suggested dose modifications are described in Section 
6.  No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
Subjects participating in this trial will fall into one of three categories: 
 
x Patients with a histologic diagnosis of OvCa who have undergone primary debulking 
and will be randomized to standard chemotherapy with metformin or placebo 
followed by metformin or placebo maintenance 
x Patients with a strong suspicion of OvCa who will participate in the correlative tissue 
collection substudy and undergo tissue biopsy prior to neoadjuvant therapy, where 
interval debulking and tissue collection is performed after three cycles of 
chemotherapy. If for any reason, a patient pre-registered turns out not to have ovarian 
cancer, they will not be registered to treatment. If, for any reason, the subject 

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22 
undergoes debulking (e.g. a laparoscopy performed upfront shows disease to be more 
resectable than previously believed) and macroscopic residual disease remains, they 
can be registered to the trial and receive adjuvant therapy. 
x Patients with a histologic or cytologic diagnosis consistent with OvCa who will be 
randomized to undergo neoadjuvant chemotherapy +/- metformin and interval 
debulking followed by metformin or placebo maintenance who will not participate in 
the correlative tissue collection substudy. 
 
At the time of registration, the treating physician will designate which of the following standard 
chemotherapy regimens the patient will receive: 
 
x R1: IV paclitaxel 175 mg/m2 plus IV carboplatin AUC 5-6 every 21 days x 6 
cycles (a total of up to 8 cycles will be allowed) 
x R2: IV docetaxel 75 mg/m2 plus IV carboplatin AUC 5-6  every 21 days x 6 
cycles (a total of up to 8 cycles will be allowed) 
x R3: IV paclitaxel 80 mg/ m2 day 1, 8, and 15 plus IV carboplatin AUC 5-6 day 1 
every 21 days x 6 cycles (a total of up to 8 cycles will be allowed) 
 
Acceptable chemotherapy regimens for elderly patients > age 70 will include any of the above 
AND the following alternative regimens: 
 
x R4: IV paclitaxel 135 mg/m2 plus IV carboplatin AUC 5* plus optional G-CSF 
every 21 days x 6 cycles (a total of up to 8 cycles will be allowed) 
x R5: IV paclitaxel 60 mg/m2 day 1, 8, and 15 plus IV carboplatin AUC 5* day 1 
every 21 days (day 15 paclitaxel optional) x 6 cycles (a total of up to 8 cycles will 
be allowed) 
x R6: IV paclitaxel 60 mg/m2 plus IV carboplatin AUC 2 day 1, 8, and 15 every 21 
days x 6 cycles (a total of up to 8 cycles will be allowed) 
 
Please be advised that the treating physician must declare at the time of registration whether 6 or 
8 cycles will be given. 
 
Please be advised that as soon as the treating physician is aware of a BRCA mutation and plans 
to administer PARP maintenance therapy after completion of chemotherapy, the study team 
should be notified. 
 
 *Patients for whom the physician deems carboplatin AUC 5 to be unsafe may be treated with 
AUC 4. 
 
Throughout this protocol, any of the above chemotherapy regimens will be referred to as 
“standard chemotherapy regimen”. 
 
Subjects will be randomized in a 1:1 ratio to receive one of the following treatments: 
 
Arm 1: Metformin 850 mg po (with food) BID with standard chemotherapy x 6 to 8 cycles 
followed by metformin 850 mg po BID. Metformin will be continued for two calendar years 

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from the date of randomization. 
 
Arm 2: Placebo tablet po (with food) BID with standard chemotherapy x 6 to 8 cycles followed 
by placebo tablet BID. Placebo will be continued for two calendar years from the date of 
randomization.  
 
5.1.1 Methods of Chemotherapy Administration 
 
Note that the following are guidelines. Minor alterations, for example in the duration of infusion, 
premedications, or dose modifications of the standard of care agents are not considered protocol 
deviations.  
 
x Paclitaxel 175 mg/m2 day 1 of a 21 day cycle will be infused IV over 2-3 hours.  
x Paclitaxel 60-80 mg/m2 days 1, 8 and 15 of a 21 day cycle will be infused over 
approximately 1 hour. 
x Patients may switch to docetaxel from a paclitaxel regimen for neuropathy. 
x Docetaxel 75 mg/m2 day 1 of a 21 day cycle will be administered IV over 
approximately 1 hour.  
x Due to the risk of immediate hypersensitivity reaction, paclitaxel should be the 
first drug infused in any combination 
x Carboplatin will be administered as a 30-60 minute infusion, following paclitaxel 
(or docetaxel) administration. 
x All drugs are dosed based on subject’s actual BSA.  BSA is only recalculated if 
there is a +/- 10% weight change (up or down). 
x Dosing of carboplatin: 
 
The carboplatin dose will be calculated to reach a target area under the curve (AUC) of 
concentration x time according to the Calvert formula using an estimated glomerular filtration 
rate (GFR) from the Cockcroft-Gault formula: 
 
Creatinine clearance Cl (ml/min) =  [140-age(years)] x weight (kg) x 0.85 
 
 
 
        72 x serum creatinine (mg/dl) 
 
The initial dose of carboplatin must be calculated using GFR. In the absence of new renal 
obstruction or other renal toxicity greater than or equal to CTC Grade 2 (serum creatinine > 1.5 x 
ULN), the dose of carboplatin will not be recalculated for subsequent cycles, but will be subject 
to dose modification as noted. 
 
In patients with an abnormally low serum creatinine (less than or equal to 0.8 mg/dl), due to 
reduced protein intake and/or low muscle mass, the creatinine clearance should be estimated 
using minimum value of 0.8 mg/dl. If a more appropriate (higher) baseline creatinine value is 
available within 4 weeks of treatment, that value may also be used for the initial estimation of 
GFR. 
 
CALVERT FORMULA: 
 

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24 
Carboplatin dose (mg) = target AUC x (GFR + 25) 
 
Note: the GFR used in the Calvert formula should not exceed 125 ml/min. 
 
Maximum carboplatin dose (mg) = target AUC (mg/ml x min) x 150 ml/min 
 
The maximum allowable doses of carboplatin are: 
 
AUC 6 = 900mg 
AUC 5 = 750 mg 
 
5.1.2 Metformin Administration 
 
USE ONLY STUDY SUPPLY OF METFORMIN 
 
Metformin will be taken with food ideally on day 1 of the standard chemotherapy regimen. 
Subjects will undergo a “ramp up” to protocol dose. A proposed schedule is as follows: 
 
x 1 tablet (850 mg) po daily for one week, then 
x 1 tablet (850 mg)  po bid for 2 years from the date of randomization  
 
A pill calendar (Appendix C) will be provided for each subject. The participating institution’s 
study nurse will make telephone contact with the subject one week after starting 
metformin/placebo. The study nurse will assess compliance and toxicity to ensure that the 
subject increases the medication to twice daily. The major side effects of metformin which limit 
tolerance are gastrointestinal (nausea, abdominal bloating, diarrhea). During the initial study 
period, subjects should be encouraged to take the tablets with food. Pills are not to be crushed or 
split, prior to taking, for any reason. If the subject is unable to increase the study medication 
because of toxicity, the study nurse at the participating institution should make recommendations 
to improve medication tolerance.  This may include encouraging the subject to take the 
medication with food in addition to ramping up slowly by taking the medication every other day 
or once per day for an additional week until a twice per day dose can be tolerated . Breaks are 
allowed to ascertain the cause of unpleasant symptoms. The highest tolerable metformin/placebo 
dose should be recorded and administered for the remainder of the study.  
 
The subject will maintain a pill calendar for each dose of medication.  The pill calendar and pill 
bottles will be returned to the study nurse. A pill count will be performed by the site pharmacist 
in order to calculate milligrams of medication taken.  
 
 
5.1.3 Pre-medication: 
 
 
5.1.3.1 Paclitaxel 
 
For all courses where paclitaxel is to be administered it recommended that a preparative regimen 
be employed one hour prior to the treatment regimen on that day to reduce the risk of 

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25 
hypersensitivity reaction. 
 
This regimen should include standard dose (s) of dexamethasone (either IV or po), an anti-
histamine H1 (diphenhydramine 25-50 mg IV or po, or an equivalent dose of an alternate H1 
blocker such as loratidine or fexofenadine) and a standard dose of anti-histamine H2 IV such as 
cimetidine, ranitidine or famotidine). For those subjects who are at risk for hypersensitivity 
reactions or cannot tolerate the preparative regimen, nab-paclitaxel can be substituted.  
 
 
5.1.3.2 Docetaxel 
 
It is recommended that subjects be premedicated with dexamethasone 8 mg orally taken the night 
before, morning of, and evening after each treatment (total dose, 24 mg/3wk).  
 
5.1.4 Anti-emetic regimens 
 
Nausea and vomiting may be a significant side effect of each regimen. The following 
representative anti-emetic regimens are suggested: 
 
 
x Ondansetron 8-32 mg IV 30 minutes prior to administration of chemotherapy and 
dexamethasone 10-20 mg IV 30 minutes prior to drug administration or 
x Granisetron 10 mcg/kg IV (or 2 mg po) 30 minutes prior to chemotherapy, with or 
without lorazepam 0.5-2.0 mg IV 30 minutes prior to chemotherapy 
 
5.1.5 Surgery 
 
For subjects undergoing primary debulking surgery, standard chemotherapy and study 
medication should be started as soon as reasonable after recovery from surgery but must be 
started within 14 business days of registration. Study medication does not necessarily need to 
commence on day 1 of chemotherapy. 
 
For subjects undergoing neoadjuvant chemotherapy, interval debulking surgery must be 
performed after cycle 3 or 4 of standard chemotherapy as soon as nadir counts permit but within 
6 weeks of completion of cycle 3 or 4. If a subject is unable to undergo interval debulking, they 
do not need to be removed from study, however, the study CRA and PI should be notified.  
Subjects enrolled in the correlative tissue collection substudy who are unable to undergo interval 
debulking should also be reported to the study CRA and PI. FOR PATIENTS ON THE 
TISSUE COLLECTION SUBSTUDY, METFORMIN MUST BE GIVEN ORALLY ON 
THE MORNING OF INTERVAL DEBULKING SURGERY AND THE TIME OF 
MEDICATION ADMINISTRATION AS WELL AS TIME OF TISSUE COLLECTION 
RECORDED. For patients on the correlative tissue collection substudy, at least 5 mm3 of tissue 
must be collected and submitted. The elimination of metformin is rapid with a half-life ranging 
from 1.7 hours to 3 hours. Therefore, in order to assess the effects of metformin on the tissue, 
administration prior to surgery is essential. Please refer to section 9.2 for detailed guidelines on 
serum and tissue collection. 
 

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26 
For patients undergoing interval debulking surgery, metformin should be restarted at the time of 
discharge from the hospital or as soon as the patient is able to restart oral medication. 
 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Metformin has not been demonstrated to inhibit or induce CYP enzymes. However, the 
elimination of metformin is dependent on renal function. Renal dysfunction increases the risk of 
lactic acidosis. This should be considered when subjects are taking ACE inhibitors, loop 
diuretics, non-steroidal anti-inflammatory drugs, cyclosporine, aminoglycosides or receiving IV 
contrast dye. Metformin is a substrate for transporters such as plasma monoamine transporters 
(PMAT), organic cation transporters (OCT) as well as efflux transporters which include the 
multidrug and toxin extrusion antiporters (MATEs). SNPS in genes encoding these transporters 
may affect the pharmacokinetics of metformin. Such medications include pyrimethamine, an 
anti-protozoal agent, which inhibits MATE1 and MATE2-K and OCT-2 at high in vitro 
concentrations. This drug can decrease the clearance of metformin and increase the AUC.    
 
Metformin/placebo should be held if the subject’s creatinine is elevated over the institutional 
normal limit. Medication may resume if the creatinine reaches baseline. The subject’s medication 
list should be reviewed for possible effect on renal function that may increase the toxicity of 
metformin. 
 
If the subject is scheduled for any CT scans requiring intravenous contrast material, 
metformin/placebo should not be taken for 24 hours prior to the investigation nor for 48 hours 
after the procedure. Study medication may be resumed at full dose (without ramp up) provided 
there is no concern about renal function. If there is concern about renal function, creatinine 
should be checked prior to resumption of study medication. 
 
5.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment with metformin or placebo 
as a single agent will continue to complete a total duration of 2 calendar years from the date of 
randomization (approximately 28 “cycles” of single agent metformin/placebo where a cycle is 
counted as three weeks of daily therapy) or until one of the following criteria applies: 
 
x Disease progression, 
 
x Intercurrent illness that prevents further administration of treatment, 
 
x Unacceptable adverse event(s), 
 
x Patient decides to withdraw from the study, or 
 
x General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 

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5.4 
Duration of Follow Up 
 
Subjects will be followed for progression and survival until the last patient randomized on study 
receives a total of 2 years (from date of randomization of that last patient) of metformin/placebo.  
 
 
       5.5      Criteria for Removal from Study 
 
Subjects will be removed from study therapy when any of the criteria listed in Section 5.3 
applies.  The reason for removal from study therapy and the date the patient was removed must 
be documented in the Case Report Form. Patients discontinuing therapy will continue to be 
followed per protocol to ascertain time to progression and secondary outcomes. A patient who 
withdraws consent to be followed must provide the withdrawal of consent in writing. 
 
Subjects in the neoadjuvant chemotherapy cohort who do not undergo interval debulking surgery 
will remain on study. Subjects participating in the correlative tissue collection substudy who 
forego an interval debulking will also remain on study; however, if clinically appropriate, they 
may undergo core biopsies to fulfill the correlative tissue endpoint.  
 
5.5 
Criteria for Unblinding of Study Medication 
 
A subject's attending physician will be unblinded only if the treatment information is critical for 
making immediate therapeutic decisions for the subject (e.g. if withholding the treatment 
information would put the subject at risk of serious adverse events or death). In this case, the 
attending physician should immediately contact the study chair at 773-845-5014. 
  
When a toxicity occurs, the site may request to know the actual treatment received to manage the 
subject. The appropriateness of this request will be determined by the study chair depending 
upon the type and grade of the toxicity and the availability of therapeutic options.   
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
General guidelines for hematologic toxicity - institutional guidelines 
may be used, and failure to follow these guidelines for standard of 
care agents does not constitute a protocol violation 
 
           6.1.1 Treatment decisions will be based on the absolute neutrophil count (ANC) and not 
the total white cell count (WBC). 
 
           6.1.2 Lower limits for ANC and platelet count 
With cytotoxic chemotherapy. Day 1 of a subsequent cycle of cytotoxic chemotherapy will not 
be administered until the ANC> 1000 cells/mcl if growth factor is planned, and 1,500 cells/mcl if 
it is not, and the platelet count is > 100,000/mcl. All cytotoxic treatment will be delayed for a 
maximum of 3 weeks until these values are achieved. METFORMIN/PLACEBO MAY BE 
CONTINUED DURING THIS TIME AS LONG AS THERE ARE NO 
CONTRAINDICATIONS.  
 

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For patients receiving paclitaxel day 1, 8 and 15, the day 8 and day 15 ANC should be > 500 
cells/mcl and the platelet count  > 50,000/mcl to receive paclitaxel. If not given, these doses are 
eliminated and not made up. 
 
6.1.3 Use of hematopoietic cytokines and protective agents 
 
It is anticipated that myelosuppression may be a side effect of each regimen. Myeloid growth 
factors (either filgrastim or pegfilgrastim) can be used utilizing NCCN and/or ASCO guidelines 
as a reference. If myeloid growth factors are used, it is recommended that filgrastim (dose as per 
institutional standard) be administered subcutaneously daily starting 24-72 hours after the last 
dose of chemotherapy and continuing through hematopoietic recovery or pegfilgrastim will be 
administered at 6 mg subcutaneously (one dose per treatment cycle) 24 to 72 hours after the last 
dose of chemotherapy. Administration of growth factors on the same day as chemotherapy is not 
recommended. Pegfilgrastim is not recommended for chemotherapy regimens given less than 
every 2 weeks. 
 
6.1.4  Patients will not receive prophylactic thrombopoeitic agents or erythropoietin 
stimulating agents. 
 
6.2 
Suggested modifications for hematologic toxicities - institutional 
guidelines may be used, and failure to follow these modifications for 
standard chemotherapy agents does not constitute a protocol violation 
 
 
6.2.1. Dose limiting neutropenia (DLT-ANC) is defined by the development of febrile 
neutropenia, prolonged grade 4 neutropenia lasting > 7 days, delay of treatment 
for more than 7 days because of neutropenia, ANC < 1,000 cells/mcl on day 1, or 
omission of day 8 or day 15 on a  weekly paclitaxel regimen because of 
neutropenia. Febrile neutropenia is defined within the CTC AE as a disorder 
characterized by an ANC < 1,000 cells/mcl and a single temperature of > 38.3 
degrees C (101 degrees F) or a sustained temperature of > 38 degrees C (100.4 
degrees F) for more than one hour. 
 
6.2.2. Dose limiting thrombocytopenia (DLT-PLT) is defined by any occurrence of 
grade 4 thrombocytopenia (< 25,000/mcl) or bleeding associated with grade 3 
thrombocytopenia (< 25,000 to <50,000/mcl), delay of treatment on day 1 of a 
cycle by more than 7 days because of thrombocytopenia, platelet count of < 
100,000/mcl on day 1, or inability to give day 8 or day 15 paclitaxel due to 
thrombocytopenia. There will be no modifications for uncomplicated grade 3 
thrombocytopenia except as listed above. 
 
 
 
 
 
 

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Table A. Modification Instructions for Dose Limiting Hematologic Toxicity-every 3 week regimen 
DLT-ANC 
DLT-PLT 
First Occurrence 
Second 
Occurrence 
Third Occurrence 
Yes 
No 
Reduce 
carboplatin by 
one AUC unit 
(and docetaxel 
by 10 mg/m2 if 
subject is on 
docetaxel) 
Add G-CSF* and 
maintain all 
current drug 
doses 
Reduce 
paclitaxel dose 
by 50 mg/m2 vs 
change 
scheduling vs 
discontinue 
cytotoxic 
chemotherapy** 
Yes 
Yes 
Reduce 
carboplatin by 
one AUC unit 
(and docetaxel 
by 10 mg/m2 if 
subject is on 
docetaxel) 
Add G-CSF* and 
reduce 
carboplatin by 
one AUC unit 
(and docetaxel 
by 10 mg/m2 if 
subject is on 
docetaxel) 
Reduce 
paclitaxel dose 
by 50 mg/m2 vs 
change 
scheduling vs 
discontinue  
cytotoxic 
chemotherapy** 
No 
Yes 
Reduce 
carboplatin by 
one AUC unit 
(and docetaxel 
by 10 mg/m2 if 
subject is on 
docetaxel) 
Reduce 
carboplatin by 
one AUC unit 
(and docetaxel 
by 10 mg/m2 if 
subject is on 
docetaxel) 
Reduce 
paclitaxel dose 
by 50 mg/m2 vs 
change 
scheduling vs 
discontinue  
cytotoxic 
chemotherapy** 
 
* See section 6.1.3 
** Specific management of cytotoxic chemotherapy dosing is left to the discretion of the 
investigator. 
 
 
 
 
 
 
 
 
 
 
 

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Table B: Modification Instructions for Dose Limiting Hematologic Toxicity-weekly regimen 
DLT-ANC 
DLT-PLT 
First Occurrence 
Second 
Occurrence 
Third Occurrence 
Yes 
No 
Reduce 
carboplatin by 
one AUC unit 
(and docetaxel 
by 10 mg/m2 if 
subject is on 
docetaxel) 
Omit day 15 
paclitaxel and 
administer G-
CSF after day 8 
paclitaxel  
Reduce 
carboplatin by 
one AUC unit 
and give G-CSF 
after day 8 
paclitaxel.** 
Yes 
Yes 
Reduce 
carboplatin by 
one AUC unit 
(and docetaxel 
by 10 mg/m2 if 
subject is on 
docetaxel) 
Omit day 15 
paclitaxel and 
administer G-
CSF after day 8 
paclitaxel and 
reduce 
carboplatin by 
one AUC unit 
Reduce day 1 
paclitaxel dose** 
No 
Yes 
Reduce 
carboplatin by 
one AUC unit  
Reduce 
carboplatin by 
one AUC unit 
Discontinue 
cytotoxic 
chemotherapy** 
 
** Specific management of cytotoxic chemotherapy dosing is left to the discretion of the 
investigator. 
 
6.3 
Metformin Toxicity 
 
      The major side effects of metformin which limit tolerance are gastrointestinal (nausea, 
abdominal bloating, diarrhea). During the ramp up period, subjects should be encouraged to take 
the tablets with food. Subjects should have less than or equal to grade 1 GI toxicity attributable 
to metformin in order to dose escalate. The dose escalation process is left to the treating 
physician. In most cases, if the medication dosing is increased slowly, it is tolerable. Possible 
modifications to ensure compliance include taking the medication every other day or once per 
day for an additional week until a twice per day dose can be tolerated. Because some of the GI 
side effects may be attributable to the cytotoxic chemotherapy, breaks of up to 2 weeks 
consecutively, are allowable to ascertain the cause of unpleasant symptoms which should subside 
after the first week if attributable to the chemotherapy. The highest tolerable dose of 
metformin/placebo should be administered and recorded on the pill calendar. Subjects will stay 
on study at the highest tolerable dose. Supportive care with anti-emetics should be provided. If 
the subject is unable to tolerate any dose of metformin in conjunction with chemotherapy, they 
will stay on study and may attempt to start metformin during the maintenance phase after 
completion of chemotherapy. 

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Nausea/Vomiting/Distention/ 
Bloating/Diarrhea 
Gastrointestinal-Other 
Management/Next Dose for 
Metformin 
Investigator Action 
≤ Grade 1 
No change in dose 
Subject should be encouraged 
to remain on full dose and 
take medication with food. 
Supportive care should be 
encouraged with anti-emetics 
and/or anti-diarrheal 
medications.  
 
 
Grade 2 (or higher) 
Hold until ≤ Grade 1.   
 
Dose should be adjusted to 
maintain < grade 1 symptoms 
If symptoms are present in 
week 1 of the 21 day cycle 
and may be attributable to the 
chemotherapy, hold 
metformin/placebo for 2 
weeks, then resume dose at 1 
tablet per day and increase as 
tolerated.  
 
Dose adjustment for 
subsequent cycles is left to 
the treating physician to 
maintain symptoms < grade 
1.  
 
For persistent grade > 3 
report as AE 
  
 
Recommended management:  anti-emetics 
Loperamide 4 mg at first onset, followed by 2 mg with each loose movement until diarrhea-free 
for 12 hours (maximum dosage 16 mg/24 hours). Adjunct anti-diarrheal therapy is permitted 
and should be recorded when used.  
 
 
 
 
 
 
 

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Event 
Grade 
Investigator Action 
Hepatic dysfunction: 
AST or ALT > 3.0X 
ULN 
Consult CTC AE for precise 
grading 
Continue study medication. Study 
medication is not associated with 
liver toxicity or exacerbation of 
liver toxicity.  
 
Renal dysfunction 
 
Creatinine >  
institutional ULN  
Please consult your institution’s 
ULN and CTC AE for precise 
grading 
Hold study drug for creatinine > 
institutional ULN 
If elevated creatinine is due to 
reversible process (i.e. 
dehydration, treatable infection), 
investigator may resume 
metformin when creatinine is 
within institutional normal limit. 
Acidosis (Lactate > 
5.0 mM) (pH< 7.3) 
Grade 3 
Stop study drug and do not re-start. 
 
Report as a serious adverse event.  
Skin reactions 
 
Major-generalized 
urticarial, bullous 
rashes, exfoliative 
dermatitis 
Generalized 
Stop study drug and do not restart 
Steven Johnson 
Syndrome 
Localized 
If the rash is thought to be 
possibly, probably or definitely 
related to study medication, 
discontinue the study medication. 
Hospitalization for 
any reason 
As per grade of event causing 
hospitalization 
If hospitalization is possibly, 
probably or definitely related to 
study medication, hold study drug 
for up to 4 weeks. The investigator 
will determine when it is safe to re-
start. If hospitalization is not 
related to study medication, the 
investigator may continue the 
study medication. 
 
Hospitalization > 24 hrs, report as 
SAE 
 
 
 

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7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. An adverse 
event is defined as any untoward medical event in a subject enrolled in a clinical trial.  The event 
does not necessarily have a causal relationship with the study agent. The investigator is 
responsible for ensuring that any adverse events observed by the investigator or reported by the 
subject are recorded in the subject’s medical record.   
 
7.1 
Adverse Event Characteristics  
 
x CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0.  A copy of the CTCAE 
version 4.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
x Special AE expedited reporting:   
AEs for metformin should undergo expedited reporting if they include lactic acidosis 
or signs of metformin overdose (grade >3 nausea, vomiting, abdominal pain, malaise, 
myalgia, mental status change, renal insufficiency, cardiovascular compromise, 
hypoglycemia or hyperglycemia). 
 
x Attribution of the AE: 
- 
Definite (5) – The AE is clearly related to the study treatment. 
- 
Probable (4) – The AE is likely related to the study treatment. 
- 
Possible (3) – The AE may be related to the study treatment. 
- 
Unlikely (2) – The AE is doubtfully related to the study treatment. 
- 
Unrelated (1) – The AE is clearly NOT related to the study treatment.  
 
7.2 
Adverse Event Definitions 
 
7.2.1 Adverse Event 
 
An adverse event is an unexpected medical problem that happens during treatment with a 
drug or other therapy. Adverse events do not have to be caused by the drug or therapy, 
and they may be mild, moderate, or severe. 
 
7.2.2 Serious Adverse Events 
 
An adverse event is considered serious if it results in ANY of the following outcomes:  
 
1) Death 

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2) Life-threatening (e.g. places subject at immediate risk of death, this does not 
include events that might have caused death if they occurred a greater severity) 
3) Results in inpatient hospitalization or prolongation of existing hospitalization for 
≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions  
5) A congenital anomaly/birth defect.  
 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon 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. 
 
7.2.3 Unexpected Events 
 
Unexpected events are those not listed at the observed specificity or severity in the 
protocol, informed consent, investigator brochure, or FDA-approved package insert.  An 
event is considered unexpected if it is listed as occurring within the class of drugs or 
otherwise expected from the drug’s pharmacological properties but which has not been 
previously observed with this specific investigational agent. 
 
7.3 
Adverse Event Reporting Requirements 
 
7.3.1 Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
using the Serious Adverse Event Reporting Form discussed below must also be 
reported in routine study data submissions. 
 
7.3.2 Serious Adverse Event Reporting to the Coordinating Center 
 
Use the UCCCC protocol number and the protocol-specific patient ID assigned during 
trial registration on all reports. 
 
All serious adverse events and all adverse events that have been specified to require 
expedited reporting in section 7.1 occurring on this study require expedited reporting to 
the University of Chicago Comprehensive Cancer Center (UCCCC) Clinical Trials Office 
(CCTO).  The responsible Research Nurse or other designated individual at the treating 
site should report the SAE to the CCTO by the end of the business day when s/he 
becomes aware of the event.  Events occurring after business hours should be reported to 
the CCTO by 12pm (noon) the next business day.  Reports should be made using the 
eVelos database ‘Serious Event Report’ Form.  
 
All serious adverse events should also be reported to the local IRB of record according to 
their policies and procedures.   
 

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7.3.3 Serious and Unexpected Adverse Event reporting by the Coordinating Center 
 
The designated UCCCC Regulatory Manager will notify all participating sites of all 
serious and all unexpected as well as both serious and unexpected adverse reactions that 
occur on this clinical trial and which are reported to the UC Institutional Review Board 
(IRB).   
 
 
8. PHARMACEUTICAL  INFORMATION 
 
8.1 
Metformin 
 
Chemical Name: N,N-dimethyl biguanide hydrochloride 
 
How Supplied: Metformin 850 mg or placebo will be supplied as white to off-white tablets 
 
Stability: 2 year expiration 
 
Storage: Store at room temperature (15º to 30ºC) in well-closed containers 
 
Route of administration: orally, with food 
 
Mechanism of action: Metformin HCL is a biguanide derivative producing an antihyperglycemic 
effect only when there is insulin secretion. It has no effects on the pancreatic beta cells. The 
mode of action is not fully understood. It has been postulated that metformin may potentiate the 
effect of insulin or reduce hepatic gluconeogenesis.  
 
Pharmacokinetics. Metformin absorption is relatively slow and may extend over about 6 hours. 
The drug is excreted in urine at high renal clearance at about 450 mL/min. The initial elimination 
is rapid with a half-life varying between 1.7 and 3 hours. The terminal elimination phase, which 
accounts for about 4 to 5% of the absorbed dose is slow, with a half-life between 9 and 1 hours. 
Metformin is not metabolized. Its main sites of concentration are the intestinal mucosa and the 
salivary glands. The plasma concentration at steady-state ranges about 1-2 mcg/mL. 
 
Certain drugs may potentiate the effect of metformin HCl, particularly sulfonylurea type of drugs 
in the treatment of diabetes. Co-administration of metformin and sulfonylurea antidiabetic drugs 
could produce a hypoglycemic reaction if they are given in patients already receiving other drugs 
which, themselves, can potentiate the effects of sulfonylureas. Examples of these drugs include: 
long-acting sulfonamides, tubercolostatics, phenylbutazone, clofibrate, monoamine oxidase 
inhibitors, salicylates, probenicid and propranolol. Metformin is negligibly bound to plasma 
proteins. 
 
Adverse Effects: Lactic acidosis (estimated incidence 3 cases/100,000 patient years, fatal in 50% 
of cases), gastrointestinal toxicities (> 1/10 diarrhea, nausea, vomiting, abdominal bloating, 
flatulence, anorexia, metallic taste), rash (<1/10,000, subnormal vitamin B12 (9% after 6 

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36 
months), hepatic dysfunction (<1/10,000), elevations in TSH (<1/10,000). Modest weight loss 
(up to five pounds) is common. Hypoglycemia does not normally occur when metformin is 
administered although extreme caloric restriction or excessive physical activity without adequate 
caloric intake may rarely lead to hypoglycemia. 
 
8.2 
Study Drug Compliance 
 
Subjects should be given clear instruction about how to take their study medication. Patients will 
self-administer the medication. A pill calendar (Appendix C) will be given to the patient upon 
registration in the study. The calendar will be kept in the subject’s institutional research chart and 
submitted to the study CRA at regular intervals.  The patient will return their study medication 
bottles at their regularly scheduled visit, when new bottles will be dispensed. At regular 
intervals, the bottles will be returned to the site pharmacy for a pill count. After completion of 
standard chemotherapy, the pill calendar and pill bottles can be collected at every 3 month visits. 
Subjects should make a notation of missed medication doses on the pill calendar. Subjects must 
return all containers and any remaining tablets at the end of the study. 
 
8.3 
Return and Retention of Study Drug 
 
Sponsor:  
University of Chicago 
5815 S. Maryland Ave.  
Chicago IL, 60637 
   
Return and retention of study drug used will be kept in a locked limited access room. 
Accountability records for the study drug will be maintained and readily available for inspections 
by regulatory authorities at any time. All study supplies and associated documentation will be 
regularly reviewed and verified. An Investigational Drug Accountability Log will be used for 
drug accountability. For accurate accountability, the following information will be noted when 
drug supplies are used during the study: 
 
1. Study identification number  
2. Patient identification number 
3. Lot number(s) dispensed for that patient 
4. Date and quantity of drug dispensed 
5. Any unused drug returned by the patient 
 
Before disposal/destruction, final drug accountability and reconciliation of empty and partially 
used drug must be performed. Drug will be destroyed at the study site in accordance with the 
Investigational Drug Services Standard Operating Procedures and/or Destruction of 
Investigational Medications Policy.  Only sites that cannot destroy unused drug on-site will be 
required to return their unused supply of investigational product to the sponsor site for 
destruction. 
 
 
 
 

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8.4 
Paclitaxel (NSC #673089) 
 
Formulation: Paclitaxel is supplied as a 6 mg/mL, non-aqueous solution in multi-dose vials 
containing 30 mg/5mL, 100 mg/16.7 mL, or 300 mg/50 mL of paclitaxel. In addition to 6 mg of 
paclitaxel, each mL of sterile non-pyrogenic solution contains 27 mg of purified 
Cremaphor®EL (polyoxyethylated castor oil) and 49.7% (v/v) dehydrated alcohol, USP. 
 
Storage: Unopened vials of paclitaxel are stable to the date indicated on the package when stored 
between 20 to 250 C (68 to 770 F). Protect from light. 
 
Preparation: Paclitaxel must be diluted prior to infusion. Paclitaxel should be diluted in 0.9% 
Sodium Chloride for Injection, USP;5% Dextrose Injection, USP; 5% Dextrose and 0.9% 
Sodium Chloride Injection, USP; or 5% dextrose in Ringer’s Injection to a final concentration of 
0.3 to 1.2 mg/mL. The solutions are physically and chemically stable for up to 27 hours at 
ambient temperature (approximately 250 C/770 F) and room lighting conditions. 
 
NOTE: In order to minimize patient exposure to the plasticizer DEHP, which may be leached 
from PVC infusion bags or sets, diluted paclitaxel solutions should be stored in bottles (glass, 
polypropylene) or plastic (Polypropylene, polyolefin) bags and administered through 
polyethylene-lined administration sets. 
 
Paclitaxel should be administered through an inline filter with a microporous membrane not 
greater than 0.22 microns. Use of filter devices such as IVEX-2® or IVEX-HP®, which 
incorporate short inlet and outlet PVC-coated tubing, has not resulted in significant leaching of 
DEHP. 
 
All patients should be premedicated with corticosteroids, diphenhydramine, and H2 antagonists 
prior to paclitaxel administration in order to prevent severe hypersensitivity reactions. Patients 
who experience severe hypersensitivity reactions to paclitaxel should not be re-challenged with 
the drug. 
 
Adverse Effects: Consult the package insert for the most current and complete information. 
 
Supplier: Commercially available both from Bristol-Myers Squibb Oncology as well as generic 
manufacturers. Consult the American Hospital Formulary Service Drug Information guide, Facts 
and Comparisons, or the package insert for additional information. 
 
8.5  Docetaxel (Taxotere® RP-56976, NSC #628503) 
 
Formulation: Docetaxel is supplied as a sterile, non-pyrogenic, non-aqueous viscous solution in 
single dose vials containing 20 mg/0.5 mL or 80 mg/2 mL of docetaxel. Each mL contains 40mg 
docetaxel (anhydrous) and 1040mg polysorbate 80. 
 
Docetaxel requires dilution prior to use. A sterile, non-pyrogenic single dose diluent is supplied 
for this purpose. The diluent for docetaxel contains 13% (w/w) ethanol in water for injection and 
is supplied in vials. 

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38 
 
Storage: Unopened vials of docetaxel are stable to the date indicated on the package when stored 
between 2 and 250 C (36 and 770F). Protect from light. 
 
Preparation: Docetaxel must be combined with its supplied diluent (final concentration = 
10mg/mL) and then further diluted prior to infusion. Docetaxel should be diluted in 0.9% 
Sodium Chloride for Injection, USP or 5% Dextrose Injection, USP to produce a final 
concentration of 0.3 to 0.74 mg/mL. The fully prepared docetaxel infusion solution should be 
used within 4 hours (including the infusion duration). 
 
NOTE: In order to minimize patient exposure to the plasticizer DEHP, which may be leached 
from PVC infusion bags or sets, the final docetaxel dilution for infusion should be stored in 
bottles (glass, polypropylene) or plastic (polypropylene, polyolefin) bags and administered 
through polyethylene-lined administration sets.  
 
All patients should be premedicated with oral corticosteroids for 3 days starting 1 day prior to 
docetaxel administration in order to reduce the incidence and severity of fluid retention as well 
as the severity of hypersensitivity reactions.  
 
Adverse Effects: Consult the package insert for the most current and complete information. 
 
Supplier: Commercially available from Aventis. Consult the American Hospital Formulary 
Service Drug Information guide, Facts and Comparisons, or the package insert for additional 
information. 
 
8.6 Carboplatin (Paraplatin® - NSC #241240) 
 
Formulation: Carboplatin is supplied as a sterile, pyrogen-free, 10 mg/mL aqueous solution in 
multi-dose vials containing 50 mg/5 mL, 150 mg/15mL, 450 mg/45mL, or 600mg/60mL of 
carboplatin. 
 
Storage: Unopened vials of carboplatin are stable to the date indicated on the package when 
stored at 250C (770F). Excursion from 15 to 300C (59 to 860 F) are permitted. Protect from light. 
Carboplatin multi-dose vials maintain microbial, chemical, and physical stability for up to 14 
days at 250C following multiple needle entries. 
 
Preparation: Carboplatin aqueous solution can be further diluted to concentrations as low as 0.5 
mg/mL with 5% Dextrose in Water or 0.9% Sodium Chloride for Injection, USP. When prepared 
as directed, carboplatin aqueous solutions are stable for 8 hours at room temperature 
(250C/770F). Since no antibacterial preservative is contained in the formulation, it is 
recommended that carboplatin solution be discarded 8 hours after dilution. 
 
Calvert Formula for Carboplatin (AUC) Dosing  
 
Total dose (mg)=target AUC (in mg/mL/minute)*[GFR(in mL/minute)+25] 
 

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39 
NOTE: Aluminum reacts with carboplatin causing precipitate formation and loss of potency; 
therefore, needles or intravenous sets containing aluminum parts that may come in contact with 
the drug must NOT be used for the preparation or administration of carboplatin. 
 
Adverse Effects: Consult the package insert for the most current and complete information. 
 
Supplier: Commercially available both from Bristol-Myers Squibb as well as generic 
manufacturers. Consult the American Hospital Formulary Service Drug Information guide, Facts 
and Comparisons, or the package insert for additional information. 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
 
9.1 
Biomarker Studies 
 
The goal of the correlative studies in this clinical trial is to begin identifying novel biomarkers 
and molecular mechanisms of metformin in OvCa. Towards this end, bio specimens (tumor 
sample and fasting serum) will be collected during the clinical trial for exploratory biomarker 
studies. Currently, the precise molecular mechanism of action by which metformin exerts its 
anticancer effects is unclear. It is hypothesized that metformin may act directly on cancer cells or 
its beneficial effects may be a result of reduction of systemic insulin and glucose levels.  
Mirroring clinical trials of metformin in breast cancer (48), the clinical trial correlative studies 
will focus in these two areas as outlined in detail below: 
 
For a comprehensive evaluation of metformin’s effects in OvCa, the correlative studies will be 
completed in three types of biospecimens (Figure 2): 
x Longitudinally collected serum samples. Longitudinal collection will allow for assessment of 
metformin’s effects on key signaling pathways over time. 
x Tumor collected from subjects prior to treatment with metformin or placebo.  Analysis of 
basal expression of metformin targets in these samples and correlation with therapeutic 
response may identify potential predictive biomarkers for use in future phase III trials.  
x Paired tumor and serum specimens (specimen #1: treatment naïve and specimen #2: 
chemotherapy±metformin).  Profiling of paired samples will give us a unique opportunity to 
identify changes in molecular markers induced by metformin use, an approach that will help 
clarify the molecular mechanisms of action of metformin in OvCa. 
 
 
 
 
 
 
 
 
 
 

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40
Figure 2
To test metformin’s systemic effects in OVCA the following assays will be performed and 
results correlated with clinical outcomes:
x
Insulin: will be measured using chemiluminescent immunoassay on a Siemens 
Immulite 2000.
x
C- reactive protein: will be measured using chemiluminescent immunoassay 
on a Siemens Immulite 2000.
x
Glucose: will be measured using the yellow springs instrument 2300
x
HOMA score: To quantify insulin resistance, homeostatic model assessment 
(HOMA) scores (fasting insulin P/ml X fasting glucose (mmol/22.5)) will be 
calculated.
These analyses will be completed in the University of Chicago Clinical Resource Center core 
laboratories and Diabetes Research Training Center Laboratories at University of Chicago.  All 
methods for serum measurements have been widely used and are accepted methods in clinical 
trials. The facility is very experienced in these methodologies and has been operational for 40 
years.

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Tumor effects: To further understand the effect of metformin on the tumor,  OVCA tumor 
microarrays (TMA) will be constructed using 5x5mm cores of tumor samples from participants 
in the tissue collection substudy of the clinical trial.  The TMAs will be stained for the following 
metformin targets and the level of expression will be correlated with clinical outcomes: 
x AMPK: One of metformin’s primary molecular effects is activation of AMPK 
signaling. AMPK maintains cellular energy balance by activating ATP 
producing processes and inhibiting pathways that consume ATP. 
x ACC: Through canonical AMPK signaling, one primary cellular target of 
metformin is lipid metabolism.  Metformin inhibits acetyl CoA carboxylase 
(ACC) activity, the key regulatory enzyme in fatty acid synthesis which 
catalyzes the irreversible conversion of acetyl-CoA to malonyl-CoA. 
x P70S6K: Also, through canonical AMPK signaling, metformin inhibits 
protein synthesis by inhibiting mammalian target of rapamycin (mTOR) 
signaling. P70S6K is a downstream target of mTOR which is involved in 
translation of mRNA. 
x FASN: Metformin inhibits fatty acid synthase, a key enzyme involved in fatty 
acid synthesis.  Increased FASN expression has been correlated with 
decreased OvCa survival (54). 
x IGF 1 and 2: Insulin like growth factors (IGF) are components of insulin 
signaling and have been associated with ovarian cancer prognosis (55, 56). 
x Ki67: Since one of metformin’s known actions impacts proliferation, tumor 
TMAs will be stained for Ki-67. 
x TUNEL: Metformin’s effect on apoptosis will be characterized by measuring 
Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). 
 
IHC staining of TMAs will be done by the University of Chicago Pathology core facility. Protein 
expression will be quantified on the stained slide using automated imaging with the Aperio 
Image Scope and software using algorithms to specifically identify tumor and surrounding 
stroma (57) and verified by pathologists at the University of Chicago. 
 
One of metformin’s primary targets is protein synthesis as a result of activation of AMPK and 
subsequent inhibition of mTOR (53). Therefore, for an unbiased approach we will also 
interrogate metformin’s effect on the OvCa proteome. The OvCa proteome in the paired tumor 
samples from the neoadjuvant cohort will be profiled before and after chemotherapy/metformin.  
This will be done using quantitative proteomics in collaboration with the Max-Planck Institute. 
 
Given the limited sample size in a phase 2 clinical trial, it is also possible that none of the targets 
measured will be differentially expressed in the biospecimens. Therefore, our approach is to use 
both candidate driven analysis of samples and unbiased methodologies (proteomics) to generate 
a focused list of potential markers for future testing in large prospective clinical trials. Given the 
exploratory status of biomarker development for metformin in cancer, we have made every effort 
to minimize risk to patients in biospecimen collection. Specifically, fasting serum and tumor 

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42 
sample collection will be timed to correspond with routine clinical care. Subjects enrolled in the 
trial will not undergo any additional biopsies, surgeries, or blood draws outside of those 
indicated for routine ovarian cancer treatment and monitoring. 
 
 
9.2 
Laboratory Correlative Studies 
 
PLEASE SEE LABORATORY MANUAL FOR HANDLING OF SPECIMENS AND 
COLLECTION OF BLOOD SAMPLES 
 
 
9.3 
 Special Studies 
 
9.3.1 Special Correlative Study #1- proteomic profiling on paired tumor samples 
9.3.1.1 
To understand the global effect of metformin plus chemotherapy on OvCa we will 
perform proteomic profiling of tumors from the neoadjuvant cohort before and after 
treatment.  This analysis will be done using frozen tumor samples collected at time – 
T0 and T2. 
9.3.1.2 
Assessment 
9.3.1.2.1 
Method of Assessment: quantitative mass spectrometry (MS) using an 
easy nano-flow HPLC to perform high-resolution shot-gun proteomics 
 
9.3.1.2.2 
Timing of Assessment: Profiling will be performed on paired tumor 
samples collected before and after neoadjuvant chemotherapy plus 
metformin or placebo. 
 
9.3.1.3 
Data Recording 
 
9.3.1.3.1 
Method of Recording: Only anonymized patient samples will be sent for 
proteomic analysis.  The proteomic profile for each sample will be 
recorded electronically identified by study ID number. 
9.3.1.3.2 TIMING OF RECORDING: ALL PROTEOMIC ANALYSIS WILL BE DONE 
AFTER THE FINAL PATIENT IN THE NEOADJUVANT COHORT UNDERGOES 
CYTOREDUCTIVE SURGERY. 
 
 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 2 weeks prior to start of protocol therapy.  Scans 
and x-rays must be done <6 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. Figure 3 illustrates timing of tests and studies. Duration of 
study treatment is defined at 2 years from time of randomization. Duration of study will 
include standard clinical follow-up until patient progresses. 
Primary debulking 
surgery 
Pre-
treatment 
During cytotoxic 
chemotherapy and 
metformin/placebo 
treatment 
Following cytotoxic chemotherapy , during 
metformin/placebo study treatment 
Post-study 
treatment 

Protocol #:UC IRB13-1235 
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43 
 
  
a:  
Includes assessment of compliance (medication diary) 
 
b: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT 
[AST], SGPT [ALT], sodium.  
c:      Laboratory values within 14 days of initial protocol treatment. Obtain CT chest, abdomen, pelvis OR chest x-ray with MRI or CT abdomen, 
pelvis after primary debulking surgery to establish a post-surgical baseline for the extent of residual disease. This should be obtained within  
4 weeks of registration. 
d:      Serum pregnancy test (women of childbearing potential). 
Observations and 
Tests 
Prior to 
initial 
study 
treatment 
Wk 
1-3 
Wk 
4 
Prior to 
each 
course 
(Course 
1-6 (up 
to  8)) 
Prior to 
initial 
course 
Every 3 
months 
Month 6 
Post-therapy 
monitoring 
every 6 
months 
Every 4-6 months 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
X 
 
X 
X 
Survival status 
 
 
 
X 
X 
X 
 
X 
X 
Concurrent meds 
X 
X 
X 
X----------------------------------------------------------------------- 
 
Physical exam 
Xa 
 
 
X 
X 
X 
 
X 
X 
Blood pressure, 
pulse, temperature 
X 
 
 
X 
X 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
X 
X 
X 
 
X 
 
Performance status 
X 
 
 
X 
X 
X 
 
X 
 
CBC w/diff, plts 
Xc 
 
 
Xg 
 
 
 
 
 
Serum chemistryb 
Xc 
 
 
Xg 
 
 
 
 
 
Toxicity assessment 
X 
 
   Xf 
       X 
       X 
      X 
 
           
 
Tumor 
measurements 
X 
 
 
 
       X 
 
 
                
 
Radiologic 
evaluation 
Xc 
 
 
Radiologic measurements should be performed at 6 
months after the completion of 6 cycles of 
chemotherapy, then every 6 months for the duration of 
the study treatment.i 
 
B-HCG 
Xd 
 
 
 
 
 
 
 
 
Serum CA-125 
level 
Xc 
 
 
X 
X 
X 
 
X 
X 
Fasting blood 
sample in Purple 
Top Tube (x2) for: 
DNA and Plasmae 
X 
 
 
Xh 
 
 
X 
 
 
Fasting blood 
sample in  Gold Top 
Tube (x1) for:  
glucose, insulin, C-
reactive protein, 
lipidse 
X 
 
 
Xh 
 
 
X 
 
 
Archival formalin-
fixed and paraffin-
embedded primary 
tumor and/or 
metastatic tumor  
X 
 
 
 
 
 
 
Xj 
 

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44 
e: 
Study medication must be taken morning of collection 
f:  
After week 1, if subject tolerates metformin, increase to 850 mg po BID. If intolerant, reassess for escalation at weeks, 2, 3 and 4 
g: 
Within 4 days of protocol therapy 
h: 
Between cycle 3-4 
i:  
Follow-up radiographic assessment of disease: in the absence of disease progression as outlined in section 11.2.1, imaging using the same 
modality and encompassing the same field as in the initial pre-treatment evaluation should be repeated with the following schedule 
regardless of whether or not the patient had measurable disease on initial CT or MRI scan: 
 
 
-at 6 months after the completion of 6 cycles of chemotherapy for all subjects whether they receive 6 or 8 cycles of 
chemotherapy 
 
 
-every 6 months for the duration of the study treatment defined as 2 years from time of randomization 
j: 
At time of recurrence if part of routine clinical care 
 
 
Neoadjuvant chemotherapy 
with interval debulking 
surgery 
Pre-
treatment 
During cytotoxic 
chemotherapy and 
metformin/placebo 
treatment 
Interval 
debulking 
surgery 
Following cytotoxic chemotherapy , during 
metformin/placebo only treatment 
 
Post-
study 
treatment 
Observations and Tests 
Prior to 
initial 
study 
treatment 
Wk 
1-3 
Prior to 
each 
course 
(Course 
1-6 (up to 
8)) 
Day of 
Surgery 
Prior to 
initial 
course 
Every 3 
months 
Month 6  
Post-
therapy 
monitoring 
every 6 
months 
Every 4-6 
months 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
X 
 
X 
X 
Survival status 
 
 
X 
 
X 
X 
 
X 
X 
Concurrent meds 
X 
X       
X----------------------------------------------------------------------- 
 
Physical exam 
Xa 
 
X 
 
X 
X 
 
X 
X 
Blood pressure, pulse, 
temperature 
X 
 
X 
 
X 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
X 
X 
 
X 
 
Performance status 
X 
 
X 
 
X 
X 
 
X 
 
CBC w/diff, plts 
Xc 
 
Xh 
 
 
 
 
 
 
Serum chemistryb 
Xc 
 
Xh 
 
 
 
 
 
 
Toxicity assessment 
X 
   Xg 
       X 
 
    X 
        X 
 
 
 
Tumor measurements 
X 
 
 
 
    X 
 
 
 
 
Radiologic evaluation 
Xc 
 
 
 
Radiologic measurements should be performed 
at 6 months after the completion of 6 cycles of 
chemotherapy, then every 6 months for the 
duration of the study treatment.i 
 
 
B-HCG 
Xd 
 
 
 
 
 
 
 
 
Serum CA-125 level 
X 
 
X 
 
X 
X 
 
X 
X 
Fasting blood sample in 
Purple Top Tube (x2) for: 
DNA and Plasmae 
X 
 
 
X 
 
 
X 
 
 
Fasting blood sample in  
Gold Top Tube (x1) for:  
glucose, insulin, C-reactive 
protein, lipidse 
X 
 
 
X 
 
 
X 
 
 
Fresh Frozen Tumor 
Xf 
 
 
Xf 
 
 
 
Xj 
 

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45
a:
Includes assessment of compliance (medication diary)
b:      Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT 
[AST], SGPT [ALT], sodium.
c:
Laboratory values within 14 days of initial protocol treatment. Obtain CT chest, abdomen, pelvis OR chest x-ray with MRI or CT abdomen, 
pelvis within 4 weeks of registration.  Imaging studies are not required at interval debulking surgery; however, if imaging studies are 
obtained before and/or after interval debulking surgery, results should be submitted.
d:
Serum pregnancy test (women of childbearing potential).
e:      Study medication must be taken morning of collection
f:      Mandatory for participants in correlative tissue substudy. 
g:
After week 1, if subject tolerates metformin, increase to 850 mg po BID. If intolerant, reassess for escalation at weeks, 2, 3 and 4
h:      Obtain within 4 days of protocol treatment
i.       Follow-up radiographic assessment of disease: in the absence of disease progression as outlined in section 11.2.1, imaging using the same     
modality and encompassing the same field as in the initial pre-treatment evaluation should be repeated with the following schedule 
regardless of whether or not the patient had measurable disease on initial CT or MRI scan:
-at 6 months after the completion of 6 cycles of chemotherapy for all subjects whether they receive 6 or 8 cycles of chemotherapy
    -every 6 months for the duration of the study treatment defined as 2 years from time of randomization
j:       If available and collected as part of routine clinical cancer
Figure 3
Archival formalin-fixed and 
paraffin-embedded primary 
tumor and/or metastatic 
tumor 
X
Xj
45

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46 
 
11. MEASUREMENT OF EFFECT 
 
Progression free survival as the primary endpoint and biochemical response and time to 
biochemical progression will be evaluated as secondary endpoints in this study.  
 
11.1.1 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].  Patients will also be followed 
for CA125 response and progression using GCIG criteria.  Progression by GCIG 
criteria may trigger a CT scan but in and of itself, will not constitute a progression 
event unless verified by progression of measurable lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm by chest 
x-ray or as ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same 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 

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47 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
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.  
 
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 6 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.  
 
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.  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans).   
 
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 

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48 
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-hold scanning techniques, if possible. 
 
PET-CT.  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound.  Ultrasound 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. 
 
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 Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 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]. 
 
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. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
 

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49 
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a 
sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the 
positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD.  If the positive FDG-PET at follow-up is not 
confirmed as a new site of disease on CT, additional follow-up CT  scans 
are needed to determine if there is truly progression occurring at that site 
(if so, the date of PD will be the date of the initial abnormal FDG-PET 
scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar 
to a biopsy in cases where a residual radiographic abnormality is thought 
to represent fibrosis or scarring.  The use of FDG-PET in this 
circumstance should be prospectively described in the protocol and 
supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
 
 
11.1.3 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with metformin. 
 
Tumor markers.  Specific guidelines for CA-125 response (in recurrent ovarian cancer)  
have been published [JNCI 96:487-488, 2004].  In addition, the Gynecologic Cancer 
Intergroup has developed CA-125 progression criteria [JNCI 92:1534-1535, 2000]. 
 
11.1.4 Progression-Free Survival 
 
PFS is defined as the duration of time from randomization to time of progression or 
death, whichever occurs first. 
 
11.2  Response Parameters 
 
 
11.2.1 Evaluation of Target Lesions 
 
 
11.2.11 Complete response (CR): Disappearance of all target lesions 

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50 
 
11.2.12  Partial response (PR): At least a 30% decrease in the sum of the longest 
diameter (LD) of target lesions, taking as reference the baseline sum LD 
 
11.2.13 Progressive disease (PD): At least a 20% increase in the sum of the LD of 
target lesions, taking as reference the smallest sum LD recorded since the treatment 
started or the appearance of one or more new lesions 
 
11.2.14 Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum LD since 
the treatment started 
 
11.2.2  Evaluation of non-target lesions 
 
11.2.21 Complete response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level 
 
Note: If serum CA125 levels are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response 
 
 
11.2.22 Incomplete response 
 
11.2.221 Stable disease (SD): Persistence of one or more non-target 
lesion(s) and/or maintenance of tumor marker level above the normal 
limits 
 
11.2.222 Progressive disease (PD): Appearance of one or more new 
lesions and/or unequivocal progression of existing non-target lesions 
 
Although a clear progression of “non-target” lesions only is exceptional, 
in such circumstances the opinion of the treating physician should prevail, 
and the progression status should be confirmed at a later time by the study 
chair 
 
 
 
11.2.223 Progression Based on Serum CA-125 
 
Progression can be based upon serum CA-125 if one of the three following 
conditions are met: 
 
1. Patients with elevated CA-125 pretreatment and normalization of 
CA-125 must show evidence of CA-125 greater than or equal to 
two times the upper normal limit on two occasions at least one 
week apart. 
 
Or 
 

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51 
2. Patients with elevated CA-125 pretreatment, which never 
normalizes must show evidence of CA-125 greater than or equal to 
two times the nadir value on two occasions at least one week apart  
 
Or 
 
3. Patients with CA-125 in the normal range pretreatment must show 
evidence of CA-125 greater than or equal to two times the upper 
normal limit on two occasions at least one week apart. 
 
When disease progression is defined by CA-125 criteria alone, 
imaging using the same modality and encompassing the same 
field as in the initial pretreatment evaluation should be 
obtained within 2 weeks of the elevated CA-125 such that 
progression is documented 
 
 
11.2.3 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).  
 
 
 
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
Note: 
 
-Patients with global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having “symptomatic deterioration”. Every effort should be made to 
document the objective progression, even after discontinuation of treatment. 
 
-In rare cases when there is evidence of disease on CT, MRI or physical examination, 
a discrepancy may exist between trends in CA-125 levels and data from either 
imaging or physical examination. If there is evidence of disease on CT, MRI or 

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52 
physical examination,  such disease is shrinking, AND there is no evidence of new 
disease, then rising CA-125 levels according to section 11.2.223 would be insufficient 
to determine disease progression 
 
-Patients who are not evaluated for response will be classified as either: having no 
target lesions at the time of enrollment onto the study, not reassessed due to early 
death or unknown (not assessable or insufficient data) 
 
 
11.2.4  Time to biochemical progression. 
 
CA-125 will be monitored on this study but will not be a criteria for progression. If GCIG 
criteria for progression are met, a CT scan should be ordered by the treating physician within 2 
weeks of CA-125 result. These criteria are:  
 
x Patients with an elevated CA-125 pretreatment and normalization of CA-125 
show evidence of CA-125 > 2X the ULN on 2 occasions at least one week 
apart 
x Patients with an elevated CA-125 pretreatment that never normalizes show 
evidence of CA-125 > 2X the nadir value on 2 occasions at least one week 
apart 
x Patients with CA-125 in the normal range pretreatment show evidence of CA-
125 > 2X ULN on 2 occasions at least one week apart 
 
 
12. DATA REPORTING  
 
Data reporting will be performed utilizing the eVelos electronic data capture system.  The 
University of Chicago CRA will provide you with the applicable user registration information.  
 
All required data must be recorded in the eVelos database at the completion of each cycle.  AEs 
are to be entered in real time. SAEs are to be entered in eVelos on the Serious Event Reporting 
Form within 24 hours of the site’s knowledge of the event. All case report forms must be 
completed by designated study personnel. Each screened (consented) patient is to be entered into 
eVelos within 48 hours of patient registration. In addition to direct data entry, you may be 
required to provide supporting source documentation. Source records are original documents, 
data, and records (e.g., medical records, raw data collection forms, pharmacy dispensing records, 
recorded data from automated instruments, laboratory data) that are relevant to the clinical trial. 
Each site will prepare and maintain adequate and accurate source documents. These documents 
are designed to record all observations and other pertinent data for each subject enrolled in this 
clinical trial. Source records must be adequate to reconstruct all data transcribed onto the case 
report form. 
 
13. STATISTICAL CONSIDERATIONS 
 

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53 
13.1 Study Design/Primary Endpoints and Analysis 
 
This is a randomized, placebo-controlled trial that will enroll 160 patients (80 per treatment arm).  
Primary analysis will be by intent to treat, including all patients randomized into the study.  The 
primary efficacy outcome variable is progression-free survival (PFS), defined as the time from 
randomization until disease progression or death from any cause. Surviving patients free of 
progression will be censored at the time of the last negative exam.  Kaplan-Meier (58) curves 
will be generated and the metformin and placebo groups compared using a logrank test stratified 
by initial treatment (primary debulking surgery or neoadjuvant therapy) and chemotherapy 
regimen (R1/R2, R3, or R4/R5/R6). A one-sided alpha level of 0.15 will be used to determine 
statistical significance and declare metformin treatment worthy of phase III testing.  Median PFS 
and associated 90% confidence interval will be estimated using the method described in 
Brookmeyer and Crowley (59).  A Cox (60) regression model will also be fit to assess and adjust 
for the effects of the stratification factor (see section 13.3) and other baseline covariates (for 
example, age, ECOG performance status).  Given that radiographic assessments will be 
performed at six months intervals, the discrete-time (proportional odds) form of the Cox model 
will be fit.  
 
Adverse events will be analyzed as described in section 13.4 below.  
 
 
13.2 Sample Size/Accrual Rate 
 
Based on other large trials including patients with macroscopic residual disease or those 
receiving neoadjuvant therapy, a median PFS of 12 months is assumed for the control group (7, 
11). Using a one-sided alpha level of 0.15 and 80% power, a total of 72 subjects in each arm 
(n=144) will be required to detect an increase in median PFS from 12 months to 17 months (HR 
=0.71) with metformin treatment. This assumes two years of accrual and two years of subsequent 
follow-up (four year study) and includes neoadjuvant and adjuvant subjects. We will increase the 
sample size by 10% to allow for the dropout rate (61, 62) reported in other trials using metformin 
for a total sample size of 160 patients. The targeted hazard ratio is consistent with the findings in 
OvCa retrospective cohort studies from the University of Chicago and the Mayo Clinic (32, 33). 
Diabetic patients on the MIMOSA trial of abagovomab who received metformin had a HR of 
progression of 0.419 [0.175-1.002] versus diabetic patients not receiving metformin and a HR of 
0.575 [0.32-1.022] versus nondiabetic patients (no metformin) (35). 
 
13.3 Stratification Factors and Randomization 
 
Randomization will be stratified by initial treatment (primary debulking surgery or neoadjuvant 
therapy) and chemotherapy regimen (R1/R2, R3, or R4/R5/R6).  Randomization lists will be 
created by the study biostatistician using computer-generated random numbers and the method of 
permuted blocks.  The web-based randomization module in REDCap (63) will be employed to 
convey the treatment assignments to the participating sites.  If there is an imbalance in 
chemotherapy regimen between groups, the analysis will be stratified first comparing the two 
treatment arms within each stratum, then getting an overall result by taking a weighted average 
of the within-stratum differences, weighted by the size of the strata.    

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54 
 
 
13.4 Analysis of Secondary Endpoints 
 
Time to biochemical (CA-125) progression, radiological progression, or death (whichever occurs 
first) and overall survival will be analyzed as described above for PFS using Kaplan-Meier 
curves, stratified logrank test, and Cox regression modeling.  Biochemical progression is defined 
in section 11.2.4; surviving patients free of either type of progression will be censored at the time 
of the last negative exam.  CA-125 response rates in the subgroup of patients with elevated CA-
125 at entry (i.e., > institutional ULN) will be compared between the two treatment arms using a 
chi-square test.  Adverse events will be summarized by type, grade, and attribution using 
CTCAE version 4.0 criteria; treatment group comparisons will be performed using chi-square or 
Fisher’s exact test.  Patients who receive any amount of study drug will be considered evaluable 
for toxicity.  
 
 
13.4.1 Correlative endpoints 
 
The goal of the correlative studies is to understand if changes in paired biospecimens are larger 
in samples from patients randomized to metformin compared to those on placebo. Sample size 
considerations are fixed by the clinical trial primary endpoint but we plan to analyze specimens 
from 30 patients per treatment arm in those undergoing neoadjuvant chemotherapy and 
participating in the tissue collection substudy.    
 
Systemic effects.  
 
Serum markers (e.g., insulin, C-reactive protein, glucose, HOMA score) will be measured on a 
continuous scale and log2 transformed for analysis as appropriate. Statistical blocking factors 
will be used to adjust for serum assay batch effects if needed. Linear mixed effects models will 
be used to test for changes from baseline to cycle 3 and 6 months  post-treatment, and to test 
whether these changes differ between those with and without metformin. Assumptions will be 
verified and non-parametric tests used if needed. 
 
Tumor effects. 
Tissue microarrays. Analysis of IHC staining will begin with automated scoring via the Aperio 
system with an H-score (64, 56).  The H-score is function of the strength of staining (0=negative, 
1=weak, 2=moderate, 3=strong) multiplied by the percent of cells staining (0-100%) for that 
intensity, yielding a continuous 0-300 score for each sample: [1 x (% cells 1+) + 2 x (% cells 2+) 
+ 3 x (% cells 3+)].  However, stain interpretation is partly hypothesis driven (i.e., is target in 
nucleus vs. cytoplasm).  Thus the statisticians will work with the investigators and pathologists 
to review scientific aims in order to customize stain interpretation, scoring, and data acquisition 
to optimize analysis plans for each stain. Associations with stage and grade will be assessed via 
linear models. Associations with PFS and overall survival, and whether these associations are 
modified by metformin, will be assessed via Kaplan Meier and Cox regression methods in an 
exploratory fashion. Assumptions will be verified and non-parametric tests used if needed. 
 
Proteomics. Our statisticians will collaborate with the statistical team at the Max Planck Institute 
regarding data processing and analysis for peptide and protein level analyses.  Mixed effects 
models will be utilized to assess paired changes, and need for BMI as a covariate will be 
assessed.  False discovery rates will be computed to assess significance (65). Model-based 
normalization strategies will be utilized if needed.  Hierarchical cluster analysis will be used to 

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understand relationships in the data and pathway analysis will be performed using String 
Analysis (http://string-db.org/).   
 
 
13.5 Reporting and Exclusions 
 
13.5.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with 
metformin. 
 
13.5.2 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 
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) will 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 will 
not result in exclusion from the analysis of the response rate.   
 
All conclusions will be based on all eligible patients.  Sub-analyses may 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 will not serve as 
the basis for drawing conclusions concerning treatment efficacy, and the reasons for 
excluding patients from the analysis will be clearly reported.   
 
14.  STUDY MANAGEMENT AND REGULATORY AFFAIRS 
 
14.1 Multicenter Guidelines 
 
The specific responsibilities of the Principal Investigator and the Coordinating Center are 
presented in Appendix B.  Clinical studies coordinated by The University of Chicago must be 
conducted in accordance with the ethical principles that are consistent with Good Clinical 
Practices (GCP) and in compliance with other applicable regulatory requirements 
The Study Lead PI/Coordinating Center is responsible for distributing all official protocols, 
amendments, and IND Action Letters or Safety Reports to all participating institutions for 
submission to their individual IRBs for action as required.   

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14.2 Institutional Review Board (IRB) Approval and Consent 
 
Unless otherwise specified, each participating institution must obtain its own IRB approval. It is 
expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations.  The IRB should approve the consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to 
ethical principles that have their origin in the Declaration of Helsinki. 
 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Each consent form must 
include all the relevant elements currently required by the FDA Regulations and local or state 
regulations. Once this essential information has been provided to the patient and the investigator 
is assured that the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an IRB-approved consent 
form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed 
and personally dated by the patient and by the person who conducted the informed consent 
discussion. 
14.3 Required Documentation 
 
Before the study can be initiated at any site, the following documentation must be provided to 
the Cancer Clinical Trials Office (CCTO) at the University of Chicago Comprehensive Cancer 
Center. 
 
x A copy of the official IRB approval letter for the protocol and informed consent 
x IRB membership list 
x CVs and medical licensure for the principal investigator and any sub-investigators who 
will be involved in the study. 
x CAP and CLIA Laboratory certification numbers and institution lab normal values 
x Investigational drug accountability standard operating procedures 
x Additionally, before the study can be initiated at any site, the required executed research 
contract/subcontract must be on file with the University of Chicago. 
14.4 Data and Safety Monitoring  
 
This study will be remotely monitored by the University of Chicago Clinical Research Associate 
(CRA) in accordance with the University of Chicago, Section of Hematology/Oncology standard 
operating procedure titled Monitoring of Multi-Institutional Investigator Initiated Clinical Trials. 
 
Prior to subject recruitment, and unless otherwise specified, a participating site will undergo site 
initiation teleconference to be conducted by the designated University of Chicago research team. 

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The site’s principal investigator and his or her study staff must attend the site initiation meeting.  
 
Monitoring will be conducted to verify the following: 
 
x Adherence to the protocol 
 
x Completeness and accuracy of study data and samples collected 
 
x Compliance with regulations 
 
x Submission of required source documents 
 
Participating sites will also undergo a site close-out teleconference upon completion, termination 
or cancellation of a study to ensure fulfillment of study obligations during the conduct of the 
study, and to ensure that the site Investigator is aware of his/her ongoing responsibilities. 
 
Unless otherwise specified, this protocol will undergo weekly review at the multi-institutional 
data and safety monitoring teleconference as per procedures specified by the UC CCC NCI-
approved Data and Safety Monitoring Plan. The conference will review: 
 
x Enrollment rate relative to expectations, characteristics of participants 
x Safety of study participants (Serious Adverse Event & Adverse Event reporting) 
x Adherence to protocol (protocol deviations) 
x Completeness, validity and integrity of study data 
x Retention of study participants 
 
Protocol deviations are to be documented using the Protocol Deviation Form and sent via e-
mail to PhaseIICRA@medicine.bsd.uchicago.edu. Deviations that are considered major 
because they impact subject safety or alter the risk/benefit ratio, compromise the integrity of 
the study data, and/or affect subjects’ willingness to participate in the study must be reported 
within 7 calendar days of awareness of the event. 
 
Monitoring Metformin Toxicity 
 
      As noted in Section 6.3 of the protocol the major side effects of metformin are 
gastrointestinal (nausea, abdominal bloating, diarrhea). Additional toxicities of concern are 
hepatic dysfunction, renal dysfunction, lactic acidosis, anemia, skin reactions, and Steven 
Johnson syndrome. Each of these types of adverse events will be specifically monitored.  To 
ensure that the addition of metformin to chemotherapy does not exacerbate chemotherapy-related 
toxicities to an unacceptable degree, the occurrence of any serious adverse event (SAE) will also 
be monitored. The protocol allows for use of olaparib as maintenance therapy after 
chemotherapy for germline BRCA patients. Toxicities noted with olaparib include nausea, 
vomiting, abdominal pain, constipation, diarrhea, loss of appetite, indigestion. The occurrence of 
any SAE during the maintenance phase will also be monitored. The following safety monitoring 
plan will be used: 
 
-A Toxicity Monitoring Report will be generated by the study statistician every 6 months 
-The report will be circulated to a Safety Monitoring Committee consisting of key principal and 

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co-investigators  
- Timing of these reports will correspond to increments of approximately 40 patients (i.e., after 
40, 80, 120, and 160 patients have been randomized).  
-Data will be broken out by treatment arm (metformin vs. placebo) and for each of the toxicities 
listed in Table 1 below 
-The proportion of patients with grade 3 or higher toxicity per CTC 4.0 criteria will be compared 
between the two groups using a chisquare or Fisher’s exact test.   
-Tables will be generated based on all reported events, and separately based on events with an 
attribution of at least possibility related to the study drug(s), including adverse events designated 
as chemotherapy-related.   
-Any differences statistically significant at the p<0.05 level will generate an “ALERT” signal 
and differences significant at p<0.01 will generate a “HIGH ALERT” signal. 
- Consideration will be given to early termination of the trial if: 
 
- High alert signals are generated OR 
 
- Alert signals indicating a consistent pattern of increased toxicity in the metformin   
arm  
 
Table 1.  Monitored Toxicities 
 
Nausea 
Vomiting 
Distention/bloating 
Diarrhea 
GI-other 
Hepatic dysfunction (AST or ALT > 1.8X ULN) 
Renal dysfunction (Creatinine >  institutional ULN)  
Acidosis (Lactate > 5.0 mM, pH< 7.3) 
Anemia (Hgb < 110 or MCV > 105) 
Skin reactions (major-generalized urticarial, bullous rashes, exfoliative dermatitis) 
Steven Johnson Syndrome 
Any Serious Adverse Event (SAE) 
 
Interim Futility Analysis (added June, 2019) 
An interim futility analysis will be performed after one-half the expected number of primary 
events (disease progressions or deaths) are observed.  The projected total number of primary 
events is 117 based on the sample size/power calculation.  Therefore, this analysis will be 
conducted after 59 events are observed across the two treatment arms.  If, at this point, the 
observed hazard ratio does not favor metformin, i.e., the HR (metformin/placebo) > 1, we will 
consider stopping the trial early for futility.  This empirical rule is associated with a minimal 
(<2%) power loss (66). 
  
14.5 Auditing 
 
In addition to the clinical monitoring procedures, the University of Chicago Comprehensive 
Cancer Center will perform routine Quality Assurance Audits of investigator-initiated clinical 

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trials as described in the NCI-approved UC CCC DSM Plan. Audits provide assurance that trials 
are conducted and study data are collected, documented and reported in compliance with the 
protocol. Further, the quality assurance audits ensure that study data are collected, documented and 
reported in compliance with Good Clinical Practices (GCP) Guidelines and regulatory 
requirements. The audit will review subjects enrolled at the University of Chicago in accordance 
with audit procedures specified in the UC CCC Data and safety Monitoring plan. For institutions 
who are formal members of the Personalized Cancer Care Consortium (PCCC), the UC CCC will 
conduct on site quality assurance audits on average every two years during the enrollment and 
treatment phase of the study. 
 
 Auditing procedures for participating sites that are not full members of the PCCC must be 
specified and approved by the UC CCC Clinical Research Advisory Committee.  In general, for 
sites that are not full members of the PCCC, auditing responsibility will be delegated to the 
participating center, with the annual audit report forwarded to the University of Chicago for 
review.   
 
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during its 
conduct or even after its completion. If an inspection has been requested by a regulatory 
authority, the site investigator must immediately inform the University of Chicago Cancer 
Clinical Trials Office and Regulatory Manager that such a request has been made. 
14.6 Amendments to the Protocol 
 
All modifications to the protocol, consent form, and/or questionnaires will be submitted to the 
University of Chicago IRB for review and approval. A list of the proposed modifications or 
amendments to the protocol and an explanation of the need of these modifications will be 
submitted, along with a revised protocol incorporating the modifications. Only the Study Lead 
PI can authorize any modifications, amendments, or termination of the protocol. Once a 
protocol amendment has been approved by the University of Chicago IRB, the Regulatory 
Manager will send the amended protocol and consent form to the affiliate institutions 
electronically. Upon receipt of the packet the affiliate institution is expected to do the 
following: 
 
x The affiliate must reply to the email from the Regulatory Manager indicating that the 
amendment was received by the institution and that it will be submitted to the local IRB.  
 
x The amendment should be submitted to the affiliate institution’s IRB as soon as 
possible after receipt. The amendment must be IRB approved by the institution within 
3 months from the date that it was received.  
 
x The  University  of  Chicago  version  date  and/or  amendment  number  must  
appear  on  the  affiliate consent form and on the affiliate IRB approval letter.  The 
version dates can be found on the header or footer of every page of the protocol and 
consent form.  The amendment number can be found on the University of Chicago IRB 
amendment approval letter that is sent with the protocol/amendment mailing.  
 

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x The IRB approval for the amendment and the amended consent form (if amended consent 
is necessary) for the affiliate institution must be sent to the designated UC Regulatory 
Manager as soon as it is received.  
14.7 Annual IRB Renewals, Continuing Review and Final Reports 
 
A continuing review of the protocol will be completed by the University of Chicago IRB and 
the participating institutions’ IRBs at least once a year for the duration of the study. The 
annual IRB renewals for participating institutions should be forwarded promptly to the 
Regulatory Manager. If the institution’s IRB requires a new version of the consent form 
with the annual renewal, the consent form should be included with the renewal letter. 
14.8 Record Retention 
 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study documentation pertaining to 
the conduct of a clinical trial must be retained by the study investigator.  In the case of a study 
with a drug seeking regulatory approval and marketing, these documents shall be retained for at 
least two years after the last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept on file until 
three years after the completion and final study report of this investigational study. 
14.9 Obligations of Study Site Investigators 
 
The Study Site Principal Investigator is responsible for the conduct of the clinical trial at the site 
in accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki.  The Study Site Principal Investigator is responsible for personally overseeing the 
treatment of all study patients.  He/she must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
 
The Study Site Principal Investigator at each institution or site will be responsible for assuring 
that all the required data will be collected and entered into the CRFs. Periodically, monitoring 
visits or audits will be conducted and he/she must provide access to original records to permit 
verification of proper entry of data.  
 
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39. Hardie DG, Ross FA, Hawley SA. AMP-activated protein kinase: a target for drugs both 
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41. Hardie DG. AMP-activated/SNF1 protein kinases:  Conserved guardians of cellular 
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Fereday S, Caldas C, DeFazio A, Bowtell DD, Brenton JD. Driver mutations in TP53 are 
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43. DeBerardinis RJ, Sayed N, Ditsworth D, Thompson CB. Brick by brick: Metabolism and 
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Luini A, Lazzeroni M, Varricchio C, Viale G, Bruzzi P, Decensi A. Dual effect of 
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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 

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2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
APPENDIX B 
MULTICENTER GUIDELINES 
 
Responsibility of the Study Lead PI  
x The Study Lead PI will be the single liaison with regulatory and data management staff, 
outside sponsor/s, FDA, and funding agencies  The Study Lead PI is responsible for the 
coordination, development, submission, and approval of the protocol as well as its 
subsequent amendments.  The protocol must not be rewritten or modified by anyone 
other than the Study Lead PI.  There will be only one version of the protocol, and each 
participating institution will use that document.  The Study Lead PI is responsible for 
assuring that all participating institutions are using the correct version of the protocol. 
x The Study Lead PI is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements are the 
responsibility of the Study Lead PI.  
x The Study Lead PI is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
x The Study Lead PI will be responsible for the review of and timely submission of data for 
study analysis. 
 
Responsibilities of the Coordinating Center 
x The Coordinating Center is responsible for maintaining copies of IRB approvals from 
each participating site.  
x The Coordinating Center is responsible for central patient registration.  The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each 
participating site prior to the first patient registration from that site. 
x The Coordinating Center is responsible for the preparation of all submitted data for 
review by the Study Lead PI. 

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x The Coordinating Center will maintain documentation of AE reports.  The Coordinating 
Center will submit AE reports to the Study Lead PI for timely review. 

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APPENDIX C 
PILL CALENDAR 
 
Subject Name: _________________________________Subject ID:_______________________ 
 
This is a pill calendar on which you are to record the number of pills (metformin or placebo) you 
take each day for each cycle on this study. You will start a new calendar for each cycle.  
x 
Begin the first cycle by taking one pill (metformin or placebo) daily for about 1 week and then increase 
to 1 pill two times a day for the rest of the study (approximately 2 years). The pills should be taken about 
12 hours apart at approximately the same time every day. 
x 
Pills should be taken with food and should not be crushed or split. Please take with about 8 ounces of 
water. 
x 
If you develop any side effects, please contact your study nurse. Please make a note of any side effects or 
reasons you did not take metformin/placebo on the back of this diary 
x 
Bring any unused pills, pill bottles and completed calendars to your next appointment. 
x 
Please record the date the pill(s) are taken in each box. If you do not take metformin/placebo, please 
indicate this by marking an X or 0 on the # of pills line. 
 
Cycle 
 
 
 
 
 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Date 
 
AM Time______ 
# of pills______ 
 
PM Time______ 
# of pills______ 
 
Date 
 
AM Time______ 
# of pills______ 
 
PM Time______ 
# of pills______ 
 
Date 
 
AM Time______ 
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PM Time______ 
# of pills______ 
 
Date 
 
AM Time______ 
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PM Time______ 
# of pills______ 
 
Date 
 
AM Time______ 
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PM Time______ 
# of pills______ 
 
Date 
 
AM Time______ 
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PM Time______ 
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Date 
 
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PM Time______ 
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Date 
 
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PM Time______ 
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Date 
 
AM Time______ 
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PM Time______ 
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Date 
 
AM Time______ 
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PM Time______ 
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Date 
 
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PM Time______ 
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Date 
 
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PM Time______ 
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Date 
 
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PM Time______ 
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Date 
 
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PM Time______ 
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Date 
 
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PM Time______ 
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Date 
 
AM Time______ 
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PM Time______ 
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Date 
 
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PM Time______ 
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Date 
 
AM Time______ 
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PM Time______ 
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Date 
 
AM Time______ 
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PM Time______ 
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Date 
 
AM Time______ 
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PM Time______ 
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Date 
 
AM Time______ 
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PM Time______ 
# of pills______ 
 
 
Date 
 
AM Time______ 
# of pills______ 
 
PM Time______ 
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Date 
 
AM Time______ 
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PM Time______ 
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Date 
 
AM Time______ 
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PM Time______ 
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Date 
 
AM Time______ 
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PM Time______ 
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Date 
 
AM Time______ 
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PM Time______ 
# of pills______ 
 
Date 
 
AM Time______ 
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PM Time______ 
# of pills______ 
 
Date 
 
AM Time______ 
# of pills______ 
 
PM Time______ 
# of pills______ 
 
 
Signature of subject  
 
 
 
 Date