Phase I/II Study OF Metformin in Combination With Cisplatin and Radiation in Head and Neck Squamous Cell Carcinoma

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.

INCLUSION CRITERIA:

1. 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. Only patients with HPV- disease will be
included in the Phase II component of the study; HPV status will be ascertained using
the currently utilized clinical standard of p16 overexpression via
immunohistochemistry.

2. Disease Status: Only patients with active, measurable disease will be included in the
study.

3. Prior Therapy: Patients must have fully recovered from the acute toxic effects of all
prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
Patients treated with chemotherapy (i.e. cisplatin) and/or EBRT for a cancer at a
different, non-head and neck site, will be eligible for the trial. Patients previously
treated with chemotherapy and/or EBRT for a cancer of the head and neck region,
irrespective of histology will not be eligible to participate in the trial.

1. Myelosuppressive chemotherapy: Must not have received within 4 weeks of
enrollment onto this study (6 weeks if prior nitrosourea).

2. Hematopoietic growth factors: At least 7 days since the completion of therapy
with a growth factor.

3. Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy
with a biologic agent.

4. Monoclonal Antibody: At least 6 weeks must have elapsed since prior therapy that
includes a monoclonal antibody.

5. Other: For agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which adverse
events are known to occur.

6. XRT: >/= 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.

7. Stem Cell Transplant or Rescue: No evidence of active graft vs. host disease and
>/= 2 months must have elapsed since transplant.

4. Age: Patients must be >/=18 years of age. Because no dosing or adverse event data are
currently available on the use of metformin in cancer patients <18 years of age,
children are excluded from this study but will be eligible for future pediatric
single-agent trials, if applicable.

5. Performance Status: ECOG performance status less than or equal to 3.

6. Organ Function: Patients must have normal organ and marrow function as defined below:

1. leukocytes >3,000/mcL

2. absolute neutrophil count >1,500/mcL

3. platelets >100,000/mcL

4. total bilirubin within normal institutional limits

5. AST(SGOT)
6. creatinine < 1.5mg/dL OR

7. creatinine clearance>60 mL/min/1.73 m2 for patients with creatinine levels >
institutional normal

7. 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) prior to study entry and for the duration
of study participation. Should a woman become pregnant or suspect she is pregnant
while participating in this study, she should inform her treating physician
immediately.

8. Informed Consent: Ability to understand and the willingness to sign a written informed
consent document.

EXCLUSION CRITERIA:

1. Concomitant Medications: Patients may not be receiving any other investigational
agents.

2. Brain metastases: Patients with known brain metastases will be excluded from this
clinical trial because of their poor prognosis and because they often develop
progressive neurologic dysfunction that would confound the evaluation of neurologic
and other adverse events.

3. Prior Allergies: History of allergic reactions attributed to compounds of similar
chemical or biologic composition to metformin.

4. Patients with diabetes mellitus (DM) will be excluded from the study. Criteria for a
diagnosis of diabetes mellitus are as follows: a) known diagnosis of DM, b) active
treatment for DM, c) fasting glucose level ≥ 126mg/dl or d) hemoglobin A1c ≥ 6.0%
obtained within 30 days prior to registration.

5. Intercurrent Illness: 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.

6. Pregnancy: Pregnant women are excluded from this study because metformin is a US FDA
class B agent with the potential for teratogenic or abortifacient effects. Because
there is an unknown but potential risk for adverse events in nursing infants secondary
to treatment of the mother with metformin, breastfeeding should be discontinued if the
mother is treated with metformin.

7. HIV: HIV-positive patients on combination antiretroviral therapy are ineligible
because of the potential for pharmacokinetic interactions with metformin. In addition,
these patients are at increased risk of lethal infections when treated with
marrow-suppressive therapy. Appropriate studies will be undertaken in patients
receiving combination antiretroviral therapy when indicated.

8. Patients taking metformin for any reason will not be eligible for inclusion in the
study.