Clinical trial NCT02325401
Conditions: Head and Neck Cancer
Sponsor: University of Cincinnati
Start date: 2015-05-11; Completion date: 2020-02-21
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this research study is to test the safety of adding metformin to standard of care. The standard of care treatment will be cisplatin once every 3 weeks for 3 treatments and radiation for 7 weeks.

Metformin is a medication that is currently used to treat diabetes. Increasing amounts of metformin will be given to groups of patients already receiving normal treatment for their cancer to see if metformin causes any good effects by killing your cancer or bad effects (side effects).

Detailed description:
Patients were registered by contacting the University of Cincinnati Clinical Trials Office. Patients must be registered and consent obtained prior to initiation of any protocol therapy.

Treatment was administered on an outpatient basis. Adverse events and potential risks for metformin and cisplatin and radiation were reported.

Patients must have screening labs performed within 2 weeks of start of treatment including a complete blood count, liver function tests, metabolic renal panel including magnesium, vitamin B12 level, lactate, and C-peptide. Renal panel must be verified within 24 hours of cisplatin administration. They must fulfill inclusion criteria.

The recommended starting dose of metformin in diabetic patients is 500mg orally twice a day which can be escalated by 500mg increments weekly as tolerated with the maximum recommended daily dose of 2550mg.

Cisplatin was given either before or after the radiation therapy fraction that is given on the same day. If radiation is held for more than 2 days (for any reason), cisplatin may be held as well until radiation resumes.

The prescribed radiotherapy dose was be 70 Gy in 2 Gy once-daily fraction size (total of 35 fractions).

Arms: arm 1: Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating.
Interventions: intervention 1: Metformin intervention 2: Cisplatin intervention 3: Radiation Therapy
Intervention descriptions: intervention 1: Escalating doses of 2000mg, 2550 mg and 3000mg. Starting 1 week prior to the initiation of chemoradiation and ending the final day of chemo or radiation. intervention 2: Dosed at 100mg/m2 on days 1, 22, and 43 intervention 3: 70 Gy in 2 Gy once daily fractions of 35 fractions

Protocol documents:
Prot_SAP_000.pdf: 
Protocol #: 
 
UCCI-HN-14-01 
 
 
TITLE:  A phase I dose-finding study of metformin in combination with concurrent cisplatin and 
radiation in patients with locally advanced head and neck squamous cell carcinoma.   
 
 
Coordinating Center:  
 
University of Cincinnati 
 
Principal Investigator: 
Trisha Wise-Draper, MD, PhD 
 
Hematology/Oncology 
 
University of Cincinnati 
 
3125 Eden Ave 
 
Cincinnati, OH 45267 
 
Telephone: 513-558-2826 
 
Fax: 513-558-6703 
 
wiseth@uc.edu 
 
 
 
 
PD/PK Laboratory Studies: 
 
J. Silvio Gutkind, PhD 
 
 
 
 
 
University of California San Diego 
 
 
 
 
 
 
Pankaj Desai, MS, PhD 
 
 
 
 
 
The James L Winkle College of Pharmacy 
 
 
 
 
 
210 Wherry Hall  
 
 
 
 
 
Telephone: 513-558-3870 
 
 
desaipb@ucmail.uc.edu 
 
Statistician: 
 
 
 
 
 
Study Coordinator: 
 
Changchun Xie, PhD  
 
 
 
University of Cincinnati Cancer Institute 
Department of Environmental Health 
 
Clinical trials Office 
University of Cincinnati 
 
 
 
200 Albert Sabin Way Suite 1012      
G43 Kettering Lab 
 
 
 
 
Cincinnati, OH 45267  
160 Panzeca Way 
 
 
 
 
Telephone: 513-584-7698 
Cincinnati, OH 45267   
 
 
 
Fax: 513-584-5680 
Telephone: 513-558-0229 
 
 
 
 
 
 
 
 
 
 
Protocol Type / Version # / Version Date:  Version #8 / Version date: 31Aug2017 


Version 8, 31Aug2017 
 
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SCHEMA 
 
 
 
 
 
 
 
 
Dose Escalation Schedule 
Dose Level 
Dose 
 
Metformin Daily 
(in divided doses) 
 
Level -1 
 
1500mg 
 
Level 1 
 
2000mg 
 
Level 2 
 
2550mg 
 
Level 3 
 
3000mg 
 
Expansion 
 
MTD 


Version 8, 31Aug2017 
 
ii 
TABLE OF CONTENTS 
 
 
Page 
SCHEMA ............................................................................................................................................ i 
 
1. OBJECTIVES ............................................................................................................................... 1 
 
1.1  
Primary Objectives ....................................................................................................... 1 
 
1.2  
Secondary Objectives ................................................................................................... 1 
 
2. BACKGROUND .......................................................................................................................... 1 
 
2.1  
Metformin .................................................................................................................... 1 
 
2.2  
Head and Neck Squamous Cell Carcinoma .................................................................. 2 
 
2.3  
Rationale for metformin for treatment of HNSCC ...................................................... 2 
 
2.4  
Rationale for metformin starting dose ....................................................................... 3 
 
2.5  
Correlative Studies Background .................................................................................. 3 
 
 
2.5.1 Pharmacodynamics Studies ...................................................................................... 3 
 
 
2.5.2 Pharmacokinetics and Pharmacogenetics Studies ................................................... 4 
 
3. PATIENT SELECTION .................................................................................................................. 5 
 
3.1  
Phase I Dose Escalation Eligibility Criteria .................................................................. 5 
3.2  
Phase I Dose Escalation Exclusion Criteria .................................................................. 6 
3.3        Dose Expansion Eligibility Criteria ............................................................................... 6 
3.4        Dose Expansion Criteria ............................................................................................... 6 
3.5        Inclusion of Women and Minorities  ........................................................................... 6 
 
4. REGISTRATION PROCEDURES ................................................................................................... 6 
 
5. TREATMENT PLAN .................................................................................................................... 7 
 
5.1  
Agent Administration ................................................................................................... 7 
 
 
5.1.1 
Metformin Dose Escalation .................................................................................... 7 
 
 
5.1.2 
Cisplatin guidelines ................................................................................................. 8 
 
 
 
5.1.2.1 Supportive Care for Cisplatin ............................................................................ 9 
 
 
5.1.3 
Radiation Therapy ................................................................................................... 9 
 
 
 
5.1.3.1 Dose Specifications ........................................................................................... 9 
 
 
 
5.1.3.2 Technical Factors .............................................................................................. 9 
 
 
 
5.1.3.3 Localization, Simulation, and Immobilization ................................................. 10 
 
 
 
5.1.3.4 Target and Normal Tissue Restrictions ........................................................... 10 
 
 
 
5.1.3.5 Treatment Planning and Delivery ................................................................... 11 
 
 
 
5.1.3.6 Compliance Criteria ........................................................................................ 12 
 
 
 
5.1.3.7 Radiation Therapy Adverse Events ................................................................. 13 
 
 
 
 
 
 
5.2  
Definition of Dose-Limiting Toxicity .......................................................................... 13 
 
 
5.2.1 Dose limiting toxicity ................................................................................................ 13 
 
 
5.2.2 Dose Escalation Phase .............................................................................................. 14 
 
 
5.2.3 Expansion Cohort ..................................................................................................... 15 


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iii 
 
5.3 
General Concomitant Medication Guidelines ........................................................... 15 
 
5.4  
Duration of Therapy ................................................................................................... 15 
 
5.5  
Duration of Follow Up ................................................................................................ 16 
 
 
5.5.1   General Follow-up .................................................................................................. 16 
 
 
5.5.2   Early Removal from Study ...................................................................................... 16 
5.6 
Criteria for Removal from Study ................................................................................ 16 
 
6. DOSING DELAYS/DOSE MODIFICATIONS ............................................................................... 16 
 
6.1        Cisplatin ...................................................................................................................... 16 
 
      6.1.1     Neutropenia .......................................................................................................... 16 
 
      6.1.2     Thrombocytopenia ................................................................................................ 17 
 
      6.1.3     Neurotoxicity ......................................................................................................... 17 
            6.1.4     Renal Adverse Events ............................................................................................ 17 
            6.1.5     Nausea and Vomiting ............................................................................................ 17 
 
     6.1.6      Mucositis ............................................................................................................... 17 
            6.1.7      Ototoxicity ............................................................................................................ 17 
 
      6.1.8      Other Toxicities .................................................................................................... 18 
 
6.2        Metformin Hydrochloride .......................................................................................... 18 
            6.2.1       Diarrhea ............................................................................................................... 18 
            6.2.2       Dehydration ......................................................................................................... 18 
 
      6.2.3       Lactic Acidosis ..................................................................................................... 18 
 
      6.2.4       Renal Dysfunction ............................................................................................... 18 
             6.2.5       Hypoglycemia ..................................................................................................... 18 
             6.2.6       Vitamin B12 Deficiency ....................................................................................... 19 
 
      6.2.7        Other toxicities ................................................................................................... 19 
 
      6.2.8        Dose Reduction for Intolerability ....................................................................... 19 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ................................................. 19 
 
7.1 
Expected Adverse Events Reporting .......................................................................... 20 
 
7.2 
Routine Adverse Event Reporting ............................................................................. 22 
 
 
8. PHARMACEUTICAL INFORMATION ........................................................................................ 22 
 
8.1  
Metformin .................................................................................................................. 22 
 
8.2  
Cisplatin ...................................................................................................................... 23 
 
9. CORRELATIVE/SPECIAL STUDIES ............................................................................................ 23 
9.1 
Laboratory Correlative Studies .................................................................................. 24 
 
9.1.1  Immunohistochemistry Methods on Paraffin embedded tissue ...................... 24 
 
9.1.2  Flow Cytometry Methods ................................................................................. 24 
 
9.1.3  Measurements of Serum Cytokines in Blood and Tissues ................................ 24 
9.2 
Pharmacokinetics/Pharmacogenetics ....................................................................... 25 
 
10. STUDY CALENDAR ................................................................................................................... 26 
 
11. MEASUREMENT OF EFFECT .................................................................................................... 28 


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11.1 
Antitumor Effect – Solid Tumors ............................................................................... 28 
 
11.1.1  Definitions ....................................................................................................... 28 
 
11.1.2 Response Criteria ............................................................................................. 28 
 
11.1.3 Duration of Response ...................................................................................... 28 
 
11.1.4 Progression-free Survival ................................................................................. 28 
 
11.1.5 Overall Survival ................................................................................................ 28 
 
 
12. DATA STORAGE ....................................................................................................................... 29 
 
13. DATA MONITORING AND SAFETY MONITORING .................................................................. 29 
 
14. STATISTICAL CONSIDERATIONS ............................................................................................. 32 
 
14.1      Study Design/Endpoints ............................................................................................ 32 
 
14.2      Sample Size/Accrual Rate .......................................................................................... 32 
 
14.3      Analysis of Secondary Endpoints .............................................................................. 33 
 
14.4      Funding, Regulatory, and Feasibility Issues .............................................................. 33 
 
REFERENCES .................................................................................................................................. 34 
 
 
APPENDICES 
 
APPENDIX A 
Performance Status Criteria ............................................................................................. 39 
 


Version 8, 31Aug2017 
 
1 
1. OBJECTIVES 
 
1.1. 
Primary Objective 
 
Determine the maximum tolerated dose of metformin in combination with concurrent cisplatin 
and radiation (CRT) for locally advanced head and neck squamous cell carcinoma (LAHNSCC). 
 
1.2. 
Secondary Objectives 
• Assess the anti-tumor effect of the addition of metformin to CRT in LAHNSCC. 
• Define toxicities associated with the addition of metformin to CRT in LAHNSCC. 
• Explore the change in critical effectors in the mTOR pathway including pS6, 
pAKTS473, and AMPK in tumor biopsies in response to metformin treatment.  
• Evaluate the change in metformin clearance and AUC when combined with 
cisplatin. 
• Estimate the distribution of levels of inflammatory cytokines (IL-6, IL-8, Gro-a), 
angiogenesis molecules (HGF, VEGF-A, VEGF-C), and glucose/insulin/c-peptide 
levels in the blood before and after administration of metformin and CRT. 
• Determine the change in immune cell subsets (CD3, CD4, CD8 and PD1) in 
response to metformin treatment. 
• PFS and OS at 2 years 
 
 
2. BACKGROUND 
 
2.1  
Metformin 
 
2.1.1 Background: 
 
Metformin is a biguanide and an oral antihyperglycemic agent, which is currently FDA approved 
for the treatment of type II diabetes.  Metformin is widely used in many diabetic patients and 
overall very well tolerated.  Unlike other antihyperglycemic agents such as the sulfonylureas, 
metformin does not usually cause hypoglycemia.  Adverse effects are relatively minimal with 
diarrhea being the most common cause of discontinuation.  However, lactic acidosis, although 
rare (estimated incidence of 4.3 cases per 100,000 person-years in metformin users), is a 
serious adverse event resulting in up to 50% mortality when it occurs1,2.  Lactic acidosis has 
been associated with high plasma concentrations of metformin (>10mg/ml) which can occur in 
the presence of renal dysfunction. Therefore, careful monitoring of renal function of patients 
on metformin is imperative to reduce the incidence of this rare side effect.  However, a recent 
retrospective study from the United Kingdom, demonstrated that there was no increase in 
lactic acidosis in patients taking metformin even in patients with severe kidney dysfunction 
(eGFR <30ml/hr)3. The latter study did not measure serum metformin levels.  Therefore, further 
investigation of the safety of metformin, dosing, and the association with lactic acidosis is 
warranted.   
 


Version 8, 31Aug2017 
 
2 
2.2  
Head and neck squamous cell carcinoma 
 
HNSCC continues to be a major public health concern resulting in 650,000 new cases and 
350,000 deaths worldwide each year.  Etiologic factors include tobacco and alcohol use, and 
more recently, infection with human papillomavirus (HPV).  Early stage tumors are often cured 
with single modality treatment, but unfortunately, up to 60% of HNSCCs present as locally 
advanced disease (LAHNSCC).  Based on a pivotal phase III trial in 2003, concurrent 
chemotherapy and radiation (CRT) using cisplatin has become the standard of care for patients 
with unresectable locally advanced disease.  In the latter study, three year overall survival was 
23% in the radiation alone arm compared to 37% in the CRT arm (p value 0.014)4.  Since this 
original study, retrospective studies have demonstrated improved survival and progression free 
survival, likely due to better supportive care, and radiation technique5,6.  Another factor is the 
increasing rates of HPV related cancers, which have been shown to have improved prognosis7.  
However, despite current definitive therapy, many of these patients are still faced with 
frequent relapse rates.  Upon recurrence or metastasis, the prognosis is dismal at only 10-15% 
with median overall survival of 10-12 months8 necessitating the development of improved 
upfront regimens with increased complete response rates. 
 
2.3  
Rationale for metformin as treatment for HNSCC 
 
Recently, activation of the PI3K, Akt and the mammalian target of rapamycin complex 1 
(mTORC1) signaling pathway was identified as being a 
prevalent molecular signature in many HNSCCs9,10, resulting 
in potential strategies to target this pathway. In fact, 
activating mutations of the mTOR pathway are now 
recognized as drivers of some HNSCCs. However, targeting 
the mTOR pathway with rapamycin analogues, such as 
everolimus, results in undesirable side effects including 
mucositis, thrombocytopenia, and increased infection risk 
making combinatorial treatment with chemotherapy and 
radiation difficult.  Interestingly, metformin, which is overall 
very well tolerated in diabetic patients, has been shown to 
inhibit the mTOR pathway. Specifically, metformin inhibits 
mTORC1 activity, through activation of the AMPK pathway 
resulting in decreased proliferation, metabolic synthesis and 
metastases in breast and colon cancer11,12.  Additionally, metformin inhibits HNSCC cell growth 
in vitro and prevents development and progression of oral cavity tumors in a HNSCC mouse 
tumor model supporting a role for metformin as a cancer preventative13.  The latter study 
demonstrated that metformin may also inhibit mTORC1 activity independent of AMPK 
activation.  In line with these animal studies, retrospective population case-control cohort 
studies have demonstrated a decreased HNSCC risk in diabetic patients treated with 
metformin14. In addition, metformin use resulted in a better overall survival in diabetic patients 
diagnosed with laryngeal squamous cell carcinoma15. The potential impact of metformin use in 
non-diabetic HNSCC patients is unknown. In addition to prevention of HNSCC, several 
preclinical studies, in which metformin is used as an anticancer therapeutic, are promising. 
Figure 1. Effect of metformin on mTOR pathway. 


Version 8, 31Aug2017 
 
3 
Metformin was shown to overcome cisplatin resistance by inhibition of STAT3 phosphorylation 
in non-small-cell lung cancer cell lines and metformin potentiated cisplatin cytotoxicity and 
prevented metastases in an ovarian cancer mouse model16,17. Additionally, metformin may act 
as a radiosensitizer in patients with HNSCC and mutant p53 preventing locoregional 
recurrence18.  These data suggest that metformin may be highly active in HNSCC and therefore 
may be a novel addition to current therapeutic options leading to our hypothesis that daily 
metformin in combination with CRT in LAHNSCC is safe and will result in enhanced tumor 
response through the inhibition of the mTOR pathway.  This protocol will investigate patients 
with LAHNSCC and combine standard CRT with metformin to determine the safety and 
tolerability of this combination as well as examine the molecular pathways involved in 
responses to metformin. 
 
2.4        Rationale for Metformin starting dose 
 
The recommended starting dose of metformin in diabetic patients is 500mg orally twice a day 
which can be escalated by 500mg increments weekly as tolerated with the maximum 
recommended daily dose of 2550mg.  However, the dose of metformin required in cancer for 
clinical efficacy is unknown.  Phase I dose finding studies in adults have not yet been 
performed. There are several trials listed on clinicaltrials.gov currently accruing that are 
evaluating a fixed dose of metformin in combination with other anti-cancer therapies ranging 
from 1000-2000mg daily.  This dose range is known to be safe and tolerable in diabetic patients 
with normal renal function.  Here we propose to start at a dose of 2000mg daily in combination 
with cisplatin and radiation.  Like in diabetics, patients on protocol will be given 500mg twice a 
day for the first several days, to allow for patient tolerance, and then escalated to assigned 
cohort dose.  We propose to exceed the current recommended dose as in pre-clinical animal 
studies, metformin doses were given at 50mg/kg/day or the equivalent of 3000mg/day in a 
60kg man when using weight based measurements.  Therefore, we will attempt to escalate to 
this dose while monitoring for safety and tolerability and change in kidney function. 
 
 
 
2.5 Correlative Studies Background 
 
2.5.1 Pharmacodynamic Studies 
 
 
As described in section 2.3, metformin has been shown both in vitro and in vivo to inhibit 
mTORC1 both dependently and independently of AMPK activation.  Inhibition of the mTOR 
pathway results in decreased proliferation as well as cytotoxic effects in HNSCC cells.  A trial to 
evaluate the pharmacodynamic effects of another mTOR inhibitor, temsirolimus, in newly 
diagnosed patients with HNSCC was published in 2010. 19 The investigators found a significant 
reduction in the levels of pS6 in the tumor biopsies, which was also reflected in reduced pS6 in 
peripheral blook monocyte cells (PBMCs), supporting that temsirolimus caused the inhibition of 
mTOR in its complex mTORC1 in the tumor tissues and in blood cells, with the latter serving as a 
surrogate marker of biochemical efficacy. Elevated activity of Akt was not observed as judged 
by Western blotting of total tumor samples, suggesting that in HNSCC tissues the inhibition of 
mTOR does not lead to a secondary increase in Akt activity. Instead, a reduction in pAktS473 was 
observed, albeit it did not reach statistical significance. As pAktS473 is a direct target of 


Version 8, 31Aug2017 
 
4 
mTORC220, these data suggest that mTOR in its complex mTORC2 may also be inhibited in 
HNSCC patients.  Therefore, we propose to evaluate pre- and post-treatment biopsies for the 
effect of metformin on mTOR pathway mediators above as well as proliferation with Ki-67 and 
apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. 
We will also determine the levels of pS6 in PBMCs pre- and post-metformin treatment. 
 
Although metformin has been shown to inhibit effectors of the mTOR pathway directly, other 
mechanisms in which metformin exerts an anti-cancer effect, have also been proposed, which 
may or may not be independent of mTOR inhibition.  Lowering of insulin levels resulting in 
decreased tumor growth21, reduction of inflammatory cytokines such as IL-6, resulting in 
decreased epithelial-mesenchymal transition22, and inhibition of angiogenesis molecules have 
all been proposed as potential mechanisms.  Therefore we will measure the distribution of 
levels of inflammatory cytokines (IL-6, IL-8, Gro-a), angiogenesis molecules (HGF, VEGF-A, VEGF-
C), and glucose/insulin/c-peptide levels in the blood before and after administration of 
metformin and CRT. 
 
2.5.2 Pharmacokinetic and Pharmacogenetic Studies 
 
Metformin is primarily excreted in unchanged form by the kidney with the mean renal 
clearance (CLR) of 500 mL/ min. This indicates that CLR of metformin is higher than glomerular 
filtration rate (GFR), and active tubular secretion is the principal mechanism of metformin 
elimination23.  Reported as a substrate of renal transporters such as organic cation transporter 
1 and 2 (OCT1 and OCT2) which are expressed in proximal tubule epithelial cells in the kidney, 
recent studies suggested that significant differences in CLR of metformin is a result of genetic 
polymorphisms of OCT1 and OCT224,25. In particular, an increase in CLR of metformin was 
observed in individuals carrying two reduced-function alleles of the p.420del and the p465G>R 
variants of OCT1, whereas the p.270A>S (c.808G>T) variant of OCT2 reduced CLR in healthy 
volunteers.  Cisplatin is well known to cause nephroxtoxicity 26.  In fact, its adverse effect on 
kidney function is one of its primary dose-limiting toxicities. Cisplatin accumulation in kidneys is 
considerably higher relative to other tissues.   Thus, in the proposed combination study the 
systemic exposure (plasma levels and the overall Area Under the Curve) of metformin may be 
considerably impacted by the co-administration of cisplatin and/or OCT1 and OCT2 genotypic 
variability.  The nephrotoxic effects of cisplatin may reduce metformin CLR resulting in an 
increase in the systemic exposure.  Likewise metformin levels may be higher in individuals 
expressing the 270A>S (c.808G>T) variant of OCT2.  Both these scenarios are likely to result in 
adverse effects of metformin such as lactic acidosis 27. The genetic variability in OCT1 (p.420del 
and the p465G>R) on the other hand may reduce metformin plasma levels.  Thus, we propose 
to assess the pharmacokinetics and pharmacogenomics of metformin in this study.  
 
 
 
3. PATIENT SELECTION 
 
 
3.1  
Phase I Dose Escalation Eligibility Criteria  
 


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5 
3.1.1 Histologically or cytologically confirmed LAHNSCC defined as stage III or IV 
disease (T1-2, N2a-3 or T3-4). All sites except nasopharyngeal allowable. 
 
3.1.2 No prior chemotherapy or radiation for HNSCC. 
 
3.1.3 Age >18 years.   
 
3.1.4 ECOG performance status 0 or 1 (Karnofsky >70%, see Appendix A). 
 
3.1.5 Life expectancy of greater than 3 months. 
 
3.1.6 CBC/differential obtained within 28 days prior to registration on study, with 
adequate bone marrow function defined as follows:  
 Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3;  
 Platelets ≥ 100,000 cells/mm3;  
 Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention 
to achieve Hgb ≥ 8.0 g/dl is acceptable).  
 
3.1.7 Adequate hepatic function, defined as follows:  
 Total bilirubin < 2 x institutional ULN within 14 days prior to 
registration;  
 AST or ALT < 3 x institutional ULN within 14 days prior to 
registration. 
3.1.8 Adequate renal function, defined as follows: Serum creatinine < institutional 
ULN within 14 days prior to registration.  Creatinine clearance (CC) ≥ 60 
ml/min within 14 days prior to registration determined by 24- hour collection 
or estimated by Cockcroft-Gault formula:CCr male = [(140 – age) x (wt in kg)] 
[(Serum Cr mg/dl) x (72)]; CCr female = 0.85 x (CrCl male) 
 
3.1.9 Negative serum pregnancy test within 2 weeks prior to registration for 
women of childbearing potential. 
 
 
3.1.10 Documented p16 status on biopsy tissue (oropharyngeal only). Tissue must 
be available for staining but status does not need to be confirmed before 
enrollment. 
 
3.1.11 Imaging prior to treatment including either: 
  
1) CT with contrast of neck and PET/CT (preferred),  
  
2) CT with contrast of neck and chest,  
  
3) MRI of neck and CT of chest or 
4) MRI of neck and PET/CT. 
 
3.1.12 Ability to understand and the willingness to sign a written informed consent 
document. 
 


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6 
 
3.2  
Phase I Dose Escalation Exclusion Criteria 
 
3.2.1 Patients with known metastatic disease. 
 
3.2.2 Patients with nasopharyngeal carcinoma are excluded. 
 
3.2.4 Patients may not be receiving any other investigational agents. 
 
3.2.4 History of allergic reactions attributed to metformin or other agents used in 
study. 
 
3.2.5 Patients with known diagnosis of diabetes requiring insulin for control. 
 
3.2.6 Administration of metformin within last 4 weeks. 
 
3.2.7 Uncontrolled intercurrent illness including, but not limited to, ongoing 
significant or serious active cardiovascular disease (CHF exacerbation, 
unstable angina or MI in last 6 months), infection including the diagnosis of 
AIDS or active hepatitis B or C infection, psychiatric illness or situations that 
would limit the patient’s ability to participate. 
 
3.2.8 Patients attempting to conceive, and pregnant or nursing women are 
excluded from this study.  
 
3.2.9 Patients may not receive any medication or substance that is known to be 
strongly associated with lactic acidosis (ex. NRTIs) within 14 days of study. 
 
3.3 Dose Expansion Eligibility Criteria 
All criteria are the same as dose escalation except for the additional requirement 
of a 2nd biopsy prior to CRT. 
 
3.4 Dose Expansion Exclusion Criteria 
All criteria are the same as dose escalation (see 3.2) 
 
3.5 Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial.   
 
 
4. REGISTRATION PROCEDURES 
Patients are registered by contacting the University of Cincinnati Clinical Trials Office at 513-
584-7698.  Patients must be registered and consent obtained prior to initiation of any protocol 
therapy.  


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7 
 
5. TREATMENT PLAN 
 
5.1  
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks for metformin and cisplatin and radiation are described in Section 7.  Appropriate dose 
modifications for metformin, cisplatin and radiation are described in Section 6.   
 
Patients must have screening labs performed within 2 weeks of start of treatment including a 
complete blood count, liver function tests, metabolic renal panel including magnesium, vitamin 
B12 level, lactate, and C-peptide.  Renal panel must be verified within 24 hours of cisplatin 
administration. They must fulfill inclusion criteria as stated in 3.1. 
 
Highly Recommended Evaluations/Management 
 Evaluation for prophylactic gastrostomy tube placement (especially if the patient 
is > 10% below ideal body weight)  
 EKG within 8 weeks prior to the start of treatment  
 Audiogram before cisplatin treatment 
 Banking of tumor tissue and blood in the UCCI Head and Neck Tumor Bank is 
highly encouraged but not required for protocol enrollment. 
 
 
Protocol treatment must begin within 3 weeks after registration. 
5.1.1 Metformin Dose Escalation 
  
Dose-Escalation Schedule 
 
 
Dose Level 
Dose 
 
Metformin Daily 
(in divided doses) 
 
Cisplatin Days 1, 22, 43 
 
Level -1 
 
1500mg 
 
100mg/m2  
 
Level 1 
 
2000mg 
 
100mg/m2  
 
Level 2 
 
2550mg 
 
100mg/m2  
 
Level 3 
 
3000mg 
 
100mg/m2  
 
Expansion 
 
MTD 
 
100mg/m2 
 
 


Version 8, 31Aug2017 
 
8 
 
Cohort 
Dose per Study Days 
Day -14 to -8 
Day -7 to -4 
Day -3 to end of study 
Level -1 
500mg BID 
500mg BID 
500mg TID 
Level 1 
500mg BID 
500mg TID 
1000mg BID 
Level 2 
500mg BID 
850mg BID 
850mg TID 
Level 3 
500mg BID 
1000mg BID 
1000mg TID 
 
Treatment: 
Patients will receive metformin starting on day -14 at the starting dose of 500mg BID. 
Treatment must start ideally on a Monday or Tuesday but Wednesday will also be acceptable. 
On day -7, patients will increase or keep the same dose depending on their assigned dose 
cohort (See above).  For cohort, or dose level 1, patients will ultimately take 1000mg BID for a 
total dose of 2000mg daily.  For Cohort 2, patients will ultimately take 850mg in the morning, 
850mg at lunch and 850mg at bedtime (850mg TID).  For cohort 3, patients will ultimately take 
1000mg TID and for cohort -1, patients will take 500mg TID.  Metformin will be continued until 
the last day of chemotherapy or radiation (which ever comes last). Patients will also receive 
cisplatin at 100mg/m2 on days 1, 22 and 43 along with concurrent radiation (2Gy per day, 5 
days per week for a total of 70 Gy).  Total treatment time assuming no delays will be 8 weeks.  
Patients will undergo weekly exams the first 4 weeks, prior to the 2nd and 3rd cisplatin dose, 
followed by 4 weeks (+/-2) after completion of treatment.  DLTs will continue to be assessed 
until 2 weeks after completion of radiation treatment.   
 
Metformin should continue throughout treatment and even through delays unless patient is 
experiencing adverse effects attributed to metformin.  Metformin should be taken with food. 
Patients will be provided with glucometers to monitor their blood glucose levels.  They will be 
instructed to check their blood sugar every morning prior to eating and logging on 
calendar.They will also be instructed to check their blood sugar if they have any symptoms of 
hypoglycemia including but not limited to chills/shakiness, cold feeling, lightheadedness, 
dizziness, etc. 
 
NOTE: Temporarily discontinue metformin in patients undergoing radiologic studies in which 
intravascular iodinated contrast media are utilized. It is generally recommended that metformin 
be temporarily discontinued prior to or at the time of intravascular administration of iodinated 
contrast media (potential for acute alteration in renal function). Continue to withhold 
metformin for 48 hours after the radiologic study.  
 
 
5.1.2 Cisplatin Guidelines 
 
Cisplatin can be given either before or after the radiation therapy fraction that is given on the 
same day. If radiation is held for more than 2 days (for any reason), cisplatin may be held as 
well until radiation resumes.   
 


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9 
(Note: cisplatin given within 24 hours of days 1 and 22 and 43 due to holidays, for example, is 
acceptable). Weekends count as days. Use the actual body weight for all patients. There should 
be no dose modifications because of obesity.  
 
Patients must be vigorously hydrated along with adequate diuresis. Patients must receive pre-
hydration with 1L 1/2NS with 1g magnesium sulfate over 2-4 hours given 1/2 hour prior to 
chemotherapy. Then cisplatin, 100 mg/m2 in 500-1000 ml NS plus 12.5 grams of mannitol is 
administered over 1-2 hours followed by an additional 1 to 1.5 liters of fluid. If a patient does 
not have central venous access, mannitol may be held from treatment at investigator 
discretion. Any pre-existing dehydration must be corrected prior to cisplatin administration. 
Additional i.v. hydration (500mls-1L) and BUN/creatinine check should be performed the 
following two days and also should be considered, if necessary, later in the week after cisplatin 
administration, in order to address any dehydration or severe fluid/electrolyte imbalance. 
 
5.1.2.1 Supportive Care for Cisplatin 
High dose cisplatin is a highly emetogenic regimen with significant incidence of delayed nausea 
and vomiting. The following guidelines will be followed:  
 
1) For acute nausea and vomiting, premedication should include a 5-HT3 
antagonist, such as granisetron 1 mg iv; ondansetron, up to 16 mg iv; or 
palonosetron, 0.25 mg iv; plus a corticosteroid, such as dexamethasone, 
up to 20 mg iv. Fosaprepitant may also be included as premedication. 
 
2) Breakthrough nausea and vomiting should be managed at the discretion 
of the medical oncologist or radiation oncologist.  
 
3) Delayed nausea and vomiting (greater than 24 hours after chemotherapy 
administration) may be managed by the addition of aprepitant 
concurrently or with metoclopramide and dexamethasone.  
 
 
5.1.3 Radiation Therapy  
5.1.3.1 Dose Specifications  
The prescribed radiotherapy dose will be 70 Gy in 2 Gy once-daily fraction size (total of 35 
fractions). Radiotherapy should begin on a Monday, Tuesday or Wednesday. The daily dose of 2 
Gy will be prescribed such that 95% of the PTV volume receives at least 95% of prescribed dose. 
The spinal cord dose may not exceed 45 Gy to any volume larger than 0.03 cc. 
5.1.3.2 Technical Factors 
Treatment Planning/Delivery: Megavoltage energy photon beam irradiation is required. IMRT 
treatment planning with simultaneous integrated boost (SIB) will be used, and treatment 
verification films must be taken daily (kv films or cone beam CT).   


Version 8, 31Aug2017 
 
10 
5.1.3.3 Localization, Simulation, and Immobilization 
• Patients must have an immobilization device (e.g., aquaplast mask) made prior to 
treatment planning CT scan.  
• All patients will undergo CT simulation for treatment planning. The treatment planning 
CT scan may be completed with or without IV contrast. The treatment planning CT scan 
must be performed with the immobilization device and in the treatment position. Slice 
thickness should be 0.3 cm or less.  
5.1.3.4 Target and Normal Tissue Volume Restrictions 
Definition of Target Volumes 
GTV70: This volume includes all gross tumor volume (primary tumor and nodal disease) based 
on clinical exam, PETCT scan and/or planning CT.   
CTV70: This volume will receive 2 Gy per fraction. CTV70 will include the primary tumor plus up 
to a 1.5cm margin added for microscopic spread. 
CTV56: This will include all other regions felt to be at risk for harboring microscopic cancer that 
do not meet the criteria for CTV70. For example, this would apply to ipsilateral or bilateral 
necks irradiated electively. This volume will receive 1.6 Gy per fraction.  
CTV63 Optional: This may be defined at the discretion of the treating radiation oncologist. This 
would include a region or regions felt to be at especially high risk for recurrence (e.g., first 
echelon nodal regions that are clinically negative). This area will be receiving a daily fraction 
size of 1.8 Gy.   
Planning Target Volumes (PTVs) 
In general, the PTV should be pulled 3mm off of skin unless the skin is clinically involved with 
tumor.  
PTV Expansion The CTV-to- PTV expansion is 3 mm as daily image guidance will be employed. 
Definition of Normal Tissues/Organs at Risk (OARs) 
Spinal Cord: The cord begins at the cranial-cervical junction (i.e., the top of the C1 vertebral 
body). Superior to this is brainstem and inferior to this is cord. The inferior border of the spinal 
cord is at approximately T3-4 (i.e., just below the lowest slice level that has PTV on it). The 
spinal cord shall be defined based on the treatment planning CT scan. In addition, however, a 
Planning Risk Volume (PRV) spinal cord shall be defined. The PRVcord = cord + 5 mm in each 
dimension. This is irrespective of whether or not IGRT is used.  
Brainstem: The inferior most portion of the brainstem is at the cranial-cervical junction where it 
meets the spinal cord. For the purposes of this study, the superior most portion of the 
brainstem is approximately at the level of the top of the posterior clinoid. The brainstem shall 
be defined based on the treatment planning CT scan. In addition, however, a Planning Risk 


Version 8, 31Aug2017 
 
11 
Volume (PRV) brainstem shall be defined. The PRVbrainstem = brainstem + 3 mm in each 
dimension.  
Lips and Oral Cavity: These should be contoured as 2 separate structures as the goal is to keep 
the lip dose much lower than the oral cavity dose. The definition of lips is self explanatory. The 
oral cavity will be defined as a composite structure consisting of the anterior 1⁄2 to 2/3 of the 
oral tongue/floor of mouth, buccal mucosa, and palate.  
Parotid Glands: Parotid glands will be defined based on the treatment planning CT scan.  
OARpharynx: This will be defined as the posterior pharyngeal wall plus adjacent constrictor 
muscles. This extends from the superior constrictor region (the inferior pterygoid plates level) 
to the cricopharyngeal inlet (posterior cricoid cartilage level). This should not overlap the PTVs.  
Cervical Esophagus: This will be defined as a tubular structure that starts at the bottom of 
OARpharynx and extends to the thoracic inlet.  
Glottic/Supraglottic Larynx (GSL): This will be defined as a “triangular prism shaped” volume 
that begins just inferior to the hyoid bone and extends to the cricoid cartilage inferiorly and 
extends from the anterior commissure to include the arytenoids. This includes the infrahyoid 
but not suprahyoid epiglottis.  
Mandible: This includes the entire boney structure of the mandible from TMJ through the 
symphysis. It is recognized that for oral cavity cancers, this may overlap with CTVs and PTVs.  
Unspecified Tissue Outside the Targets: This will be defined as tissue located between the skull 
base and thoracic inlet that is not included in either the target volumes or the normal tissues 
described above.  
5.1.3.5 Treatment Planning and Delivery 
Dose Prescription to PTVs 
As described in Section 5.1.3.1, prescribed radiotherapy dose will be 70 Gy in 2 Gy once-daily 
fraction size. For inverse planning IMRT, the goal is for 95% of the PTV70 to receive 95% of 2 Gy 
with a minimum dose (cold spot) of no less than 63 Gy.  
For IMRT prioritization, PTV70 will be the highest priority target structure. PTV63 and PTV56, if 
applicable, will be ranked in the IMRT planning as lower priority than PTV70 although higher 
priority than normal structures other than spinal cord and brain stem.  
Dose Constraints to Normal Structures  
Spinal Cord: The PRVcord (as defined in Section 6.4.2.1) should not exceed 45 Gy to any volume 
in excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm). The spinal cord PRV should not 
exceed 50 Gy to any volume in excess of 0.01 cc. In treatment planning, the spinal cord PRV 
should be given the highest priority.  


Version 8, 31Aug2017 
 
12 
Brainstem: The PRVbrainstem (as defined in Section 6.4.2.2) should not exceed 50 Gy to any 
volume in excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm). In treatment planning, the 
PRVbrainstem should be given less priority than the PRVcord but more priority than the other 
critical structures listed below.  
Lips: Reduce the dose as much as possible unless lips involved with primary tumor. The mean 
dose should be < 20 Gy. The maximum dose will be < 30 Gy.  
Oral Cavity: Reduce the dose as much as possible. The mean dose should be < 30 Gy.  
Parotid Glands: In most cases, it will be easier to spare one parotid than the other. The 
treatment planning goal will be for this individual parotid gland to receive a mean dose of < 26 
Gy. Additional planning goals may include: 1) At least 50% of one parotid will receive < 30 Gy; 
and/or 2) At least 20 cc of parotid tissue (from the combination of both glands) will receive < 20 
Gy.  
OARpharynx: Reduce the dose as much as possible to uninvolved regions. Some recommended 
(but not mandatory) treatment goals include: 1) No more than 33% of the OARpharynx exceeds 
50 Gy; 2) Mean dose < 45 Gy; 3) No more than 15% of the OARpharynx exceeds 60 Gy.  
Cervical Esophagus: Reduce the dose as much as possible to uninvolved regions. For oral or 
oropharyngeal cancer, some recommended (but not mandatory) treatment goals include: 1) No 
more than 33% of the esophagus exceeds 45 Gy; 2) Mean dose < 35 Gy; 3) No more than 15% of 
the esophagus exceeds 54 Gy. For larynx cancer, higher doses are expected and permitted. 
Some recommended doses (but not mandatory) treatment goals include: 1) No more than 33% 
of the esophagus exceeds 50 Gy; 2) Mean dose < 45 Gy; 3) No more than 15% of the esophagus 
exceeds 60 Gy.  
Glottic and Supraglottic larynx (GSL): Mean < 35Gy to uninvolved regions. 
Mandible: Reduce the dose as much as possible, hot spots within the mandible should be 
avoided. It is recommended that maximum dose within the mandible be < 66 Gy. For tumors 
that were not clinically or pathologically involving the mandible, the CTV should be contoured 
off the mandible. 
Unspecified Tissue Outside the Targets: For the typical case in which there is no CTV66, no more 
than 5% of unspecified tissue can receive greater than 58 Gy and no more than 1% or 1cc of 
unspecified tissue can receive 64 Gy or more. When a boost is used to increase the dose to high 
risk regions to as much as 66 Gy, these numbers can be increased. In this case, no more than 
5% of the unspecified dose should exceed the level of the boost dose, and no more than 1% or 
1 cc should exceed the boost dose value plus 10%.  
5.1.3.6  Compliance Criteria 
Treatment breaks must be clearly indicated in the treatment record along with the reason(s) for 
the treatment break(s). Treatment breaks, if necessary, ideally should not exceed five 


Version 8, 31Aug2017 
 
13 
treatment days at a time and ten treatment days total. Treatment breaks should be allowed 
only for resolution of severe acute toxicity and/or for intercurrent illness and not for social or 
logistical reasons. 
 
5.1.3.7 Radiation Therapy Adverse Events  
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE), version 4.03 will be utilized for grading all adverse events.  Placement 
of a feeding tube should be recorded as should use of a feeding tube during and after 
treatment (e.g., greater than or less than 50% of nutrition by tube). Other common radiation 
adverse events include: fatigue, weight loss, regional alopecia, xerostomia, hoarseness, 
transient ear discomfort, and skin erythema and desquamation within the treatment fields. Less 
common long-term treatment adverse events include: hypothyroidism, loss of hearing, chronic 
swallowing dysfunction requiring permanent feeding tube, and skin/soft tissue fibrosis. Much 
less common radiation adverse events include: mandibular osteoradionecrosis, and cervical 
myelopathy (< 1% with restriction of spinal cord dose to max dose of 45 Gy). 
 
5.2  
Definition of Dose-Limiting Toxicity 
 
5.2.1 Dose Limiting Toxicity 
 
Dose limiting toxicity (DLT) is defined as the appearance of side effects during treatment that 
are severe enough to prevent further increase in dosage or strength of the treatment agent 
(metformin in this study), or to prevent continuation of treatment at any dosage level. Dose 
limiting toxicity is defined as grade 3 or 4 non-hematologic toxicities other than alopecia, 
nausea or vomiting. In addition, the following adverse effects are considered to be attributed to 
cisplatin or radiation and not to metformin:  
 Grade 3 or 4 renal impairment 
 Grade 2-4 neurotoxicity including ototoxicity 
 Grade 3 or 4 mucositis 
 Grade 3 or 4 myelosuppression 
 Any other Grade 3 or 4 toxicity that clinician feels is attributed to chemotherapy 
rather than metformin 
 
Although the above should result in dose modifications or delays as stated in section 6, they will 
NOT be considered DLTs for metformin on this study, and will NOT result in a dose cohort 
change in metformin. If a patient is taken off study due to the above and has not yet reached 
evaluation for toxicity attributed to metformin, they will be replaced with another patient on 
study. 
 
Lactic acidosis is automatically considered a DLT due to its high mortality. 
 
A patient is considered evaluable for toxicity if they complete ≥3 days of metformin. 


Version 8, 31Aug2017 
 
14 
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 6. 
 
5.2.2 Dose Escalation for Phase I 
 
Dose escalation and the MTD will be defined through the modified toxicity probability interval 
design (mTPI)28.   A schematic of the dose escalation is below. It is expected that the de-
escalation cohort (level -1) will unlikely be necessary based on prior metformin experience.  
Based on a traditional 3+3 design, for the remaining 3 cohorts, a total of 9-18 patients would be 
expected to be enrolled based on severity of toxicities.  Therefore, the sample size for this study 
will include 18 total patients in phase I based on expected toxicities.  Three patients can be 
enrolled into any cohort but only 1 cohort should be activated and only 3 patients may be 
under treatment at any one time. DLTs will be measured up and until 2 weeks after the 
completion of radiation.  Dose-limiting toxicity (DLT) is defined above.  The number of DLTs will 
determine which cohort the following patients will be enrolled based on the chart below.   
Subsequent cohorts are not to begin until assessments of DLTs (28 days after starting 
metformin) are completed for at least the first enrolled patient in the prior cohort but patients 
may be enrolled on rolling basis as long as no more than 3 patients are enrolled in any cohort at 
a time.  If no DLTs are identified in the cohort, then up to three patients may be enrolled at the 
next cohort level.  However, if two total DLTs are experienced in any cohort level at any time 
during the process, the following patients will only be enrolled one at a time (cohorts of one 
patient each) until DLTs are assessed for the rest of the enrolled 18 patients.  


Version 8, 31Aug2017 
 
15 
 
 
The phase I portion will not be considered complete until all 18 patients have been enrolled or 
the number of observed DLTs have resulted in an unacceptable dose at the lowest dose level 
(level -1).  The MTD will be the dose that is assigned most often to patients in the study and is 
usually the dose assigned to the last patient.  Furthermore, if the first 9 patients are enrolled 
and none experience a DLT, the next 9 patients (who are likely to all receive the highest dose) 
will be enrolled into the study and will also be consented for biopsy as part of the expansion 
cohort (see below). 
 
 
5.2.3 Expansion Cohort 
 
 
Schematic for patient dose assignment based on mTPI design.  The x-axis represents the total number of 
patients in each cohort where the y-axis represents the total number of patients with ≥ 1 DLT that have been 
recorded at that dose level. The shaded area represents the first 3 patients in the first cohort.  If no patients 
experience a DLT in the first cohort, then the next 3 patients are escalated (E) to the next cohort.  If 1 patient out 
of 3 has a DLT, then the next 3 are enrolled at the same dose level.  If 2 patients experience a DLT, then only 1 
patient will be enrolled at a time for the rest of the study and the next patient will de-escalate (D) to the next 
lower dose level.  If all 3 patients experience a DLT, the dose level is considered to have unacceptable toxicity 
(DU) and therefore, no patients can be escalated back to this dose for the remaining of the study.  However, the 
next patient can be de-escalated to the next lower dose until no further cohorts are available.   


Version 8, 31Aug2017 
 
16 
An expansion cohort of 12 patients will be added after completion of dose escalation at the 
MTD (If dose expansion is ended early, the following nine patients that are enrolled as part of 
expansion [see previous section] will count towards the total of 12).  These patients will 
undergo the same treatment with the MTD found in the phase I dose escalation portion.  They 
will also be consented for a biopsy, for research purposes only, after 1 week of metformin and 
prior to starting CRT.    
 
 
5.3  
General Concomitant Medication Guidelines 
 
Metformin is not affected by p450 enzymes and therefore p450 inhibitors are allowed.  
 
Concomitant use of furosemide results in increased levels of metformin and therefore should 
be avoided if possible. However, furosemide may be used if needed for further diuresis.  
 
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.  Therefore, these medications are to be avoided if possible while 
patient is on study but are allowable if felt to be necessary by patient’s physician.  However, it 
must be documented that patient was on these medications. 
 
Nifedipine results in enhanced absorption of metformin.  It must be documented if a patient is 
on nifedipine during the study but is allowable. 
 
5.4  
Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment will continue until 
completion of CRT or until one of the following criteria applies: 
 
• Disease progression, 
• Intercurrent illness that prevents further administration of treatment, 
• Unacceptable adverse events(s), 
• Patient decides to withdraw from the study, or 
• General or specific changes in the patient’s condition render the patient unacceptable 
for further treatment in the judgement of the investigator. 
 
 
5.5 
Treatment and Duration of Follow-up  
 
5.5.1 General Follow-up: 
 
Patients will be followed during treatment as above in section 5.1.1.  Patients will then be 
evaluated at conclusion of treatment and then monthly for first 3 months, and then every 3 
months for the first year followed by every 6 months for the following 2 years. DLTs will be 


Version 8, 31Aug2017 
 
17 
assessed until 2 weeks after completion of radiation.  Patients will undergo a PET/CT at 12 
weeks to assess for response.   
 
5.5.2 Early Removal from study: 
 
If patients did not complete CRT, patients will be followed for 4 weeks after removal from study 
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.  Patients who do 
not complete DLT period (28 days after metformin initiation) will be replaced for assessment of 
MTD but will still be used for safety analysis. 
 
5.6  Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.4 applies.  The 
reason for study removal and the date the patient was removed must be documented in the 
Case Report Form. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1. Cisplatin 
 
6.1.1. Neutropenia: If on the day of scheduled treatment with cisplatin the absolute neutrophil 
count (ANC) is < 1000/mm3, hold chemotherapy treatment but not the radiation until ANC ≥ 
1000/mm3, then treat at 100% dose. Neutropenic fever (i.e. any fever > 38.5°C with an ANC 
<1000/mm3) will require a 25% dose reduction of the next cisplatin dose. If neutropenic fever 
occurs with both the first and second dose, cisplatin should be discontinued. 
 
6.1.2 Thrombocytopenia: If on the day of scheduled treatment with cisplatin the platelet count 
is < 75,000/mm3, hold chemotherapy treatment but not the radiation until platelets are ≥ 
75,000/mm3, then treat at 100% dose. Thrombocytopenia that results in bleeding will require a 
25% dose reduction of the following cisplatin dose.  
 
6.1.3 Neurotoxicity: If grade 2 neurotoxicity develops, hold cisplatin (but continue RT) until 
toxicity improves to < grade 1, then reduce the following cisplatin dose to 80 mg/m2. If any 
signs of grade 3 or greater neurotoxicity occur, discontinue cisplatin, but continue RT.  
 
6.1.4 Renal Adverse Events: Cisplatin dose should be based on the serum creatinine or 
creatinine clearance immediately prior to the second and third cisplatin dose using the 
following guidelines:  
Note: If creatinine is > 1.5 mg/dl, creatinine clearance must be calculated (Cockcroft-
Gault) in order to make dose adjustment. If the calculated clearance is 50 mL/min or 
above, a 24-hour urine collection is not needed, but if the calculation is less than 50 
mL/min, a 24-hour urine collection is mandated, and the cisplatin dose will be 
determined as follows:  


Version 8, 31Aug2017 
 
18 
 
Serum Creatinine Creatinine Clearance Cisplatin Dose 
≤ 1.5 mg/dl or > 50 ml/min then administer 100 mg/m2 
> 1.5 mg/dl and 40-50 ml/min then administer 50 mg/m2 
> 1.5 mg/dl and < 40 ml/min Hold drug* 
 
*Cisplatin should be held (but the RT continued) and the creatinine measured weekly, 
until it is  < 1.5 mg/dl or the creatinine clearance is > 50 ml/min, and it is recommended 
that the next and following doses of cisplatin should be given at the reduced dose of 50 
mg/m2 but the latter will be left to investigator discretion. 
.  
6.1.5 Nausea and Vomiting: Maximum supportive therapy will be given, and cisplatin will be 
continued at full dose for ≤ grade 2 nausea and vomiting. For grade 3 nausea and vomiting 
refractory to supportive therapy, cisplatin will be held until recovery to < grade 2. No dose 
reductions will be made.  
 
6.1.6 Mucositis: Significant mucositis (grade 3-4, CTCAE, v. 4) is expected from radiation and 
cisplatin and should not be a reason for a treatment break, unless it significantly interferes with 
fluid intake or nutrition. Aggressive supportive care is encouraged as well as consideration of a 
PEG tube if not already done.  
 
6.1.7 Ototoxicity: For clinical hearing loss not requiring a hearing aid, reduce cisplatin to 50 
mg/m2. For hearing loss requiring a hearing aid, discontinue cisplatin. For grade 2-3 tinnitus 
(CTCAE, v. 4) at the time of retreatment, hold cisplatin until improvement to grade 1 or less and 
then reduce the following doses of cisplatin to 50 mg/m2. If tinnitus does not improve to grade 
1 or less by the last day of radiation therapy, discontinue cisplatin.  An audiogram is 
recommended when there is any report of significant change in hearing and/or an increase in 
tinnitus.  
 
6.1.8 Other Toxicities: For any other grade 3-4 adverse events, hold cisplatin until toxicities 
have recovered to grade 1 or less.  
 
If the second or third dose of cisplatin is delayed more than 21 days because of hematologic, 
neurologic, renal, or other adverse events, that dose will be omitted. If a weight change of 
≥10% occurs, the following cisplatin doses should be adjusted. 
 
 
6.2 Metformin hydrochloride 
 
  
6.2.1 Diarrhea: For grade 1 and 2 diarrhea, loperamide can be used without dose reduction or 
discontinuation. However, if diarrhea is grade 3 or 4, metformin should be held until ≤ grade 1.  
Metformin may be restarted at full dose using dose escalation chart in 5.1.1. 
 
6.2.2 Dehydration: Although metformin itself does not cause dehydration, in patients with 
dehydration grade 2 or above should have metformin doses held until dehydration corrected 


Version 8, 31Aug2017 
 
19 
either by oral or IV hydration. 
 
6.2.3 Lactic acidosis: In a very small proportion of patients, lactic acidosis defined as lactate 
levels >5 can occur with metformin especially those with renal impairment.  Due to the 
seriousness of this event, metformin should be permanently discontinued. 
 
6.2.4 Renal dysfunction: Although metformin does not cause renal dysfunction, the clearance of 
metformin and therefore risk of lactic acidosis increases.  Therefore, metformin should be 
decreased by 50% if eGFR is 30 to 45ml/min and held if creatinine is above 1.5mg/dl (1.4mg/dl 
in women) or eGFR is <30ml/min.  Metformin may be restarted at full dose (using dose 
escalation as provided) once kidney function improves above these parameters. 
 
6.2.5 Hypoglycemia: Metformin should be held in the event of hypoglycemia until it resolves.  If 
grade 1 or 2, metformin may be started at full dose using dose escalation. If grade 3 or 4, 
metformin can be restarted at recovery to normal but should be dose reduced as follows: 
 
 
 
For grade 3 or 4 hypoglycemia 
Cohort 
Current Cohort Daily Dose 
Dose reduction 
-1 
1500mg 
850mg 
1 
2000mg 
1500mg 
2 
2550mg 
2000mg 
3 
3000mg 
2500mg 
 
 
6.2.6 Vitamin B12 deficiency: Metformin does not need to be held for this indication as long as 
B12 is replaced. 
 
6.2.7 Other Toxicities: For any other grade 3-4 adverse events (besides those mentioned in 
5.2.1), hold metformin until toxicities have recovered to grade 1 or less.  
 
6.2.8 Dose Reduction for Intolerability: If patients have side effects that are considered 
intolerable to patient but are less than grade 3, support patients with supportive medications 
(loperamide, omeprazole, anti-emetics, etc) and try alteration of their dosing schedule by 
reducing by 1 tablet (500mg or 850mg depending on cohort) at a time until toxicity is ≤ grade 1 
for 1 week.  Then attempt to re-escalate per chart in 5.1.1 or by adding 500mg/day every 3-5 
days if unable to escalate at rate in chart.  Every attempt should be made to keep metformin 
dose at assigned cohort but if unable to achieve the assigned dose, then metformin should be 
maintained at highest dose tolerated for remainder of treatment. 
 
NOTE: Temporarily discontinue metformin in patients undergoing radiologic studies 
in which intravascular iodinated contrast media are utilized. It is generally 
recommended that metformin be temporarily discontinued prior to or at the time of 
intravascular administration of iodinated contrast media (potential for acute 


Version 8, 31Aug2017 
 
20 
alteration in renal function). Continue to withhold metformin for 48 hours after the 
radiologic study.  
 
NOTE: If metformin is held at any time for any reason, upon restarting the drug, it 
must be dose escalated again in reference to chart in 5.1.1.   
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting in addition to routine reporting. 
 
Adverse Event Characteristics  
 
AE description and grade:  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be utilized 
for AE reporting.  All appropriate treatment areas will have access to a copy of the 
CTCAE version 4.03.  A copy of the CTCAE version 4.03 can be downloaded from the 
CTEP web site (http://ctep.cancer.gov). 
An adverse event or suspected adverse reaction is considered "serious" if, in the 
view of either the investigator or sponsor, it results in any of the following 
outcomes: Death, a life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant incapacity or 
substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect. 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. 
 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.1 
Expedited Adverse Event Reporting 
 
Expedited AE reporting for this study will be submitted to the PI, the FDA and the IRB. 
 
To FDA: 
 
Serious and unexpected adverse events that are likely to be related to metformin must be 


Version 8, 31Aug2017 
 
21 
reported quickly in the form of an IND Safety Report.  
 
The time frame for reporting an IND Safety Report is: 
• 
7 calendar days for a fatal or life-threatening adverse drug experience  
• 
15 calendar days for a serious and unexpected adverse drug experience  
 
Follow-up reports will be submitted as relevant information is available. 
 
Reports will use FDA Form 3500A and be submitted to the attention of the person identified 
by the FDA in the initial IND notification letter.  Reports for drug INDs are sent to the Food 
and Drug Administration, Center for Drug Evaluation and Research, Central Document 
Room, 5901-B Ammendale Road, Beltsville, MD 20705-1266 
 
Phase 1 Trials 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 51 
Unexpect
ed  
and 
Expected 
 
Unex-
pected 
 
 
Expected 
Unexpected 
Expected 
Unexpect
ed  
and 
Expected 
with  
Hospitali
zation 
without 
Hospitali
zation 
with  
Hospitali
zation 
without 
Hospitali
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 
Calendar 
Days 
24-Hour; 
5 
Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 
Calendar 
Days 
 Adverse events with attribution of possible, probable, or definite that occur greater than 
30 days after the last dose of treatment with an agent under an IND require reporting as 
follows: 
FDA Form 3500A 24-hour notification followed by complete report within 5 calendar 
days for: 
• Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• Grade 4 unexpected events  
• Grade 5 expected events and unexpected events 
 
1 Although FDA Form 3500A 24-hour notification is not required for death clearly related to 
progressive disease, a full report is required as outlined in the table. 
 
 
Note: All deaths on study require both routine and expedited reporting regardless of 


Version 8, 31Aug2017 
 
22 
causality.  Attribution to treatment or other cause must be provided. 
 
Expedited AE reporting timelines defined: 
• 
“24 hours; 5 calendar days” – The investigator must initially report the AE via 
the University of Cincinnati within 24 hours of learning of the event followed 
by a complete report within 5 calendar days of the initial 24-hour report. 
• 
“10 calendar days” - A complete report on the AE must be submitted within 
10 calendar days of the investigator learning of the event.  
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported 
regardless of attribution and designation as expected or unexpected with the 
exception of any events identified as protocol-specific expedited adverse 
event reporting exclusions. 
• 
Any event that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via Form 3500A if 
the event occurs following treatment with an agent under an IND. 
• 
Use the protocol number and the protocol-specific patient ID assigned 
during trial registration on all reports. 
 
To UC IRB: 
 
An adverse event or injury that is serious, and unexpected, and definitely, probably or 
possibly related to the study requires prompt reporting to the UC IRB within 10 business 
days of the research staff being notified of the event.  A fatal or life threatening adverse 
drug experience requires prompt reporting within 24 hours.  Reports will be submitted by 
completion of the New Reportable Event Form in ePAS.   
 
Follow-up reports will be submitted as relevant information is available. 
 
7.2 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
through FDA Form 3500A must also be reported in routine study data submissions. 
  
 
 
8. PHARMACEUTICAL INFORMATION 
 
 
8.1  
Metformin hydrochloride 
Formulation: Metformin tablets come in 500mg, 850mg, and 1000mg tablets.  Each 
tablet contains the inactive ingredients povidone and magnesium stearate. In addition, 
the coating for the 500 mg and 850 mg tablets contains hypromellose and the coating 
for the 1000 mg tablet contains hypromellose and polyethylene glycol. The pKa of 
metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. 


Version 8, 31Aug2017 
 
23 
Metformin is soluble in water. 
 
Mechanism of Action: 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 normally 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. 
 
Administration: Metformin will be given orally in either BID or TID dosing dependent on 
assigned cohort. 
 
Pharmacokinetics:  The bioavailability of metformin when administered orally in a 
fasting state is around 50-60%23.  Food does decrease absorption reflected in a decrease 
in Cmax of 40% and 25% decrease in area under the curve (AUC). Metformin is negligibly 
bound to plasma proteins and steady state plasma concentrations of metformin are 
reached within 24 to 48 hours.  Metformin is excreted unchanged in the urine and does 
not undergo hepatic metabolism.  Renal clearance is approximately 3.5 times greater 
than creatinine clearance indicating that tubular secretion is the major route for 
metformin elimination. Following oral administration, approximately 90% of the 
absorbed drug eliminated via the renal route within 24 hours.  Plasma elimination half-
life is approximately 6.2 hours but 17.6 hours in blood indicating possible accumulation 
in erythrocytes. 
 
Storage and Stability: Metformin should be stored at 20°–25° C (68°–77° F).  It should be 
dispensed in light resistant containers.  Metformin is stable at room temp for up to 2 
years. 
 
Adverse events: The most common human toxicities include diarrhea, abdominal pain, 
nausea and vomiting, and flatulence.  In a small proportion of patients, especially those 
with renal impairment are at risk for lactic acidosis.  
 
Supply:  Metformin is commercially available for use in diabetes.  Our pharmacy will 
supply the medication to patients on trial. 
 
      8.2 Cisplatin 
 
Formulation: Each vial contains 10 mg of DDP, 19 mg of sodium chloride, 100 mg of 
mannitol, and hydrochloric acid for pH adjustment. One vial is reconstituted with 10 ml 
of sterile water. The pH range will be 3.5 to 4.5. Cisplatin injection also is available from 
the manufacturer in aqueous solution, each ml containing 1 mg cisplatin and 9 mg NaCl 
and HCL or NaOH to adjust pH.  
 
Mechanism of Action: The dominant mode of action of cisplatin is inhibition of the 


Version 8, 31Aug2017 
 
24 
incorporation of DNA precursors, although protein and RNA synthesis are also inhibited. 
Although cisplatin is thought to act as an alkylating agent, there are data to indicate that 
its mode and sites of action are different from those of nitrogen mustard and other 
standard alkylating agents.  
 
Administration: Cisplatin will be given as a bolus, infused over 1-2 hours along with 
appropriate hydration and anti-emetics.  
 
Storage and Stability: Reconstituted solution of cisplatin is stable for 20 hours when 
stored at 27°C and should be protected from light if not used within 6 hours. The vials 
and injection should not be refrigerated. Cisplatin has been shown to react with 
aluminum needles, producing a black precipitate within 30 minutes.  
 
Adverse Events: Human toxicity includes nausea, vomiting, renal toxicity (with an 
elevation of BUN and creatinine and impairment of endogenous creatinine clearance, as 
well as renal tubular damage, which appears to be transient), ototoxicity (with hearing 
loss that initially is in the high-frequency range, as well as tinnitus), and hyperuricemia. 
Much more severe and prolonged toxicity has been observed in patients with abnormal 
or obstructed urinary excretory tracts. Myelosuppression, often with delayed 
erythrosuppression, is expected as well.  
 
Supply: Cisplatin is commercially available. The use of drug(s) or combination of drugs in 
this protocol meet the criteria described under Title 21 CFR 312.2(b) for IND exemption. 
 
 
9. CORRELATIVE/SPECIAL STUDIES 
 
9.1        Laboratory Correlative Studies 
 
9.1.1 Immunohistochemistry Methods on Paraffin embedded tissue 
 
For IHC, the fixed tissues will be dehydrated and embedded in paraffin following standard 
procedures. Hematoxylin-eosin stained 5 µm sections will be used for diagnosis. Unstained 
sections will be deparaffinized and processed for IHC, which will be performed using highly 
specific monoclonal or polyclonal antibodies. The antibodies to be used and the procedures to 
be carried out, which involve overnight incubation with the primary antibody, biotinylated 
secondary antibodies, and the ABC method to detect the presence of reactive antibodies 
recognizing each protein, have been previously described 9,29-31.  
 
Two pathologists who will be blinded to any clinical information will independently analyze the 
biopsy slides. For every case, the whole tumor area will be quantified. The number of positive 
cells will be visually evaluated for each tissue and the results will re-expressed as a percentage 
of stained cells/total number of cells32. The intensity of immunoreactivity will also be evaluated 
(1 weak, 2 moderate, 3 strong). A score will be calculated by multiplying both parameters. 
 


Version 8, 31Aug2017 
 
25 
Collection, Handling and shipping of Biopsies 
Pre-treatment biopsies will be obtained from the department of pathology at UC or the UCCI 
tumor bank.  2nd biopsy specimens from the expansion cohort will be performed as an 
outpatient procedure in the ENT office under standard procedures. The subject will be 
consented as per standard of care and hospital policy using the standard consent form for 
procedures. The tissue collection from these biopsies will be for research purposes only and will 
not be reviewed by a pathologist for clinical care purposes.  
 
The tissue from the biopsy will be divided into two similar size aliquots. One will be immediately 
snap frozen on dry ice and transferred to a labeled cryovial and placed into dry ice in a 
Styrofoam bucket. The other will be placed in a standard pathology container for tissue fixation 
in Z-fix solution and labeled. Labels will contain unique accession numbers, but not subject ID 
numbers. Personal identifiers will not be included on sample labels. The tissues are then 
transported to the lab and shipped to Dr. Gutkind’s laboratory at University of San Diego. 
 
 
 
9.1.2 
Flow Cytometry methods  
 
Whole blood will be collected in EDTA tubes during screening before treatment begins and on 
days 1 and 22 and week 11 (see study calendar) and transferred at room temperature to UC 
pathology department or the Vontz Translational Laboratory for flow cytometry. Routine flow 
cytometry will be performed using antibodies directed at CD3, CD4, CD8, FoxP3, CD25 and PD1 
to determine T cell subsets. 
 
9.1.3    
Measurements of Serum Cytokines in Blood and Tissues  
Serum from subjects obtained before treatment and on Days 1, and 22, and week 11  (see 
Study Calendar for visit windows) will be analyzed using the Luminex 100 instrument with 
individual bead kits for multiple inflammatory and angiogenic cytokines detectable in patients 
with HNSCC, including but not limited to interleukin (IL)-6, IL-8, growth-related oncogene-1 
(GRO-1), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) 
(Biosource, Invitrogen), as described [65]. 
 
Collection, Handling and shipping of Blood/Serum 
Before venipuncture, the phlebotomist will prepare lavender top (EDTA) plastic 10 ml tubes and 
a red top plastic 5 ml blood collection tube and affix a label to each blood collection tube. 
Information to be encoded on labels for tubes being sent to Dr. Gutkind’s laboratory will 
include a unique accession number, not a subject ID number. Personal identifiers will not be 
included on sample labels. The tubes will be placed in a test tube rack, in order of collection 
(lavender tops, then red tops). The phlebotomist will use standard venipuncture techniques. 
Following the collection of blood, lavender top tubes will be inverted 5 times to prevent clotting 
and platelet clumping. Approximate blood volume to be collected in each tube is 10 mls in 
lavender top, 5 ml in red top tube. The red top tube will be used for the separation of serum, as 
described in the following: 
 
 
 
• Allow blood to clot for 15-30 minutes at room temperature 


Version 8, 31Aug2017 
 
26 
 
 
 
• Centrifuge blood at 3000 rpm for 10-15 minutes to separate out the serum 
• Transfer the serum from the red top vacutainer into appropriately labeled new 
vial 
• Immediately store serum in a -70°C or colder freezer, in liquid nitrogen, or in a  
 
 
 
 
Styrofoam container surrounded by excess dry ice 
 
 
 
•    Ship by courier on dry ice to Dr. Gutkind’s laboratory at the University of San 
Diego 
The lavender top (EDTA) tube collected at UC will be transported at room temperature (RT) 
from the clinical collection site to the sample processing laboratory at UC and Dr. Wise-Draper’s 
laboratory at the Vontz. It will be used for the separation of peripheral blood mononuclear cells 
(PBMCs) using Ficoll gradients.  PBMCs will be washed 2x with PBS and frozen at -80C in 
aliquots for future analysis. 
 
 
9.2 
Pharmacokinetics/Pharmacogenetics 
 
For pharmacokinetic analysis, serial blood samples (5 mL per time point) will be collected at 
baseline (pre-dose), 0.5, 1, 2, 4, 8 (optional) and 24 hours after metformin administration on 
Days -14 and 1.  If patients are undergoing routine blood draws at additional timepoints, a PK 
sample may be obtained at that time as well to increase PK data. Blood will be collected into BD 
vacutainer tubes containing EDTA mixed and centrifuged at approximately 1500 x g for 
approximately 10 minutes at 4°C. Plasma will be transferred into a storage tube and maintained 
on dry ice until stored in a -20°C freezer.  A validated LC/MS method will be employed for 
metformin bioanalysis. Samples will be delivered on ice to Dr. Pankaj Desai in pharmacology at 
the University of Cincinnati. DNA will be also be extracted from whole blood for genotyping of 
OCT 1 and 2 in Dr. Desai’s laboratory.   
 
 


Version 8, 31Aug2017 
 
27 
10. 
STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy.  
Scans must be done <4 weeks prior to the start of therapy.  (If scans were done prior to this 
timepoint, then it is acceptable to use radiation oncology simulation scans prior to starting 
treatment as long as original scans meet inclusion criteria). In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior 
to initiation of the next cycle of therapy. 
 
   
 
Pre- 
Study 
Wk 
-2 
 
Wk 
-1 
 
Wk 
1 
 
Wk 
2 
 
Wk 
3 
 
Wk 
4 
 
Wk 
5 
 
Wk 
6 
 
Wk 
7 
 
Wk 
8 
 
Wk 
9 
 
Wk 
10 
 
Wkg 
11 
 
Wk 
19h 
 
Off Studyc 
 
Metformin (daily) 
 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cisplatin (days 1,22,43) 
 
 
 
 
 
B 
 
 
 
 
 
B 
 
 
 
 
 
B 
 
 
 
 
 
 
 
 
 
 
 
Radiation 
 
 
 
 
 
C 
 
C 
 
C 
 
C 
 
C 
 
C 
 
C 
 
 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
 
X 
 
X------------------------------------------------------------------------------------------------------------X 
 
 
 
Physical exame 
 
X 
 
 
x 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
ENT exam 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Audiogramf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Performance status 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
CBC w/diff, plts 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
Serum chemistrya 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
Adverse event evaluation 
 
 
 
X------------------------------------------------------------------------------------------------------------X 
X 
 
Radiologic evaluation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
B-HCG 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vitamin B12, Lactate, C-
peptide 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
PD blood draws 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
PK blood draws 
 
 
X 
  
 
x 
 
 
  
 
 
 
 
 
 
 
 
 
 
2nd biopsy (expansion only) 
 
 
 
 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A: Metformin:  Dose as assigned 
B: Cisplatin:  Dose as assigned 
C:  Radiation: Dose as assigned 
a: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorus, potassium, total protein, SGOT 
[AST], SGPT [ALT], sodium. 
b: Serum pregnancy test (women of childbearing potential). 
c: Off-study evaluation.   
d:  prior to cisplatin and radiation 


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28 
 
e: Must occur within 48hrs of planned cisplatin days 
f: if felt to be clinically indicated, not required 
g: Can be done at week 9-11 
h: +/- 2 weeks 
 
Follow-up after completion every 3 months for 1st year, then every 6 months for the following year 
 


Version 8, 31Aug2017 
 
29 
11. MEASUREMENT OF EFFECT 
 
Although response is not the primary endpoint of this trial, patients with measurable disease 
will be assessed to determine the rate of complete response (CR).  For the purposes of this 
study, patients should be re-evaluated at approximately 12 weeks post-completion of radiation 
and then as indicated after during follow-up period.   
 
11.1 
Antitumor Effect – Solid Tumors 
 
Response and progression will be evaluated in this study by assessing for the disappearance of 
tumors/lesions and PET FDG avidity.  
 
11.1.1 
Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with metformin. 
 
Evaluable for objective response.  Only those patients who have measurable disease present at 
baseline (using RECIST 1.1), have completed CRT, and have had their disease re-evaluated by 
PET/CT 12 weeks after radiation completion will be considered evaluable for response.  These 
patients will have their response classified according to the definitions stated below.   
 
11.1.2 Response Criteria 
 
Complete Response (CR):  
Disappearance of all measurable disease and FDG avidity 
 
Incomplete/Partial Response (PR): 
At least a 30% decrease in the sum of the longest diameter 
(LD) of target lesions, taking as reference the baseline sum LD; or the continued presence of 
FDG avidity.  In patients with this category, suspicious areas should be re-imaged or biopsied to 
verify persistent disease or CR. 
 
Persistent Disease (PD):  
Biopsy proven disease after CRT 
 
 
11.1.3 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
 
 
11.1.4 Progression-Free Survival 


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30 
 
PFS is defined as the duration of time from start of treatment to time of progression.  PFS will 
be evaluated for 2 years. 
 
 
11.1.5 Overall Survival 
OS is defined as the duration of time a patient is alive from start of treatment until time of 
death.  OS will be evaluated for 2 years. 
 
12  
Data Storage 
 
Data collection and storage will be managed by the University of Cincinnati Cancer Institute, 
Clinical Trials Office (UCCI CTO).  The UCCI CTO will maintain storage of all clinical data in 
accordinace with federal guidelines and GCP.  Data will be entered in a secure, password 
protected storage database, OnCore.  All hardcopies of data will be securely maintained (in a 
locked room or cabinet) and will only be accessible to members of the study team. 
 
 
13.  
Data and Safety Monitoring 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
Any new significant finding that may affect the patient’s willingness to continue in the study will 
be shared with patients. Immediately after the study is approved and before the first patient is 
enrolled, investigators will meet, develop and finalize all measurements/variables for the study. 
A dictionary will be created to record variables and their definitions, followed by a data file 
template created by the statistician that includes all variables used in the study. The master 
template may be partitioned into several sub data files (such as blood, urine, tissue, and 
imaging files) for convenience of entry from different investigators. All sub files will be 
connected by study id as a link and later compiled into a synchronized file for analyses at 
interims and the final stage. Each patient, once being enrolled, will be provided a unique id 
from the study and their personal information, such as name, SSN, address, phone number and 
DOB, will be de-identified whenever necessary to the researchers.  
 
Data entry will be monitored regularly by the “Data Safety Monitoring Board” which is an 
independent group of experts who will advise the study investigators. The members of the 
DSMB serve in an individual capacity and provide their expertise and recommendations. 
Membership consists of persons independent of the investigators and any conflict of interest 
with the trial. Written documentation attesting to absence of conflict of interest is required. 
The DSMB includes experts in or representatives of the fields of relevant clinical expertise, and 
biostatistics. The DSMB will be provided feedback on a regular basis, including findings from 
adverse-event reports, and recommendations derived from data and safety monitoring, and 
members of the DSMB will have no personal or financial stake in the study.  Interim reports will 
be prepared at least twice each year by the PI with the help of the study coordinator 1 month 


Version 8, 31Aug2017 
 
31 
prior to DSMB meeting for DSMB review.  These reports will contain information about the 
accrual rate with projected completion date for the accrual phase, exclusion rates and reasons, 
pretreatment characteristics of patients accrued, compliance rate of treatment delivered with 
respect to the protocol prescription, and the frequency and severity of adverse events.  All 
serious adverse events will be reported by the PI to the DSMB and IRB within 24 hours of 
knowledge of the occurrence.   
HIPAA confidentiality will be maintained during the phases of the trial including monitoring, 
preparation of interim results, review, and response to monitoring recommendations.  
Exceptions may be made under circumstances where there are serious adverse events or when 
it is deemed appropriate for patient safety.  The DSMB will function in an advisory capacity and 
recommendations that emanate from monitoring activities will be reviewed by the responsible 
official (the principal investigator) and addressed.   
 
The initial responsibility of the DSMB will be to approve the initiation of this clinical trial. After 
this approval and at periodic intervals during the course of the trial, the DSMB responsibilities 
are to: 
 
o 
•Periodically review and evaluate the accumulated study data for participant 
safety, study conduct and progress, and when appropriate, efficacy 
o 
•Make recommendations to the study investigators and regulatory agencies (IRB, 
IBC, FDA, etc.) concerning the continuation, modification, or termination of the 
trial. 
 
UCCI Site Visit by DSMB 
Prior to enrollment of the first subject on this trial, the DSMB will meet, preferably via a site 
visit, the principal investigator, study investigators, data coordinators and review the study 
protocol and consent, data collection/capture format, and formalize the process for data 
presentation/study reports to the DSMB. A teleconference or web conference may substitute 
for an onsite visit. 
 
It is the responsibility of the study sponsor to ensure that the DSMB is apprised of all new safety 
information relevant to the study IND and the study. This includes providing the DSMB with a 
copy of the study protocol in advance as well as providing all IRB/Regulatory Protocol revisions 
and all safety data reports. 
 
Serious Adverse Events: 
All serious and related adverse events will be reported immediately to the Chair and other 
members of the DSMB by the study sponsor or designee. The decision to meet by 
teleconference or on site to discuss the adverse event will be left to the discretion of the 
members of the DSMB. If the DSMB determines that the study procedures present a greater 
risk than expected, the board may recommend to the P.I. and the IRB that the study enrollment 
be suspended pending further evaluation. 
 


Version 8, 31Aug2017 
 
32 
Written reports: 
Written reports should be sent to DSMB members prior to the meeting and should allow 
sufficient time for review. Written reports may consist of 2 separate parts: 
 
Open Session Report: 
This report provides information on study conduct, such as accrual, appropriate 
demographic representation, baseline characteristics, protocol compliance, site 
performance, quality control, currency of follow-up. General (ungrouped) 
adverse events and toxicity issues will be included in the open report. 
Open Session reports will be distributed at least a week prior to a scheduled 
meeting to DSMB members, study investigators and other appropriate persons 
as directed by the DSMB. 
 
Closed Session Report: 
This report may contain data on study outcomes, including safety data and efficacy data. Closed 
session reports are distributed on the same schedule, but only to DSMB members, the 
chairman of the IRB, and others as designated by the DSMB Chair. This report is confidential 
and marked accordingly. 
 
Verbal Report: 
At the conclusion of the DSMB meeting, the DSMB should discuss its findings and 
recommendations with the study investigator and sponsor (or sponsor designee). The DSMB 
will issue a written summary report that identifies topics discussed by the DSMB and describes 
their individual findings, overall safety assessment and recommendations. The report should 
conclude with a recommendation to continue or terminate the study. The DSMB Chair or 
designee is responsible for drafting, circulating and obtaining approval from other DSMB 
members within 2 weeks of the meeting. 
 
A final summary report: will be forwarded to the Study Sponsor and PI. The UCCI Regulatory 
Coordinator will forward the summary report to regulatory authorities as a part of the annual 
report unless immediate action is required. 
 
Closed Session Report (optional: The DSMB may also prepare confidential minutes that include 
details of closed session discussions. These meeting minutes are to be held in strict confidence 
and only accessible to DSMB members until such a time when the study is closed or the DSMB 
recommends early termination or in the event the minutes are requested by the FDA for 
participant safety reasons or for regulatory purposes. 
 
Immediate Action Report: The DSMB Chair will notify the Study Sponsor (or sponsor designee) 
directly of any findings of a serious and immediate nature or recommendations to discontinue 
all or part of the trial. The report will be submitted to UCCI Regulatory Coordinator for 
appropriate dissemination to regulatory authorities. This will be done in order to identify 
significant adverse event trends, missing and incorrect inputs, and other outliers. A log file will 
be created and record any change/modification of data inputs for purpose of future inspection. 
Data files will be safely stored in the server of the cancer clinical trials office, with authorized 


Version 8, 31Aug2017 
 
33 
access to researchers and staffs only; and protected by double firewalls from both UC Health 
and the University of Cincinnati Information Technology (UCIT). All active study patients are 
reviewed at the weekly study team meeting. Confidentiality will be maintained as much as 
possible, consistent with applicable regulations. Names of participants or identifying material 
will not be released without patient permission, except when such release is required by law. 
No patient’s name or identifying information will be released in any publication or 
presentation. Records are maintained according to current legal requirements, and are made 
available for review according to the requirements of the Food and Drug Administration (FDA) 
or other authorized user, only under guidelines established by the Federal Privacy Act. 
 
14. STATISTICAL CONSIDERATIONS 
 
14.1 
Study Design/Endpoints 
 
Primary Endpoint: Presence or absence of DLT, which is defined as any grade 3-4 toxicity 
outlined in NCI CTCAE v4.03. 
 
The MTD will be defined through the mTPI design (see schematic in section 5.2.2).  Three 
patients will be enrolled into the initial cohort and DLTs will be measured at four weeks after 
the completion of radiation.  The number of DLTs will determine the dose assignments of future 
patients.  If no DLTs are identified in the first three-patient cohort, then another three patients 
will be enrolled at the next highest dose.  However, if a total of two DLTs are experienced at any 
dose level during the study, accrual will be slowed and future patients will only be enrolled one 
at a time until the previously enrolled patient has been completely followed for DLT.  
 
 
 
 
14.2 
Sample Size/Accrual Rate 
 
The dose-finding portion of this study will enroll a maximum of 18 patients.  This sample size 
was chosen based on the maximum number of patients that could have been 
enrolled on a traditional 3+3 design studying three doses (dose -1 is not part of the 
sample size calculation, as it is only a “fall-back” dose should dose 1 be unacceptably 
toxic).  An expansion cohort of 12 patients will be added at MTD in order to show a 
50% response rate measured as a decrease in mTOR pathway markers.  With an 
observed response rate of 50%, 12 patients will be sufficient to produce a 95% 
confidence interval with a lower bound of 20%, which we view as an acceptable 
margin of error. 
 
 
 
 
We see about 150 new HNSCC patients per year and of those, approximately 90 
have LAHNSCC.  About 25 patients will undergo concurrent CRT and we expect to 
enroll about 9 of these per year on this study.  Therefore, we expect to complete the 
study within 3 years including the expansion cohort. 
 
 
 
 
Due to the inclusion criteria requiring a second biopsy for the dose expansion 
cohort, it may be difficult to accrue quickly.  If at least 6 patients are not accrued 


Version 8, 31Aug2017 
 
34 
within one year in the expansion phase, then the study will be terminated and an 
analysis will be performed with samples available.   
 
 
14.3 
Analysis of Secondary Endpoints 
 
 
 
 
Secondary Endpoint(s):  
• Complete response defined by RECIST criteria. 
• All grade 1-5 toxicities outlined in CTCAE v4.1. 
• Measurement of downstream effectors in the mTOR pathway by IHC using 
%+ staining and intensity of staining (0-4+) analyzed by a certified pathologist 
in the extension cohort; a decrease in the multiplication of the intensity of 
staining and percentage of at least 25% will be considered a response for 
that patient. 
• Measurement of angiogenic and inflammatory cytokines by ELISA. 
• Measurement of T cell subsets in peripheral blood by flow cytometry. 
• Measurement of AUC, Cmax, and clearance of metformin and cisplatin in 
combination. 
 
 
 
 
All secondary measures will be summarized with descriptive statistics, i.e, 
percentages for categorical outcomes and means/medians for continuous outcomes, 
with corresponding standard errors and 95% confidence intervals.  Responses will be 
tabulated by determined response and toxicities will be tabulated by type and 
grade. For IHC, the percentage of positive cells per area will be multiplied by the 
staining intensity for each tumor to determine quantitative expression pre- and 
post-treatment; a 25% change in expression will be considered a positive response.  
We will use descriptive statistics and graphical displays to evaluate change in serum 
markers between pre- and post-treatment.  Pharmacokinetic parameters will be 
graphically displayed using boxplots and summary statistics. 
 
14.4 
Funding, Regulatory, and Feasibility Issues:  
 
The proposed chemotherapy and radiotherapy in this trial are currently FDA approved for this 
indication of LAHNSCC.  Therefore they are both billable to insurance.  Metformin is not FDA 
approved for this indication in LAHNSCC.  The Department of Internal Medicine Grant awarded 
to Trisha Wise-Draper for $20,000 (grant period 8/1/14-7/31/15) will fund the metformin costs, 
some of the coordinator/personnel costs, and handling of specimens.  Silvio Gutkind from the 
NIH will support the PD studies. We will also be applying for additional funding including the 
Cancer Conquer foundation to help support the PK studies. According to UCCI Cancer Institute 
administration, cost of the clinical trials office will be absorbed by the UCCI Cancer Institute. 
 


Version 8, 31Aug2017 
 
35 
REFERENCES 
 
1. Silvestre J, Carvalho S, Mendes V, et al. Metformin-induced lactic acidosis: A case series. J 
Med Case Rep. 2007;1:126. 
2. Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis 
with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 
2010;(4):CD002967. doi(4):CD002967. 
3. Richy FF, Sabido-Espin M, Guedes S, Corvino FA, Gottwald-Hostalek U. Incidence of lactic 
acidosis in patients with type 2 diabetes with and without renal impairment treated with 
metformin: A retrospective cohort study. Diabetes Care. 2014;37(8):2291-2295. 
4. Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation 
therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable 
squamous cell head and neck cancer. J Clin Oncol. 2003;21(1):92-98. 
5. Ley J, Mehan P, Wildes TM, et al. Cisplatin versus cetuximab given concurrently with 
definitive radiation therapy for locally advanced head and neck squamous cell carcinoma. 
Oncology. 2013;85(5):290-296. 
6. Riaz N, Sherman E, Koutcher L, et al. Concurrent chemoradiotherapy with cisplatin versus 
cetuximab for squamous cell carcinoma of the head and neck. Am J Clin Oncol. 2014. 
7. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with 
oropharyngeal cancer. N Engl J Med. 2010;363(1):24-35. 


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36 
8. Patel PR, Salama JK. Reirradiation for recurrent head and neck cancer. Expert Rev Anticancer 
Ther. 2012;12(9):1177-1189. 
9. Molinolo AA, Hewitt SM, Amornphimoltham P, et al. Dissecting the akt/mammalian target of 
rapamycin signaling network: Emerging results from the head and neck cancer tissue array 
initiative. Clin Cancer Res. 2007;13(17):4964-4973. 
10. Amornphimoltham P, Patel V, Sodhi A, et al. Mammalian target of rapamycin, a molecular 
target in squamous cell carcinomas of the head and neck. Cancer Res. 2005;65(21):9953-9961. 
11. Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M. Metformin is an AMP kinase-
dependent growth inhibitor for breast cancer cells. Cancer Res. 2006;66(21):10269-10273. 
12. Zakikhani M, Dowling RJ, Sonenberg N, Pollak MN. The effects of adiponectin and 
metformin on prostate and colon neoplasia involve activation of AMP-activated protein kinase. 
Cancer Prev Res (Phila). 2008;1(5):369-375. 
13. Vitale-Cross L, Molinolo AA, Martin D, et al. Metformin prevents the development of oral 
squamous cell carcinomas from carcinogen-induced premalignant lesions. Cancer Prev Res 
(Phila). 2012;5(4):562-573. 
14. Yen YC, Lin C, Lin SW, Lin YS, Weng SF. Effect of metformin on the incidence of head and 
neck cancer in diabetes. Head Neck. 2014. 


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15. Sandulache VC, Hamblin JS, Skinner HD, Kubik MW, Myers JN, Zevallos JP. Association 
between metformin use and improved survival in patients with laryngeal squamous cell 
carcinoma. Head Neck. 2013. 
16. Lin CC, Yeh HH, Huang WL, et al. Metformin enhances cisplatin cytotoxicity by suppressing 
signal transducer and activator of transcription-3 activity independently of the liver kinase B1-
AMP-activated protein kinase pathway. Am J Respir Cell Mol Biol. 2013;49(2):241-250. 
17. Rattan R, Graham RP, Maguire JL, Giri S, Shridhar V. Metformin suppresses ovarian cancer 
growth and metastasis with enhancement of cisplatin cytotoxicity in vivo. Neoplasia. 
2011;13(5):483-491. 
18. Skinner HD, Sandulache VC, Ow TJ, et al. TP53 disruptive mutations lead to head and neck 
cancer treatment failure through inhibition of radiation-induced senescence. Clin Cancer Res. 
2012;18(1):290-300. 
19. Ekshyyan O, Mills GM, Lian T, et al. Pharmacodynamic evaluation of temsirolimus in patients 
with newly diagnosed advanced-stage head and neck squamous cell carcinoma. Head Neck. 
2010;32(12):1619-1628. 
20. Sarbassov DD, Ali SM, Sengupta S, et al. Prolonged rapamycin treatment inhibits mTORC2 
assembly and akt/PKB. Mol Cell. 2006;22(2):159-168. 
21. Berstein LM. Metformin, insulin, breast cancer and more.. Future Oncol. 2009;5(3):309-312. 


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22. Zhao Z, Cheng X, Wang Y, et al. Metformin inhibits the IL-6-induced epithelial-mesenchymal 
transition and lung adenocarcinoma growth and metastasis. PLoS One. 2014;9(4):e95884. 
23. Graham GG, Punt J, Arora M, et al. Clinical pharmacokinetics of metformin. Clin 
Pharmacokinet. 2011;50(2):81-98. 
24. Shu Y, Brown C, Castro RA, et al. Effect of genetic variation in the organic cation transporter 
1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther. 2008;83(2):273-280. 
25. Song IS, Shin HJ, Shin JG. Genetic variants of organic cation transporter 2 (OCT2) significantly 
reduce metformin uptake in oocytes. Xenobiotica. 2008;38(9):1252-1262. 
26. Arany I, Safirstein RL. Cisplatin nephrotoxicity. Semin Nephrol. 2003;23(5):460-464. 
27. Lalau JD, Race JM. Metformin and lactic acidosis in diabetic humans. Diabetes Obes Metab. 
2000;2(3):131-137. 
28. Ji Y, Wang SJ. Modified toxicity probability interval design: A safer and more reliable method 
than the 3 + 3 design for practical phase I trials. J Clin Oncol. 2013;31(14):1785-1791. 
29. Allen C, Duffy S, Teknos T, et al. Nuclear factor-kappaB-related serum factors as longitudinal 
biomarkers of response and survival in advanced oropharyngeal carcinoma. Clin Cancer Res. 
2007;13(11):3182-3190. 
30. Granville CA, Warfel N, Tsurutani J, et al. Identification of a highly effective rapamycin 
schedule that markedly reduces the size, multiplicity, and phenotypic progression of tobacco 
carcinogen-induced murine lung tumors. Clin Cancer Res. 2007;13(7):2281-2289. 


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39 
31. Amornphimoltham P, Sriuranpong V, Patel V, et al. Persistent activation of the akt pathway 
in head and neck squamous cell carcinoma: A potential target for UCN-01. Clin Cancer Res. 
2004;10(12 Pt 1):4029-4037. 
32. Rossi E, Villanacci V, Bassotti G, et al. Her-2/neu in barrett esophagus: A comparative study 
between histology, immunohistochemistry, and fluorescence in situ hybridization. Diagn Mol 
Pathol. 2006;15(3):125-130. 
  
 
 
 
 


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40 
APPENDIX A 
 
 
Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent Description 
0 
Normal activity.  Fully active, able 
to 
carry 
on 
all 
pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, 
but 
ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
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. 
 
 
 
 
 
 
 
 
 
 
 
 

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UNIVERSITY OF CINCINNATI 
CONSENT TO PARTICIPATE IN A RESEARCH STUDY 
 
Study Title:  A phase I dose-finding study of metformin in combination with concurrent 
cisplatin and radiation in patients with locally advanced head and neck squamous cell 
carcinoma.  Dose Escalation Phase 
 
UC IRB Study #: 2014-6312 
Sponsor Name: Investigator initiated 
 
Investigator Information: 
 
 Trisha Wise-Draper, MD, PhD 
513-584-7698/513-584-7661 
Principal Investigator Name 
 
  Telephone Number/24 hr Emergency Contact 
 
Subject Name: ______________________________ Date of Birth: _____/_____/____ 
 
 
INTRODUCTION 
 
A biomedical or health-related research study is performed to answer specific questions 
about a disease.    
 
Before you agree to participate in this research study, it is important that you be told the 
purpose, procedures, benefits, risks, discomforts, and precautions of the research. You 
should also be told what alternative procedures are available to you if you do not 
participate in the research study.  The informed consent document is a written summary of 
this information. Be sure to ask questions while you read this consent document and ask 
questions if there is anything that you do not understand.   
 
Your participation in this research study is entirely voluntary.  
 
You may choose either to take part or not to take part in this research study. If you decide 
to take part, you may decide to leave the study at any time. Leaving the study will not 
result in any penalty or loss of benefits to you.  
 
The researcher and sponsor of this study do not promise that you will receive any benefits 
from this study. 
 
 
WHY IS THIS RESEARCH BEING DONE?  
 
The purpose of this research study is to test the safety of adding metformin to treatment 
that you will already be getting for your cancer.  You will be offered “standard of care” 
treatment whether you participate in this study or not.  The standard of care treatment will 
be cisplatin once every 3 weeks for 3 treatments and radiation for 7 weeks.  The risks and 


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benefits of the standard of care treatment will be discussed by your regular doctor. 
Metformin is a medication that is currently used to treat diabetes.  Overall, patients do well 
on this medication and are often taking it for long periods of time.  There is research in 
animals that suggest that metformin may be useful for treating cancer.  We do not know if 
it will work in humans, which is why we are doing this study.  We will be giving increasing 
amounts of metformin to groups of patients already receiving normal treatment for their 
cancer. We would like to see if metformin causes any good effects by killing your cancer or 
bad effects (side effects) on you. 
 
This is a Phase I study. A Phase I study is the first step in testing an investigational (new) 
drug in humans.  An investigational drug is a drug that has not been approved by the Food 
and Drug Administration for a certain disease (in this case, metformin can be used for 
diabetes but not for cancer). The purpose of a Phase I study is to find the best way to give 
an investigational drug and/or the best dose. In Phase I studies, the dose is usually 
increased a little at a time until participants have serious side effects (which may or may 
not occur even at high doses). 
 
 
WHY HAVE YOU BEEN ASKED TO TAKE PART IN THIS RESEARCH STUDY?  
 
You are being asked to take part in this research study because you have head and neck 
cancer that requires treatment with cisplatin and radiation. 
 
The study doctor will determine if you are eligible for participation in this study on a case 
by case basis. 
 
 
HOW LONG WILL YOU BE IN THE RESEARCH STUDY?  
 
You will receive treatment with metformin starting 2 weeks before starting cisplatin and 
radiation.  You will continue taking the metformin every day until you have finished cisplatin 
and radiation treatment.   
 
You will be followed by the research team for 2 years after completion of the study 
treatment, in addition to your regular follow up care.   
 
The researcher may decide to take you off this research study if you experience severe 
side effects or your cancer worsens or if drug supply is insufficient or new information 
becomes available. 
 
You may withdraw from the study at any time. If you decide to stop participating in the 
study, we encourage you to talk to the researcher and your regular doctor first so that 
stopping can be done safely. Another reason to tell your doctor that you are thinking about 
stopping is to discuss what follow-up care and testing could be most helpful to you. 
 


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You may be contacted in the future by representatives of the University of Cincinnati who 
are interested in asking you survey questions about your participation in this research 
study. If you choose to participate in the survey, your responses will be used for quality 
assurance purposes only. 
 
 
WHO IS CONDUCTING THE RESEARCH STUDY?    
 
The study is directed by Dr. Trisha Wise-Draper MD, PhD,  a medical oncologist and 
researcher at The University of Cincinnati; University of Cincinnati and the facilities of the 
affiliated health system located at UCMC and UCPC, including West Chester Hospital. 
 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THE RESEARCH STUDY?  
 
Up to 18 people will take part in this study at The University of Cincinnati.  
 
 
WHAT IS INVOLVED IN THE RESEARCH STUDY?  
 
You will be asked to read and sign this consent before any study-specific tests or 
procedures are performed.  If you wish to participate in this study, the following tests and 
procedures will be performed to find out if you can participate in the study. 
 
 
Screening Visit: 
• A medical history will be obtained from you to make sure you do not have any 
conditions or past treatments that could interfere with your taking part in this study. 
• Samples of your tumor (that have already been removed by surgery or biopsy) will 
be obtained for testing.  This may allow us to understand how the treatment works 
on your tumor.  
• A review of the medications you are taking, including prescriptions for conditions as 
high blood pressure, diabetes, or allergies and non-prescription medications as 
vitamins, herbal supplements, aspirin, etc. will be done. 
• Physical examination will be performed. 
• Measurement of your weight, height, blood pressure, respiratory rate and 
temperature will be done. 
• Either a CT scan (or MRI) of your neck and chest and/or a PET/CT will be 
performed to evaluate your tumor before treatment is started.  You may already 
have this done by your regular oncologist.  
• In women able to have children, a pregnancy test will be done.  The results of the 
pregnancy test must be negative for you to participate in this study. 
• Blood sample will be taken (approx. 1-2 tablespoons) for laboratory tests. 


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Treatment 
You will receive treatment for a total of 9 weeks.  It may be longer if breaks are needed.  
You will take metformin for the entire 9 weeks.  You will be told how much metformin that 
you will take at the beginning of the study.  This is not done at random.  The dose will be 
decided by how well the patients did on the treatment prior to you.  This is for your safety 
to try to avoid any severe side effects.  You will start your normal required treatment with 
cisplatin and radiation the second week.   
 
You will receive treatment in this study as follows: 
• Day -14 – You will begin to take metformin orally (by mouth) on this day.  You will 
take metformin either once in the morning and once at night or once in the morning, 
at lunch and at night.  Your research doctor will let you know how often. This will be 
14 days before the start of your normal treatment of cisplatin and radiation.   
• Every day – you will take metformin orally (by mouth) every day until you finish 
cisplatin and radiation. 
• Day 1, 22 and 43 – you will receive cisplatin through a vein in your arm (this will be 
described in detail by your regular doctor as part of your normal treatment) 
• Day 1 through Day 49 – you will receive radiation every day, 5 days a week (details 
will be given by your radiation oncologist as part of your normal treatment) 
 
Please see the following chart for your medication regimen:  
 
Drug or radiation 
Day -14to 
Day1 
Day1 
Day 2-21 
Day 22 
Day 23-42 
Day 43 
Day 44-49 
Metformin (A) Everyday 
(2 or 3 times a day) 
A 
A 
A 
A 
A 
A 
A 
Cisplatin (B)  
 
B 
 
B 
 
B 
 
Radiation(C) (M-F only) 
 
C 
C 
C 
C 
C 
C 
 
There will be additional laboratory tests to find the amount of metformin in your blood over 
several hours for the first 2 days.  We will also ask for additional blood to be taken during 
your normal lab times. The following tests will also be done: 
 
• Blood samples will be taken to understand how your body reacts to the metformin 
and the chemotherapy (cisplatin).  Blood will be collected as follows: 
o Day 1 - One teaspoon of your blood will be drawn just before you receive 
Metformin, then half an hour, one hour, two hours, four hours and eight hours 
afterwards (eight hour timepoint optional). 


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o Day -14 - One teaspoon of your blood will be drawn just before you receive 
metformin, then half an hour, one hour, two hours, four hours and eight hours 
afterwards (The eight hour timepoint is optional). We will also collect a 
sample the next day. 
o Day -14, Day 1 and week 11 - Three extra teaspoons of your blood will be 
withdrawn. You will already be giving blood for routine labs so this will not 
require an extra blood draw. This blood will help us understand how 
metformin may be affecting the tumor. 
 
• During your clinical visits: 
o You will be asked questions about side effects and health concerns to 
evaluate if you are doing well with the treatment or if you are having side 
effects. 
o Blood samples will be taken (approx. 1 tablespoon) to make sure you are not 
having side effects from either your normal treatment or from the metformin. 
o A review of the medications you are taking, including prescriptions for 
conditions as high blood pressure, diabetes, or allergies and non-prescription 
medications as vitamins, herbal supplements, aspirin, etc. 
o A physical exam will be performed. 
o Measurement of your weight, height, blood pressure, respiratory rate and 
temperature. 
 
All the blood draws will take place in the infusion center location where you receive your 
treatment as well.  The standard labs needed before your standard chemotherapy may be 
incorporated at the same time instead of having extra blood draws. 
 
You will be provided with a glucometer to monitor glucose levels in case you develop 
symptoms of hypoglycemia. 
 
The metformin doses given in this study may be higher than what would be given in other 
diseases such as diabetes. 
 
Follow-Up: 
• Follow-up will not be any different for this study than your normal follow-up. 
 
 
WHAT ARE YOUR RESPONSIBILITIES IF YOU PARTICIPATE IN THIS STUDY? 
 
You will be responsible for coming to the researcher’s office or hospital throughout the 
treatment period and follow-up period of the study. 
 
You will be asked not to participate in any other clinical research studies taking another 
investigational medicine during this study.  
 
You will have to inform your health provider and research team about your medications or 


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any herbal supplements. We may ask you to choose alternative medications with no or 
minimal suppression of the study drug activity or toxicity. 
 
 
 
 
WHAT ARE THE RISKS AND DISCOMFORTS OF THE RESEARCH STUDY?  
 
You may have side effects while on the study.  Everyone taking part in the study will be 
watched carefully for any side effects.  There may be unknown or unforeseen risks 
associated with study participation. Side effects may be mild or very serious.  
 
You should talk to your study doctor about any side effects that you have while taking part 
in the study.    
 
Risks and side effects include: 
 
Possible Side Effects of Metformin  
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Metformin, more than 20 and up to 100 may have: 
• Diarrhea, nausea, vomiting 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Metformin, from 4 to 20 may have: 
• Heartburn, passing gas 
• Headache 
• Tiredness 
 
RARE, AND SERIOUS 
In 100 people receiving Metformin, 3 or fewer may have: 
• Lactic acid build up which may cause muscle aches, shortness of breath, or 
severe belly pain 
• Renal (kidney) failure 
 
 
Some side effects of metformin may occur that usually do not need medical attention. 
These side effects may go away during treatment as your body adjusts to the medicine. 
Also, your health care professional may be able to tell you about ways to prevent or reduce 
some of these side effects.  
 
Stop using metformin and call your doctor at once if you have a serious side effect such 
as: 
• Severe uncontrolled vomiting 
• Shortness of breath 


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Monitoring/Precautions/Safeguards for toxicity: 
1. We will closely monitor your blood counts and treat any abnormality according to 
the standard guidelines. 
2. We will have well planned visit schedules for physical exam and assessment of any 
toxicity. 
3. Patients who are on any medications or herbal supplements that expose them to 
more toxicity or decreased effectiveness of therapy, will be counseled to either 
replace this medicine or not take part in the trial.  
 
Risks of combining metformin with cisplatin: 
 
We are not sure of all the risks of combining metformin with cisplatin.  This is why we are 
performing this study.  However, cisplatin can cause your kidneys not to work well.  This 
could cause the amount of metformin in your body to stay longer.  This could then result in 
increased side effects of metformin which are listed above. 
 
Risk of hypoglycemia: 
 
Metformin does not usually cause hypoglycemia in the treatment of diabetes, but in 
combination with cisplatin, metformin may cause hypoglycemia when caloric intake is 
deficient.  Signs and symptoms of hypoglycemia include: 
• Shakiness 
• Nervousness or anxiety 
• Sweating, chills and clamminess 
• Irritability or impatience 
• Confusion, including delirium 
• Rapid/fast heartbeat 
• Lightheadedness or dizziness 
• Hunger and nausea 
• Sleepiness 
• Blurred/impaired vision 
• Tingling or numbness in the lips or tongue 
• Headaches 
• Weakness or fatigue 
• Anger, stubbornness, or sadness 
• Lack of coordination 
• Nightmares or crying out during sleep 
• Seizures 
• Unconsciousness 
 
Hypoglycemia can be treated with the following: 
1. Consume 15-20 grams of glucose or simple carbohydrates 
2. Recheck your blood glucose after 15 minutes 


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3. If hypoglycemia continues, repeat. 
4. Once blood glucose returns to normal, eat a small snack if your next planned meal 
or snack is more than an hour or two away. 
 
Risks of combining metformin with radiation: 
 
We are unsure if there are any risks of this combination.  We will be watching for side 
effects while you are on study. 
Blood Draws 
 
There may be risks of drawing blood (venipuncture).  Risks of having your blood drawn 
include faintness, inflammation of the vein, pain, bruising, bleeding at the site of the 
puncture and, rarely, infection. 
 
 
WHAT ARE THE REPRODUCTION RISKS?  
 
Because the drug(s) in this research study can affect an unborn baby, and metformin may 
increase these risks, you should not become pregnant or cause a pregnancy while in this 
research study. You should not nurse your baby while on this research study.  You must 
notify the study doctor and your treating physician immediately if you become pregnant or 
suspect that you have caused a pregnancy.  You should use an adequate method of birth 
control during this study.  You should discuss birth control options with your study doctor. 
 
If you or your partner become pregnant, the treatment used in this research study might 
involve unknown risks to the embryo or fetus. The study doctor will wish to follow the 
outcome of any pregnancy and condition of any newborn. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THE RESEARCH STUDY?  
 
If you agree to take part in this study, it is unlikely that there will be a direct medical benefit 
to you.  The addition of metformin may allow better response to the standard treatment of 
cisplatin and radiation.  However, we are conducting this research study to determine if 
this benefit seen in animals can also be confirmed in humans.  We hope the information 
learned from this research study will benefit other patients with advanced head and neck 
cancer in the future. 
The information obtained from this study may benefit the study Sponsor Trisha Wise-
Draper, MD, PhD. 
There is a small possibility that the tumor may decrease in size, cancer spread could be 
limited, and other problems associated with the tumor could decrease.  However, these 
effects may not improve your quality of life or make you live longer. 
 
 
WHAT OTHER CHOICES FOR CARE ARE THERE?  


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Your other choices may include: 
• Receiving standard chemotherapy without the addition of metformin. 
• Getting treatment or care for your cancer without being in a study. 
• Taking part in another study. 
• Getting no treatment.  
 
Talk to your study doctor about your choices before you decide if you will take part in this 
study. 
 
 
HOW WILL INFORMATION ABOUT YOU BE KEPT PRIVATE AND CONFIDENTIAL?  
 
Every effort will be made to maintain the confidentiality of your medical and research 
records related to this study.  The University of Cincinnati, the monitor, the auditor, the 
Institutional Review Board (IRB), and other regulatory authority(ies) will be granted direct 
access to your original medical and research records for verification of clinical trial 
(research study) procedures or study data without violating your confidentiality, to the 
extent permitted by the applicable laws and regulations.  By signing this consent form, you 
are authorizing such access.  The data from the study may be published; however, you will 
not be identified by name. Your identity will remain confidential unless disclosure is 
required by law.   
 
Your research information will be saved in your UC Health medical record. UC Health 
employees providing service or care to you will be able to see it. 
 
 
AVAILABILITY OF INFORMATION 
 
You will receive a copy of this signed and dated consent form.  
 
You will be told about any new information from this or other studies that may affect your 
health, welfare, or willingness to stay in this study. 
 
 
WHAT ARE YOUR COSTS TO BE IN THIS STUDY?  
 
You will receive the study medication, metformin, and the study-related blood draws at no 
cost.  
 
You and/or your health plan/ insurance company will need to pay for some of the costs of 
treating your cancer in this study including the standard chemotherapy with cisplatin and 
radiation. Some health plans will not pay these costs for people taking part in studies. 
Check with your health plan or insurance company to find out what they will pay for. Taking 
part in this study may or may not cost your insurance company more than the cost of 


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getting regular cancer treatment. 
 
 
WILL YOU BE PAID TO PARTICIPATE IN THIS RESEARCH STUDY?  
 
You will not be paid to participate in this research study. 
 
 
 
WHAT COMPENSATION IS AVAILABLE IN CASE OF INJURY? 
 
In the event that you become ill or injured from participating in this research study, 
emergency medical care will be provided to you. The University of Cincinnati will decide on 
a case by case basis whether to reimburse you for your out of pocket health care 
expenses.  
 
 
WHAT ARE YOUR RIGHTS AS A PARTICIPANT?  
 
You may choose either to take part or not to take part in this research study. If you decide 
to take part, you may decide to leave the study at any time. Leaving the study will not 
result in any penalty or loss of benefits to you. The investigators will tell you about new 
information that may affect your health, welfare, or willingness to stay in this study.  
 
If you have questions about the study, you will have a chance to talk to one of the study 
staff or your regular doctor. Do not sign this form unless you have had the chance to ask 
questions and have received satisfactory answers.  
 
Nothing in this consent form waives any legal rights you may have nor does it release the 
investigator, the sponsor, the institution, or its agents from liability for negligence.  
 
WHOM DO YOU CALL IF YOU HAVE QUESTIONS OR PROBLEMS?  
 
If you have questions, concerns or complaints about this research study or to report a 
research-related injury, please contact the researcher Trisha Wise-Draper, MD, PhD at 
513-584-7698. 
 
Please call the University of Cincinnati Institutional Review Board at 513-558-5259 
(Monday – Friday 8 am to 5 pm) if you:  
• Think the research has hurt you.  
• Have general questions about giving consent or your rights as a research 
participant in this research study. 
• Have questions, concerns, or complaints about the research.  
• Cannot reach the research team or you want to talk to someone else. 
 


IRB #: 2014-6312 
 
 
 
Approved:  
2/7/2018 
Do Not Use After: 
2/6/2019 
 
 
UCCI-HN-14-01 Protocol v 8 
Page 11 of 12 
31Aug2017 
To report complaints or concerns to an independent agency in an anonymous and 
confidential manner, please call the Research Compliance Hotline at 1-800-889-1547.  
 


IRB #: 2014-6312 
 
 
 
Approved:  
2/7/2018 
Do Not Use After: 
2/6/2019 
 
 
UCCI-HN-14-01 Protocol v 8 
Page 12 of 12 
31Aug2017 
UNIVERSITY OF CINCINNATI 
CONSENT TO PARTICIPATE IN A RESEARCH STUDY 
 
Study Title:  A phase I dose-finding study of metformin in combination with concurrent 
cisplatin and radiation in patients with locally advanced head and neck 
squamous cell carcinoma.  Dose Escalation Phase 
 
UC IRB Study #: 2014-6312 
Sponsor Name: Investigator-Initiated 
 
Investigator Information: 
 Trisha Wise-Draper, MD, PhD 
     (513) 584-7698                  (513) 584-7661 
Principal Investigator Name 
     Telephone Number 
  24 hr Emergency Contact 
 
SIGNATURES  
 
I have read or someone has read to me, this Informed Consent Document which describes 
the purpose and nature of this research.  I have had time to review this information and 
have been encouraged to ask questions.  I have received answers to my questions.  If I do 
not participate or if I discontinue my participation, I will not lose any benefits.  I will not lose 
any legal rights if I discontinue.  My participation in this research is completely voluntary.  I 
give my consent to participate in this study.  I have received (or will receive) a copy of this 
form for my records and future reference. 
 
 
 
 
Participant   
 
 
 
 
 
 
Date  
 
 
PERSON OBTAINING CONSENT 
I have read this form to the participant and/or the subject has read this form.  An 
explanation of the research was given and questions from the subject were solicited and 
answered to the subject’s satisfaction.  In my judgment, the subject has demonstrated 
comprehension of the information.  
 
 
 
 
 
Signature and Title of Person Obtaining  
 
 
Date  
Consent and Identification of Role in the Study