Clinical trial NCT02949700
Conditions: Head and Neck Squamous Cell Carcinoma
Keywords: metformin head and neck cancer
Sponsor: Baylor College of Medicine
Start date: 2017-01-26; Completion date: 2022-07-07
Enrollment: 26 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this research is to see whether metformin can improve the response rate in patients undergoing chemotherapy and radiation for squamous cell carcinoma of the oral cavity, oropharynx, larynx or hypopharynx. The purpose of this research is also to see the effects, good and bad, of metformin therapy for this disease. Researchers will also analyze tumor and blood samples from study patients to test and understand the characteristics of tumors which respond to metformin.

Detailed description:
Information from laboratory studies and retrospective studies of patients with this disease has shown that the addition of metformin (a commonly used medicine for treating diabetes) to chemotherapy and radiation can improve the rate at which the cancer responds to treatment. Metformin is used frequently in the treatment of patients with diabetes and other illness, but has not yet been used to treat patients with this type of cancer. In this research study, we want to see if using metformin during treatment with chemotherapy and radiation will increase the chance that the cancer will respond to treatment and not return.

Arms: arm 1: Patients in the Phase I trial will be assigned to a single arm, experimental treatment which will test dose escalation for metformin in the context of chemo-radiation, with toxicity as the primary outcome.

Patients in the Phase II trial will be assigned to a single arm, experimental treatment consisting of metformin plus chemo-radiation.
Interventions: intervention 1: Metformin
Intervention descriptions: intervention 1: Metformin will be administered orally twice daily during treatment with chemo-radiation for head and neck squamous cell carcinoma. This will occur 7 to 11 days prior to chemotherapy and radiation.

Protocol documents:
Prot_SAP_000.pdf: 
A Phase I/II Study of Metformin in Combination with 
Cisplatin and Radiation in Head and Neck Squamous Cell Carcinoma 
Coordinating Center: 
Dan L Duncan Comprehensive Cancer Center 
Baylor College of Medicine 
 
Principal Investigator: 
Vlad C. Sandulache MD 
Assistant Professor 
Department of Otolaryngology Head and Neck Surgery 
One Baylor Plaza MS: NA-102 
Houston, TX 77030 
Telephone: 713-798-7218 
Fax: 713-798-5078 
Email: vlad.sandulache@bcm.edu 
 
Co-Investigators: 
Anita Sabichi, MD 
Assistant Professor, Dept. of Medicine 
Section of Hemagology/Oncology 
One Baylor Plaza, Houston, TX 
Telephone: 713-798-3750 
Email: sabichi@bcm.edu 
 
Courtney Miller-Chism MD 
Assistant Professor 
Department of Medicine, 
Section of Hematology/Oncology 
One Baylor Plaza, Houston, TX 
Telephone: 713-798-5273  
Email: cnmiller@bcm.edu 
 
Pavan Jhaveri MD 
Assistant Professor 
Department of Radiation Oncology 
One Baylor Plaza, Houston, TX 
Telephone: 713-566-3757 
Email: jhaveri@bcm.edu 
 
Quillan Huang MD 
Assistant Professor 
Department of Medicine, 
Section of Hematology/Oncology 
One Baylor Plaza, Houston, TX 
Telephone: 713-798-0144  
Email: quillanh@bcm.edu 
 
 
 
 
 
 


Aparna Jotwani MD 
Assistant Professor 
Department of Medicine, 
Section of Hematology/Oncology 
One Baylor Plaza, Houston, TX 
Telephone: 713-873-2000  
Email: Aparna.jotwani@bcm.edu 
 
Susan Hilsenbeck PhD 
Professor, Smith Breast Center 
BCM-Cullen Building; BCMC 333A 
MS BCM600, Houston, TX 77030 
Telephone: 713-798-1627 
Email: sgh@bcm.edu 
 
Statisticians: 
Shaun Bulsara 
Senior Biostatistician 
BCM-Cullen Building; BCMC 529D  
MS BCM305, Houston, TX 77030 
Telephone: 713-798-8014 
Email: shaun.bulsara@bcm.edu   
 


Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ............................................................ 3 
2.0 
OBJECTIVES ................................................................................................................... 5 
2.1 Primary Objective ...................................................................................................... 5 
2.2 Secondary Objective ................................................................................................... 5 
3.0 
BACKGROUND AND RATIONALE ............................................................................ 5 
3.1 Study Disease .............................................................................................................. 5 
3.2 Agent/Drug Information ........................................................................................... 5 
3.3 Rationale for Development ........................................................................................ 6 
3.4 Correlative Studies Background .............................................................................. 7 
4.0 
PATIENT SELECTION .................................................................................................. 8 
5.0 
REGISTRATION PROCEDURES ............................................................................... 10 
5.1 General Guidelines................................................................................................... 10 
5.2 Registration Process................................................................................................. 10 
6.0 
TREATMENT/ INTERVENTION PLAN ................................................................... 10 
6.1 Agent Administration .............................................................................................. 10 
6.2 Other Modality(ies) or Procedures ......................................................................... 13 
6.3 Concomitant Medication and Supportive Care Guidelines ................................. 15 
6.4 Duration of Treatment ............................................................................................ 15 
6.5 Criteria for Removal from Study ........................................................................... 15 
6.6 Duration of Follow-Up ............................................................................................. 15 
7.0 
DOSING DELAYS/ DOSE MODIFICATION ............................................................ 16 
8.0 
CORRELATIVE STUDIES ........................................................................................... 18 
8.1 Laboratory Correlative Studies .............................................................................. 19 
9.0 
TREATMENT EVALUATION ..................................................................................... 20 
9.1 Study Calendar......................................................................................................... 23 
10.0 
PHARMACEUTICAL INFORMATION ..................................................................... 24 
10.1 Agent #1 .................................................................................................................. 24 
10.2 Agent Ordering ...................................................................................................... 25 
10.3 Agent Accountability ............................................................................................. 25 
10.4 Commercial Agents ................................................................................................ 26 
11.0 
TOXICITIES/SIDE EFFECTS ..................................................................................... 32 
12.0 
MEASUREMENT OF EFFECT ................................................................................... 33 
12.1 Antitumor Effects - Solid Tumors ........................................................................ 33 


13.0 
STATISTICAL CONSIDERATIONS .......................................................................... 37 
13.1 Study Design/ Endpoints ....................................................................................... 37 
13.2 Sample Size/ Accrual Rate .................................................................................... 37 
13.3 Stratification Factors ............................................................................................. 38 
13.4 Analysis of Secondary Endpoints ......................................................................... 38 
13.5 Reporting and Exclusions ..................................................................................... 38 
14.0 
DATA MANAGEMENT ................................................................................................ 39 
15.0 
QUALITY ASSURANCE .............................................................................................. 40 
16.0 
DATA AND SAFETY MONITORING ........................................................................ 40 
17.0 
PROTECTION OF HUMAN SUBJECTS ................................................................... 40 
18.0 
ADVERSE EVENTS ...................................................................................................... 41 
18.1 Adverse Event Characteristics .............................................................................. 41 
18.2 Adverse Event Reporting ...................................................................................... 42 
18.3 Safety Reporting Requirements for IND Holders ............................................... 42 
18.4 Multicenter Guidelines .......................................................................................... 42 
19.0 
PREGNANCY ................................................................................................................. 42 
20.0 
REFERENCES ................................................................................................................ 44 
21.0 
APPENDICES ................................................................................................................. 46 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Study Title: A phase I/II study of metformin in combination with cisplatin and radiation 
in head and neck squamous cell carcinoma. 
 
Study Concept: The purpose of this study is to investigate the safety and efficacy of 
metformin when used in combination with standard of care cisplatin and external beam 
radiotherapy (EBRT) for patients with stage III/IV squamous cell carcinoma of the 
oropharynx, larynx, hypopharynx and oral cavity. Metformin is an anti-diabetic medication 
which has been widely utilized for nearly 2 decades, with a proven safety profile. 
Utilization of metformin during treatment of head and neck squamous cell carcinoma 
(HNSCC) has been shown to be associated with improved disease response, disease free 
survival and overall survival in retrospective studies. In combination with extensive pre- 
clinical studies, these data support the hypothesis that metformin can improve chemo- 
EBRT effectiveness in a prospective clinical trial. The proposed study is designed to 
determine whether metformin utilization in combination with standard of care cisplatin and 
EBRT demonstrates increased toxicity (phase I) and whether metformin utilization can 
improve the primary outcome of disease response (phase II) compared to historical controls 
treated with chemo-EBRT. 
 
Study Design: This is a prospective study involving stage III/IV patients with squamous 
cell carcinoma of the oropharynx, larynx, hypopharynx and oral cavity. The phase I portion 
of the study will test 2 doses of metformin which are within the standard range used for 
management of diabetes mellitus. The goal of this phase I component is to determine 
whether metformin use is associated with increased systemic and locoregional treatment 
toxicity. The phase II portion will use the maximum tolerated dose (MTD) from the phase 
I to evaluate metformin efficacy in a prospective cohort of 20 patients using disease 
response as the primary outcome measure. 
 
Number of Patients: 45 
 
Primary Endpoint: The primary endpoint for the phase I component will be toxicity. The 
primary endpoint for the phase II component will be disease response ascertained via 
imaging following completion of treatment. 
 
Secondary Endpoints: Secondary endpoints for the phase II component will include: 
progression free survival and overall survival.  


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2.0 
OBJECTIVES 
 
2.1 
Primary Objectives 
The primary objective for the phase I component is to define the maximum tolerated dose 
(MTD) of metformin and to document the safety of this compound when used in 
combination with cisplatin and external beam radiotherapy (EBRT). 
 
The primary objective for the phase II component is to measure the effect of metformin in 
combination with standard of care cisplatin and EBRT on disease response when compared 
to historical controls treated with standard of care cisplatin and EBRT. 
 
2.2 
Secondary Objectives 
Secondary endpoints for the phase II component will include: progression free survival and 
overall survival.  
 
3.0 
BACKGROUND AND RATIONALE 
3.1 
Study Disease 
Every year, over 500,000 patients are diagnosed with a squamous cell carcinoma 
of the oral cavity, oropharynx, larynx and hypopharynx of which over 100,000 will 
be diagnosed in the US alone.1 Non-operative management of these cancers has 
become the preferred approach over the last decade (NCCN guidelines). Advances 
in combinations of systemic therapy (cisplatin) and external beam radiotherapy 
(EBRT) technology has succeeded in decreasing treatment related toxicity, but 
survival rates for patients with advanced, stage III-IV disease remain low. This is 
particularly true for patients with stage III-IV SCC of the oropharynx, larynx, 
hypopharynx and oral cavity which do not exhibit evidence of infection with the 
human papilloma virus (HPV).2-6 In contrast to HPV+ patients, HPV- patients 
continue to demonstrate low rates of disease control, disease free and overall 
survival. The overall goal of this study is to test the potential of metformin as an 
adjunct to standard of care non-operative management consisting of cisplatin and 
EBRT for patients with stage III/IV, HPV- SCC. 
3.2 
Agent/Drug Information 
Metformin is a well-tolerated anti-hyperglycemic agent used by more than 120 
million patients worldwide. Metformin has a demonstrated safety and efficacy 
profile in preventing diabetes and improving metabolic and hormonal parameters 
in non-diabetic patients with insulin resistance and polycystic ovary syndrome 
(PCOS).7 Metformin safety has also been demonstrated in patients with non- 
alcoholic fatty liver disease.8 
3.2.1 
Antitumor Activity 
Metformin has been shown by multiple investigators (including the principal 
investigator) to possess antitumor activity in preclinical models of squamous cell 


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carcinoma of the oral cavity, lung carcinoma, prostate carcinoma and breast 
carcinoma.9-11 Retrospective data series have also shown improved clinical 
outcomes in patients taking metformin during treatment with standard of care 
regimens.11-14 
3.2.2 
Summary of Preclinical Studies 
Over the last few years, multiple investigators have demonstrated an important 
relationship between radiation effects on tumor cells and tumor cell metabolism. 
This relationship is dictated to a large degree by the master metabolic regulators 
AMPK and mTOR.9, 10, 15-17 We and others have shown that AMPK acts not only as 
a metabolic but also a genomic stress sensor that mediates cell cycle checkpoints and 
activates signaling events leading to radio-sensitization and cell death.15, 16, 18 
Metformin can exhibit profound effects on cellular metabolism, activate AMPK 
signaling and radiosensitize tumors in a variety of pre-clinical models.9, 10, 19 In 
addition, 
metformin 
can 
potentiate 
the 
effectiveness 
of 
conventional 
chemotherapeutic agents in the pre-clinical setting.20, 21 Importantly, metformin 
effects occur at doses that can be safely achieved in the serum of patients treated 
with standard oral doses of metformin.22 
3.2.3 
Summary of Clinical Studies 
Clinical evidence to date indicates that utilization of metformin during cancer 
treatment can improve clinical outcomes in tumors of the upper aero-digestive 
tract.10, 13, 23 To date, we have not detected evidence of increased treatment 
(chemotherapy + EBRT) toxicity in diabetic patients treated with metformin who 
received standard of care chemotherapy and EBRT. 
 
3.3 
Rationale for Development 
Patients with stage III/IV HPV- SCC of the oral cavity, oropharynx, larynx and 
hypopharynx continue to demonstrate low rates of disease response and survival 
when treated with current standard of care chemotherapy and EBRT.2-4, 6 There is a 
need to identify novel agents which can be added to standard of care regimens in 
order to improve disease outcomes. Because the toxicity of conventional 
chemotherapy and radiation is often additive and can prevent treatment escalation, 
there is a need to identify agents whose toxicity profile does not overlap with that 
of conventional treatment regimens. Metformin has an excellent safety record to 
date despite nearly 2 decades of widespread utilization in the Unites States. Phase 
I and II studies have demonstrated safe metformin use in non-diabetic patients.24-27 
Metformin does not cause hypoglycemia, has favorable metabolic effects on insulin 
resistance and obesity, and is not associated with lactic acidosis at standard 
therapeutic doses.28,29 
Although metformin is currently being investigated in multiple other 
disease sites, there are no active clinical trials investigating the efficacy of 
metformin in combination with cisplatin and EBRT in the treatment of SCC of the 
oral cavity, oropharynx, larynx and hypopharynx. A single phase I trial is currently 
underway at the University of Cincinnati using dose of metformin higher than those 
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mellitus. A phase I component was included in the current trial in order to evaluate 
any potential increase in toxicity associated with the combination of metformin, 
cisplatin and EBRT. The phase II component of this trial is the first of its kind in 
this disease site, and will provide the first prospective data regarding the potential 
efficacy of metformin in improving clinical outcomes for patients with stage III/IV 
HPV- SCC of the oral cavity, oropharynx, hypopharynx and larynx. 
 
3.4 
Correlative Studies Background 
The preclinical data summarized above suggests that metformin can improve the 
cytotoxicity of chemotherapy and radiation, in part through perturbation of tumor 
metabolic pathways.9, 10 We and others have shown that tumor cells which exhibit 
a less flexible metabolic phenotype are more susceptible to metformin effects.9, 10 
As a result, it is important to evaluate the metabolic phenotype of the patient tumors 
included in this study, in order to identify potential metabolic signatures of those 
tumors which are most responsive to metformin. To that end, tumors from patients 
enrolled in this study will be subjected to a multi-platform (mass spectroscopy / 
liquid chromatography) metabolomics analysis.30 
Our 
preliminary 
studies 
indicate 
that 
metformin 
preferentially 
radiosensitizes tumor cells which express mutant TP53.9, 10 Since metformin 
effectiveness can be impacted by the presence or absence of this and potentially 
other oncogenic events, we will evaluate the mutational landscape of tumors 
evaluated in this study using targeted sequencing. 
Metformin has recently been shown to regulate the immune response 
associated with tumor development by regulating T cell survival and apoptosis.31 
Since the immune response can play an important role in regulation of tumor 
growth and treatment response, we will perform correlative studies for the 
following: 1) changes in circulating immune cells (i.e. effector T cells, myeloid 
derived suppressor cells, regulatory T cell) levels in patients before and after 
treatment completion; 2) changes of other cellular and humoral immune response 
related parameters before and after treatment completion. The correlative studies 
performed as part of this clinical trial will not impact treatment selection and will 
not be available to the treatment team. All correlative studies will be performed 
following completion of the prospective therapeutic trial. 


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4.0 
PATIENT ELIGIBILITY: PATIENT INITIALS (FML):  
 
          a. Diagnosis: Patients must have histologically or cytologically confirmed squamous cell 
carcinoma (SCC) of the oral cavity, oropharynx, hypopharynx or larynx. Patients 
eligible for inclusion must have stage III-IV SCC of the above sites based on 
current AJCC clinical and imaging based staging (see Appendix A for staging 
criteria). For the phase II component, patients should present with: 1) HPV- SCC 
or 2) HPV+ SCC and a concomitant ≥10pack-year smoking history documented 
in the clinical record; HPV status will be ascertained using the currently utilized 
clinical standard of p16 overexpression via immunohistochemistry for all 
patients. Immunohistochemistry to determine p16 overexpression is only a 
requirement for oropharyngeal disease.2, 4 
          b. Disease Status: Patients must have active, measurable disease to be included in the study. 
c. Prior Therapy: Patients must have fully recovered (ECOG 0-1) from the acute toxic 
effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to 
entering this study. 
d. Myelosuppressive chemotherapy: Must not have received within 4 weeks of registration 
onto this study (6 weeks if prior nitrosourea). 
  
e. Hematopoietic growth factors: Patients must be at least 7 days since the completion of 
therapy with a growth factor prior to registration. 
  
f. Biologic (anti-neoplastic agent): Patients must be at least 7 days since the completion of 
therapy prior to registration. 
  
g. Monoclonal Antibody: At least 6 weeks must have elapsed since prior therapy that 
includes a monoclonal antibody prior to registration. 
          h. XRT: Prior to registration, patients must be  14days for local palliative XRT (small 
port);  90days must have elapsed if prior TBI, craniospinal XRT or if  50% 
radiation of pelvis;  45days must have elapsed if other substantial bone marrow 
radiation. 
  
i. Stem Cell Transplant or Rescue: No evidence of active graft vs. host disease and  2 
months must have elapsed since transplant prior to registration. 
  
j. Age: Patients must be >18 years of age. 
  
k. Performance Status: ECOG performance status less than or equal to 3. 
  
l. Organ Function: Patients must have normal organ and marrow function as defined below, 
within 14 days of registration: 
i. 
leukocytes 
>3,000/mcL 
ii. 
absolute neutrophil count 
>1,500/mcL 
iii. 
platelets 
>100,000/mcL 
iv. 
total bilirubin 
within normal institutional limits 
v. 
AST(SGOT) 
2.5X institutional upper limit of normal 
vi. 
ALT /(SGPT) 
2.5X institutional upper limit of normal 
vii. 
creatinine < 1.5mg/dL OR creatinine clearance>60 mL/min/1.73 m2 for 
patients with creatinine levels > institutional normal 


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m. Patients must be candidates for standard of care treatment consisting of chemotherapy 
(cisplatin) and radiation. 
 
          n. Willingness to Use Contraception: The effects of metformin on the developing human 
fetus at the recommended therapeutic dose are unknown. For this reason, women 
of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence), 30 days prior to study 
drug initiation and 30days post completion of study drug administration. Should 
a woman become pregnant or suspect she is pregnant while participating in this 
study, she should inform her treating physician immediately. 
          o. Informed Consent: Patients must have the ability to understand and the willingness to 
sign a written informed consent document. 
 
  
p. Patients may not be receiving any other investigational agents. 
 
  
q. Brain metastases: Patients may not have diagnosed brain metastases. 
 
  
r. Prior Allergies: Patients may not have a history of allergic reactions attributed to 
compounds of similar chemical or biologic composition to metformin. 
 
  
s. Patients must not have a diagnosis of diabetes mellitus (DM) or be receiving active 
treatment for DM. If patient does not have known DM diagnosis, the patient must have 
either fasting glucose or hemoglobin A1C test within 30 days of registration. Patient is 
not eligible if glucose level ≥ 126mg/dl or hemoglobin A1c ≥ 6.0%. (Either test is 
sufficient for eligibility; both tests are not needed.) 
 
          t. Patients may not have an uncontrolled intercurrent illness including, but not limited to, 
ongoing or active infection, symptomatic congestive heart failure, unstable 
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
 
  
x. Patients may not be pregnant or breastfeeding. 
 
 
  
y Patients may not have diagnosed HIV. 
 
 
  
z. Patients may not be taking metformin for a reason other than study participation. 


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aa. Patients may not have been treated for another SCC of the oral cavity, oropharynx, 
hypopharynx or larynx in the past. 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
Approximately 40% of the patient population in Harris County is Hispanic and many are primarily 
Spanish speaking, thus we will provide a fully translated and IRB approved Spanish consent to 
these subjects. 
 
 
5.0 REGISTRATION PROCEDURES 
5.1 General Guidelines 
5.1.1 
Eligible patients will be entered on study centrally at the Clinical Trials 
Support Unit in the Dan L. Duncan Comprehensive Cancer Center at the 
Baylor College of Medicine by the Study Coordinator. Coordinators at each 
facility will discuss eligibility with the study PI. Patient eligibility checklist 
must be completed prior to enrollment. Study consent must be obtained 
prior to performing any study related procedures. 
5.1.2 
Following Registration, patient should begin treatment within 30 days. 
Issues that would cause treatment delays should be discussed with the 
Principal Investigator. 
 
5.2 Registration Process 
5.2.1 
Eligibility will be determined as per CTSU policy, according to the criteria 
in Section 4. 
5.2.2 
Eligible subjects will be registered into OnCore, and assigned a study ID 
number. 
5.2.3 
Issues that would cause treatment delays should be discussed with the 
Principal Investigator. 
5.2.4 
Filing of the signed consent form will be done per CTSU policy. 
 
 
6.0 
TREATMENT/INTERVENTION PLAN 
 
6.1 
Agent Administration 
 
All patients will receive immediate release metformin in a pill form that allows for 
it to be crushed and administered via gastrostomy tube if necessary. 
 
Metformin should be taken 60-90 minutes prior to a meal. The first dose of the day 
should be taken prior to administration of the daily radiation fraction. On days on 


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which the patient will undergo cisplatin infusion, metformin should be taken at least 
90 minutes prior to cisplatin infusion. 
 
The drug will be dispensed to the patient from the institutional pharmacy with 
appropriate self-administration instructions. The patients will be provided with a 
drug log and will be asked to provide the drug log on a weekly basis to the treating 
team in order to ascertain compliance with administration schedule and 
instructions.  
 
Dose Level 
Drug 
DL -1 
500 mg, PO, BID 
DL 1 
850 mg, PO, BID 
DL 2 
1500 mg, PO, BID 
 
 
Phase I component: 
 
All patients will undergo a 2 week “lead in” period in order to decrease the 
gastrointestinal toxicity associated with metformin. During this “lead-in” period, 
all patients will start metformin at the dose of 500mg PO BID. Dose increases to 
the targeted Dose levels are delineated in detail below. The start of radiation is Day 
1. 
 
The following modification is planned for the Phase I component. We will forgo 
escalation to Dose level 2 and proceed to the Phase II component using Dose level 
1. The previous Dose level 2 information has been left in the protocol for the 
purpose of documentation (12/19/2018). 
 
 
Dose level 1: 850mg per os (PO) twice daily (BID). All patients will start metformin 
14 days (Day -14) (+/-24hr) prior to initiation of radiation at the starting dose of 
500mg PO BID (administered prior to breakfast and prior to dinner), 7 days/week. 
On day -7 (+/-24hr), the dose will be escalated to 850mg PO BID for the first 3 
patients enrolled in the phase I component. The dose of 850mg PO BID will then 
be continued for the entire duration of chemoradiation, administered 7 days/week. 
If the timing of radiation start is altered following metformin initiation patient may 
continue on the study as follows. 
- 
If the timing of radiation is moved up (i.e. sooner than planned), the patient may 
continue the “lead in” phase as described above, and initiate the target Dose 
level once the “lead in” phase has been completed. 
- 
If the timing of radiation start is delayed following the “lead in” phase, the 
patient will initiate the target Dose level once the “lead in” phase has been 
completed and continue taking metformin while waiting for radiation start. 


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Dose level 2: 1500mg per os (PO) twice daily (BID). All patients will start 
metformin 14 days (Day -14) (+/-24hr) prior to initiation of radiation at the starting 
dose of 500mg PO BID (administered prior to breakfast and prior to dinner), 7 
days/week. On day -7 (+/-24hr), the dose will be escalated to 850mg PO BID. On 
day -4 (+/-24hr) the dose will again be escalated to 1500mg PO BID. Patients will 
then continue the 1500mg PO BID regimen for the entire duration of 
chemoradiation, administered 7days/week. If the timing of radiation start is altered 
following metformin initiation patient may continue on the study as follows. 
- 
If the timing of radiation is moved up (i.e. sooner than planned), the patient may 
continue the “lead in” phase as described above, and initiate the target Dose 
level once the “lead in” phase has been completed. 
- 
If the timing of radiation start is delayed following the “lead in” phase, the 
patient will initiate the target Dose level once the “lead in” phase has been 
completed and continue taking metformin while waiting for radiation start. 
 
Dose level -1: 500 mg per os (PO) twice daily (BID). Although the 850mg PO BID 
dose is well within the current clinical range for metformin, the phase I component 
will also include a Dose level -1. If patients experience metformin related toxicity 
(see below) on the 850mg dose, we will de-escalate to a dose of 500mg PO BID. 
Patients will start metformin 14 days (Day -14) (+/-24hr) prior to initiation of 
radiation at the starting dose of 500mgPO BID (administered prior to breakfast and 
prior to dinner), 7days/week and continue at this dose for the entire treatment 
course. This dose will then be utilized for the entire phase I component of the trial. 
All patients will receive immediate release metformin in a pill form that allows for 
it to be crushed and administered via gastrostomy tube if necessary. If the timing of 
radiation start is altered following metformin initiation patient may continue on the 
study as follows. 
- 
If the timing of radiation is moved up (i.e. sooner than planned), the patient may 
continue the “lead in” phase as described above, and initiate the target Dose 
level once the “lead in” phase has been completed. 
- 
If the timing of radiation start is delayed following the “lead in” phase, the 
patient will initiate the target Dose level once the “lead in” phase has been 
completed and continue taking metformin while waiting for radiation start. 
 
Determination regarding maximum tolerated dose (MTD) for the phase I 
component will be performed as described. See section 7.2 specific metformin 
evaluable toxicities and dose limiting toxicities (DLTs). All patients who are 
enrolled and receive the study drug will be evaluated for toxicity, but only patients 
which complete ≥70% of the total planned study drug dose to be administered 
during the standard of care radiation treatment period will be used to ascertain 
absence of DLT as part of the Phase I component and planned escalation strategy 
detailed in the table in section 13.2. 


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Assignment of patients to a Dose levels will be performed by the PI or one of the 
co-investigators listed on the protocol if the PI is not immediately available. Study 
coordinators will not be expected to assign patients to Dose levels. All decisions 
regarding dose escalation or dose reduction will be made by the PI or one of the co- 
investigators listed on the protocol if the PI is not immediately available, using the 
general schema listed above and the toxicity driven modifications listed in Section 
7. Modifications to the standard of care treatment consisting of chemotherapy and 
radiation will be made by the treating physicians, per standard clinical practice. 
 
Phase II component: 
All patients used for evaluation of the phase II component will be treated using one 
of the Dose levels determined by the process described in section 13.2.To be 
evaluable for response patients must have taken ≥70% of the total metformin dose 
to be administered during the standard of care radiation treatment period 
Regardless of the determined MTD, all patients will start with a 1  week  “lead-
in” period of 500mg PO BID. If the timing of radiation start is altered following 
metformin initiation patient may continue on the study as follows. If the timing of 
radiation is moved up, the patient may continue the “lead in” phase as described 
above, and initiate the target Dose level once the “lead in” phase has been 
completed. If the timing of radiation start is delayed following the “lead in” phase, 
the patient will initiate the target Dose level once the “lead in” phase has been 
completed and continue taking metformin while waiting for radiation start. 
 
 
6.2 
Other Modality(ies) or Procedures 
Chemotherapy: Weekly cisplatin will be administered at the discretion of the 
treating physicians. Below is a suggested regimen for administration that is 
recommended in order to standardize administration and treatment of side effects. 
Deviations from this regimen are allowed, but should be documented by the treating 
physician. It is recommended that cisplatin be infused over 60 minutes 
intravenously at 40 mg/m2 weekly, starting on week 1 day 1 of radiation, for a 
maximum of 7 weeks. 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. The 
administration of cisplatin should follow the standard anti-emetic premedication 
and hydration as follows: Ondansetron 16mg + Dexamethasone 8 mg should be 
infused 30 minutes prior to cisplatin infusion. Normal saline 1000 mL + KCl 20 
mEq / L + 1 gm MgSO4 will be infused over 2 hours prior to administration of 
cisplatin. Normal saline 500ml should be infused after completion of cisplatin. Any 
pre-existing dehydration should be corrected prior to cisplatin administration. 
Should extravasation occur, the treating physician should follow institutional 
guidelines for additional management. Breakthrough nausea and vomiting should 
be managed at the discretion of the medical oncologist or radiation oncologist. 
Delayed nausea and vomiting (greater than 24 hours after chemotherapy 


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administration) may be managed by the addition of aprepitant concurrently or with 
metoclopramide and dexamethasone. Potential delayed nausea regimens include: 
1. The NK-1 antagonist, aprepitant (125 mg p.o.), may be added for prevention of 
delayed emesis on the day of cisplatin administration and for two consecutive days 
thereafter (80, 80), with a corticosteroid, such as dexamethasone on days 1-4. 
Fosaprepitant 115 mg iv may be substituted for the aprepitant 125 mg on day 1. 
Dexamethasone should be reduced on day 1 to 12 mg and delivered at up to 8 mg 
total daily for the 3 days following cisplatin administration. A 5HT3 antagonist 
(e.g. granisetron, ondansetron) may be also given for the 3 days following cisplatin 
administration, only if palonosetron was not given prior to chemotherapy. 
2. Delayed emesis also may be managed by the addition of dexamethasone 8 mg 
bid x 2 days, followed by dexamethasone 4mg bid x 2 days, beginning on the day 
after chemotherapy; and oral metoclopramide 0.5 mg/kg (usually 20-40 mg) qid x 
2-4 days. A 5HT3 antagonist (e.g. granisetron, ondansetron) may also be given for 
up to 3 days after cisplatin. 
 
External beam radiotherapy (EBRT): EBRT will be administered at the discretion 
of the treating physician as deemed appropriate for the individual patient and tumor 
characteristics. Below is a suggested regimen for administration that is 
recommended in order to standardize administration and treatment of side effects. 
Deviations from this regimen are allowed, but should be documented by the treating 
physician. For oral cavity and oropharynx primary tumors, the prescribed 
radiotherapy dose will be 69.96 Gy in 2.12 Gy once-daily fraction size (total of 33 
fractions). For larynx and hypopharynx tumors primary tumors, the prescribed 
radiotherapy dose will be 70 Gy in 2 Gy once-daily fraction size (total of 35 
fractions). The daily dose of 2.12 Gy will be prescribed such that 95% of the 
PTV69.96 volume receives 69.96 Gy. Radiotherapy should begin on a Monday, 
Tuesday or Wednesday. Treatment breaks must be clearly indicated in the treatment 
record along with the reason(s) for the treatment break(s). Treatment breaks should 
be allowed only for resolution of severe acute toxicity and/or for inter-current 
illness and not for social or logistical reasons. Any treatment break(s) exceeding 2 
treatment days for reasons other than toxicity/illness will be considered a protocol 
deviation. Missed treatments due to holidays or for logistic reasons can be 
compensated for by delivering an additional treatment (BID, two fractions in one 
day at least 6 hours apart) during the week, or treating on the Saturday or Sunday 
of that week, or adding to the end of treatment. IMRT will be utilized for treatment 
planning, and planning will consist of a single plan utilizing a simultaneous 
integrated boost (SIB) technique as outlined below. Daily image-guidance in the 
form of cone-beam CT is required to ensure accurate daily set-up and 
reproducibility. 
 
Target and Normal Tissue Volume Definitions For Oral Cavity and Oropharynx 
CTV69.96: This volume will receive 2.12 Gy per day in 33 fractions over 6.5 
weeks. CTV69.96 consists of the primary tumor and grossly involved 


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lymphadenopathy with a 0.5 cm expansion of the gross tumor volume (GTV) to 
cover potential local invasion. A 0.3 cm expansion to CTV69.96 will be utilized to 
create PTV69.96. CTV63 will receive 1.91 Gy in 33 fractions and consists of 
intermediate-risk disease sites and is defined as a 1 cm expansion on the GTVs 
along with the remainder of neck levels with grossly involved disease (i.e. left level 
II with a grossly involved left level II node). Additionally, it includes anatomical 
patterns of microscopic spread defined at the discretion of the treating radiation 
oncologist. A 0.3 cm expansion to CTV63 will be utilized to create PTV63. CTV57 
will receive 1.73 Gy per day in 33 fractions and consists of low-risk sub-clinical 
disease sites, including the uninvolved contralateral neck, and uninvolved 
ipsilateral low neck. A 0.3 cm expansion to CTV57 will be utilized to create 
PTV57. 
 
Target and Normal Tissue Volume Definitions For Larynx and Hypopharynx 
CTV70: This volume will receive 2.0 Gy per day in 35 fractions over 7 weeks. 
CTV70 consists of the primary tumor and grossly involved lymphadenopathy with 
a 0.5 cm expansion of the gross tumor volume (GTV) to cover potential local 
invasion. A 0.3 cm expansion to CTV70 will be utilized to create PTV70. CTV63 
will receive 1.8 Gy in 35 fractions and consists of intermediate-risk disease sites 
and is defined as a 1 cm expansion on the GTVs along with the remainder of neck 
levels with grossly involved disease (i.e. left level II with a grossly involved left 
level II node). Additionally, it includes anatomical patterns of microscopic spread 
defined at the discretion of the treating radiation oncologist. A 0.3 cm expansion to 
CTV63 will be utilized to create PTV63. CTV57 will receive 1.63 Gy per day in 
35 fractions and consists of low-risk sub-clinical disease sites, including the 
uninvolved contralateral neck, and uninvolved ipsilateral low neck. A 0.3 cm 
expansion to CTV57 will be utilized to create PTV57. 
 
Radiation Treatment Related Toxicity 
Grade 3 therapy-induced mucositis and/or dysphagia are expected to develop in 
about one third to two thirds of patients. Nutritional evaluation prior to the initiation 
of therapy for a prophylactic gastrostomy (PEG) tube placement is recommended. 
Other common radiation adverse events include: fatigue, weight loss, regional 
alopecia, xerostomia, hoarseness, transient ear discomfort, dysgeusia, and skin 
erythema and desquamation within the treatment fields. These side effects vary in 
intensity and are typically managed during the weekly visit with the treating 
radiation oncologist. Less common long-term treatment adverse events include: 
hypothyroidism, loss of hearing, chronic swallowing dysfunction requiring 
permanent feeding tube, and cervical fibrosis. Much less common radiation adverse 
events include: mandibular osteoradionecrosis (<5% incidence with proper pre- 
therapy dental evaluation), and cervical myelopathy (<1% with restriction of spinal 
cord dose to ≤45 Gy). 
 
6.3 
Concomitant Medication and Supportive Care Guidelines 


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All supportive therapy for optimal medical care will be given during the study 
period at the discretion of the attending physician(s) within the parameters of the 
protocol and documented on each site’s source documents as concomitant 
medication. 
 
6.4 
Duration of Treatment 
Patients will be on metformin treatment for approximately 14 days prior to initiation 
of concurrent chemo-radiation in order to complete a metformin dose- escalation 
phase designed to decrease metformin toxicity. Patients will then complete a 6-7 
week course of metformin + concurrent chemoradiation. Patients will continued to 
be monitored for toxicity (phase I) for 30 days following completion of radiation 
treatment prior to proceeding to the next dose level in the phase I component. 
 
6.5 
Criteria for Removal from Study 
Criteria for removal from the study include: intercurrent illness that prevents further 
treatment administration, patient’s decision to withdraw from the study, 
progression of disease, development of a 2nd primary tumor (lung, esophagus, oral 
cavity, oropharynx, larynx or hypopharynx) and delay in protocol initiation and/or 
completion. If the protocol is discontinued, all patient follow up will continue in 
accordance with institutional standard of care protocols. 
 
6.6 
Duration of Follow-Up 
All patients will be followed for 2 years following radiation treatment completion. 
In the first year, patients will be evaluated every 3 months, in the second year every 
4 months which is consistent with institutional practice and clinical guidelines for 
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7.0 
DOSING DELAYS/DOSE MODIFICATION 
7.1 
Cisplatin dose modifications. A suggested dose modification protocol is offered 
below; however, treating physicians may utilize other protocols which are 
consistent with current standard of care for this agent. 
7.1.1 
Leukopenia: hold cisplatin infusion if absolute neutrophil counts (ANC) falls below 
1500/ml, and proceed with radiotherapy only. Check CBC in one week, resume 
cisplatin at 40mg/m2 if ANC ≥1500/ml; continue to hold cisplatin infusion and 
proceed with radiation only if ANC less than 1500/ml. 
7.1.2 
Thrombocytopenia: hold cisplatin infusion if platelet counts falls below 
100,000/ml, and proceed with radiotherapy only. Check CBC every week, resume 
cisplatin at 40mg/m2 only if platelet count is over 100,000/ml, but continue 
radiation as scheduled. 
7.1.3 
Neurotoxicity: If grade 2 neurotoxicity developed, hold cisplatin (but continue RT) 
until toxicity improves to < grade 1, then resume cisplatin. If any signs of grade 3 
or greater neurotoxicity occur, discontinue cisplatin, but continue RT. 
7.1.4 
Renal Adverse Events: If creatinine > 1.5 mg / dL, hydrate the patient over a 24hr 
period using normal saline 2000 mL + KCl 20 mEq / L + 1 gm MgSO4 and 
administer the 100% dose if creatinine <1.5 mg / dL, reduce to 50% if creatinine> 
1.5 mg / dL and <1.9 mg / dL. Hold cisplatin if creatinine increase to more than 
1.9mg/dl, but continue on radiation as scheduled. 
7.1.5 
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. 
7.1.6 
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. 
7.1.8 For any other grade 3-4 non-hematologic adverse events possibly related to cisplatin, 
hold cisplatin until toxicities have recovered to grade 1 or less. 
 
7.2 
Metformin dose modifications. All metformin dose modifications refer to the 
BID dosing. For example, “decreased by 350mg” refers to a reduction from 
500mg PO BID to 250mg PO BID or from 850mg PO BID to 500mg PO BID. 
7.2.1 
Hypoglycemia: Although the risk of hypoglycemia in euglycemic patients 
receiving metformin is very low, patients in this trial might have a low caloric 
intake due to complications of treatment, and will undergo weekly blood glucose 
monitoring. 
If based on these lab values or associated symptoms, the treating physician 
diagnoses hypoglycemia (Grade 1 or greater), study drug treatment will be halted, 
while concurrent chemoradiation will continue. Once blood glucose normalizes, 
metformin will be restarted and the dose should be decreased to the next available 
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be provided equipment and supplies for twice daily blood glucose checks, along 
with a form used to record values. 
 
Instructions for Metformin Dose Reductions due to Adverse Events 
Starting Dose (mg PO BID) 
Reduced Dose (mg PO BID) 
1500 mg 

1350 mg 
1350 mg 

1000 mg 
1000 mg 

850 mg 
850 mg 

500 mg 
500 mg 

0 (off treatment) 
If hypoglycemia resolves to < Grade 1 after 7 days, daily monitoring will be 
discontinued and the patient will resume the previous dose. All dose de-escalation 
and re-escalation will be recorded in source documentation. If hypoglycemia 
symptoms persist for more than 7 days, the study drug will be stopped and this 
will be considered a DLT. 
7.2.2 
Gastrointestinal toxicity: In the event of grade 2-4 gastrointestinal toxicity 
(typically involving flatulence or diarrhea), patients will be supported with 
loperamide, at dosing schedules recommended in the package insert. 
Gastrointestinal side effects typically subside within 4-6 weeks of initiating 
metformin treatment. 
Efforts should be made to maintain the dose as close to the planned total daily 
treatment dose as much as possible. Before dose-reducing, alterations to the daily 
intake schedule of metformin should be taken to reduce gastrointestinal symptoms, 
including taking metformin with food rather than before meals. 
If alterations in intake schedule are insufficient in reducing gastrointestinal toxicity 
to ≤ grade 1, the metformin dose should be decreased to the next available lower 
dose for 1 week with loperamide support until symptoms subside. 
If GI toxicity has not resolved to ≤ grade 1 after 1 week of dose reduction, then 
decrease the dose again to the next available lower dose; do this weekly until GI 
toxicity resolves. If toxicity does not resolve despite de-escalation, metformin 
will be stopped and this will be considered a DLT. 
For patients in the Phase I component who experience toxicity, efforts should be 
made to re-escalate the dose of metformin back to the planned Dose level 2 weeks 
after the patients remain free of grade 2 toxicity. 
For patients in the Phase II component who experience toxicity, efforts should be 
made to re-escalate the dose of metformin back to the MTD identified in Phase I 2 
weeks after patients remain free of grade 2 toxicity. At least 2 attempts should be 
made to re-escalate the dose to the MTD identified in Phase I after each dose de- 
escalation takes place. In the event that re-escalation to a higher dose cannot be 
achieved without grade 2 toxicity, patients will be maintained at the highest 
tolerable dose for the remainder of the metformin treatment period. 
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Metformin treatment interruption will be permitted according to institutional 
guidelines at the time of routine CT scans with contrast infusion. 
7.2.3 
Criteria for discontinuation of metformin treatment include: toxicity (see 7.2.2) 
which cannot be improved with the measures listed above; progression of disease; 
development of a 2nd primary tumor (lung, esophagus, oral cavity, oropharynx, 
larynx or hypopharynx); or delay in protocol initiation and/or completion. If 
radiation is terminated prior to completion of the prescribed standard of care dose, 
metformin will be stopped. 
7.2.4 
If creatinine > 1.5 mg / dL, hydrate the patient over a 24hr period using normal 
saline 2000 mL + KCl 20 mEq / L + 1 gm MgSO4 and administer 100% of the 
planned metformin dose if creatinine <1.5 mg / dL. If Cr remains >1.5mg/dL hold 
metformin for 1 week and repeat creatinine. If creatinine <1.5mg/dL resume 
metformin at the previous dose; if not, continue to hold metformin unto Cr 
<1.5mg/dL. 
7.2.5 
Lactic acidosis is a historical concern in patients with normal renal function. There 
is no evidence of increased lactic acidosis risk in patients taking metformin. As 
such, screening for lactic acidosis will not be incorporated into this trial.29 
7.2.6 
If cisplatin regimen is discontinued or de-escalated to a lower dose of cisplatin or 
changed to a different cytotoxic or non-cytotoxic agent, metformin will be 
continued unless metformin related toxicity is observed and the data from that 
patient will be recorded as part of the study as long as the patient can continued to 
receive the prescribed dose of radiation. 
7.2.5 If radiation is terminated prior to completion of the prescribed standard of care dose, 
metformin will be stopped. 
 
7.3 
Radiation dose modification 
Consistent with current institutional and national standards, de-escalation of the 
radiation component will not be allowed during the protocol. Adjustments to 
specific components of the radiation field will be allowed at the discretion of the 
treating radiation oncologist based on tumor response, consistent with current 
institutional practice protocols. Treatment breaks must be clearly indicated in the 
treatment record along with the reason(s) for the treatment break(s). Treatment 
breaks should be allowed only for resolution of severe acute toxicity and/or for 
inter-current illness and not for social or logistical reasons. Missed treatments due 
to holidays or for logistic reasons can be compensated for by delivering an 
additional treatment (BID, two fractions in one day at least 6 hours apart) during 
the week, or treating on the Saturday or Sunday of that week, or adding to the end 
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8 
CORRELATIVE STUDIES (Optional For Patients) 
NOTE: Optional correlative studies have been removed from the protocol with R10 due to 
insufficient evaluable data being available to draw meaningful conclusions. 
 
 
 
9 
TREATMENT EVALUATION 
9.1 
Pre-treatment evaluation 
9.1.1 
A complete history and physical examination by a medical, radiation or surgical 
(ENT or Head and Neck Surgery) oncologist, and baseline laboratory studies, 
including complete blood count (CBC), complete metabolic panel (CMP) and 
fasting glucose or non-fasting HgbA1c will be performed within 30 days of starting 
metformin escalation. Negative pregnancy test is required 10-14 days before 
registration for women of child bearing age who maintain reproductive potential 
(i.e. have not undergone hysterectomy). 
9.1.2 
Sample collection for baseline correlative studies will be performed before 
initiation of metformin escalation as outlined in the study calendar. 
9.1.3 
One of the following combinations of imaging is required within 8-12 weeks prior 
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a) A CT scan of the neck (with contrast) and a chest CT scan (with or without 
contrast), or 
b) A CT scan of neck (with contrast) and a PET/CT of neck and chest (with or 
without contrast). Note: A CT scan of neck and/or PET/CT performed for 
radiation planning and read by a radiologist may serve as both staging and 
planning tools. 
 
Staging (T, N, M) will be performed by the treatment team following diagnosis and 
discussion at multi-disciplinary tumor conference, per standard of care practice. For 
the purpose of the study, the clinical TNM staging for each patient will be obtained 
by the PI or clinical coordinator from the medical record and entered into the study 
prior to treatment initiation. 
 
9.1.4 
Evaluation by a nutritionist and/or swallowing therapist is highly recommended 
within 2-4 weeks prior to the start of chemo-radiation treatment and should include 
evaluation for placement of prophylactic gastrostomy or other type of feeding tube. 
The decision to place a feeding tube should be individualized and may consider a 
number of factors including: prior weight loss, current nutritional status, size and 
location of the primary tumor (impacting high dose target volume), availability of 
feeding tube placement services, availability of speech and swallowing specialists, 
and social support. Feeding tubes may be placed after start of treatment at the 
discretion of the clinical team. If a tube is placed, documentation will be provided 
in the patient’s protocol file if the tube was placed prophylactically (as a 
preventative measure) or therapeutically (because of nutritional compromise or 
other clinical indications). 
9.2 
Evaluation during treatment 
9.2.1 
Patients will be evaluated weekly by the treating team during the escalation phase 
of metformin administration. Patients will be evaluated weekly by the radiation 
oncology team during concurrent chemoradiation as per current institutional 
protocol. The drug log will be reviewed on a weekly basis. Study staff may contact 
patients via telephone to discuss investigational drug compliance and/or any other 
study related questions or tasks. Additional visits will be obtained as clinically 
indicated. History and physical exams, along with appropriate laboratory studies 
(CBC, BMP) will be performed at each additional visit. 
9.1.2 Sample collection for baseline correlative studies will be performed during treatment 
as outlined in the study calendar. 
9.3 
Evaluation following treatment 
9.3.1 
A brief history and physical examination by a medical, radiation or surgical (ENT 
or Head and Neck Surgery) oncologist, including laryngopharyngoscopy (mirror 
and/or fiberoptic and/or direct procedure), should be done at 10 weeks following 
completion of radiation then every 3 months through year 1 and every 4 months 
through year 2. A 30 day visit or telephone interview is required for evaluation of 
Adverse Events. Radiographic imaging (CT, MRI, or PET as appropriate) at these 
time points is highly recommended if disease progression is suspected by the 
treating physician. If performed, radiographic imaging to evaluate the patient for 
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9.3.2 
Chest imaging: A chest CT or a PET/CT of chest is recommended once per year. 
9.3.3 
Biopsy of any lesion(s) suspicious for tumor recurrence is recommended as 
clinically indicated. 
9.3.4 
The initial post-radiation imaging evaluation (CT at 8-10weeks or PET-CT at 10- 
12weeks) after the completion of chemoradiation is recommended to assess disease 
response. The imaging can be contrast enhanced CT (neck and chest) or PET-CT 
of the head and neck or “whole body” PET/CT (minimum neck and chest) based 
on the preference of the treating clinician, but must be consistent with the pre- 
treatment imaging modality. 


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9.2 Study Calendar 
Pre- 
study 
wk -2
(d3+/-
2d) 
wk 1 
(d3+/- 
2d) 
wk 2 
(d3+/- 
2d) 
wk 3 
(d3+/- 
2d) 
wk 4 
(d3+/- 
2d) 
wk 5 
(d3+/- 
2d) 
wk 6 
(d3+/- 
2d) 
wk 7 
(d3+/- 
2d) 
30 days post 
radiation 
completion 
Post- 
study 
(wk17+/- 
2wk) 
Post- 
study 
(yr1 
Q3mos) 
Post- 
study 
(yr2 
Q4mos) 
Metformin tx 
<--------------------------BID metformin -------------------------- > 
Chemo-radiation tx 
<-------XRT (Daily); chemotherapy (weekly) --------- > 
Collected information (ONCORE ) 
Metformin pill diary/ 
compliance form 
X 
X 
X 
X 
X 
X 
X 
X 
Eligibility checklist 
X 
Informed consent 
X 
T, N, M staging 
X 
Demographics 
X 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history 
X 
Vital signs 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event 
evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMP 
X 
CBC, BMP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Glucose monitoring (if 
applicable) (A) 
X 
X 
X 
X 
X 
X 
X 
X 
Disease 
response/ 
radiologic evaluation 
X 
X 
X 
Pregnancy test 
X (B) 
Imaging (C) 
X 
X 
X 
X 
Laryngopharyngoscopy 
X 
X 
X 
pre-study items to be collected within 30 days of initiation of metformin treatment 
Pill diary/compliant may be discussed or completed via telephone.  
A: patients wih hypoglycemia(<=60mg/dl ) will receive instructions and supplies for BID glucose monitoring and recording 
B: Serum or urine pregnancy test (women of childbearing potential). 
C: Required within 8-12 weeks prior to registration, at end of radiation treatment, and at regular intervals following treatment completion. 
D= day, Wk= week, Mos= months, Yr= year; d3+/-2d= to be completed on day 3 of any given week, +/- 2days 


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10 PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section 11.0. 
 
10.1 
Metformin. Metformin hydrochloride is an oral antihyperglycemic drug used in 
the management of type 2 diabetes. Metformin hydrochloride (N, N-dimethl- 
limidodicarbonimidic 
diamide 
hydrochloride) 
is 
not 
chemically 
or 
pharmacologically related to any other classes of oral anti-hyperglycemic agents. 
Metformin hydrochloride is a white to off-white crystalline compound with a 
molecular formula of C4H,,N5.1-lCI and a molecular weight of 165.63. Metformin 
hydrochloride is freely soluble in water and is practically insoluble in acetone, ether 
and chloroform. The pK, of metformin is 12.4. The pH of a 1% aqueous solution of 
metformin hydrochloride is 6.68. 
Mechanism of Action: Metformin is an anti-hyperglycemic agent which improves 
glucose tolerance in patients with type 2 diabetes, lowering both basal and 
postprandial plasma glucose. Its pharmacologic mechanisms of action are different 
from other classes of oral anti-hyperglycemic agents. Metformin decreases hepatic 
glucose production, decreases intestinal absorption of glucose, and improves 
insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike 
sulfonylureas, metformin does not produce hypoglycemia in either patients with 
type 2 diabetes or normal subjects (except in special circumstances) 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. 
Absorption and Bioavailability: The absolute bioavailability of a metformin 
hydrochloride 500 mg tablet given under fasting conditions is approximately 50- 
60%. Studies using single oral doses of metformin tablets of 500 mg and 1500 mg, 
and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with 
increasing doses, which is due to decreased absorption rather than an alteration in 
elimination. Food decreases the extent of and slightly delays the absorption of 
metformin, as shown by approximately a 40% lower mean peak concentration and 
25% lower area under the plasma concentration versus time curve (AUC), and a 35 
minute prolongation of time to peak plasma concentration (Tmax) following 
administration of a single 850 mg tablet of metformin with food, compared to the 
same tablet strength administered fasting. The clinical relevance of these decreases 
is unknown. 
Distribution: The apparent volume of distribution (V/F) of metformin following 
single oral doses of 850 mg averaged 654 + 358 L. Metformin is negligibly bound 
to plasma proteins in contrast to sulfonylureas which are more than 90% protein 
bound. Metformin partitions into erythrocytes, most likely as a function of time. At 
usual clinical doses and dosing schedules of metformin hydrochloride tablets, 
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and are generally c 1 pg/mL. During controlled clinical trials, maximum metformin 
plasma levels did not exceed 5 ug/mL, even at maximum doses. 
Metabolism and Elimination: Intravenous single-dose studies in normal subjects 
demonstrate that metformin is excreted unchanged in the urine and does not 
undergo hepatic metabolism (no metabolites have been identified in humans) nor 
biliary excretion. Renal clearance is approximately 3.5 times greater than creatinine 
clearance which indicates that tubular secretion is the major route of metformin 
elimination. Following oral administration, approximately 90% of the absorbed 
drug is eliminated via the renal route within the first 24 hours, with a plasma 
elimination half-life of approximately 6.2 hours. In blood, the elimination half-life 
is approximately 17.6 hours, suggesting that the erythrocyte mass may be a 
compartment of distribution. 
Special Populations 
Patients with Type 2 Diabetes. In the presence of normal renal function, there are 
no differences between single or multiple dose pharmacokinetics of metformin 
between patients with type 2 diabetes and normal subjects, nor is there any 
accumulation of metformin in either group at usual clinical doses. 
Renal Insufficiency. In subjects with decreased renal function (based on measured 
creatinine clearance), the plasma and blood half-life of metformin is prolonged and 
the renal clearance is decreased in proportion to the decrease in creatinine 
clearance. 
Hepatic Insufficiency. No pharmacokinetic studies have been conducted in subjects 
with hepatic insufficiency. 
Geriatrics. Limited data from controlled pharmacokinetic studies of metformin in 
healthy elderly subjects suggest that total plasma clearance of metformin is 
decreased, the half-life is prolonged, and C max is increased, compared to healthy 
young subjects. From these data, it appears that the change in metformin 
pharmacokinetics with aging is primarily accounted for by a change in renal 
function. Metformin treatment should not be initiated in patients >80 years of age 
unless measurement of creatinine clearance demonstrates normal renal function. 
Availability. Metformin is a commercially available anti-diabetic drug which will 
be purchased by the institutional pharmacy and dispensed to the study patients. 
 
10.2 
Agent Ordering 
Metformin will be purchased by the study PI from the institutional pharmacy. 
Metformin will be dispensed from the institutional pharmacy to the patient along 
with appropriate self-administration instructions. The study PI will not dispense the 
medication. Metformin will be provided to research subjects for the duration of 
their participation in this trial at no charge to them or to their insurance provides. 
Only enough metformin for completion of the treatment protocol will be supplied 
to each patient. 
 
10.3 
Agent Accountability 


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Agent Inventory Records – The investigator, or a responsible party designated by 
the investigator, must maintain a careful record of the inventory and disposition of 
all agents utilizing the electronic medical record and pill diary. 
 
10.4 
Commercial Agent(s) 
Cisplatin. Cisplatin is a commercially available chemotherapeutic agent. Cisplatin 
Injection infusion concentrate is a clear, colorless, sterile aqueous solution available 
in amber vials. Each 50 mL or 100 mL amber vial of infusion concentrate contains: 
1 mg/mL cisplatin, 9 mg/mL sodium chloride, hydrochloric acid and sodium 
hydroxide to approximate pH of 4.0, and water for injection to a final volume of 50 
mL or 100 mL, respectively. The active ingredient, cisplatin, is a yellow to orange 
crystalline powder with the molecular formula PtCl2H6N2, and a molecular weight 
of 300.1. Cisplatin is a heavy metal complex containing a central atom of platinum 
surrounded by two chloride atoms and two ammonia molecules in the cis position. 
It is soluble in water or saline at 1 mg/mL and in dimethylformamide at 24 mg/mL. 
It has a melting point of 207° C. Plasma concentrations of the parent compound, 
cisplatin,  decay monoexponentially with  a  half-life  of  about  20  to  30 minutes 
2 
following bolus administrations of 50 or 100 mg/m doses. Monoexponential decay 
and plasma half-lives of about 0.5 hour are also seen following 2-hour or 7-hour 
2 
infusions of 100 mg/m  . After the latter, the total-body clearances and volumes of 
2 
distribution at steady-state for cisplatin are about 15 to 16 L/h/m 
2 
and 11 to 12 L/m . 
Due to its unique chemical structure, the chlorine atoms of cisplatin are more 
subject to chemical displacement reactions by nucleophiles, such as water or 
sulfhydryl groups, than to enzyme-catalyzed metabolism. At physiological pH in 
the presence of 0.1M NaCl, the predominant molecular species are cisplatin and 
monohydroxymonochloro 
cis-diammine 
platinum 
(II) 
in 
nearly 
equal 
concentrations. The latter, combined with the possible direct displacement of the 
chlorine atoms by sulfhydryl groups of amino acids or proteins, accounts for the 
instability of cisplatin in biological matrices. The ratios of cisplatin to total free 
(ultrafilterable) platinum in the plasma vary considerably between patients and 
2 
range from 0.5 to 1.1 after a dose of 100 mg/m . 
Cisplatin does not undergo the instantaneous and reversible binding to 
plasma proteins that is characteristic of normal drug-protein binding. However, 
the platinum from cisplatin, but not cisplatin itself, becomes bound to several 
plasma proteins, including albumin, transferrin, and gamma globulin. Three hours 
after a bolus injection and two hours after the end of a three-hour infusion, 90% 
of the plasma platinum is protein bound. The complexes between albumin and the 
platinum from cisplatin do not dissociate to a significant extent and are slowly 
eliminated with a minimum half-life of five days or more. Following cisplatin 
2 
doses of 20 to 120 mg/m , the concentrations of platinum are highest in liver, 
prostate, and kidney; somewhat lower in bladder, muscle, testicle, pancreas, and 
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Platinum is present in tissues for as long as 180 days after the last administration. 
With the exception of intracerebral tumors, platinum concentrations in tumors are 
generally somewhat lower than the concentrations in the organ where the tumor is 
located. Different metastatic sites in the same patient may have different platinum 
concentrations. Hepatic metastases have the highest platinum concentrations, but 
these are similar to the platinum concentrations in normal liver. Maximum red 
blood cell concentrations of platinum are reached within 90 to 150 minutes after 
2 
a 100 mg/m  dose of cisplatin and decline in a biphasic manner with a terminal 
2 
half-life of 36 to 47 days. Over a dose range of 40 to 140 mg cisplatin/m  given as 
a bolus injection or as infusions varying in length from 1 hour to 24 hours, from 
10% to about 40% of the administered platinum is excreted in the urine in 24 
2 
hours. Over five days following administration of 40 to 100 mg/m doses given as 
rapid, 2-to 3-hour, or 6-to 8-hour infusions, a mean of 35% to 51% of the dosed 
platinum is excreted in the urine. Similar mean urinary recoveries of platinum of 
about 14% to 30% of the dose are found following five daily administrations of 
2 
20, 30, or 40 mg/m /day. Only a small percentage of the administered platinum is 
excreted beyond 24 hours post-infusion and most of the platinum excreted in the 
urine in 24 hours is excreted within the first few hours. Platinum-containing 
species excreted in the urine are the same as those found following the incubation 
of cisplatin with urine from healthy subjects, except that the proportions are 
different. 
The parent  compound, cisplatin, is excreted in the urine  and accounts  for 
2 
13% to 17% of the dose excreted within one hour after administration of 50 mg/m . 
The mean renal clearance of cisplatin exceeds creatinine clearance and is 62 and 50 
2 
mL/min/m 
2 
following administration of 100 mg/m 
as 2-hour or 6-to 7-hour 
infusions, respectively. The renal clearance of free (ultrafilterable) platinum also 
exceeds the glomerular filtration rate indicating that cisplatin or other platinum- 
containing molecules are actively secreted by the kidneys. The renal clearance of 
free platinum is nonlinear and variable and is dependent on dose, urine flow rate, 
and individual variability in the extent of active secretion and possible tubular 
reabsorption. There is a potential for accumulation of ultrafilterable platinum 
plasma concentrations whenever cisplatin is administered on a daily basis but not 
when dosed on an intermittent basis. No significant relationships exist between the 
renal clearance of either free platinum or cisplatin and creatinine clearance. 
Although small amounts of platinum are present in the bile and large intestine after 
administration of cisplatin, the fecal excretion of platinum appears to be 
insignificant. 
Contraindications. Cisplatin is contraindicated in patients with preexisting renal 
impairment. Cisplatin should not be employed in myelosuppressed patients, or in 
patients with hearing impairment. Cisplatin is contraindicated in patients with a 
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Teratogenicity. Cisplatin can cause fetal harm when administered to a pregnant 
woman. Cisplatin is mutagenic in bacteria and produces chromosome aberrations 
in animal cells in tissue culture. In mice cisplatin is teratogenic and embryotoxic. 
If this drug is used during pregnancy or if the patient becomes pregnant while taking 
this drug, the patient should be apprised of the potential hazard to the fetus. Patients 
should be advised to avoid becoming pregnant. The carcinogenic effect of cisplatin 
was studied in BD IX rats. Cisplatin was administered intraperitoneally (i.p.) to 50 
BD IX rats for 3 weeks, 3 X 1 mg/kg body weight per week. Four hundred and 
fifty-five days after the first application, 33 animals died, 13 of them related to 
malignancies: 12 leukemias and 1 renal fibrosarcoma. The development of acute 
leukemia coincident with the use of cisplatin has been reported. In these reports, 
cisplatin was generally given in combination with other leukemogenic agents. 
Injection site reactions may occur during the administration of cisplatin. Given the 
possibility of extravasation, it is recommended to closely monitor the infusion site 
for possible infiltration during drug administration. A specific treatment for 
extravasation reactions is unknown at this time. 
Drug interactions. Plasma levels of anticonvulsant agents may become 
subtherapeutic during cisplatin therapy. In a randomized trial in advanced ovarian 
cancer, response duration was adversely affected when pyridoxine was used in 
combination with altretamine (hexamethylmelamine) and cisplatin. 
Pregnancy. Pregnancy Category D 
Nursing Mothers. Cisplatin has been reported to be found in human milk; patients 
receiving cisplatin should not breast-feed. 
Pediatric Use. Safety and effectiveness in pediatric patients have not been 
established. All children should have audiometric monitoring performed prior to 
initiation of therapy prior to each subsequent dose, and for several years post 
therapy. Advanced testing methods may allow for earlier detection of hearing loss 
in an attempt to facilitate the rapid initiation of interventions that can limit the 
potential adverse impact of hearing impairment on a child's cognitive and social 
development. 
Geriatric Use. Insufficient data are available from clinical trials of cisplatin in the 
treatment of metastatic testicular tumors or advanced bladder cancer to determine 
whether elderly patients respond differently than younger patients. In four clinical 
trials of combination chemotherapy for advanced ovarian carcinoma, 1484 patients 
received cisplatin either in combination with cyclophosphamide or paclitaxel. Of 
these, 426 (29%) were older than 65 years. In these trials, age was not found to be 
a prognostic factor for survival. However, in a later secondary analysis for one of 
these trials, elderly patients were found to have shorter survival compared with 
younger patients. In all four trials, elderly patients experienced more severe 
neutropenia than younger patients. Higher incidences of severe thrombocytopenia 
and leukopenia were also seen in elderly compared with younger patients, although 
not in all cisplatin-containing treatment arms. In the two trials where 
nonhematologic toxicity was evaluated according to age, elderly patients had a 
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reported clinical experience suggests that elderly patients may be more susceptible 
to myelosuppression, infectious complications, and nephrotoxicity than younger 
patients. Cisplatin is known to be substantially excreted by the kidney and is 
contraindicated in patients with preexisting renal impairment. Because elderly 
patients are more likely to have decreased renal function, care should be taken in 
dose selection, and renal function should be monitored. 
Adverse reactions 
Nephrotoxicity. Dose-related and cumulative renal insufficiency, including acute 
renal failure, is the major dose-limiting toxicity of cisplatin. Renal toxicity has been 
2 
noted in 28% to 36% of patients treated with a single dose of 50 mg/m . It is first 
noted during the second week after a dose and is manifested by elevations in BUN 
and creatinine, serum uric acid and/or a decrease in creatinine clearance. Renal 
toxicity becomes more prolonged and severe with repeated courses of the drug. 
Renal function must return to normal before another dose of cisplatin can be given. 
Elderly patients may be more susceptible to nephrotoxicity. Impairment of renal 
function has been associated with renal tubular damage. The administration of 
cisplatin using a 6-to 8-hour infusion with intravenous hydration, and mannitol has 
been used to reduce nephrotoxicity. However, renal toxicity still can occur after 
utilization of these procedures. 
Ototoxicity. Ototoxicity has been observed in up to 31% of patients treated with a 
2 
single dose of cisplatin 50 mg/m , and is manifested by tinnitus and/or hearing loss 
in the high frequency range (4000 to 8000 Hz). The prevelance of hearing loss in 
children is particularly high and is estimated to be 40-60%. Decreased ability to 
hear normal conversational tones may occur. Deafness after the initial dose of 
cisplatin has been reported. Ototoxic effects may be more severe in children 
receiving cisplatin. Hearing loss can be unilateral or bilateral and tends to become 
more frequent and severe with repeated cisplatin doses. It is unclear whether 
cisplatin-induced ototoxicity is reversible. Vestibular toxicity has also been 
reported. Ototoxic effects may be related to the peak plasma concentration of 
cisplatin. Ototoxicity can occur during treatment or be delayed. Audiometric 
monitoring should be performed prior to initiation of therapy, prior to each 
subsequent dose, and for several years post therapy. The risk of ototoxicity may be 
increased by prior or simultaneous cranial irradiation, and may be more severe in 
patients less than 5 years of age, patients being treated with other ototoxic drugs 
(e.g. aminoglycosides and vancomycin), and in patients with renal impairment. 
Genetic factors (e.g. variants in the thiopurine S-methyltransferase [TPMT] gene) 
may contribute to cisplatin-induced ototoxicity; although this association has not 
been consistent across populations and study designs. 
Hematologic. Myelosuppression occurs in 25% to 30% of patients treated with 
cisplatin. The nadirs in circulating platelets and leukocytes occur between days 18 
to 23 (range 7.5 to 45) with most patients recovering by day 39 (range 13 to 62). 
Leukopenia and thrombocytopenia are more pronounced at higher doses (>50 
2 
mg/m ). Anemia (decrease of 2 g hemoglobin/100 mL) occurs at approximately the 


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same frequency and with the same timing as leukopenia and thrombocytopenia. 
Fever and infection have also been reported in patients with neutropenia. Potential 
fatalities due to infection (secondary to myelosuppression) have been reported. 
Elderly patients may be more susceptible to myelosuppression. In addition to 
anemia secondary to myelosuppression, a Coombs' positive hemolytic anemia has 
been reported. In the presence of cisplatin hemolytic anemia, a further course of 
treatment may be accompanied by increased hemolysis and this risk should be 
weighed by the treating physician. The development of acute leukemia coincident 
with the use of cisplatin has been reported. In these reports, cisplatin was generally 
given in combination with other leukemogenic agents. 
Gastrointestinal. Marked nausea and vomiting occur in almost all patients treated 
with cisplatin, and may be so severe that the drug must be discontinued. Nausea 
and vomiting may begin within 1 to 4 hours after treatment and last up to 24 hours. 
Various degrees of vomiting, nausea and/or anorexia may persist for up to 1 week 
after treatment. Delayed nausea and vomiting (begins or persists 24 hours or more 
after chemotherapy) has occurred in patients attaining complete emetic control on 
the day of cisplatin therapy. Diarrhea has also been reported. 
Other toxicities. Vascular toxicities coincident with the use of cisplatin in 
combination with other antineoplastic agents have been reported. The events are 
clinically heterogeneous and may include myocardial infarction, cerebrovascular 
accident, thrombotic microangiopathy (hemolytic-uremic syndrome [HUS]), or 
cerebral arteritis. Various mechanisms have been proposed for these vascular 
complications. There are also reports of Raynaud's phenomenon occurring in 
patients treated with the combination of bleomycin, vinblastine with or without 
cisplatin. It has been suggested that hypomagnesemia developing coincident with 
the use of cisplatin may be an added, although not essential, factor associated with 
this event. However, it is currently unknown if the cause of Raynaud's phenomenon 
in these cases is the disease, underlying vascular compromise, bleomycin, 
vinblastine, hypomagnesemia, or a combination of any of these factors. 
Serum Electrolyte Disturbances. Hypomagnesemia, hypocalcemia, hyponatremia, 
hypokalemia, and hypophosphatemia have been reported to occur in patients treated 
with cisplatin and are probably related to renal tubular damage. Tetany has been 
reported in those patients with hypocalcemia and hypomagnesemia. Generally, 
normal serum electrolyte levels are restored by administering supplemental 
electrolytes and discontinuing cisplatin. Inappropriate antidiuretic hormone 
syndrome has also been reported. 
Hyperuricemia. Hyperuricemia has been reported to occur at approximately the 
same  frequency  as  the   increases  in  BUN   and  serum  creatinine.   It   is more 
2 
pronounced  after  doses  greater  than  50  mg/m  ,  and  peak  levels  of  uric acid 
generally occur between 3 to 5 days after the dose. Allopurinol therapy for 
hyperuricemia effectively reduces uric acid levels. 
Neurotoxicity. Neurotoxicity, usually characterized by peripheral neuropathies, has 
been reported. The neuropathies usually occur after prolonged therapy (4 to 7 


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months); however, neurologic symptoms have been reported to occur after a single 
dose. Although symptoms and signs of cisplatin neuropathy usually develop during 
treatment, symptoms of neuropathy may begin 3 to 8 weeks after the last dose of 
cisplatin. Cisplatin therapy should be discontinued when the symptoms are first 
observed. The neuropathy, however, may progress further even after stopping 
treatment. Preliminary evidence suggests peripheral neuropathy may be irreversible 
in some patients. Elderly patients may be more susceptible to peripheral 
neuropathy. Lhermitte's sign, dorsal column myelopathy, and autonomic 
neuropathy have also been reported. Muscle cramps, defined as localized, painful, 
involuntary skeletal muscle contractions of sudden onset and short duration, have 
been reported and were usually associated in patients receiving a relatively high 
cumulative dose of cisplatin and with a relatively advanced symptomatic stage of 
peripheral neuropathy. 
Ocular Toxicity. Optic neuritis, papilledema, and cerebral blindness have been 
reported in patients receiving standard recommended doses of cisplatin. 
Improvement and/or total recovery usually occurs after discontinuing cisplatin. 
Steroids with or without mannitol have been used; however, efficacy has not been 
established. Blurred vision and altered color perception have been reported after the 
use of regimens with higher doses of cisplatin or greater dose frequencies than 
recommended in the package insert. The altered color perception manifests as a loss 
of color discrimination, particularly in the blue-yellow axis. The only finding on 
funduscopic exam is irregular retinal pigmentation of the macular area. 
Anaphylactic-Like Reactions. Anaphylactic-like reactions have been reported in 
patients previously exposed to cisplatin. The reactions consist of facial edema, 
wheezing, tachycardia, and hypotension within a few minutes of drug 
administration. Reactions may be controlled by intravenous epinephrine with 
corticosteroids and/or antihistamines as indicated. Patients receiving cisplatin 
should be observed carefully for possible anaphylactic-like reactions and 
supportive equipment and medication should be available to treat such a 
complication. 
Hepatotoxicity. Transient elevations of liver enzymes, especially SGOT, as well as 
bilirubin, have been reported to be associated with cisplatin administration at the 
recommended doses. 
Other events. Cardiac abnormalities, hiccups, elevated serum amylase, rash, 
alopecia, malaise, asthenia, and dehydration have been reported. Local soft tissue 
toxicity has been reported following extravasation of cisplatin. Severity of the local 
tissue toxicity appears to be related to the concentration of the cisplatin solution. 
Infusion of solutions with a cisplatin concentration greater than 0.5 mg/mL may 
result in tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema. 
Overdosage. Caution should be exercised to prevent inadvertent overdosage with 
cisplatin. Acute overdosage with this drug may result in kidney failure, liver failure, 
deafness, ocular toxicity (including detachment of the retina), significant 
myelosuppression, intractable nausea and vomiting and/or neuritis. In addition, 
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for cisplatin overdosage. Hemodialysis, even when initiated four hours after the 
overdosage, appears to have little effect on removing platinum from the body 
because of cisplatin's rapid and high degree of protein binding. Management of 
overdosage should include general supportive measures to sustain the patient 
through any period of toxicity that may occur. 
Dosage and administration. Cisplatin Injection is administered by slow intravenous 
infusion. CISPLATIN INJECTION SHOULD NOT BE GIVEN BY RAPID 
INTRAVENOUS INJECTION. Patients will undergo prehydration with a 1 liter of 
D5NS over 2-4 hours and mannitol, 12.5g iv bolus immediately prior to cisplatin. 
Cisplatin, in 500-1000 ml NS is administered over 1-2 hours followed by an 
additional 1 to 1.5 liters of fluid. Any pre-existing dehydration must be corrected 
prior to cisplatin administration. Should extravasation occur, the treating physician 
should follow institutional guidelines for additional management. 
Preparation of intravenous solutions 
Preparation Precautions. Caution should be exercised in handling the aqueous 
solution. Procedures for proper handling and disposal of anticancer drugs should be 
utilized. Several guidelines on this subject have been published. To minimize the 
risk of dermal exposure, always wear impervious gloves when handling vials and 
IV sets containing cisplatin. Skin reactions associated with accidental exposure to 
cisplatin may occur. The use of gloves is recommended. If cisplatin contacts the 
skin or mucosa, immediately and thoroughly wash the skin with soap and water and 
flush the mucosa with water. More information is available in the references listed 
below. 
Instructions for Preparation. The aqueous solution should be used intravenously 
only and should be administered by IV infusion over a 6-to 8-hour period. 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. 
NOTE  TO  PHARMACIST:  Exercise  caution  to  prevent  inadvertent  cisplatin 
2 
overdosage. Please call prescriber if dose is greater than 100 mg/m  per cycle. 
Aluminum  and  flip-off  seal  of  vial  have  been  imprinted  with  the  following 
2 
statement: CALL DR. IF DOSE>100 MG/M /CYCLE. 
Stability. Cisplatin Injection is a sterile, multidose vial without preservatives. Store 
at 15° C to 25°C (59° to 77°F). Do not refrigerate. Protect unopened container from 
light. The cisplatin remaining in the amber vial following initial entry is stable for 
28 days protected from light or for 7 days under fluorescent room light. 
 
11 TOXICITIES/SIDE EFFECTS 
The most frequently reported side effect for the study drug metformin is gastrointestinal 
toxicity, more specifically flatulence and/or diarrhea. These side effects generally subside 
within several weeks of initiation of treatment and the risk of these side effects can be 
decreased through a dose-escalation phase such as the one built into the proposed trial. 
Gastrointestinal toxicity will be measured for all patients following initiation of metformin 


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treatment, and will be used as the primary measure for the Phase I component of the 
proposed trial. 
 
Due to its mechanism of action (see above), the risk of hypoglycemia with metformin 
treatment is very low. However, since patients in this trial may experience a low caloric 
intake due to the side effects of the conventional treatment component (cisplatin- nausea, 
mucositis; radiation- xerostomia, altered taste) patients will undergo weekly blood glucose 
monitoring. If based on these lab values or associated symptoms, the treating physician 
diagnoses hypoglycemia, study drug treatment will be halted, while concurrent 
chemoradiation will continue. Once blood glucose normalizes, metformin will be restarted 
and the dose should be decreased by 250mg with daily monitoring of blood glucose. If 
there are no symptoms or signs of hypoglycemia in 1 week, daily monitoring will be 
discontinued. All dose de-escalation and re-escalation will be recorded in source 
documentation. Hypoglycemia will be measured for all patients following initiation of 
metformin treatment, and will be used as a secondary measure for the Phase I component 
of the proposed trial. 
Toxicity recording will commence once patients start taking metformin and will be 
completed at 30days following completion of treatment. 
 
12.0 
MEASUREMENT OF EFFECT 
Response and progression will be evaluated using the new international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST1.1) Committee [Eur J 
Cancer. 2009 Jan; 45(2):228-47]. Changes in only the largest diameter (uni-dimensional 
measurement) of the tumor lesions are used in the RECIST 1.1 criteria. 
 
12.1 
Antitumor Effect – Solid Tumors 
For the purposes of this study, patients should be reevaluated for response following 
completion of treatment as per current institutional protocol for this disease site: 1) 
spiral contrast enhanced computed tomography (CECT) at 8-10 weeks following 
completion of treatment or 2) positron emission tomography (PET) at 10-12 weeks 
following completion of treatment. No additional imaging or tests will be 
performed as part of the current protocol. Following the first post treatment scan, 
patients will continue routine surveillance using CECT or PET per institutional 
protocols. 
 
12.1.1. Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the 
time of their first treatment with metformin until 30 days following 
treatment completion. 
Evaluable for objective response. All patients included in the study must be 
assessed for response to treatment, even if there are major protocol 


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treatment deviations. These patients will have their response classified 
according to the definitions stated below. 
12.1.2 Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as >10 mm with spiral CECT scan. All tumor measurements must 
be recorded in millimeters (or decimal fractions of centimeters). 
Non-measurable disease. All other lesions (or sites of disease), including 
small lesions (longest diameter <10 mm using spiral CECT scan), are 
considered non-measurable disease. Bone lesions, leptomeningeal disease, 
ascites, 
pleural/pericardial 
effusions, 
lymphangitis 
cutis/pulmonis, 
inflammatory breast disease, abdominal masses (not followed by CT or 
MRI), and cystic lesions are all non-measurable. 
Target lesions. All measurable lesions up to a maximum of 5 lesions per 
organ and 10 lesions in total, representative of all involved organs, should 
be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repeated measurements (either 
by imaging techniques or clinically). A sum of the longest diameter (LD) 
for all target lesions will be calculated and reported as the baseline sum LD. 
The baseline sum LD will be used as reference by which to characterize the 
objective tumor response. 
Non-target lesions. All other lesions (or sites of disease) including any 
measurable lesions over and above the 10 target lesions should be identified 
as non-target lesions and should also be recorded at baseline. Measurements 
of these lesions are not required, but the presence or absence of each should 
be noted throughout follow-up. 
 
12.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a 
ruler or calipers. All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before 
the beginning of the treatment. The same method of assessment and the 
same technique should be used to characterize each identified and reported 
lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have 
been used to assess the antitumor effect of a treatment. 
Spiral contrast enhanced CT. Spiral CT should be performed using the 
approved institutional head and neck protocol. 
Ultrasound (US). When the primary endpoint of the study is objective 
response evaluation, US should not be used to measure tumor lesions. It is, 
however, a possible alternative to clinical measurements of superficial 
palpable lymph nodes, subcutaneous lesions, and thyroid nodules. US might 
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lesions usually assessed by clinical examination. 
Endoscopy. The utilization of this technique for objective tumor evaluation 
has not yet been fully and widely validated. Its use in this specific context 
require sophisticated equipment and a high level of expertise that may only 
be available in some centers. Therefore, the utilization of such a technique 
for objective tumor response should be restricted to validation purposes. 
However, such a technique may be useful to confirm complete pathological 
response when biopsies are obtained. 
Tumor markers. Tumor markers alone cannot be used to assess response. 
Cytology, Histology. These techniques can be used to differentiate between 
partial responses (PR) and complete responses (CR) in rare cases (e.g., 
residual lesions in tumor types, such as germ cell tumors, where known 
residual benign tumors can remain). The cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment 
when the measurable tumor has met criteria for response or stable disease 
is mandatory to differentiate between response or stable disease (an effusion 
may be a side effect of the treatment) and progressive disease. 
 
12.1.4 Response Criteria 
12.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions 
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 
Progressive Disease (PD): At least a 20% increase in the sum of 
the LD of target lesions, taking as reference the smallest sum LD 
recorded since the treatment started or the appearance of one or 
more new lesions 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, taking as reference the 
smallest sum LD since the treatment started 
 
12.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions 
and normalization of tumor marker level Note: If tumor markers 
are initially above the upper normal limit, they must normalize for 
a patient to be considered in complete clinical response. 
Incomplete Response/Stable Disease (SD): Persistence of one or 
more non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits 
Progressive Disease (PD): Appearance of one or more new lesions 
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Although a clear progression of “non-target” lesions only is 
exceptional, the opinion of the treating physician should prevail in 
such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal 
Investigator). 
 
12.1.4.3 
Overall Response: overall response will be ascertained via 
clinical exam and imaging at 8-12 weeks post treatment 
completion according to the table below. 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall Response (measured at 8-12wk 
post treatment) 
CR 
CR 
No 
CR 
CR 
Non-CR/Non- 
PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
12.1.5 Duration of Response 
Duration of overall response: The duration of overall response is measured 
from the time measurement criteria are met for CR or PR (whichever is first 
recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). The duration 
of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented. 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started. 
12.1.6 Progression-Free Survival: Defined as the duration of time from the date 
of study registration to the date of documented radiographic progression. 
12.1.7 Overall survival: Defined as the duration of time from the date of study 
registration to the date of the patient’s death due to any cause. 
 
12.1.7 Response Review 


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All imaging will be reviewed by a trained head and neck clinical radiologist 
blinded to study participation, at the completion of the study. 
 
 
13.0 STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
This is a single arm combination Phase I/II trial of Metformin to determine the maximum 
tolerated dose (MTD) of metformin among 2 dose levels (850mg, 1500mg administered 
orally, twice daily) and to evaluate the disease response rate at the MTD. Standard of care 
conventional chemotherapy (cisplatin) will be administered using current clinical 
protocols. Dose-limiting toxicity will be ascertained using the Common Terminology 
Criteria for Adverse Events v4.0. The dose-limiting toxicities ascertained for the phase I 
component will be gastrointestinal toxicity and hypoglycemia requiring dose reduction. 
The primary outcome for the phase II component will be disease response rate (RECIST 
criteria) at 8-12 weeks post treatment completion. 
The secondary outcomes will be disease free and overall survival. All analysis of 
secondary studies will be performed post hoc and will not be used to influence clinical 
decision making during the therapeutic trial. 
This study began as a Phase I “3+3”/ Phase II “Simon” design, but was converted into 
Bayesian Optimal Interval (BOIN) design before completion of the Phase I to provide 
monitoring of toxicity beyond the Phase I cohort. BOIN design has algorithmic 
escalation/de-escalation rules easy to implement like a traditional 3+3 design but allows 
for specification of the target DLT rate, different size cohorts, is more likely to correctly 
select the MTD and allocate more patients to the MTD and expands consistent toxicity 
monitoring to the entire cohort. BOIN design with a target DLT rate of 0.3 and cohort size 
of 3 begins exactly in the same fashion as the “3+3” allowing for the implemented design 
change in early stages. Calculations were done using R package BOIN.32 
 
13.2 
Sample Size/Accrual Rate 
Phase I component considerations. 
The study is designed to escalate the dose if the observed toxicity rate at the current dose is 
<= 0.2365, and de-escalate the dose if the observed toxicity rate at the current dose is >= 
0.3585. If the observed toxicity rate is between 0.2365 and 0.3585, additional patients will be 
treated at the current dose. For cohorts of size 3, the decision boundaries are shown in table 
below. Two doses levels of Metformin (850 mg and 1500 mg) are evaluated, beginning with 
the lower dose. 


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DLT Regulation of Dose Escalation and De-Escalation 
Number of patients treated 
3 
6 
9 
12 
15 
18 
21 
24 
27+1 
Escalate*** if number of DLT <= 
0 
1 
2 
2 
3 
4 
4 
5 
6 
Treat additional 3 pts on current dose if number of DLT= 
1 
2 
3 
3,4 
4,5 
5,6 
5,6,7 
6,7,8 
7,8,9 
Deescalate* if number of DLT >= 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Eliminate** if number of DLT >= 
3 
4 
5 
7 
8 
9 
10 
11 
12 
* At the lowest dose level, if the recommendation is to de-escalate AND the dose level has not been eliminated from 
consideration, 3 additional pts will be accrued at the same dose level; otherwise the trial will stop. Last cohort has 4 
patients to reach the required sample size of 28. 
** Eliminate dose level and all higher doses from further use. 
*** At the time of the design change the study escalated to the highest dose and will continue enrolling additional 
patients at this dose unless de-escalation is recommended. 
 
 
 
Phase II component considerations. 
A response rate 60% would be considered effective for patients undergoing metformin 
plus standard of care, while a response rate 40% is not considered as effective. The 
phase II portion of the trial would require at least 28 evaluable patients treated at the 
MTD. For the purposes of this study, a response will be defined as overall complete 
response (CR) or overall partial response (PR) (see Table in section 12.1.4.3). Stable 
disease or progressive disease will be defined as a non-response. The criterion for 
significance (alpha) has been set at 0.10. The test is 1-tailed, which means that an effect 
in one direction (improvement) is expected and will be interpreted. Calculation are based 
on the assumptions of uniform accrual over time. With the proposed sample size of 28 
patients the study will have power of 80% to yield a statistically significant result. The 
treatment strategy (metformin plus standard of care) is considered effective if 17 or more 
responses are observed among the 28 patients. 
 
Total study sample size. 
This study will enroll at least 3 patients at each dose level and at least 28 patients at the 
MTD level. Participants will continue to be enrolled and monitored for toxicity according 
to the rules specified above until 28 efficacy evaluable participants have been enrolled to 
any single dose level. For the purposes of this analysis, a subject is considered evaluable 
for the primary endpoint after completing at least one dose of Metformin. It is expected 
that all dose levels will be safe and assuming that even the highest dose level has a DLT 
rate substantially lower than the target (i.e. <10%), which is what we expect, we will 
have more than 99% chance of selecting the top dose level at the end of the trial. In this 
case the total number of patients enrolled would be 31 (3+28). Retrospective clinical 
studies have not demonstrated an increase in treatment toxicity for patients undergoing 
cisplatin for HNSCC while taking metformin. It is anticipated that 1-2 patients per month 


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will be accrued to the study. Depending on the toxicity, this will allow for completion of 
study within 33-39 months of study initiation. 
 
 
 
13.3 
Stratification Factors 
No additional stratification will be utilized in this trial. 
 
13.4 
Analysis of Secondary Endpoints 
Secondary endpoints including disease free and overall survival will be analyzed 
by Kaplan-Meier method. All of the analyses will be considered exploratory in 
nature. 
 
13.5 
Reporting and Exclusions 
13.5.1 Evaluation of toxicity. All patients will be evaluable for toxicity from the 
time of their first treatment with metformin. 
13.5.2 Evaluation of response. All patients included in the study must be assessed 
for response to treatment, even if there are major protocol treatment 
deviations. Each patient will be assigned one of the following categories: 
1) complete response, 2) partial response, 3) stable disease, 4) progressive 
disease, 5) early death from malignant disease, 6) early death from toxicity, 
7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data). [Note: By arbitrary convention, category 9 usually 
designates the “unknown” status of any type of data in a clinical database.] 
All of the patients who met the eligibility criteria (with the possible 
exception of those who received no study medication) should be included 
in the main analysis of the response rate. Patients in response categories 4- 
9 should be considered to have a treatment failure (disease progression). 
Thus, an incorrect treatment schedule or drug administration does not result 
in exclusion from the analysis of the response rate. Precise definitions for 
categories 4-9 will be protocol specific. 
All conclusions should be based on all eligible patients. Subanalyses may 
then be performed on the basis of a subset of patients, excluding those for 
whom major protocol deviations have been identified (e.g., early death due 
to other reasons, early discontinuation of treatment, major protocol 
violations, etc.). However, these subanalyses may not serve as the basis for 
drawing conclusions concerning treatment efficacy, and the reasons for 
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confidence intervals should also be provided. 
 
14.0 DATA MANAGEMENT 
 
Subjects will be assigned a 4-digit study number (study ID) by the OnCore system which 
is the Clinical Trials Monitoring system utilized by the DLDCCC. The study number will 
not contain any identifiers. Study numbers will be assigned sequentially starting at 
“0001”. The study number list will be stored electronically and only accessible to 
authorized study personnel. Physical research data (including patient records and consent 
forms) will be secured in a confidential manner in a locked room at the appropriate 
clinic/hospital, and in secure manner in the DLDCCC offices (Suite 450A Cullen at 
BCM). Electronic research data will be stored at BCM on BCM servers which are 
password-protected. Electronic research data will be kept on a DLDCC-specific shared 
drive on BCM servers; access is limited to authorized study personnel. Electronic 
research data will also be kept in the OnCore database on BCM secure server with 
limited user-specific, password-protected access. Data are entered into the web 
application by authorized research personnel via secure HTTPS connections. BCM 
Research staff are authenticated securely with BCM’s LDAP/Active Directory. BCM IT 
maintains a firewall, intrusion protection service, and F5 Big IP servers for further 
protecting data within OnCore. All hardware systems are housed in HIPAA-compliant 
facilities that have 24-hour guards and access restricted by proximity cards and keys. 
 
12.1 Study Documentation 
Flow sheets documenting dates and doses of therapy as well as clinical chemistries, 
hematological parameters, the clinical status and occurrence of any adverse events and 
subsequent interventions are to be kept on all patients. 
- Imaging reports 
- Clinic notes 
- Laboratory reports 
- Surgical summaries 
- Autopsy summaries, where appropriate 
- Informed consent documents 
12.2 Clinical Data Management and Analysis 
All required clinical evaluation records are the responsibility of the study Principal 
Investigator, Dr. Vlad Sandulache, who will also be responsible for analysis of the clinical 
outcome and toxicity. 
 
15.0 QUALITY ASSURANCE 
This study will be monitored by the DLDCC Quality Assurance program for study conduct 
and quality of data, according to CTSU policy. Protocol compliance, eligibility verification, 
informed consent procedure verification and data accuracy will be monitored. 


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16.0 
DATA AND SAFETY MONITORING 
This study will be reviewed regularly by the Data Review Committee of the Dan L. Duncan 
Comprehensive Cancer Center, in accordance with the DLDCCC Data and Safety 
Monitoring Plan. The Data Review Committee will monitor the study for progress and 
enrollment, toxicities, adverse events, and soundness of data. 
The frequency of data review by the DRC is determined by the Protocol Review and 
Monitoring Committee at the time of initial review and is based on the level of risk to the 
study subjects. Information reviewed by the committee includes: 
a. 
Overall protocol accrual and expected number of patients to be treated 
b. 
Patient registrations with regard to eligibility and evaluability 
c. 
All adverse events and their relationship to the protocol therapy (e.g., by dose level, 
treatment arm, etc.), in order to determine if participants are being exposed to unanticipated 
or excessive toxicity 
d. 
All serious adverse events or unanticipated problems requiring expedited reporting 
as defined in the protocol 
e. 
Results of any planned interim analyses 
f. 
Response evaluations, if relevant 
g. 
Any issues with protocol conduct or compliance 
h. 
Status of participation rate in correlative biology and/or imaging studies, if 
applicable 
i. 
Study amendments or modifications that may have occurred since last review 
j. 
Date of next planned review 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
This is a voluntary study and all patients will undergo informed consent prior to 
participation. Patients will be allowed to withdraw from the study at any time; all patient 
data and samples will be destroyed at patient request upon withdrawal from the study. 
Patients will not be offered financial or other inducements to participate in the study. All 
patients who wish to receive standard of care in lieu of study participation will be offered 
standard of care treatment consistent with national guidelines and institutional standards. 
 
Retrospective studies have demonstrated that patients taking metformin during chemo- 
radiation demonstrate improved response to conventional treatment and improved survival. 
No prospective studies to date have confirmed this effect, hence the current proposal. It is 
possible that patients enrolled in this study will in fact demonstrate improvement in clinical 
outcomes as detailed in the study. However, we would not expect that every individual 
patient in this trial will experience a clinical benefit from the proposed study. 
 
This is the first and only (to date) proposed, prospective clinical trial testing the hypothesis 
that metformin can improve clinical outcomes in patients undergoing chemo-radiation for 
head and neck cancer. If our hypothesis is proven to be correct, it is possible that metformin 
will be incorporated into future clinical practice following additional prospective validation 


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of our results. Introduction of a cheap, readily available drug, with proven clinical 
effectiveness, would greatly impact large numbers of patients with head and neck cancer. 
The risks associated with this clinical trial are relatively small. Although metformin, the 
investigational drug, can generate some systemic toxicity (i.e. gastrointestinal 
disturbances), the expected toxicity from current standard of care regimens consisting of 
chemo-radiation (i.e. xerostomia, mucositis, nausea, vomiting) greatly exceeds that of the 
investigational agent. Furthermore, clinical outcomes for the patient subset included in this 
study remain poor. As such, the potential to identify an effective potentiator of chemo- 
radiation effectiveness, with relatively low expected toxicity should outweigh the risks 
associated with conducting the trial. 
 
18.0 
ADVERSE EVENTS 
 
18.1 
Adverse Event Characteristics 
 
18.1.1 
The AE collection/reporting period will begin with the first day of 
treatment with metformin and will be completed at 30days following 
treatment completion. AEs after study registration but prior to the first day 
of study treatment will be captured as ongoing concurrent secondary 
diagnoses and symptoms present at the start of study. AEs will be graded 
in accordance with the NCI Common Terminology Criteria for Adverse 
Events v4.0 (CTCAE) http://ctep.cancer.gov/ reporting/ctc.html. If not 
described in the NCI-CTCAE, AEs will be graded according to their 
severity using the following criteria: grade 1 (mild), grade 2 (moderate), 
grade 3 (severe), and grade 4 (life threatening). 
 
18.1.2 
This is the attribution scale which will be utilized to attribute relatedness 
of toxicity to the study: 
- 
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. 
 
18.1.3 
A definition of expected adverse event and unexpected adverse event: 
18.1.3.1 
Expected adverse events are those that have been previously 
identified as resulting from administration of the agent. For 
purposes of this study, an adverse event is considered expected 
when it appears in the current adverse event list in the 
Investigator’s Brochure, the package insert, or is included in 
the informed consent document as a potential risk. 
18.1.3.2 
An adverse event is considered unexpected when it varies in 
nature, intensity, or frequency from information provided in 


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the current adverse event list in the Investigator’s Brochure, 
the package insert or when it is not included in the informed 
consent document as a potential risk. 
 
18.2 
Adverse Event Reporting 
18.2.1 
All adverse events (all grades), regardless of perceived relationship to study 
treatment, will be reported and recorded on the appropriate CRFs. New AEs 
and SAEs that are ongoing at the end of the study will be followed for 30 
days from the patient’s receipt of the last dose of protocol therapy, unless 
they have resolved earlier. SAEs and drug related AEs ongoing at the end 
of study will be followed until resolution. 
18.2.2 
The AE description will include the nature of the experience, the date of 
onset, the resolution date, the severity of each sign or symptom reported 
using the NCI-CTCAE (version 4.0), the seriousness of the event, the 
potential relationship to study treatment, the course of action taken, and the 
outcome of the experience. 
18.2.3 
Serious adverse events are to be reported to the institutional review board 
(IRB) according to each board’s reporting requirements and required time 
frame. 
18.2.4 
The Study Chair/Principal Investigator will be responsible for reporting all 
adverse events to the FDA as per their reporting requirements and time 
frame. 
18.2.5 
Any event that is reportable to the BCM IRB must also be reported to the 
DLDCCC Data Review Committee (DRC), via the Patient Safety Officer 
at dldcc-pso@bcm.edu. 
 
18.3 Safety Reporting Requirements for IND Holders 
NA 
 
18.4 
Multicenter Guidelines 
NA 
 
  19.0    Pregnancy 
This study will exclude pregnant women. A subject who has a positive hCG pregnancy 
test result at any time after the first dose of investigational therapy will be immediately 
withdrawn from participation in the study. All study conclusion/withdrawal assessments 
will be collected at the time of discontinuation as described in Section 9.0. Pregnancy 
information is to be recorded in the Case Report Forms. Pregnancy information will be 
collected from the first dose of investigational product to 30 days after the last dose. While 
pregnancy itself is not considered to be an SAE, it may result in an SAE. Any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be recorded 
as an SAE and will be reported as such. 
A spontaneous abortion is always considered an SAE and will be reported as such. 


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20.0 
REFERENCE(S) 
 
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3. Sandulache VC, Kubik MW, Skinner HD, Malsky JA, Gelbard AH, Zevallos JP. Impact 
of race/ethnicity on laryngeal cancer in patients treated at a Veterans Affairs Medical 
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4. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with 
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5. Granata R, Miceli R, Orlandi E, et al. Tumor stage, human papillomavirus and smoking 
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6. Dahlstrom KR, Calzada G, Hanby JD, et al. An evolution in demographics, treatment, 
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7. Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Insulin-sensitising drugs 
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8. Shyangdan D, Clar C, Ghouri N, et al. Insulin sensitisers in the treatment of non- 
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10. Skinner HD, Sandulache VC, Ow TJ, et al. TP53 disruptive mutations lead to head and 
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Cancer Res. 2012;18: 290-300. 
11. Honjo S, Ajani JA, Scott AW, et al. Metformin sensitizes chemotherapy by targeting 
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574. 
12. Skinner HD, Crane CH, Garrett CR, et al. Metformin use and improved response to 
therapy in rectal cancer. Cancer Med. 2013;2: 99-107. 
13. Skinner HD, McCurdy MR, Echeverria AE, et al. Metformin use and improved 
response to therapy in esophageal adenocarcinoma. Acta Oncol. 2013;52: 1002-1009. 
14. Spratt DE, Beadle BM, Zumsteg ZS, et al. The Influence of Diabetes Mellitus and 
Metformin on Distant Metastases in Oropharyngeal Cancer: A Multicenter Study. Int J 
Radiat Oncol Biol Phys. 2016;94: 523-531. 
15. Sanli T, Storozhuk Y, Linher-Melville K, et al. Ionizing radiation regulates the 
expression of AMP-activated protein kinase (AMPK) in epithelial cancer cells: modulation 
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16. Sanli T, Steinberg GR, Singh G, Tsakiridis T. AMP-activated protein kinase (AMPK) 
beyond metabolism: a novel genomic stress sensor participating in the DNA damage 
response pathway. Cancer Biol Ther. 2014;15: 156-169. 
17. Storozhuk Y, Sanli T, Hopmans SN, et al. Chronic modulation of AMP-Kinase, Akt and 
mTOR pathways by ionizing radiation in human lung cancer xenografts. Radiat Oncol. 
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18. Sanli T, Rashid A, Liu C, et al. Ionizing radiation activates AMP-activated kinase 
(AMPK): a target for radiosensitization of human cancer cells. Int J Radiat Oncol Biol 
Phys. 2010;78: 221-229. 
19. Storozhuk Y, Hopmans SN, Sanli T, et al. Metformin inhibits growth and enhances 
radiation response of non-small cell lung cancer (NSCLC) through ATM and AMPK. Br J 
Cancer. 2013;108: 2021-2032. 
20. Iliopoulos D, Hirsch HA, Struhl K. Metformin decreases the dose of chemotherapy for 
prolonging tumor remission in mouse xenografts involving multiple cancer cell types. 
Cancer Res. 2011;71: 3196-3201. 
21. Rocha GZ, Dias MM, Ropelle ER, et al. Metformin amplifies chemotherapy-induced 
AMPK activation and antitumoral growth. Clin Cancer Res. 2011;17: 3993-4005. 
22. Graham GG, Punt J, Arora M, et al. Clinical pharmacokinetics of metformin. Clin 
Pharmacokinet. 2011;50: 81-98. 
23. 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. 2014;36: 1039-1043. 
24. Kjotrod SB, Carlsen SM, Rasmussen PE, et al. Use of metformin before and during 
assisted reproductive technology in non-obese young infertile women with polycystic ovary 
syndrome: a prospective, randomized, double-blind, multi-centre study. Hum Reprod. 
2011;26: 2045-2053. 
25. Kjotrod SB, von During V, Carlsen SM. Metformin treatment before IVF/ICSI in 
women with polycystic ovary syndrome; a prospective, randomized, double blind study. 
Hum Reprod. 2004;19: 1315-1322. 
26. Kim BH, Shin KH, Kim J, et al. Pharmacokinetic comparison of a new glimepiride 1- 
mg + metformin 500-mg combination tablet formulation and a glimepiride 2-mg + 
metformin 500-mg combination tablet formulation: a single-dose, randomized, open-label, 
two-period, two-way crossover study in healthy, fasting Korean male volunteers. Clin Ther. 
2009;31: 2755-2764. 
27. Schwimmer JB, Middleton MS, Deutsch R, Lavine JE. A phase 2 clinical trial of 
metformin as a treatment for non-diabetic paediatric non-alcoholic steatohepatitis. Aliment 
Pharmacol Ther. 2005;21: 871-879. 
28. Bosi E. Metformin--the gold standard in type 2 diabetes: what does the evidence tell us? 
Diabetes Obes Metab. 2009;11 Suppl 2: 3-8. 
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acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2010: 
CD002967. 


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30. Kaushik AK, Vareed SK, Basu S, et al. Metabolomic profiling identifies biochemical 
pathways associated with castration-resistant prostate cancer. J Proteome Res. 2014;13: 
1088-1100. 
31. Eikawa S, Nishida M, Mizukami S, Yamazaki C, Nakayama E, Udono H. Immune- 
mediated antitumor effect by type 2 diabetes drug, metformin. Proc Natl Acad Sci U S A. 
2015;112: 1809-1814. 
32. R package BOIN. 


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21.0 
APPENDICES 
 
APPENDIX A: 
Staging criteria (AJCC Cancer Staging Manual 6th edition, 2002) 
 
Oral Cavity 
TX 
Primary tumor cannot be assessed. 
T0 
There is no evidence of primary tumor. 
Tis 
Carcinoma is in situ. 
T1 
Tumor is 2 cm or less in greatest dimension. 
T2 
Tumor is more than 2 cm but not greater than 4 cm in greatest 
dimension. 
T3 
Tumor is more than 4 cm in greatest dimension. 
T4 (lip) 
Tumor invades through cortical bone, inferior alveolar nerve, floor 
of mouth, or skin of face—i.e., chin or nose. 
T4a (oral cavity) 
Tumor invades adjacent structures (e.g., through cavity) cortical 
bone, into deep [extrinsic] muscle of tongue [genioglossus, 
hypoglossus, palataglossus, and styloglossus], maxillary sinus, skin 
of face). 
T4b 
Tumor invades masticator space, pterygoid plates, or skull base 
and/or encases the internal carotid artery. 
Oropharynx 
T1 
Tumor is 2 cm or less in greatest dimension. 
T2 
Tumor is more than 2 cm but not more than 4 cm in greatest 
dimension. 
T3 
Tumor is more than 4 cm in greatest dimension. 
T4a 
Tumor invades the larynx, deep/extrinsic muscle of the tongue, 
medial pterygoid, hard palate, or mandible. 
T4b 
Tumor invades the lateral pterygoid muscle, pterygoid plates, 
lateral nasopharynx, or skull base or encases the carotid artery. 
Larynx 
Primary Tumor (T) 
TX 
Primary tumor cannot be assessed. 
T0 
There is no evidence of primary tumor. 
Tis 
Carcinoma is in situ. 
 
Supraglottis 
T1 
Tumor is limited to one subsite of the supraglottis, with normal 
vocal cord mobility. 
T2 
Tumor invades mucosa of more than one adjacent subsite of the 
supraglottis or glottis or region outside the supraglottis (e.g., 
mucosa of base of tongue, vallecula, medial wall of pyriform 
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Glottis 
T3 
Tumor is limited to the larynx with vocal cord fixation and/or 
invades any of the following: postcricoid area, pre-epiglottic 
tissues, paraglottic space, and/or minor thyroid cartilage erosion 
(e.g., inner cortex). 
T4a 
Tumor invades through the thyroid cartilage and/or invades tissues 
beyond the larynx (e.g., trachea, soft tissues of neck, including 
deep extrinsic muscle of the tongue, strap muscles, thyroid, or 
esophagus). 
T4b 
Tumor invades prevertebral space, encases the carotid artery, or 
invades mediastinal structures. 
 
T1 
Tumor is limited to the vocal cords(s) (may involve anterior or 
posterior commissure), with normal mobility. 
T1a 
Tumor is limited to one vocal cord. 
T1b 
Tumor involves both vocal cords. 
T2 
Tumor extends to the supraglottis and/or subglottis, and/or with 
impaired vocal cord mobility. 
T3 
Tumor is limited to the larynx with vocal cord fixation and/or 
invades paraglottic space, and or minor thyroid cartilage erosion 
(e.g., inner cortex). 
T4a 
Tumor invades through the thyroid cartilage and/or invades tissues 
beyond the larynx (e.g., trachea, soft tissues of the neck, including 
deep extrinsic muscle of the tongue, strap muscles, thyroid, or 
esophagus). 
T4b 
Tumor invades prevertebral space, encases the carotid artery, or 
invades mediastinal structures. 
Subglottis 
T1 
Tumor is limited to the subglottis. 
T2 
Tumor extends to the vocal cord(s), with normal or impaired 
mobility. 
T3 
Tumor is limited to the larynx, with vocal cord fixation. 
T4a 
Tumor invades cricoid or thyroid cartilage and/or invades tissues 
beyond the larynx (e.g., trachea, soft tissues of neck, including 
deep extrinsic muscles of the tongue, strap muscles, thyroid, or 
esophagus). 
T4b 
Tumor invades prevertebral space, encases the carotid artery, or 
invades mediastinal structures. 
Hypopharynx 
T1 
Tumor is limited to one subsite of the hypopharynx and 2 cm or 
less in greatest dimension. 
T2 
Tumor invades more than one subsite of the hypopharynx or an 
adjacent site, or measures more than 2 cm but not more than 4 cm 
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T3 
Tumor is more than 4 cm in greatest dimension or with fixation of 
the hemilarynx. 
T4a 
Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, 
esophagus, or central compartment soft tissue. 
T4b 
Tumor invades prevertebral fascia, encases the carotid artery, or 
involves mediastinal structures. 
 
Neck Staging Under the TNM Staging System for Head and Neck Tumors (excluding 
nasopharynx and thyroid) 
NX 
Regional lymph nodes cannot be assessed. 
N0 
There is no regional nodes metastasis. 
N1 
Metastasis is in a single ipsilateral lymph node, 3 cm or less in 
greatest dimension. 
N2 
Metastasis is in a single ipsilateral lymph node, more than 3 cm but 
not more than 6 cm in greatest dimension; or metastasis is in 
multiple ipsilateral lymph nodes, none more than 6 cm ingreatest 
dimension; or metastasis is in bilateral or contralateral lymph 
nodes, none greater than 6 cm in greatest dimension. 
N2a 
Metastasis is in a single ipsilateral lymph node, more than 3 cm but 
not more than 6 cm in greatest dimension. 
N2b 
Metastasis is in multiple ipsilateral lymph nodes, none more than 6 
cm in greatest dimension. 
N2c 
Metastasis is in bilateral or contralateral lymph nodes, none more 
than 6 cm in greatest dimension. 
N3 
Metastasis is in a lymph node more than 6 cm in greatest 
dimension. 
 
TNM Staging for the Larynx, Oropharynx, Hypopharynx, Oral Cavity, Salivary Glands, and 
Paranasal Sinuses 
Stage Grouping 
Stage 0 
Tis N0 M0 
Stage I 
T1 N0 M0 
Stage II 
T2 N0 M0 
Stage III      T3 N0 M0 T1 
N1 M0 T2 
N1 M0 T3 
N1 M0 
Stage IVA       T4a N0 M0 
T4a N1 M0 
T1 N2 M0 
T2 N2 M0 
T3 N2 M0 
T4a N2 M0 


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Stage IVB 
T4b Any N M0 
Any T N3 M0 
Stage IVC 
Any T Amy N M1 
Clinical Stage Grouping by T and N Status 
T1 
T2 
T3 
T4a 
T4b 
N0 
I 
II 
III 
IVa 
IVb 
N1 
III 
III 
III 
IVa 
IVb 
N2 
IVa 
IVa 
IVa 
IVa 
IVb 
N3 
IVb 
IVb 
IVb 
IVb 
IVb 


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APPENDIX B 
Pregnancy testing guidelines and acceptable birth control methods 
The safety of metformin in pregnant females has not been definitively established. Therefore, a risk minimization 
plan to prevent pregnancy must be observed. 
Criteria for females of childbearing potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature female who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal for at least 24 consecutive 
months (i.e., has had menses at any time in the preceding 24 consecutive months). 
The investigator must ensure that: 
- Females of childbearing potential comply with the conditions for pregnancy risk minimization, including 
confirmation that she has an adequate level of understanding 
- Females NOT of childbearing potential acknowledge that she understands the hazards and necessary precautions 
associated with the use of metformin 
 
Contraception 
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use a reliable forms of 
contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following 
time periods related to this study: 1) for at least 28 days before starting metformin; 2) throughout the entire duration 
of metformin treatment; 3) during dose interruptions; and 4) for at least 28 days after metformin discontinuation. 
FCBP must be referred to a qualified provider of contraceptive methods if needed. The following are examples of 
highly effective and additional effective methods of contraception: 
 
Highly effective methods: 
- oral contraceptive pills 
- Intrauterine device (IUD) 
- Hormonal (birth control pills, injections, implants) 
- Tubal ligation 
- Partner’s vasectomy 
Additional effective methods: 
- Male condom 
- Diaphragm 
- Cervical Cap 
 
The risk of venous thromboembolism continues for 4−6 weeks after discontinuing combined oral contraception. The 
efficacy of contraceptive steroids may be reduced during co-treatment with dexamethasone. Implants and 
levonorgestrel-releasing intrauterine systems are associated with an increased risk of infection at the time of 
insertion and irregular vaginal bleeding. Prophylactic antibiotics should be considered particularly in patients with 
neutropenia. 
Pregnancy testing 
Medically supervised pregnancy tests with a minimum sensitivity of 50 mIU/mL must be performed for females of 
childbearing potential, including females of childbearing potential who commit to complete abstinence, as outlined 
below. 
Before starting metformin 
Female Patients: 
FCBP must have one pregnancy tests (sensitivity of at least 50 mIU/mL) prior to starting metformin. 
During study participation and for 28 days following metformin discontinuation 
Female Patients: 
At each visit, the Investigator must confirm with the FCBP that she is continuing to use a reliable method of birth 
control at each visit during the time that birth control is required. If pregnancy or a positive pregnancy test does 
occur in a study patient, metformin must be immediately discontinued. Pregnancy testing and counseling must be 


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performed if a patient misses her period or if her pregnancy test or her menstrual bleeding is abnormal. Metformin 
treatment must be temporarily discontinued during this evaluation. 


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APPENDIX C 
 
H-39773 Head and Neck Cancer Study 
Medicine Intake Calendar 
 
Patient Name:   
 
Instructions to Participant: 
Use this calendar as a reminder to take your study medication every day. Record the number of 
pills/tablets that you take each day. Take the pills at about the same time every day. 
Bring this calendar and your pills/tablets with you to each study visit. 


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APPENDIX B 
 
Blood glucose monitoring form 
 
Patient Name:   
 
 
Instructions to Participant: 
If your blood glucose is high, your doctor will ask you to monitor your glucose at home each day. Your 
doctor will give you the test you will need to do this. 
 
You will do this for one week, two times a day. 
Each day, write the date, and write your blood glucose value from each test on the form below. Bring 
this form back to your doctor or the research staff at your next visit. 
 
 
 
DATE COLLECTED:  
 
(MM/DD/YYYY) 
 
 
 
 
Day of the week, Date 
AM value 
PM value 
Monday,   
 
value (mg/dl) 
value (mg/dl) 
Tuesday,   
 
value (mg/dl) 
value (mg/dl) 
Wednesday,   
 
value (mg/dl) 
value (mg/dl) 
Thursday,   
 
value (mg/dl) 
value (mg/dl) 
Friday,   
 
value (mg/dl) 
value (mg/dl) 
Saturday,   
 
value (mg/dl) 
value (mg/dl) 
Sunday,   
 
value (mg/dl) 
value (mg/dl)