Clinical trial NCT01579812
Conditions: Ovarian, Fallopian Tube, and Primary Peritoneal Cancer
Keywords: Ovarian, Fallopian Tube, and Primary Peritoneal Cancer
Sponsor: University of Michigan Rogel Cancer Center
Start date: 2011-10-01; Completion date: 2017-07-01
Enrollment: 90 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to determine if metformin administered in combination with chemotherapy to women with advanced ovarian, primary peritoneal or fallopian tube cancer will improve recurrence-free survival at 18 months compared to controls.

Detailed description:
Despite 70% remission rates with surgery and chemotherapy, the majority of patients with stage III/IV ovarian cancer will relapse and die of their disease. This is consistent with a cancer stem cell (CSC) model in which a few residual treatment resistant stem cells persist and initiate disease recurrence. Laboratory studies indicate therapies targeting CSC will greatly improve cancer outcomes. We have recently characterized a population of CSC in ovarian cancer. Importantly, similar to that observed in breast cancer, we have found that the diabetes drug metformin can restrict ovarian CSC growth and proliferation. In addition metformin increases tumor cell sensitivity to chemotherapy. Consistent with this, epidemiologic studies demonstrate that diabetic patients with ovarian cancer taking metformin have better outcomes than those not taking metformin. However, metformin has not been tested as an anti-cancer stem cell agent in ovarian cancer. Thus we propose to perform a phase II clinical trial using metformin as an anti-cancer stem cell agent in ovarian cancer patients. Patients who plan to receive primary surgical debulking will initiate metformin therapy prior to surgery and then continue after surgery along with chemotherapy. Patients who will be treated neoadjuvantly will initiate metformin with chemotherapy prior to surgery and then continue both metformin and chemotherapy after surgery. Tumor specimens will be acquired for all patients at the time of primary surgery. The primary objective of this study will be to determine if metformin improves the recurrence-free survival (RFS) of patients relative to historical controls. Secondary objectives of this study will be: (a) to compare the amount of CSC in primary tumor specimens in metformin treated patients versus matched controls from our tumor bank, (b) to determine if metformin improves overall survival relative to historical controls, (c) to confirm the safety of metformin in non-diabetic ovarian cancer patients, and (d) as laboratory studies indicate that metformin is most active in p53 mutant cells and p53 is mutated in \~50% of ovarian cancers, we will assess whether response rates correlate with p53 mutation status. If successful, this well tolerated FDA approved drug could be immediately translated into phase III trials and impact patient outcomes.

Arms: arm 1: None
Interventions: intervention 1: Metformin
Intervention descriptions: intervention 1: Patients receiving primary surgical debulking followed by adjuvant chemotherapy will initiate metformin prior to primary surgery. Following surgery patients will be initiated on metformin prior to the initiation of chemotherapy.

Patients treated with neoadjuvant chemotherapy will be initiated on metformin prior to the initiation of chemotherapy. Following surgery patients will be initiated on metformin prior to the re-initiation of chemotherapy.

Protocol documents:
Prot_SAP_000.pdf: 
 
Last revised August 10, 2017 
1 
 
Protocol Number:    
HUM00047900 
 
 
Version Date: 
  
 August 10, 2017 
 
 
Title: 
 
A Phase II Evaluation of Metformin, Targeting Cancer Stem Cells for the 
Prevention of Relapse in Patients with Stage IIC/III/IV Ovarian, Fallopian 
Tube, and Primary Peritoneal Cancer  
 
 
 
Principal Investigator: 
*Carolyn Johnston, MD 
University of Michigan Cancer Center  
Obstetrics and Gynecology 
L4606 Women’s Hospital 
Ann Arbor, MI  48109-0276 
Phone:  734-936-6884 
Fax:  734-764-7261 
E-mail:  johnstob@med.umich.edu 
 
Co-Investigators: 
*R. Kevin Reynolds, MD 
 
University of Michigan Cancer Center 
 
Obstetrics and Gynecology 
L4000 Women’s Hospital 
 
Ann Arbor, MI  48109-0276 
 
Phone:   734-764-9106 
Fax:  734-764-7261 
 
 E-mail:  rkr@med.umich.edu 
 
*Rebecca Liu, MD 
University of Michigan Cancer Center  
Obstetrics and Gynecology 
L4000 Women’s Hospital 
Ann Arbor, MI  48109-0276 
Phone:  734-936-3024 
Fax:  734-764-7261 
E-mail:  rliu@med.umich.edu 
 
 
  *Karen Mclean, MD, PhD 
University of Michigan Cancer Center  
Obstetrics and Gynecology 
L4606 Women’s Hospital 
Ann Arbor, MI  48109-0276 
Phone:  734-936-6886 
Fax:  734-764-7261 
E-mail:  karencl@med.umich.edu 
 
*Shitanshu Uppal  
University of Michigan Cancer Center  
Obstetrics and Gynecology 
L4000 Women’s Hospital 
Ann Arbor, MI  48109-5276 
Phone:  734-936-6886 
Fax:  734-764-7261 
 


 
Last revised August 10, 2017 
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Statistician: 
  Kent Griffith, M.S. 
Senior Research Associate 
UMCCC Biostatistics Unit, 8D17  
300 North Ingalls Building 
Ann Arbor, MI  48109-0473 
Phone:  (734) 615-0601 
Fax:  (734) 936-9582 
Email:  kentg@med.umich.edu 
 
 
 
* Authorized to consent 
 
 


 
Last revised August 10, 2017 
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Summary 
 
 
Despite 70% remission rates with surgery and chemotherapy, the majority of patients with stage III/IV ovarian 
cancer will relapse and die of their disease. This is consistent with a cancer stem cell (CSC) model in which a 
few residual treatment resistant stem cells persist and initiate disease recurrence. Laboratory studies indicate 
therapies targeting CSC will greatly improve cancer outcomes. We have recently characterized a population of 
CSC in ovarian cancer. Importantly, similar to that observed in breast cancer, we have found that the diabetes 
drug metformin can restrict ovarian CSC growth and proliferation. In addition metformin increases tumor cell 
sensitivity to chemotherapy. Consistent with this, epidemiologic studies demonstrate that diabetic patients with 
ovarian cancer taking metformin have better outcomes than those not taking metformin. However, metformin 
has not been tested as an anti-cancer stem cell agent in ovarian cancer. Thus we propose to perform a phase 
II clinical trial using metformin as an anti-cancer stem cell agent in ovarian cancer patients. Patients will receive 
metformin neoadjuvantly for two weeks prior to primary debulking surgery. Tumor specimens will be acquired 
for all patients at the time of primary surgery. All patients will then receive metformin concurrent with traditional 
neo-adjuvant or adjuvant chemotherapy. The primary objective of this study will be to determine if metformin 
improves the recurrence-free survival (RFS) of patients relative to historical controls.  Secondary objectives of 
this study will be: (a) to compare the amount of CSC in primary tumor specimens in metformin treated patients 
versus matched controls from our tumor bank, (b) to determine if metformin improves overall survival relative to 
matched historical controls, (c) to confirm the safety of metformin in non-diabetic ovarian cancer patients, and 
(d) as laboratory studies indicate that metformin is most active in p53 mutant cells and p53 is mutated in ~50% 
of ovarian cancers, we will assess whether response rates correlate with p53 mutation status. If successful, 
this well tolerated FDA approved drug could be immediately translated into phase III trials and impact patient 
outcomes. 
 
 


 
Last revised August 10, 2017 
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Table of Contents 
 
1. Objectives ............................................................................................................................................ 5 
2. Background and Preliminary Results ............................................................................................... 6 
3. Drug Information ................................................................................................................................. 9 
4. Staging Criteria ................................................................................................................................. 13 
5. Eligibility/ Exclusion Criteria ........................................................................................................... 13 
6. Treatment Plan .................................................................................................................................. 14 
7. Toxicities/ Dose Modifications ........................................................................................................ 17 
8. Study Calendar ................................................................................................................................. 21 
9. Evaluation Criteria ............................................................................................................................ 23 
10. Adverse Events and Reporting Definitions .................................................................................. 23 
11. Data and Safety Monitoring ........................................................................................................... 27 
12. Statistical Considerations .............................................................................................................. 28 
13. Registration Guidelines ................................................................................................................. 30 
14. Data Forms, Submission and Distribution Information .............................................................. 31 
15. Specific Instructions ...................................................................................................................... 31 
Appendix 1: Eligibility Checklist ......................................................................................................... 33 
Appendix 2: Protocol Specific Data and Safety Monitoring Report ................................................. 35 
Appendix 3: Medication Diary ............................................................................................................. 36 
Appendix 4: Performance Status Criteria ........................................................................................... 41 
Appendix 5: References ....................................................................................................................... 42 


 
Last revised August 10, 2017 
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1. Objectives 
1.1. Clinical Objectives:  
 
1. 
Primary clinical objective: Determine if metformin administered in combination with 
chemotherapy to women with advanced ovarian, primary peritoneal or fallopian tube cancer 
will improve recurrence-free survival (RFS) at 18 months compared to matched historical 
controls.   We have strong preclinical evidence that metformin increases the activity of 
traditional chemotherapy in the treatment of ovarian cancer.  Metformin is currently being 
used in clinical trials for patients with other types of cancer. 
 
2. 
Secondary clinical objectives: 
 
a. 
Determine if metformin therapy is associated with an improvement in overall survival at 
2 years compared to matched historical controls.  
 
b. 
Confirm the safety of metformin in non-diabetic patients with ovarian cancer.  Metformin 
is a well-tolerated FDA approved drug used in millions of patients with and without 
cancer. It has been safely used in diabetic ovarian cancer patients receiving 
chemotherapy and in non-diabetic patients with polycystic ovarian syndrome.  It has not 
been used in combination with chemotherapy in non-diabetic ovarian cancer patients. 
 
1.2. Translational Objectives:  
 
1. 
Primary translational objective: Compare the percentage and absolute number of cancer 
stem cells (CSC) in primary tumor specimens in metformin treated patients compared to 
matched controls from our tumor bank. We have demonstrated that aldehyde 
dehydrogenase activity (ALDH) alone and in combination with the cell surface marker 
CD133+ identify cancer stem cells in ovarian cancer patients. Our preliminary data suggests 
that metformin reduces the percentage of ALDH+ tumor cells in vitro. We hypothesize that 
neo-adjuvant treatment with metformin will reduce the number of CSC in ovarian cancer 
patient’s primary tumor specimens. The primary objective of our study is to assess the 
percentage of CSC in the tumors of control and metformin treated patients. We further 
hypothesize that the number of CSC in tumors will correlate with clinical outcomes. We 
therefore propose to:  
 
a. 
Quantify the percentages of ALDH+ and ALDH+CD133+ cells using Fluorescence-
activated cell sorting (FACS) and AQUA co-immunofluorescence.  
 
b. 
Determine if percentage of ALDH+ and/or ALDH+CD133+ CSC in primary tumor 
specimens is altered by treatment with metformin.  
 
2. 
Secondary translational objective: Correlate numbers of CSC in primary tumor specimens 
and patient recurrence-free survival. 
 
3. 
Exploratory translational objective:  Assess p53 mutation status and response to 
metformin.  p53 mutation status has been proposed to be a predictor of response to 
metformin. We therefore plan a subset analysis comparing the outcomes of metformin 
treated patients outcome based on p53 status (mutant in 50% of ovarian cancer patients). 
 
 


 
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2. Background and Preliminary Results 
 
2.1.  Ovarian Cancer Epidemiology: Ovarian cancer is the most deadly gynecologic malignancy, and the fifth 
most deadly malignancy of women in the United States.  Approximately 22,000 women will be diagnosed 
with ovarian cancer in 2011 and approximately 15,000 will die of this disease1.  Seventy percent of 
ovarian cancer patients present with late stage disease.  Of the women with stage III/IV disease, 70% 
will have a complete response with surgical debulking and adjuvant chemotherapy.  Unfortunately, the 
majority will relapse.  Thus, even with modern chemotherapy, the majority of patients diagnosed with 
ovarian cancer will die of their disease.  Although multimodality treatment regimens, including 
cytoreductive surgery and cisplatin-containing combination chemotherapy have prolonged survival, the 
overall cure rate of the ovarian cancer has not changed dramatically. There have been few new 
developments in the treatment of ovarian cancer patients since the standardization of platinum and 
paclitaxel which has been the mainstay of ovarian cancer adjuvant therapy for the last 20 years. For 
these reasons there is a clear need for novel therapeutics.  Recent laboratory studies suggest that 
cancer stem cells may be the cause of disease recurrence and a critical target for new therapies.   
 
2.2. Cancer Stem Cells as a Therapeutic Target: The cancer stem cell hypothesis suggests that, unlike most 
cancer cells within a tumor, cancer stem cells resist chemotherapeutic drugs and are able to regenerate 
the various cell types within a tumor, thereby causing relapse of the disease.  Ovarian cancer appears to 
be a stem cell driven tumor.  Of the 70% of women that respond to therapy, the majority will recur and 
die of their disease.  This is consistent with the CSC theory that a small number of cells within a tumor 
are resistant to chemotherapy and are able to regenerate the tumor. In fact, we have recently 
characterized a population of cancer stem cells in ovarian cancer patients2.  Our studies indicate that 
aldehyde dehydrogenase activity (ALDH) can be used to identify ovarian cancer stem cells both in 
human tumor cell lines and in primary tissues.  Small numbers of ALDH+ cells initiate tumors in mice, 
while a 10-fold excess of ALDH (-) tumor cells cannot.  Interestingly, ALDH used in combination with 
CD133 enriches CSC isolation in certain tumor specimens. These ALDH+ cells are inherently resistant 
to chemotherapy, with increasing percentages of ALDH+ cells observed with increasing doses of 
chemotherapy.   
 
If the cancer stem cell hypothesis is correct, drugs that target cancer stem cells offer great promise in 
cancer treatment.  Several recent studies have identified agents that appear to specifically target 
cancer stem cells.  One compound, salinomycin, reduces the proportion of CSC by >100-fold relative 
to paclitaxel, a commonly used chemotherapeutic drug3. More recently studies in breast cancer 
identified IL8 signaling as critical in breast cancer stem cells.  Importantly, inhibition of IL8 signaling 
with the CXCR1 inhibitor, repertaxin, potently restricted cancer growth and maintenance repertaxin 
therapy prevented cancer recurrences4.  Similarly in ovarian cancer, the mullerian inhibitory 
substance was shown to inhibit ovarian cancer stem cell growth and potently augment therapy in 
chemoresistant tumors 5.  This data strongly suggests that targeting cancer stem cells will improve 
patient outcomes.  
 
2.3.  Using Metformin to Target Cancer Stem Cells: Recently metformin, a traditional type 2 diabetes 
medication, was found to target cancer stem cells in breast cancer.  Metformin inhibited cellular 
transformation and selectively killed breast cancer stem cells in vitro and in vivo6.  Another recent 
publication showed that metformin impedes the formation of breast cancer stem cells to form 
mammospheres 7.  Importantly, the combination of standard chemotherapy with metformin reduced 
tumor mass and prevented relapse in a xenograft mouse model6. Metformin has also been associated 
with transcriptional repression of the epithelial-mesenchymal transition, which has been specifically 
correlated with CSC 7.  A third study in breast cancer demonstrated that metformin synergistically 
interacts with trastuzumab, the anti-HER2 monoclonal antibody, to suppress self-renewal and 


 
Last revised August 10, 2017 
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proliferation of cancer stem cells in HER-2 positive carcinomas 8. These data strongly implicate 
metformin as a cancer stem cell targeting agent.  
 
Metformin may have similar activity in ovarian cancer.  Metformin appears to be acting via regulation 
of the insulin/glucose/IGF pathways. There is significant evidence that the insulin/glucose/IGF 
pathways are critical for ovarian cancer growth.  Insulin depresses the IGF binding proteins IGF-BP-1 
and 2 thereby leading to increases in IGF-I and IGF-II. IGFs in turn act via the PI3K/mTor pathway to 
promote ovarian tumor cell proliferation and inhibit apoptosis. IGF signaling activation has been 
correlated with poor outcomes in ovarian cancer patients.  Metformin has been shown to inhibit 
several enzymes associated with this pathway and reduces levels of circulating insulin and IGF-I9,10.  
We recently demonstrated that type 2 diabetes has a negative impact on the survival of ovarian 
cancer patients 11. Type 2 diabetes was an independent prognostic factor with implications as 
significant as debulking status—one of the primary prognostic factors in ovarian cancer patients.  
Importantly, patients whose diabetes was better controlled appeared to have a better outcome, 
suggesting that the impact of diabetes in ovarian cancer patients may be directly related to biologic 
alterations in diabetics' cancer cell biology. Consistent with this, diabetic patients were more likely to 
have a poorly differentiated histology 11. Decreased states of tumor differentiation would be consistent 
with an increase in tumor “stemness.”  
 
2.4.  Metformin and Cancer Patients: While currently the primary data for metformin as a potential anti-
cancer agent is laboratory based, there is significant epidemiologic data supporting the possibility of 
metformin as an active anti-cancer agent in humans.  In a variety of tumor types, metformin has been 
correlated with decreased rates of malignancy.  Recent studies demonstrate that users of metformin are 
at lower risk of cancer compared with people with type 2 diabetes on other treatments12,13.  Metformin 
use is also associated with a lower cancer mortality compared to nonuse of metformin14.  Type 2 
diabetics receiving neoadjuvant chemotherapy for breast cancer as well as metformin were more likely 
to have a complete remission than patients not receiving metformin15.  Patients receiving metformin 
seem to have a lower incidence of prostate and pancreatic cancers16,17.  Metformin has also been shown 
to be a potent inhibitor of cell proliferation in two endometrial cancer cell lines18.  Epidemiological studies 
have confirmed that metformin significantly reduces cancer incidence and improves cancer patients’ 
survival in type 2 diabetics 19.  Interestingly, metformin has also been demonstrated to be most active in 
p53 mutant cancer cells20.  p53 is the most commonly mutated gene in ovarian cancer patients, mutated 
in ~50% of ovarian cancers 21. p53 gene mutations occur more often in stage III and IV ovarian cancers 
when compared to stage I and II (58% in stage III/IV vs. 37% in stage I/II) 22.   There seems to be a trend 
that p53 mutation status, as determined by immunohistochemical (IHC) analysis and in univariate 
analyses, might be of prognostic value in ovarian cancer patients in relation to prognosis, prediction of 
response to adjuvant chemotherapy and in disease progression or survival 23. 
 
2.5. Metformin in Non-diabetic Patients:  In an early study conducted to determine metformin 
pharmacokinetics, there were no significant differences in metformin kinetics in patients with 
non-insulin dependent diabetes compared with healthy subjects. In healthy subjects, 
metformin showed no effect on plasma glucose, but significantly attenuated the rise in 
immediate postprandial insulin levels.24 In addition, metformin has been safely used in 
thousands of polycystic ovarian syndrome patients and is also being explored for use in 
pregnancy25,26.  Metformin is currently being investigated in a number of clinical trials involving 
cancer patients. Currently on clinicaltrials.gov there are 24 clinical trials using metformin 
involving 8 different tumor types (breast, colorectal, pancreas, head and neck, thyroid, acute 
lymphocytic leukemia, prostate and endometrial).  There are no ongoing trials of metformin in 
ovarian cancer patients.  Metformin is being investigated alone, in combination with surgery, in 
combination with chemotherapy, and in combination with surgery and chemotherapy.  All 
doses used are within the typical range for type 2 diabetics receiving metformin.  


 
Last revised August 10, 2017 
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2.6. Metformin in Ovarian Cancer Patients, the Rationale: While the majority of patients with ovarian cancer 
will respond to first-line chemotherapy, over 70% will relapse and ultimately succumb to the disease.  
This indicates a clear need for better therapy.  One attractive potential mechanism to prevent tumor 
recurrence is to target the cancer stem cell population.  In breast cancer, CSC can be targeted by 
metformin.  One study evaluating the effect of metformin in ovarian cancer demonstrated potential anti-
cancer activity of metformin alone and in combination with chemotherapy27.  This study did not assess 
the impact of metformin on ovarian cancer stem cells.  Another recent publication demonstrated that 
metformin treatment of ovarian cancer xenografts resulted in reduced tumor size and metastatic lung 
nodules, as well as diminished angiogenesis compared to controls28.  
 
1. 
Identification of Ovarian Cancer Stem Cells: We recently performed an extensive 
characterization of CSC in ovarian cancer 2.  We have demonstrated that in CD133 (-) cell lines 
and in human primary tumors, aldehyde dehydrogenase enzymatic activity (ALDH) acts a 
marker of CSC.  Treatment of ovarian cancer cell lines with chemotherapy leads to an increase 
in the percentage of ALDH+ cells, suggesting that these cells are chemoresistant.  Similarly, 
FACS isolated ALDH+ cells treated with cisplatin demonstrated greater survival than ALDH- 
cells confirming chemoresistance.  In vivo, limited numbers of ALDH+ cells were able to initiate 
tumors, whereas ALDH- cells could not.  Importantly we were able to generate tumors from 
ALDH+ tumors cells directly isolated from human tumors in 2/9 tumor specimens.  Interestingly, 
in CD133+ cell lines, the combination of ALDH and CD133 identifies a population of cancer stem 
cells with even greater tumor initiation capacity.  This was confirmed using human primary tumor 
cells in sphere forming assays.  Importantly, we were able to generate primary tumor xenografts 
from 10-1000 cells from 5/10 ALDH+CD133+ tumors.  We found that the presence of 
ALDH+CD133+ cells strongly correlated with poor outcome in ovarian cancer patients. 
 
2. 
Metformin as an Anti-Neoplastic in Ovarian Cancer: We have now performed extensive studies 
on the activity of metformin in ovarian cancer. Results indicate that metformin alone can inhibit 
the proliferation of ovarian cancer cells in a dose-dependent manner.  We have found that 
metformin treatment inhibits growth rates ~50% at 1mM, a dose easily achieved in patients with 
standard dosing of metformin.  We observed this for both the SKOV3 and A2780 ovarian cancer 
cell lines. We assessed the activity of metformin when used in combination with cisplatin 
chemotherapy.  Once again we used SKOV3 cells, a cisplatin-resistant ovarian cancer cell line, 
and A2780DK, a cisplatin-sensitive ovarian cancer cell line.  Toxicity was dose-dependent with 
increasing doses of metformin while maintaining a stable dose of cisplatin. We observed this for 
both the SKOV3 and A2780 ovarian cancer cell lines.  As to be expected, the cisplatin-sensitive 
cell line, A2780DK, needed much less of either medication to see the additive effect of the 
metformin. 
 
3. 
Metformin and Ovarian Cancer Stem Cells: Given previous studies in breast cancer stem cells, 
we have specifically investigated the impact of metformin on ovarian cancer stem cells.  As 
discussed above we have shown that ALDH is a CSC marker in ovarian cancer.  We therefore 
analyzed the percent of ALDH+ SKOV3 cells treated with cisplatin and metformin.  We observed 
that cisplatin therapy actually leads to an increase in the percentage of ALDH+ cells, i.e. 
standard chemotherapy enriches the stem cell population and causes these cells to become 
more stem-like.  However, when metformin is added to the treatment regimen we see the cancer 
stem cell population decrease below pretreatment levels.  To confirm an effect on primary 
human tumor specimens we performed tumor sphere assays with primary human tumor ascites 
cells. In the presence of metformin we observed a 2 fold decrease in the number of tumor 
spheres. Next we sorted the same patient’s cells into ALDH+ and ALDH (-) cells.  Again we 
performed tumor sphere assays in the presence and absence of metformin.  As expected very 


 
Last revised August 10, 2017 
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few spheres form in the ALDH (-) groups since the stem cells have been removed from this cell 
population.  In ALDH+ group in the presence of metformin we observed an even greater effect of 
metformin, almost a 3-fold decrease in the number of tumor spheres. 
 
4. 
Metformin as an Anti-Neoplastic in Ovarian Cancer in a Xenograft Mouse Model: The cancer 
stem cell hypothesis for the progression of human cancers is based on the differential tumor-
forming properties and response to chemotherapy of cancer stem cells and non-cancer stem 
cells. Therefore we hypothesize that if metformin reduces the number of cancer stem cells, it will 
significantly reduce tumor growth rates when added to cisplatin chemotherapy.  In addition we 
hypothesize that metformin therapy will significantly slow or even prevent recurrences after 
traditional platinum chemotherapy.  We have performed in vivo experiments in which tumors are 
treated with cisplatin alone or concurrently with cisplatin and metformin.  After 6 weeks of tumor 
growth, we clearly see the effects of metformin. The cisplatin and metformin group appears to 
have a greater effect than cisplatin alone with 3 of the 8 mice in this group have complete 
resolution of the tumors and the other mice have tumors half the size of the cisplatin group.  
Thus combination therapy has a dramatic effect on these otherwise treatment resistant tumors.  
 
2.7. Our data strongly indicates that metformin is an active therapeutic in ovarian cancer and that metformin 
acts by targeting the ovarian cancer stem cell population. Importantly our studies observed significant 
activity with one quarter the dose achieved with traditional dosing in humans.  When used alone, 
metformin slows ovarian cancer cell growth.  When used in combination with chemotherapy, metformin 
blocks the chemotherapy induced enrichment of ALDH+ CSC.  This leads to a synergistic reduction in 
cancer cell growth.  Furthermore we have observed that metformin reduces the growth of ovarian tumor 
spheres, an attribute of cancer stem cells.  Finally, similar to that seen in breast cancer, metformin 
combined with chemotherapy slows the rates of ovarian tumor growth in mice.   
 
We hypothesize that metformin will specifically target ovarian cancer stem cells in ovarian cancer 
patients.  Metformin is currently FDA approved for use in patients with type 2 diabetes and has proven 
safe for human use. It is inexpensive, readily available and well tolerated in most patients. Based on 
preclinical data from our laboratory, we believe that metformin used in combination with 
chemotherapy will improve progression free survival.  Furthermore, given the oral availability of the 
drug and the minimal side effects, metformin represents an ideal therapy to prevent or prolong the 
time to disease relapse. 
 
3. Drug Information29 
 
3.1. Other Names: ActoplusMet, Avandamet, Fortamet, Glucophage, Glucophage XR, Glucovance, 
Glumetza, Metaglip, Riomet 
 
3.2. Classification: Biologic therapeutic 
 
3.3. CAS Registry Number: 1115-70-4 
 
3.4. Description: Metformin hydrochloride is an oral anti-hyperglycemic drug used in the management of 
type 2 diabetes. Metformin hydrochloride (N, N-dimethylimidodicarbonimidic diamide hydrochloride) is a 
white to off-white crystalline compound with a molecular formula of C4H11N5 • HCl and a molecular 
weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in 
acetone, ether, and chloroform. The pKa of Metformin is 12.4. The pH of a 1% aqueous solution of 
metformin hydrochloride is 6.68. 
 
3.5. Mode of Action: Metformin is an anti-hyperglycemic agent which improves glucose tolerance in patients 


 
Last revised August 10, 2017 
10 
 
with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic 
mechanisms of action are different from other classes of oral anti-hyperglycemic agents. Metformin 
decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin 
sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does 
not produce hypoglycemia in either patients with type 2 diabetes or normal subjects and does not cause 
hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin 
levels and day-long plasma insulin response may actually decrease. The mechanism of action of 
metformin on ovarian cancer stems cells is currently unknown.    
 
3.6. How Supplied: Metformin is supplied as tablets for oral administration containing 500 mg, 850 mg, or 
1000 mg of Metformin hydrochloride.  
 
3.7. Source of Drug: Metformin will be purchased from the pharmacy at the University of Michigan by the 
study team. 
 
3.8. Drug Accountability: Metformin tablets will be ordered by the study team and stored/dispensed by 
investigational drug services in accordance with applicable regulatory requirements. Medication that is 
returned from patients will be stored separately from medication that needs to be dispensed. 
 
Accountability for metformin tablets at the study site is the responsibility of the investigator. The 
investigator will ensure that the study drug is used only in accordance with this protocol. The 
investigator may assign the drug accountability responsibilities to a pharmacist. Drug accountability 
records will indicate the drug’s delivery date to the site, the inventory at the site, and the use by each 
patient. At a minimum, accountability records will include dates, quantities, lot numbers, expiration 
dates (if applicable), patient initials and study number, and doses.  
 
All used, unused or expired metformin tablets will be disposed of at the study site according to local 
regulations for the disposition of prescription drugs and documented.  
 
3.9. Storage and Stability:  Store at controlled room temperature (59° to 86°F). 
 
 
3.10. 
Route of Administration: Oral. 
 
3.11. 
Adverse reactions: In a U.S. double-blind clinical study of metformin in patients with type 2 
diabetes, 141 patients received metformin therapy (up to 2550 mg per day) and 145 patients received 
placebo. Adverse reactions were reported in greater than 5% of the metformin patients, and were more 
common in metformin than placebo-treated patients, are: diarrhea (53.2% vs. 11.7%), nausea/ vomiting 
(25.5% vs. 8.3%), flatulence (12.1% vs. 5.5%), asthenia (9.2% vs. 5.5%), indigestion (7.1% vs. 4.1%), 
abdominal discomfort (6.4% vs. 4.8%), headaches (5.7% s. 4.8%)  Diarrhea led to discontinuation of 
study medication in 6% of patients treated with metformin.  Additionally, the following adverse reactions 
were reported in ≥ 1 to ≤ 5% of metformin patients and were more commonly reported with metformin 
than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, 
sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation.  
 
3.12. 
Contraindications: 
  
1. 
Renal disease or renal dysfunction (as suggested by serum creatinine levels ≥ 1.5 mg/dL 
[males], ≥ 1.4 mg/dL [females] or abnormal creatinine clearance) which may also result from 
conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia. 
 
2. 
Known hypersensitivity to metformin hydrochloride.  


 
Last revised August 10, 2017 
11 
 
 
3. 
Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. 
  
3.13. 
Potential Drug Interactions:  
 
1. 
Furosemide: A single-dose, metformin-furosemide drug interaction study in healthy subjects 
demonstrated that pharmacokinetic parameters of both compounds were affected by co-
administration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood 
AUC by 15%, without any significant change in metformin renal clearance. When administered 
with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, 
than when administered alone, and the terminal half-life was decreased by 32%, without any 
significant change in furosemide renal clearance. No information is available about the 
interaction of metformin and furosemide when co-administered chronically. 
 
2. 
Nifedipine: A single-dose, metformin-nifedipine drug interaction study in normal healthy 
volunteers demonstrated that co-administration of nifedipine increased plasma metformin Cmax 
and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Tmax 
and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. 
Metformin had minimal effects on nifedipine. 
 
3. 
Cationic drugs: Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, 
quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular 
secretion theoretically have the potential for interaction with metformin by competing for 
common renal tubular transport systems. Although such interactions remain theoretical (except 
for cimetidine), careful patient monitoring and dose adjustment of metformin and/or the 
interfering drug is recommended in patients who are taking cationic medications that are 
excreted via the proximal renal tubular secretory system. 
 
4. 
Cimetidine: Interaction between metformin and oral cimetidine has been observed in normal 
healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction 
studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 
40% increase in plasma and whole blood metformin AUC. There was no change in elimination 
half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. 
 
5. 
Other: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. 
These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid 
products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium 
channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving 
metformin, the patient should be closely observed for loss of blood glucose control. When such 
drugs are withdrawn from a patient receiving metformin, the patient should be observed closely 
for hypoglycemia. 
 
3.14. 
Precautions: 
  
1. 
Monitoring of renal function: Metformin is known to be substantially excreted by the kidney 
and the risk of metformin accumulation and lactic acidosis increases with the degree of 
impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of 
normal for their age should not receive metformin. In patients with advanced age, metformin 
should be carefully titrated to establish the minimum dose for adequate glycemic effect, because 
aging is associated with reduced renal function. In elderly patients, particularly those ≥ 80 years 


 
Last revised August 10, 2017 
12 
 
of age, renal function should be monitored regularly and, generally, metformin should not be 
titrated to the maximum dose. 
 
2. 
Radiologic studies: This refers to radiologic studies involving the use of intravascular iodinated 
contrast materials (for example, intravenous urogram, intravenous cholangiography, 
angiography, and computed tomography (CT) scans with intravascular contrast materials).  
Intravascular contrast studies with iodinated materials can lead to acute alteration of renal 
function and have been associated with lactic acidosis in patients receiving metformin. 
Therefore, in patients in whom any such study is planned, metformin should be temporarily 
discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to 
the procedure and reinstituted only after renal function has been re-evaluated and found to be 
normal. 
 
3. 
Hypoxic states: Cardiovascular collapse (shock) from whatever cause, acute congestive heart 
failure, acute myocardial infarction and other conditions characterized by hypoxemia have been 
associated with lactic acidosis and may also cause prerenal azotemia. When such events occur 
in patients on metformin therapy, the drug should be promptly discontinued.  
 
4. 
Surgical procedures: Metformin therapy should be temporarily suspended for any surgical 
procedure (except minor procedures not associated with restricted intake of food and fluids) and 
should not be restarted until the patient's oral intake has resumed and renal function has been 
evaluated as normal. 
 
5. 
Alcohol intake: Alcohol is known to potentiate the effect of metformin on lactate metabolism. 
Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while 
receiving metformin. 
 
6. 
Impaired hepatic function: Since impaired hepatic function has been associated with some 
cases of lactic acidosis, metformin should generally be avoided in patients with clinical or 
laboratory evidence of hepatic disease. 
 
7. 
Hypoglycemia: Hypoglycemia does not occur in patients receiving metformin alone under usual 
circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise 
is not compensated by caloric supplementation, or during concomitant use with other glucose-
lowering agents (such as sulfonylureas and insulin) or ethanol. 
 
8. 
Lactic Acidosis: Lactic acidosis is a rare, but serious, metabolic complication that can occur 
due to metformin accumulation during treatment with metformin; when it occurs, it is fatal in 
approximately 50% of cases.  Lactic acidosis may also occur in association with a number of 
pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue 
hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels 
(>5 mM/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an 
increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, 
metformin plasma levels >5 mcg/mL are generally found.  The reported incidence of lactic 
acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 
cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more 
than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic 
acidosis. Reported cases have occurred primarily in diabetic patients with significant renal 
insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting 
of multiple concomitant medical/surgical problems and multiple concomitant 
medications.  Patients with congestive heart failure requiring pharmacologic management, in 


 
Last revised August 10, 2017 
13 
 
particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion 
and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with 
the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, 
be significantly decreased by regular monitoring of renal function in patients taking metformin 
and by use of the minimum effective dose.  In particular, treatment of the elderly should be 
accompanied by careful monitoring of renal function.  Metformin treatment should not be 
initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates 
that renal function is not reduced, as these patients are more susceptible to developing lactic 
acidosis.  
 
4. Staging Criteria FIGO Staging for Ovarian Cancer, Revised 198930 
 
4.1. Stage I: Growth limited to the ovaries. 
 
1. 
IA: Growth limited to one ovary; no tumor on external surface; capsule intact; no ascites 
2. 
IB: Growth limited to both ovaries; no tumor on external surface; capsule intact; no ascites 
3. 
IC: Tumor on the surface of one or both ovaries; or ruptured capsule(s); or ascites containing 
malignant cells; or positive peritoneal washings 
 
4.2. Stage II: Growth involving one or both ovaries with pelvic extension. 
 
1. 
IIA: Extension and/or metastases to the uterus and/or fallopian tubes 
2. 
IIB: Extension to other pelvic tissues 
3. 
IIC: Tumor of stage II with tumor on the surface of one or both ovaries; or ruptured capsule(s); or 
ascites containing malignant cells; or positive peritoneal washings 
 
4.3. Stage III: Tumor involving one or both ovaries with peritoneal implants outside the pelvis and/or positive 
retroperitoneal or inguinal lymph nodes. Superficial liver metastasis equals stage III. 
 
1. 
IIIA: Histologically confirmed microscopic seeding of abdominal peritoneal surfaces 
2. 
IIIB: Histologically confirmed implants of peritoneum <=2cm in diameter and nodes negative 
3. 
IIIC: Abdominal peritoneal implants of >2cm and/or positive retroperitoneal or inguinal lymph 
nodes 
 
4.4. Distant metastases. If pleural effusion is present, there must be positive cytologic test results to allow 
stage IV.  Parenchymal liver metastasis equals stage IV. 
 
5. Eligibility/ Exclusion Criteria 
 
5.1.  Eligibility Criteria 
 
1. 
Patients with potential diagnosis of ovarian, fallopian, or primary peritoneal cancer. Care plan 
including surgical debulking and traditional adjuvant or neo-adjuvant chemotherapy (6-9 cycles 
of platinum and taxane based therapy).  
2. 
ECOG performance status 0-2.  
3. 
Age > 18 years or < 80 years.  
4. 
Adequate renal function (serum creatinine <1.4mg/dL). 
5. 
Adequate liver function (bilirubin < 1.5 times ULN). 
a. ALT or AST < 5X ULN in case of liver metastases.    
b. ALT or AST < 2.5X ULN in absence of liver metastases.  
6. 
Ability to understand and complete written informed consent.  


 
Last revised August 10, 2017 
14 
 
7. 
Mentally, physically, and geographically able to undergo treatment and follow up.  
 
5.2. Exclusion Criteria 
 
1. 
Patients with diabetes mellitus. (Patients with only a history of gestational diabetes will be 
allowed to be included in the study.) 
2. 
Metformin use in the last 6 months. 
3. 
A known hypersensitivity to metformin.  
4. 
A history of metabolic acidosis, including ketoacidosis or increased risk of lactic acidosis. 
5. 
Pregnancy or Lactation.  
6. 
Patients who have any severe and/or uncontrolled medical conditions.  
7. 
Patients with a history of renal disease. 
8. 
Patients with other known active malignancy (excluding adequately treated basal cell / 
squamous cell skin cancer, in situ cancer, or other cancer for which the patient has been 
disease free for 2 years). 
9. 
Patients receiving any other investigational agents.  
 
6. Treatment Plan 
 
6.1. Recruitment: We plan to recruit all patients at the University of Michigan Health System with new 
diagnoses of stage IIC/III/IV ovarian, fallopian tube and primary peritoneal cancers who   are planned to 
receive both chemotherapy and surgical debulking.  Patients will be included regardless of whether the 
patient is optimally debulked (less than 1 cm of remaining tumor) at the time of primary surgery.  
Eligibility and exclusion criteria are given in Section 5.  All eligible patients will be given the opportunity to 
participate.  
 
6.2. Agent Administration:  
 
1. 
Patients treated with primary debulking surgery: All patients receiving primary surgical 
debulking followed by adjuvant chemotherapy will initiate metformin therapy 11+/- 4 days prior to 
primary surgery.  Patients will take 500mg tablets orally once daily for 3 days then the dose will 
be increased to 500mg twice daily (this stepwise increase is to minimize the mild gastrointestinal 
side effects often associated with initiation of metformin therapy). Metformin therapy will be held 
48 hours prior to surgery. Following surgery patients will be initiated on metformin 7 days (+/- 4 
days) prior to the initiation of chemotherapy.  Patients will begin with metformin 500mg tablets 
orally once daily for 3 days then the dose will be increased to 500mg twice daily. (This stepwise 
increase is to minimize the mild gastrointestinal side effects often associated with initiation of 
metformin therapy.) Metformin will be used daily concurrent with chemotherapy and 
discontinued after the patient’s last cycle of primary adjuvant chemotherapy.  Patients will be 
removed from the study whose surgical specimen is determined to be something other than 
epithelial ovarian, fallopian tube or primary peritoneal cancer or the stage is less than IIC.  
 
2. 
Patients treated with neoadjuvant chemotherapy: Patients treated with neoadjuvant 
chemotherapy will be initiated on metformin with the initiation of chemotherapy.  Patients will 
begin with metformin 500mg tablets orally once daily for 3 days then the dose will be increased 
to 500mg twice daily. (This stepwise increase is to minimize the mild gastrointestinal side effects 
often associated with initiation of metformin therapy.) Metformin will be used daily concurrent 
with chemotherapy (for 3-6 cycles of chemotherapy, and discontinued 48 hours prior to surgical 
debulking.  Patients will be removed from the study whose surgical specimen is determined to 
be something other than epithelial ovarian, fallopian tube or primary peritoneal cancer.  
Following surgery, if additional adjuvant therapy is indicated, patients will be initiated on 


 
Last revised August 10, 2017 
15 
 
metformin 7 days (+/- 4 days) prior to the re-initiation of chemotherapy.  Patients will begin with 
metformin 500mg tablets orally once daily for 3 days then the dose will be increased to 500mg 
twice daily. (This stepwise increase is to minimize the mild gastrointestinal side effects often 
associated with initiation of metformin therapy.) Metformin will be used daily concurrent with 
chemotherapy and discontinued  after the patient’s last cycle of primary chemotherapy.   
 
6.3. Dose Levels of Metformin: All patients will initiate drug at dose level 1.  The dose escalation schedule 
for individual patients is indicated here: 
 
Dose-Escalation Schedule 
 
Dose Level 
Dose of Metformin 
 
 (-)1 
500mg PO Daily 
 
1 
500mg PO BID 
 
 
 
6.4. Dose justification: The dose of metformin that we have chosen is the typical dose used in the treatment 
of type 2 diabetes and polycystic ovarian syndrome.  It is also the dose currently being used in many on-
going clinical trials of metformin in other cancers.  In our experiments in the ovarian cancer xenograft 
mouse, we use a dose of 150mg/kg.  This dose can be translated to the human equivalent dose using 
the well-established method as described by Reagan-Shaw et al.31 According to the formula, the human 
equivalent dose (mg/kg) = animal dose (mg/kg) x animal Km/human Km.  Species and Km values are 
based on body surface area.  Km for a 60kg human adult is 37 and a 20g mouse is 3.  On the basis of 
this formula, the human equivalent dose of 150mg/kg in a mouse is 730mg in an average sized woman 
of 60kg. This suggests that the minimum efficacy is 730mg. This is less than one third the maximum 
dose of 2550mg/day recommend by the Food and Drug Administration29 and less than half of the 
1000mg/day our patients will ultimately receive.  
 
6.5. Primary Chemotherapy: All neo-adjuvant and adjuvant platinum-taxane combinations of therapy and 
number of treatment cycles will be determined by the patients’ primary oncologist.  Some of the typical 
treatment regimens are listed below. 
 
1. 
Most common: Paclitaxel (175mg/m2) i.v. + carboplatin (AUC=5-6 mg/ml per minute) i.v. every 
21 days. 
2. 
IP Regimen 1: Docetaxel (75mg/m2) i.v. + cisplatin i.p. (70-100mg/m2) on day 1, paclitaxel i.p. 
(60mg/m2) on day 8 every 21 days 
3. 
IP Regimen 2: Paclitaxel i.v.(135mg/m2) day 1, cisplatin (75mg/m2) i.p. day 2, paclitaxel 
(60mg/m2) i.p. day 8 every 21 days 
4. 
Dose Dense Paclitaxel Regimen: Paclitaxel (80mg/m2) i.v. on days 1,8, and 15 +  carboplatin 
(AUC=6) on day 1 every 21 days   
 
6.6. Frequency of Monitoring: Patients will be monitored prior to every chemotherapy cycle and after 
completion of chemotherapy, patients will be monitored every 12 weeks +/-2 weeks during the first year 
after therapy, and every 4 months +/-2 weeks in the second year, or until evidence of progression.  
 
6.7. Radiologic studies: Metformin should be temporarily discontinued at the time of or prior to and withheld 
for 48 hours subsequent to any radiologic study involving the use of intravascular iodinated contrast 
materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed 
tomography (CT) scans with intravascular contrast materials).  If renal compromise is a concern of the 
patient’s treating physician, metformin should be reinstituted only after renal function has been re-


 
Last revised August 10, 2017 
16 
 
evaluated and found to be normal. 
 
6.8. Surgical procedures: Metformin therapy should be temporarily suspended 48 hours prior to any 
surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and 
should not be restarted until the patient's oral intake has resumed. In the case of the patient’s primary 
debulking surgery, metformin will be re-started 7 days (+/- 4 days) prior to the initiation of chemotherapy 
as long as the patient’s oral intake has resumed.   
 
6.9. Hypoxic states: Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, 
acute myocardial infarction and other conditions characterized by hypoxemia have been associated with 
lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on metformin 
therapy, the drug should be promptly discontinued. Metformin should be reinstituted only after renal 
function has been re-evaluated and found to be normal. 
 
6.10. 
Laboratory Monitoring:  Blood sampling will be performed prior to the first administration of 
metformin. For data collection purposes samples will be obtained (i) prior to surgery, (ii) prior to each 
chemotherapy cycle and (iii) prior to every surveillance visit after the completion of chemotherapy while 
on study.  Delays of two weeks will be accepted.   Labs to be drawn include: 
 
1. 
CBCPD 
2. 
Electrolytes (including serum creatinine and glucose levels) 
3. 
Liver Function Tests (including AST, ALT, and Bilirubin) 
4. 
CA-125 will be drawn prior to every surveillance visit after completion of primary chemotherapy. 
5. 
Hemoglobin A1C will be drawn once with pre-study blood work. 
 
Physicians will be allowed to collect additional labs at their discretion. 
 
6.11. 
Duration of Therapy: In the absence of treatment delays due to adverse events, treatment may 
continue until  after the completion of primary chemotherapy or until one of the following criteria applies: 
 
1. 
Disease progression 
2. 
Intercurrent illness that prevents further administration of treatment 
3. 
Unacceptable adverse event(s) 
4. 
Patient decides to withdraw from the study 
5. 
General or specific changes in the patient's condition render the patient unacceptable for further 
treatment in the judgment of the investigator. 
6. 
If there is any evidence of a negative impact of metformin therapy, therapy will be discontinued 
(see safety sections 8.3 and 12.6). 
 
6.12. 
Monitoring Compliance: Patients will be asked to bring pill bottles/blister packs to doctors’ 
appointments.  In addition patients will be asked to maintain a medication diary to share with their doctor 
at each visit. 
  
6.13. 
Supportive Care Guidelines: Patients will be permitted to receive appropriate supportive care 
measures as deemed necessary by the treating physician. 
  
6.14. 
Duration of Follow-up: Patients will be followed for up to 24 months after completion of 
chemotherapy or until death, whichever occurs first.  Patients removed from study for unacceptable 
adverse events will be followed until resolution or stabilization of the adverse event or a total of 24 
months after completion of chemotherapy, whichever occurs last. 
 


 
Last revised August 10, 2017 
17 
 
7. Toxicities/ Dosage Modifications 
 
7.1. Toxicities.  Given the various treatment protocols allowed, for uniformity, mandatory monitoring of 
adverse events will be performed with each primary chemotherapy appointment (every three weeks for 
all protocols).  Physicians will be allowed to monitor interim labs at their discretion. 
 
1. 
Adverse Events That Can Be Attributed to Metformin Therapy:29 
 
a. Gastrointestinal: diarrhea, nausea and vomiting, flatulence, indigestion, abdominal 
discomfort 
b. Neurologic: Headache, asthenia  
c. Lactic Acidosis: Lactic acidosis is a rare, but serious, metabolic complication that can occur 
due to metformin accumulation during treatment with metformin.  Lactic acidosis may also 
occur in association with a number of pathophysiologic conditions, including diabetes 
mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic 
acidosis is characterized by elevated blood lactate levels (>5 mM/L), decreased blood pH, 
electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate 
ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels 
>5 mcg/mL are generally found.  The reported incidence of lactic acidosis in patients 
receiving metformin is very low (approximately 0.03 cases/1000 patient-years, with 
approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years 
exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported 
cases have occurred primarily in diabetic patients with significant renal insufficiency, 
including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple 
concomitant medical/surgical problems and multiple concomitant medications.  Patients with 
congestive heart failure requiring pharmacologic management, in particular those with 
unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, 
are at increased risk of lactic acidosis.  
d. Other: The following adverse reactions were reported in ≥ 1 to ≤ 5% of metformin patients 
and were more commonly reported with metformin than placebo: abnormal stools, 
hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste 
disorder, chest discomfort, chills, flu syndrome, flushing, palpitation.  
 
2. 
Adverse Events That Can Be Attributed to Platinum Therapy:29 
 
a. Renal: renal insufficiency 
b. GI: nausea and vomiting, diarrhea, hiccups, elevated serum amylase 
c. Neurologic: sensory polyneuropathy, autonomic neuropathies, seizures, encephalopathy, 
myasthenic syndrome, and cortical blindness. Ototoxicity (tinnitus, high frequency hearing 
loss), headache, encephalopathy, and strokes  
d. Hematologic: myelosuppression, Coombs’ positive hemolytic anemia 
e. Ocular: optic neuritis, papilledema, cortical blindness, focal deficits, cerebral blindness, 
blurred vision, altered color perception 
f. 
Vascular: myocardial infarction, cerebrovascular accident, thrombotic microangiopathy 
(hemolytic uremic syndrome), cerebral arteritis 
g. Cardiovascular: chronic lipid and blood pressure abnormalities, possible cardiotoxicity (ST-T 
wave abnormalities and bundle branch block), atrial fibrillation, supraventricular tachycardia 
h. Endocrine: syndrome of inappropriate antidiuretic hormone  
i. 
Hypersensitivity: anaphylactic-like reactions (facial edema, wheezing, tachycardia, and 
hypotension) 
j. 
Hepatic: transient elevations of liver enzymes (SGOT and bilirubin) 
k. Dermatologic: rash, alopecia 
 
3. 
Adverse Events That Can Be Attributed to Paclitaxel Therapy:29 
 


 
Last revised August 10, 2017 
18 
 
a. 
Hematologic: Myelosuppression 
b. 
Gastrointestinal: Nausea and vomiting, diarrhea, stomatitis, mucositis, pharyngitis, typhlitis, 
ischemic colitis, neutropenic enterocolitis 
c. 
Heart: Arrhythmia, heart block, ventricular tachycardia, myocardial infarction (MI), 
bradycardia, atrial arrhythmia 
d. 
Pulmonary: Pneumonitis 
e. 
Blood Pressure: Hypotension, hypertension (possibly related to concomitant medication--
Dexamethasone) 
f. 
Neurologic: Sensory (taste), peripheral neuropathy, seizures, mood swings, hepatic 
encephalopathy, encephalopathy 
g. 
Skin: Infiltration: erythema, induration, tenderness, rarely ulceration, radiation recall 
reactions, erythema multiforme (e.g., Stevens-Johnson syndrome, toxic epidermal 
necrolysis) 
h. 
Allergy: Anaphylactoid and urticarial reactions (acute), flushing, rash, pruritus 
i. 
Liver: Increased SGOT, SGPT, bilirubin and alkaline phosphatase, hepatic failure, hepatic 
necrosis 
j. 
Other: Alopecia, fatigue, arthralgia, myalgia, light-headedness, myopathy 
k. 
Other, Vision: Sensation of flashing lights, blurred vision, scintillating scotomata 
 
4. Amount of expected toxicities of platinum and paclitaxel therapy as determined by 3 
previous clinical trials: 
Frequency of Grade 3/ 4 
Events 
CT IP vs. CT IV32 
Dose Dense CT vs. 
CT IV33 
ICON4: CT IV vs. 
Platinum alone 
(grades 2-4)34 
Leukopenia/ Neutropenia 
76% v 64% 
92% v 88% 
NR 
Other heme event 
94% v 90% 
NR 
29% v 46% 
Thrombocytopenia 
NR 
44% v 38% 
NR 
Anemia 
NR 
69% v 44% 
NR 
GI event/ 
Nausea+Vomitting+Diarrhea 
46% v 24% 
16% v 18% 
35% v 40% 
Metabolic event 
27% v 7% 
NR 
NR 
Neuro event/ Motor + 
sensory 
19% v 9% 
12% v 10% 
20% v 1% 
Fatigue 
18% v 4 % 
5% v 3% 
NR 
Infection/ Febrile 
neutropenia 
16% v 6% 
9% v 9% 
17% v 14% 
Renal 
7% v 2% 
NR 
8% v 9% 
Hepatic 
3% v <1% 
NR 
NR 
Alopecia 
NR 
NR 
86% v 25% 
NR = not reported 
 
a. 
Intraperitoneal (CT IP) = paclitaxel 135mg/m2 i.v. over 24 hours + cisplatin 100mg/m2 i.p. 
on day 2 + paclitaxel 60mg/m2 on day 8 vs. CT IV = paclitaxel 135mg/m2 iv over 24 hours + 
cisplatin 75mg/m2 iv on day 232 
b. 
Dose Dense = paclitaxel 80mg/m2 i.v. over 1 hour on days 1, 8, and 15 + carboplatin AUC 
6mg/ml/min on day 1 of a 21 day cycle vs. Conventional (CT IV) = paclitaxel 180mg/m2 iv 
over 3h + carboplatin AUC 6mg/ml/min on day 1 of 21 days cycle33 
c. 
ICON4/AGO-OVAR-2.2: CT IV = Paclitaxel 175mg/m2 iv over 3hr + Carboplatin AUC 5-6mg 
or Cisplatin 50 mg/m2 iv on day 1 ever 21 days vs. Cisplatin 75mg/m2 on day 1 every 21 
days34 
 
 
7.2. Dose Modifications for Metformin 
 
1. 
Toxicities should be attributable to the study drug to constitute Dose-Limiting Toxicity (DLT).  


 
Last revised August 10, 2017 
19 
 
Patients who have one DLT will be allowed to reduce the metformin dose to 500mg  daily.  If a 
second DLT occurs, the patient will be removed from the study. 
 
2. 
Hematologic toxicities are known (expected) adverse events associated with standard 
adjuvant chemotherapy (platinum and paclitaxel).  There are no hematologic toxicities 
associated with metformin; therefore there will be no metformin dose modifications due to 
hematologic toxicities. For Grade 4 hematologic toxicities, growth factor support is 
recommended.  It is unexpected that metformin will exacerbate hematologic toxicities, however, 
if greater than 30% grade 4 hematologic toxicities are observed, new patients will be enrolled at 
dose level (-)1.   
 
3. 
Non-hematologic toxicity 
a. 
Diarrhea:  Grade 2 diarrhea can be managed with loperamide and i.v. fluid hydration as 
needed at the discretion of the patients physician.  Diarrhea is expected to resolve within 2 
weeks of starting metformin.  If Grade 3 diarrhea persists greater than 2 weeks despite 
optimal medical management hold until recovery to Grade 1 and then dose reduce to Level 
-1. Any patient with Grade 4 diarrhea despite optimal medical management will be removed 
from the trial.      
b. 
Nausea, Vomiting, Constipation: It is expected that patients with nausea, vomiting, or 
constipation will receive appropriate medical management without dose modification. 
However, patients with persistent grade 3 (or greater) toxicity despite of optimal medical 
management require metformin dose reduction of -1 level. 
c. 
Headache: It is expected that patients with headache will receive appropriate medical 
management without dose modification. 
d. 
Renal Toxicity: Any patient with a creatinine >1.4 mg/dl, hold metformin until recovery to 
normal renal function (up to 2 weeks) then restart at dose level -1. If no recovery within 2 
weeks or a second event, the patient will be removed from the trial.   
e. 
Hepatic Toxicity: Any Grade 3 (or greater) elevations in SGOT (AST), SGPT (ALT), or 
bilirubin due to any medication (a known toxicity of paclitaxel), hold metformin until recovery 
to patients baseline and restart at -1 dose reduction. 
f. 
Peripheral Neuropathy: Peripheral neuropathy is a known adverse event associated with 
paclitaxel therapy.  It is not associated with Metformin use, therefore there will be no 
metformin dose modifications based on peripheral neuropathy.  
g. 
Alopecia, Fatigue: There will be no dose modifications for alopecia or fatigue. 
h. 
Other Non-hematologic Toxicities: Any other non-hematologic abnormal laboratory 
criteria (Grade > 3) will be considered DLT if clinically significant and not clearly attributable 
to another cause. If baseline value is elevated prior to drug therapy, an increase will not be 
considered a DLT unless there is an elevation by more than 2 grades and it is of clinical 
significance. This DLT will require reduction of one dose level.  
 
 
7.3. Safety Analysis: In order to protect patients in the event that metformin treatment was not a safe as we 
believe a priori, we have implemented a series of stopping rules that will be applied after sequential 
cohorts of 10 patients are accrued.  The acceptable levels of toxicity for each category have been 
determined based upon our own experience with the chemotherapy regimens used at the University of 
Dose Modifications 
Dose level 
Metformin 
-1 
500 mg PO daily 
1 
500 mg PO BID 
 
 


 
Last revised August 10, 2017 
20 
 
Michigan and from published toxicity rates in the literature (see section 7.1 #4). Section 12.6 outlines 
specific details for stopping the trial.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.4. Dose Escalations: Other than with the initiation of drug pre/post-surgery or post CT scans, there will be 
no dose escalations (or re-escalations) on this study. 
 
Type of Toxicity 
Expected Grade 3/ 4 
Events due to 
chemotherapy 
Allowed Grade 3/ 4 
Events with addition 
of metformin 
Amount of Grade 3/ 
4 Events to stop trial
Hematologic 
toxicities: 
-Neutropenia 
 
 
-Thrombocytopenia 
 
-Anemia 
90% 
Any 
 
>20% of patients 
requiring dose delays 
not manageable with 
growth factor 
45% 
<70% 
70% 
95% 
Any 
>20% of patients 
requiring blood 
transfusions 
Nephrotoxicity 
10% 
<20% 
20% 
Neurotoxicity 
20% 
<40% 
40% 
Hepatic toxicities 
5% 
<15% 
15% 
GI toxicities 
45% 
<70% 
70% 


 
Last revised August 10, 2017 
21 
 
 
8. Study Calendar A-Patients treated with primary surgical debulking and adjuvant chemotherapy. 
 
 
 
Study Calendar 
 
Treatment 
Follow Up Year 
1 
Follow up  
Year 2 
Timeline 
Pre-Study 
Pre- surgery 
Surgery 
Post-surgery 
 
Chemotherapyg
Month 3f 
Month 6f 
Month 9f 
Month 12f 
Month 16f 
Month 20f 
Month 24f 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Metformin 500mg 
PO 
 
For 3 days 
 
Resume 1 week 
prior  to initiation 
of chemotherapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
Metformin 500mg 
BID 
 
Begin after 3 
days of dose 
level -1 up 
until 48 hours 
prior to 
surgery 
 
 
X 
Stop after last cycle  
of chemotherapy 
 
 
 
 
 
 
 
Adjuvant 
Chemotherapy 
 
 
 
 
X 
Chemotherapy 
regimen and start 
time as determined 
by Gyn Onc
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent Meds 
Xd 
X 
X 
 
X X X X X X
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
including weight 
Xd 
 
 
 
X X X X X X
X 
X 
X 
X 
X 
X 
X 
Height 
Xd 
 
 
 
X X X X X X
 
 
 
 
 
 
 
Physical Exam 
Xd 
 
 
 
X X X X X X
X 
X 
X 
X 
X 
X 
X 
Performance Status 
Xd 
 
 
 
X X X X X X
X 
X 
X 
X 
X 
X 
X 
CBC (w/diff, plts) 
Xd 
 
 
 
X X X X X X
 
 
 
 
 
 
 
Serum Chemistrya 
Xd 
 
 
 
X X X X X X
 
 
 
 
 
 
 
LFTsb 
Xd 
 
 
 
X X X X X X
 
 
 
 
 
 
 
CA-125 
Xd 
 
 
 
X X X X X X
X 
X 
X 
X 
X 
X 
X 
PT/INR/PTTc 
Xd 
 
 
 
X X X X X X
 
 
 
 
 
 
 
HgBA1C 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event 
Evaluation 
X 
X 
X 
 
X X X X X X
X 
X 
X 
X 
X 
X 
X 
Radiologic Studiese 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tissue Collection 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a: sodium, potassium, chloride, bicarbonate, BUN, creatinine, calcium 
b: albumin, alkaline phosphatase, total bilirubin, total protein, AST, ALT 
c: for patients on Warfarin only or per surgeon’s discretion  
d: 14 days prior to registration 
e: if clinically indicated, not required for registration, may include X-rays, CT scans, MRI, and PET scans  
f: +/- 2 weeks 
g:  Patients will be monitored prior to every chemotherapy cycle at their pre-chemotherapy clinic appointment.


 
Last revised August 10, 2017 
22 
 
Study Calendar B—Patients treated with neoadjuvant chemotherapy 
 
 
 
9. Evaluation Criteria 
 
9.1. Definition of progression or recurrence and survival will be defined as increasing clinical, 
radiological or histological evidence of disease since study entry or two serum values of CA-125 greater 
Study Calendar 
 
Treatment 
Follow up 
 
Timeline 
Pre-Study 
Pre- Chemotherapy 
Neo-adjuvant 
Chemotherapyg 
Surgery 
Pre-Adjuvant 
Chemotherapy 
Adjuvant  
Chemotherapy
h 
Year 1 
Year 2 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4h 
Cycle 5h 
Cycle 6h 
Cycle 1 
Cycle 2 
Cycle 3 
Month 3f 
Month 6f 
Month 9f 
Month 12f 
Month 16f 
Month 20f 
Month 24f 
Metformin 500mg 
PO  for 3 days 
 
X i 
 
 
 
 
 
 
 
X i 
 
 
 
 
 
 
 
 
 
 
Metformin 500mg 
BID 
 
Begin after 3 
days of dose 
level -1  
X 
Stop 48 hours prior to 
surgery 
 
 
X  
stop after last cycle  
of chemotherapy 
 
 
 
 
 
 
 
Chemotherapy 
 
 
X 
Chemotherapy regimen 
and start and stop time as 
determined by Gyn Onc 
 
 
X 
Chemotherapy 
regimen and start 
and stop time as 
determined by Gyn 
Onc
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent Meds 
Xd 
 
X 
X X 
X
X
X
X 
 
X 
X 
X 
X 
X 
X
X
X
X
X
Vital Signs 
including weight 
Xd 
 
X 
X X
X
X
X
 
 
X 
X 
X 
X 
X 
X
X
X
X
X
Height 
Xd 
 
X 
X X
X
X
X
 
 
X 
X 
X 
 
 
 
 
 
 
 
Physical Exam 
Xd 
 
X 
X X
X
X
X
 
 
X 
X 
X 
X 
X 
X
X
X
X
X
Performance 
Status 
Xd 
 
X 
X X
X
X
X
 
 
X 
X 
X 
X 
X 
X
X
X
X
X
CBC (w/diff, plts) 
Xd 
 
X 
X X
X
X
X
 
 
X 
X 
X 
 
 
 
 
 
 
 
Serum Chemistrya 
Xd 
 
X 
X X
X
X
X
 
 
X 
X 
X 
 
 
 
 
 
 
 
LFTsb 
Xd 
 
X 
X X
X
X
X
 
 
X 
X 
X 
 
 
 
 
 
 
 
CA-125 
Xd 
 
X 
X X
X
X
X
 
 
X 
X 
X 
X 
X 
X
X
X
X
X
PT/INR/PTTc 
Xd 
 
X 
X X
X
X
X
 
 
X 
X 
X 
 
 
 
 
 
 
 
HgBA1C 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event 
Evaluation 
X 
 
X 
X X
X
X
X
X 
 
X 
X 
X 
X 
X 
X
X
X
X
X
Radiologic 
Studiese 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tissue Collection 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
a: sodium, potassium, chloride, bicarbonate, BUN, creatinine, calcium 
b: albumin, alkaline phosphatase, total bilirubin, total protein, AST, ALT 
c: for patients on Warfarin only or per surgeon’s discretion  
d: 14 days prior to registration 
e: if clinically indicated, not required for registration, may include X-rays, CT scans, MRI, and PET scans 
f: +/- 2 weeks 
g:  Patients will be monitored prior to every chemotherapy cycle at their pre-chemotherapy clinic appointment. 
h: if indicated --3-6 cycles of neoadjuvant chemotherapy and an additional 3 cycles of adjuvant therapy are allowed as determined by the primary 
physician.  
i: start the day of  initiation of chemotherapy 


 
Last revised August 10, 2017 
23 
 
than or equal to two times the upper limits of normal (ULN) performed at least one week apart, 
regardless of CT scan results. Since disease progression based only on rising CA-125 involves two 
observations on two different dates, the date of progression will be defined as the first date on which the 
CA-125 was greater than or equal to two times the upper limit of normal. In the event of increasing 
symptoms and no elevation of CA-125, a CT scan will be performed to evaluate for progression. Patients 
with progressing disease based on rising CA-125 must have CT scan of the abdomen and pelvis 
performed. 
 
9.2. Recurrence-Free Interval will be defined as date from start of chemotherapy to the date of first clinical, 
biochemical, or radiological evidence of progression or death due to any cause. RFS will be censored at 
the last assessment of disease progression for living patients who have not progressed. 
 
9.3. Overall Survival (OS) will be defined as observed length of life from entry onto the protocol to death due 
to any cause, or for living patients, date of last contact (regardless of whether or not this contact is on a 
subsequent protocol).   
 
9.4. All conclusions should be based on all evaluable patients. Sub-analyses may then be performed on the 
basis of a subset of patients, excluding those for whom major protocol deviations have been identified 
(e.g., early death due to other reasons, early discontinuation of treatment, major protocol violations, 
etc.).  However, these sub analyses may not serve as the basis for drawing conclusions concerning 
treatment efficacy, and the reasons for excluding patients from the analysis should be clearly reported. 
The 95% confidence intervals should be provided.  
 
9.5. Evaluable patients  
 
1. 
For clinical endpoints “evaluable patients” will be defined as all patients with a final pathologic 
diagnosis of at least Stage IIC/III/IV and have taken metformin for at least 1 complete cycle of 
chemotherapy (regardless of whether it is during neoadjuvant or adjuvant chemotherapy). 
Patients who enroll and are not considered evaluable will be replaced in the trial. 
2. 
For translational endpoints will be defined as all patients with a final pathologic diagnosis of at 
least Stage IIC/III/IV and have taken metformin for at least 11+/- 4 days prior to primary surgery 
or at least 1 complete cycle of neoadjuvant chemotherapy. 
 
 
10. Adverse Event and Reporting Definitions 
 
In the event of an adverse event, the first concern will be for the safety of the subject. Investigators are 
required to report any serious adverse event, whether expected or unexpected, and which is felt by the 
investigator to be reasonably or possibly related to or caused by Metformin. All events meeting these 
criteria will be reported for the time period beginning with any amount of exposure to Metformin through 
the protocol-defined follow-up period. Serious criteria, definitions, and guidance for reporting follows. 
 
 
 
 
 
 
10.1    Definitions 
 
Adverse event 
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  
 


 
Last revised August 10, 2017 
24 
 
An adverse event (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a drug, without any judgment about causality. An adverse event can 
arise from any use of the drug (e.g., off-label use, use in combination with another drug) and 
from any route of administration, formulation, or dose, including an overdose.  
 
Adverse reaction 
An adverse reaction means any adverse event caused by a drug. Adverse reactions are a 
subset of all suspected adverse reactions for which there is reason to conclude that the drug 
caused the event.  
 
 
Pre-existing condition 
 Any medical condition or laboratory abnormality with an onset date before initial investigation 
agent/intervention administration is considered to be pre-existing in nature. 
 
Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
‘reasonable possibility’ means there is evidence to suggest a causal relationship between the 
drug and the adverse event. A suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any adverse event caused by a drug. 
  
Unexpected 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the protocol, informed consent, investigator brochure, or is not listed at the specificity or severity 
that has been observed; or, if an investigator brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or elsewhere in 
the current application. For example, under this definition, hepatic necrosis would be 
unexpected (by virtue of greater severity) if the investigator brochure referred only to elevated 
hepatic enzymes or hepatitis. Similarly, cerebral vasculitis would be unexpected (by virtue of 
greater specificity) if the investigator brochure listed only cerebral vascular accidents. 
"Unexpected," as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned 
as occurring with the particular drug under investigation. 
 
Serious 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or sponsor (UNIVERSITY OF MICHIGAN), it results in any of the following 
outcomes:  
o Death 
o A life-threatening adverse event 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
o A congenital anomaly/birth defect.  
o Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
Previously planned (prior to signing the informed consent form) surgeries should not be reported 


 
Last revised August 10, 2017 
25 
 
as SAEs unless the underlying medical condition has worsened during the course of the study. 
Preplanned hospitalizations or procedures for preexisting conditions that are already recorded in 
the patient’s medical history at the time of study enrollment should not be considered SAEs. 
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for example, 
for the administration of study therapy or other protocol-required procedure) should not be 
considered SAEs. However, if the preexisting condition worsened during the course of the 
study, it should be reported as an SAE. 
  
Life-threatening 
An adverse event or suspected adverse reaction is considered “life-threatening” if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk 
of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
 
 
 
10.2 
Reporting of Serious Adverse Events Associated with Metformin 
 
Event reporting for ovarian cancer protocols can be complicated and confusing to investigators, 
data managers, and regulatory oversight bodies because patients typically develop numerous 
complications such as infections, chemotherapy- related organ damage, medication side effects, 
etc. as part of the typical course of treatment for ovarian cancer and not related to the study 
therapy. Furthermore, ovarian cancer- related complications often occur both simultaneously 
and in series, as one complication leads to a series of additional downstream events, making 
time-sensitive reporting of events difficult. Therefore, a well-conceived event reporting plan will 
separate complications that might be seen with any cancer, from study-related events that are 
relevant to subject safety. In order  to achieve this goal,  the DSM  plan  for this  study  will focus  
on rapid  and specific  identification and reporting  of the following as SAEs: 
 
a) Events which are serious and likely (probably or definitely) related to the investigational 
component of study therapy. 
b) Events occurring at unusual frequency or severity in study subjects compared to non-study 
subjects undergoing similar treatment.. 
c) Events resulting in death regardless of attribution. 
d) Events that are serious and unexpected  
 
Therefore, we will not report as SAEs events that are expected and coincident with a typical 
ovarian cancer chemotherapy course unless they are either fatal or related to the investigational 
therapy. 
 
 
All serious adverse events (SAEs) that are definitely or probably related to Metformin (this 
applies to both expected and unexpected events) will be recorded on the CTO Standard 
Serious Adverse Event form.  
 
 
All serious adverse events that are definitely or probably related to Metformin will be 
reported to the IRB per current institutional standards. 
 
 
 
          Reporting Procedures 
     Serious adverse Events (SAE’s) should be reported to: 
 
Data Manager:  Michelle Smith 
Phone: (734) 232-0758 
Fax:  (734) 936-0645 


 
Last revised August 10, 2017 
26 
 
Email:   smimiche@med.umich.edu 
 
Principal Investigator: Ronald J. Buckanovich, MD, PhD 
Phone: (734) 764-2395 
Fax: (734) 936-7376 
E-mail:ronaldbu@umich.edu 
 
 
The Clinical Trials Office (CTO) staff will coordinate the reporting process between the Investigator 
and the IRBMED as well as any other applicable reporting. Copies of all related correspondence 
and reporting documents will be maintained in the subject research chart and/or regulatory file as 
appropriate. 
 
The data manager will complete the CTO SAE Report form for all adverse events meeting one or 
more of the serious criteria listed in Section 10.1. The SAE Report form will be submitted to the IRB 
within seven calendar days of the event or investigator's receipt of notification of the event.  
 
Death: Deaths occurring within 30 days of the last study intervention are reportable events 
regardless of whether or not the investigators deem the death to be related to the study and 
must be submitted to the IRB within 7 calendar days of the event or investigator’s receipt of 
notification of the event.  
If death occurs later than 30 days after the last study intervention with metformin, then the death 
is not reportable unless related to metformin. 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. 
Serious Adverse Events (SAEs) will continue to be followed until resolution or clearly determined 
to be due to a patient’s stable or chronic condition or intercurrent illness(es). 
 
The investigator is responsible for the detection, documentation, grading and assignment of 
attribution of events meeting the criteria and definition of an AE or SAE. The definitions of AEs 
and SAEs are given below. It is the responsibility of the principal investigator to ensure that all 
staff involved in the trial is familiar with the content of this section. 
 
All adverse events occurring from the initial investigational agent/intervention administration 
through 30 days following the last dose of the investigational agent/intervention must be 
recorded as an adverse event in the patient’s source documents and on the CRF regardless of 
frequency, severity (grade) or assessed relationship to the investigational agent/intervention. 
 
Any known pre-existing conditions that are ongoing at time of study entry should be considered 
medical history and recorded in the appropriate section of the case report form. In addition to 
new events, any increase in the frequency or severity (i.e., toxicity grade) of a pre-existing 
condition that occurs after the patient begins taking the investigational agent/intervention is also 
considered an adverse event. 
 
 
10.3 
Adverse Event Characteristics 
 
 
CTCAE term  
Adverse events (AE’s) will use the descriptions and grading scales found in the revised National 
Cancer Institute (NCI) Common Terminology for Adverse Events Criteria (CTCAE). 
 
A copy of the CTCAE version 4.0 can be downloaded from the CTEP home page: 
http://ctep.info.nih.gov/reporting/ctc.html 


 
Last revised August 10, 2017 
27 
 
 
CTCAE v4.0 can also be found as a PDF file on the Cancer Center Intranet Clinical Trials Office 
page: 
http://www.cancer.med.umich.edu/i/cto.htm 
 
Attribution of the AE: The investigator is responsible for assignment of attribution. 
Definite – The AE is clearly related to the investigational agent/intervention. 
Probable – The AE is likely related to the investigational agent/intervention. 
Possible – The AE may be related to the investigational agent/intervention. 
Unlikely – The AE is doubtfully related to the investigational agent/intervention. 
Unrelated – The AE is clearly NOT related to the investigational agent/intervention. 
 
11. Data and Safety Monitoring 
 
Scheduled meetings will occur every quarter or more frequently depending on the activity of the protocol. 
These meetings will include the protocol investigators and data managers involved with the conduct of the 
protocol. Scheduled meetings by the study specific Data and Safety Monitoring Committee (DSMC) will 
occur quarterly or more frequently depending on the activity of the protocol. This committee will include the 
protocol investigators, data manager or designee, and other members of the study team involved with the 
conduct of the trial. 
 
During these regular meetings, the DSMC will discuss matters related to: 
 
1. Safety of study participants (SAE/UaP reporting) 
2. Validity and integrity of the data 
3. Enrollment rate relative to expectations, characteristics of participants 
4. Retention of participants, adherence to protocol (potential or real protocol deviations) 
5. Data completeness 
 
 DSMC meetings will be documented by the Protocol Specific Data and Safety Monitoring Report (DSMR).  
The   data manager or designee assigned to the trial will be responsible for completing the report.  DSMRs 
will be signed by the Principal Investigator or by one of the co-investigators and will be kept on file in the 
Cancer Center CTO. (See Appendix 2 for DSMR.) 
 
The University of Michigan Comprehensive Cancer Center Data and Safety Monitoring Board (UMCCC 
DSMB) will provide independent oversight of the safety and data integrity for this trial.  DSMRs and any 
other pertinent documents will be submitted to the UMCCC DSMB for review on a quarterly basis unless 
specified more frequently by a DSMB ruling. 
 
The Principal Investigator or designee will forward all correspondence and recommendations generated by 
the UMCCC DSMB to the Institutional Review Board. 
 
 
 
12. Statistical Considerations 
 
12.1 
Primary objectives: This trial has two primary objectives: 1- to determine the impact of adding 
metformin to traditional chemotherapy on recurrence-free survival when measured at 18 months 
following the initiation of adjuvant chemotherapy with metformin treatment following surgical resection, 
as compared to matched historical data, and 2 - to determine the impact of adding a short course of 
metformin prior to surgery on the proportion of cancer stem cells in the surgical specimen when 
compared to non-study, matched control patients. 


 
Last revised August 10, 2017 
28 
 
  
12.2 
Secondary objectives: This trial has three secondary objectives: 1 – to determine the overall 
survival of ovarian cancer patients from the initiation of treatment with adjuvant metformin and 
traditional chemotherapy following surgical resection, 2 – to confirm the safety of metformin treatment 
in non-diabetic ovarian cancer patients, and 3 - to correlate the number of CSC in the primary tumor 
specimens and recurrence-free survival. 
  
12.3 
Exploratory objectives: This trial will assess the impact of p53 status of tumor tissue on the 
patient’s response to metformin treatment. 
 
12.4 
Power and sample size considerations: This trial will accrue 50 patients meeting the evaluable 
criteria (see section 9.5 for evaluable criteria).  This trial will further assess the CSC proportion for 50 
matched control patients for whom tissue is already stored or that will be stored by the Gynecologic 
Oncology Program during the conduct of this trial.  The sample size for this trial was chosen after 
careful consideration of the statistical power to address the study’s two primary objectives. 
 
Historically 50% of ovarian cancer patients meeting our study’s eligibility criterion would be alive and 
recurrence-free at 18 months following surgical resection. We hypothesize that with the addition of 
metformin to standard chemotherapy regimens, the proportion will increase to 70%.  If we test this 
dichotomous outcome using a one-sided, one-sample exact binomial test (DTPLAN, Version 4.2) 
allowing at most 2.5% type I error (equivalent to 5% for two-sided test), then 49 patients are 
necessary for the test to have at least 80% power.  As we believe adherence to protocol will be 
extremely high and loss to follow-up or treatment discontinuation to be extremely low, 50 patients are 
recommended for this trial. 
 
The CSC proportion from surgical resection specimens after a short neoadjuvant course of metformin 
treatment will be compared to non-metformin treated, control ovarian cancer specimens.  Control 
cases must meet the eligibility criteria set forth for this trial and will consist of frozen tissue samples 
currently available to the Gynecologic Oncology Program or from non-study patients with tumor 
resection at the University of Michigan.  Untreated controls will be matched with primary surgery 
patients and controls who have received prior treatment will be matched with neoadjuvant patients. 
Preliminary data suggests that the ovarian cancer stem cell proportion is known to vary between 1 
and 7% for resected specimens with an approximate mean of 3%.  So it is expected that average 
CSC proportion for control cases will be 3%. With metformin treatment, it is hypothesized that the 
CSC proportion will be reduced by half, to 1.5%.  In order to calculate power, the scale of the 
measurements will be transformed to their angular equivalents using an adaptation of the arcsine 
transformation of the square root of the proportion, in order to normalize the otherwise skewed 
distribution.  On the transformed scale, the mean of the metformin treated cases and the control 
cases are expected to be 403.07 and 571.48, respectively.  We expect mild variability, an assumption 
formalized by setting the standard deviation equal to ½ of the mean for each group.  With 50 treated 
and 50 control cases, using a two-sample, two-sided, t-test will yield over 90% power to detect the 
hypothesized difference significantly, with at most 5% type I error. 
 
12.5 Analysis Plan:  The proportion of CSCs per patient will be calculated based upon the ALDH+ or 
ALDH+/CD133+ phenotype as measured by FACS.  The proportion will be summarized graphically by 
histogram with the mean, median, 25th and 75th percentiles, and the minimum and maximum 
proportions reported.  The results will be stratified by treatment versus control status and the p-value 
from the arcsine transformed t test comparison of the mean proportions reported. 
 
The crude proportion of patients alive and recurrence-free at 18 months will be reported.  Given that 
loss to follow-up is expected to be minimal or non-existent, the crude proportion should equal the 


 
Last revised August 10, 2017 
29 
 
product-limit estimate of Kaplan and Meier which will also be used to estimate the recurrence-free 
survival experience over the entire follow-up period available.  Point-wise confidence interval will be 
constructed using Greenwood’s estimate of the variance using the log-log transformation of the RFS 
estimate. 
 
Recurrence-free survival will be summarized for those patients with CSC proportions at or above the 
median study value versus below the median for a crude comparison of differences in RFS by CSC 
number.  If visual evidence exists that patients with CSC proportion values below the median have 
longer RFS, then more sophisticated analyses may be explored using the Cox proportional hazard 
model.  Categorical or continuous transformed values for the CSC proportion may be modeled along 
with clinical and patient characteristics known to influence RFS, including but not limited to patient’s 
age, stage of disease, and CA125 levels. 
 
The overall survival of the treated population will be reported by the product-limits estimates of Kaplan 
and Meier.  Point-wise confidence intervals will be reported as described for RFS. 
 
The safety of metformin treatment in non-diabetic ovarian cancer will be monitored throughout the 
conduct of the trial by the stopping rules discussed in the following section.  At the conclusion of the 
trial, if observed toxicity has not triggered the study’s stopping rules, the highest graded toxicity 
(CTCAE, version 4.0) will be reported for each patient in the following categories:  hematologic 
(separated into neutropenia, anemia, and thrombocytopenia), nephrologic, neurologic, hepatic, and 
gastrointestinal.  The number and proportion of the highest graded toxicity for each category will be 
reported. 
 
The p53 mutation status will be determined for each treated patient, with patients grouped as wild-
type or mutant p53.  A priori we expect the patients to be equally divided, with approximately 25 
patients in each group.  We further expect that metformin treatment may be more likely to benefit p53 
mutant patients than wild-type. RFS and OS will be summarized by group and differences tested for 
using the log-rank test statistic.  If we accept our hypothesis that 70% of patient will be alive and 
recurrence-free at 18 months and that the sample size of mutant and wild-type p53 are equal, then it 
might be plausible to expect that 80% of p53 mutant patients are alive and recurrence-free at 18 
months, while only 60% of wild-type are. The trial as constructed would only have 35% power to 
detect such a difference significantly, hence this objective designation as exploratory. 
 
 
 


 
Last revised August 10, 2017 
30 
 
12.6 
Safety Stopping Rule:  In order to protect patients in the event that metformin treatment was not a 
safe as we believe a priori, we have implemented a series of stopping rules that will be applied after 
sequential cohorts of 10 patients are accrued.  The stopping rules have been constructed based upon 
CTCAE version 4.0 grading of toxicity as grade 3 or 4 in 5 categories: nephrologic, neurologic, hepatic, 
thrombocytopenic, and gastrointestinal. The rules were created using the Bayesian beta-binomial 
framework, so that if at the assessment points we becoming at least 90% confident that the probability 
of toxicity in any one of the toxicity categories is above our acceptable level, the trial will halt for further 
investigation and possible changes in treatment, or trial termination.  The acceptable levels of toxicity 
for each category have been determined based upon our own experience with the chemotherapy 
regimens used at the University of Michigan and from published toxicity rates in the literature (see 
section 7.1 #4). That information suggests that over the differing chemotherapy used, that with 
chemotherapy alone (without metformin treatment) that 10%, 20%, 5%, 45%, and 45% of ovarian 
cancer patients undergoing therapy would experience grade 3 or 4 nephrologic, neurologic, hepatic, 
thrombocytopenic, and gastrointestinal toxicity.  The prior probabilities of toxicity with chemotherapy 
alone were used to create beta prior distributions for each toxicity category, minimally informative with 
the distribution centered at the mean, with the equivalent of 2 patients worth of information. For 
example, the prior beta distribution for nephrologic toxicity was B (0.20, 1.80). The following table lists 
the stopping rules for each toxicity category and the acceptable threshold applied.  With the 
implementation of these rules we believe this patient population will be protected from undue increases 
in treatment related toxicity attributable to the addition of metformin. 
 
Number of patients experiencing the listed toxicity (grade 3/4) that would trigger the stopping rule  
(acceptable threshold in parentheses) 
# patients on 
treated on trial 
Hepatic 
(15%) 
Nephrologic 
(20%) 
Neurologic 
(40%) 
Thrombocytopenia 
(70%) 
Gastrointestinal 
(70%) 
10 
4 
5 
7 
9 
9 
20 
6 
7 
12 
17 
17 
30 
8 
10 
17 
25 
25 
40 
10 
12 
21 
32 
32 
 
13. Registration Guidelines  
 
13.1 
When it has been verified that a patient meets the inclusion and exclusion criteria and has 
consented for this trial, the study data manager,  Michelle Smith, should be contacted to register the 
patient.  Please fax a completed eligibility checklist, required laboratory tests and signed consent form 
to  Michelle Smith and the PI (Ronald Buckanovich), between 9 a.m. and 4 p.m. Monday through 
Friday.  
 
Michelle Smith 
Phone: (734) 232-0758 
Fax:  (734) 936-0645 
Email:   smimiche@med.umich.edu 
 
Ronald J. Buckanovich, MD, PhD 
Phone: (734) 764-2395 
Fax: (734) 936-7376 
E-mail: ronaldbu@umich.edu 
 
13.2 
At the time of registration, personnel will verify the following: 
 
1. Patient eligibility checklist 


 
Last revised August 10, 2017 
31 
 
2. Existence of a signed consent form 
3. Existence of a signed authorization for use and disclosure of protected health information. 
 
13.3 
Treatment on this protocol must be administered under the supervision of an oncologist. 
 
13.4 
Treatment cannot begin prior to registration, and must begin within 14 days of registration. 
 
13.5 
Pre-study tests must be completed within the guidelines specified in the Study Calendar.  
 
 
14. Data Forms, Submission and Distribution Information 
 
Data Forms Submission Schedule 
Forms to be submitted 
When 
To What Location 
Eligibility Checklist 
At enrollment 
CTO 
Consent Form 
At enrollment 
CTO 
Data and Safety Monitoring 
Reports 
Quarterly 
CTO 
Medication Diary 
Prior to each chemotherapy cycle 
CTO 
Response to Treatment 
Every 3 cycles while on therapy 
Every 12 weeks post chemo year 
1 and every 4 months year 2.  
CTO 
Adverse Events Report 
As dictated in section 11.3 
PI and Data Manager in CTO 
 
15. Specific Instructions Used to describe special samples, cores or other procedures (including pathology 
review) if used in the protocol.  For in-house protocols, defines areas of responsibility. 
 
15.1 
Personnel Responsibilities: Kun Yang (Research assistant): Dr. Yang will be responsible for all 
laboratory analysis of patient tissue specimens including tumor processing for FACS analysis and IHC 
staining. Mr. Yang will also do all batch analysis of stem cell specimens in conjunction with Dr. Shank.  
 
15.2 
Tumor Processing:  At the time of primary debulking surgery we will obtain tumor specimens from 
all treated and non-treated patients. Kun Yang, Lula Cabrera or one of their representatives will be 
obtaining the tissue specimens directly from the operating room.  Half of each tumor specimen will be 
mechanically dissected into single cell suspensions as previously described35.  Isolated cells will then 
be frozen for future batch FACS analysis (see below).  The remaining portion of each sample will be 
split again, with one portion snap frozen and the remaining piece fixed in formalin and embedded for 
IHC analysis 
 
15.3 Cancer Stem Cell Assessment:  Cancer stem cells in each tumor sample will be assayed in 
batches of 10 specimens (5 treated and 5 untreated).  For each sample we will assess tumor sphere 
formation from whole tumor single cell suspensions as previously described 2.  Briefly, ~4,000 viable 
cells will be plated in triplicate in ultra-low attachment plates (Corning, Acton, MA, USA) in serum-free 
DMEM/F12 (Invitrogen) or EBM-2 (Lonza) supplemented with 5 μg/mL insulin (Sigma), 20 ng/mL 
human recombinant epidermal growth factor (EGF; Invitrogen), 10 ng/mL basic fibroblast growth 
factor (bFGF; Invitrogen), and 0.4% bovine serum albumin (BSA; Sigma). Sphere formation is 
counted 2 weeks after seeding the cells. Spheres are then photographed in overlapping high power 
fields (90-100% coverage). Sphere number is then compared between groups using a two-sided 
student's t-test.  Spheres are then mechanically separated and re-plated to assess the ability to 
passage.  This is repeated for a total of 3 passages. 


 
Last revised August 10, 2017 
32 
 
 
For each sample we will also assess the percentage of ovarian CSC.  We will use both FACS and 
AQUA co-immunofluorescence to determine the percentage of ALDH+ and CD133+, or 
ALDH+/CD133+ cells in primary ovarian tumors.  We found that the presence of ALDH+CD133+ cells 
was strongly predictive of poor outcome.  Whereas, consistent with previous studies, ALDH strong 
tumors were associated with a good outcome.  We will therefore quantify these populations in the 
metformin treated and non-treated tumors to determine if metformin has an impact on the percentage 
of each of these putative CSC populations.  FACS analysis and AQUA analysis will be performed as 
previously described2.   
 
Finally, we will confirm the functional activity of the CSC in these tumor specimens.  From each of the 
isolated tumors will we inject tumors in NOD/Shi-scid/IL-2Rγnull (NOG) mice and assess (1) 
engraftment and (2) rates of growth.  All tumors are weighed at the time of resection and then a 
portion of each tumor is snap frozen for histological analysis and another portion is processed into a 
single cells suspension as described above. Tumor volumes are calculated using the (L*W*W)/2 
formula. Tumor weights are compared using a student’s t-test. Tumor growth curves are compared 
using ANOVA and a student’s t-test.  
 
 


 
Last revised August 10, 2017 
33 
 
Appendix 1 
 
 
The University of Michigan Comprehensive Cancer Center 
Clinical Trials Office 
 
Protocol Number: UMCC 2011.037 
A Phase III Evaluation of Metformin, Targeting Cancer Stem Cells for the Prevention of Relapse in 
Patients with Stage IIC/III/IV Ovarian, Fallopian Tube and Primary Peritoneal Cancer 
 
Registration and Eligibility Checklist 
 
Date:________________   Patient Initials: (first, middle, last)______________        Date of Birth ___________ 
 
Eligibility 
 
Answers 1-10 must be ‘Yes’ to be eligible for this study. Record all dates in (mm/dd/yyyy) format. 
 
1. Does the subject have a potential diagnosis of ovarian, fallopian tube or peritoneal cancer?  __Yes  __No 
 
2. Does the patient’s plan of care include either (1) neo-adjuvant chemotherapy and surgical debulking  
    OR (2) primary debulking surgery and adjuvant chemotherapy? (Patients for whom surgical debulking  
    is not planned are not eligible). 
 
 
 
 
 
 
 
            __Yes  __No 
 
3. Is the ECOG performance status 0-2? 
 
 
 
 
 
 
 
__Yes  __No 
 
ECOG:__________ 
 
4. Is the patient > 18 years or older? 
 
 
 
 
 
 
 
__Yes  __No 
 
5. Is the patient < 80 years old 
 
 
 
 
 
 
 
            __Yes  __No 
 
6. Does the patient have normal organ function as defined in the protocol Section 5.1, obtained  
    within 14 days prior to registration? (ULN = upper normal limit)  
 
 
 
__Yes  __No                  
 
Date of labs: ___________ 
Creatinine <1.4mg/dl:  __________  
 
 
 
 
Bilirubin <1.5x UNL:  _________         ULN: _________________ 
 
 
 
 
ALT < 2.5x UNL (<5x ULN for liver metastases): ______________ULN: _______________ 
AST < 2.5x UNL (<5x ULN for liver metastases):______________ ULN: _______________  
 
7. Is the patient willing to provide blood samples for correlative studies and paraffin blocks/slides  
    from prior diagnostic samples? 
 
 
 
 
 
 
 
           __Yes  __No  
 
8. Does the patient consent to fresh tissue sample donation? 
 
 
 
           __Yes  __No 
 
9. Is the patient competent and willing to provide written documentation of informed consent?  __Yes  __No 
 
10. Is the patient mentally, physically and geographically able to undergo treatment and                                      
follow up?  
 
 
 
 
 
 
 
 
 
 
__Yes  __No 
 
11. Does the patient have diabetes mellitus? 
 
 
 
 
 
_Yes  __No  __NA 
 
12. Has the patient been treated with Metformin in the last 6 months? 
 
          __Yes  __No  __NA 
 
13. Does the patient have a known hypersensitivity to Metformin? 
 
          __Yes  __No  __NA 
 


 
Last revised August 10, 2017 
34 
 
 
The University of Michigan Comprehensive Cancer Center 
Clinical Trials Office 
 
Protocol Number: UMCC 2011.037 
A Phase III Evaluation of Metformin, Targeting Cancer Stem Cells for the Prevention of Relapse 
in Patients with Stage IIC/III/IV Ovarian, Fallopian Tube and Primary Peritoneal Cancer 
 
14. Does the patient have a history of metabolic acidosis, including ketoacidosis  
       or increased risk of lactic acidosis? 
 
 
 
 
 
 
__Yes  __No  __NA 
 
15. Is the patient pregnant or lactating? 
 
 
 
 
 
 
__Yes  __No  __NA 
 
16. Does the patient have any severe or uncontrolled medical conditions? 
 
__Yes  __No  __NA 
 
17. Does the patient have a history of renal disease? 
 
 
 
 
__Yes  __No  __NA 
 
18. Does the patient have any other known malignancy (excluding adequately treated  
      basal cell or squamous cell skin cancer, in situ cancer, or other cancer for which the  
      patient has been disease free for 2 years)? 
 
 
 
 
 
__Yes  __No  __NA 
 
19. Is the patient receiving any other investigational agents? 
 
 
 
__Yes  __No  __NA 
 
 
Pretreatment Evaluations: The following tests must be performed within 2 weeks of study enrollment: 
 
History & Physical Exam: 
 
 
Date: _ _ /_ _ /_ _ _ _ 
Height, Weight, & ECOG Status: 
 
Date: _ _ /_ _ /_ _ _ _ 
CBC w/differential & platelets: 
 
Date: _ _ /_ _ /_ _ _ _ 
HgBA1C 
 
 
 
 
Date: _ _ /_ _ /_ _ _ _ 
Chemistries: (sodium, potassium, chloride, bicarbonate, BUN, Creat, Calcium)  
 Date: _ _ /_ _ /_ _ _ _ 
Liver Function Tests: (albumin, alkaline phosphatase, total bilirubin, total protein, AST, ALT)        Date: _ _ /_ _ /_ _ _ _                 
Coagulation Profile (PT, PTT, INR) (For patients on Coumadin only or per surgeon’s discretion)  Date: _ _ /_ _ /_ _ _ _  or  
___NA 
 
 
Is the patient eligible? 
__Yes  __No 
 
 
Investigator Signature: _____________________________________  
Date: __________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


 
Last revised August 10, 2017 
35 
 
Appendix 2
 
 
 
 
 


 
Last revised August 10, 2017 
36 
 
Appendix 3 
HUM00047900/ UMCC 2011.037        
 
 
 
 
Patient Initials:  ____ ____ ____
 
Day
Date
Time
Dose
CIRCLE Number of Tablets 
Taken
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
20
PRE-SURGERY METFORMIN MEDICATION DIARY
•Fill out this diary every day
•Bring this diary and metformin bottles (empty or not) to your clinic appointment and give to the study team
•Remember to STOP TAKING METFORMIN 48 HOURS PRIOR TO YOUR SURGERY DATE
** INCREASE TO 500 MG TWICE DAILY UNLESS TOLD OTHERWISE BY YOUR DOCTOR**
15
16
17
12
13
14
9
10
11
6
7
8
4
5
18
19
1
2
3


 
Last revised August 10, 2017 
37 
 
HUM00047900/UMCC 2011.037 
 
 
 
 
Patient Initials:  ____ ____ ____ 
 
REMEMBER TO STOP METFORMIN 48 HOURS PRIOR TO YOUR SURGERY DATE 
 
 
Patient Signature: ________________________________  Date: ______________ 
 
 
 
The following should be filled out by clinic staff only: 
 
Number of Metformin tablet remaining in the bottle:  _________ 
 
Signature of person doing the tablet count:  _________________________________  Date:  ____________ 
 
 
Day
Date
Time
Dose
CIRCLE Number of Tablets 
Taken
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
35
32
33
34
29
30
31
26
27
28
23
24
25
PRE-SURGERY METFORMIN MEDICATION DIARY
21
22


 
Last revised August 10, 2017 
38 
 
 HUM00047900/UMCC 2011.037 
 
 
 
 
 
Patient Initials:  ____ ____ ____ 
 
 
 
 
Patient Signature: ________________________________  Date: ______________ 
 
 
 
 
 
The following should be filled out by clinic staff only: 
 
Number of Metformin tablet remaining in the bottle:  _________ 
 
 
Signature of person doing the tablet count:  _________________________________  Date:  ____________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day
Date
Time
Dose
CIRCLE Number of Tablets 
Taken
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
** INCREASE TO 500 MG TWICE DAILY UNLESS TOLD OTHERWISE BY YOUR DOCTOR **
• Please fill out this diary every day.
• Please bring this diary and your Metformin bottle (EMPTY OR NOT) to your clinic appointment and give them to the 
study team. Thank you
POST-SURGERY METFORMIN MEDICATION DIARY
7
4
5
6
1
2
3


 
Last revised August 10, 2017 
39 
 
HUM00047900/UMCC 2011.037 
 
 
 
 
 
Patient Initials:  ____ ____ ____ 
 
 
Day
Date
Time
Dose
CIRCLE Number of Tablets 
Taken
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
20
17
18
19
14
15
16
11
12
13
8
9
10
5
6
7
3
** INCREASE TO 500 MG TWICE DAILY UNLESS TOLD OTHERWISE BY YOUR DOCTOR**
4
METFORMIN MEDICATION DIARY
•Fill out this diary every day
•Bring this diary and metformin bottles (empty or not) to your clinic appointment and give to the study team
1
2


 
Last revised August 10, 2017 
40 
 
 
 
HUM00047900/UMCC 2011.037 
 
 
 
 
 
Patient Initials:  ____ ____ ____ 
 
 
 
Patient Signature: ________________________________  Date: ______________ 
 
 
 
 
The following should be filled out by clinic staff only: 
 
Number of Metformin tablet remaining in the bottle:  _________ 
 
Signature of person doing the tablet count:  _________________________________  Date:  ____________ 
Day
Date
Time
Dose
CIRCLE Number of Tablets 
Taken
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
AM
500 mg
1
PM
500 mg
1
33
34
35
30
31
32
27
28
29
24
25
26
21
22
23
METFORMIN MEDICATION DIARY


 
Last revised August 10, 2017 
41 
 
 
Appendix 4 
 
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. 
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. 
 


 
Last revised August 10, 2017 
42 
 
Appendix 5  
 
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