Testing Pioglitazone and Metformin to Prevent Oral Cancer in Patients with High Risk Oral Preneoplasia

Inclusion Criteria

• Biopsy proven hyperplasia in high risk anatomic areas (floor of mouth, mobile tongue, and oropharynx). Mild, moderate or severe dysplasia, within the lesion, at any site of the oral cavity or oropharynx. Hyperplasia or any level of dysplasia in an erythroplakia lesion
• Must have objective evidence of oral leukoplakia that is measurable in 2 dimensions. The lesion(s) may be clinically characterized by leukoplakia, erythroplakia, erythro/leukoplakia. Lesions may be located in the oral cavity or oropharynx. However, the index lesion must be located in an anatomic site accessible by punch biopsy and be a minimum of 4mm x 8 mm to permit a 4mm punch biopsy
• Age 18 years or older at the time of consent
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 or 2
• Has an expected life expectancy of > 6 months in the judgement of the treating investigator
• Hemoglobin ≥ 10 g/dl (within 14 days prior to Day 1)
• White blood cells ≥ 3,000/microliter (within 14 days prior to Day 1)
• Platelets ≥ 100,000/microliter (within 14 days prior to Day 1)
• Total bilirubin ≤ 1.2 x institutional upper limit of normal, or, if diagnosis of Gilbert’s disease, up to 1.5 x institutional upper limit of normal (within 14 days prior to Day 1)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) ≤ 1.2 x institutional upper limit of normal (within 14 days prior to Day 1)
• Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 1.2 x institutional upper limit of normal (within 14 days prior to Day 1)
• Glucose, serum < 200 mg/dL (within 14 days prior to Day 1)
• Estimated glomerular filtration rate (eGFR) > 45 mL/min using the following Cockcroft-Gault calculator (within 14 days prior to Day 1): http://www.mdcalc.com/creatinine-clearance-cockcroft-gault-equation (Note: the participant’s sex, age, height, weight and creatinine will be required to complete the calculation)
• Hemoglobin A1c (HbA1c) < 8% (within 14 days prior to Day 1)
• Able to comply with treatment (i.e. able to swallow a tablet whole, not crushed) and complete a 12 week course of twice daily medication as required by this study in the opinion of the treating investigator
• Body mass index (BMI) is ≥ 18.5
• Sexually active persons of child-bearing potential agrees to use adequate contraception (a hormonal method that has been in continual use for a minimum of 3 months prior to the study screening visit, a barrier method, or abstinence) for the duration of study participation
• Provides voluntary written consent prior to the performance of any research related activity

Exclusion Criteria

• Pregnant or breastfeeding or planning to become pregnant. If of childbearing potential regardless of method of birth control must have a negative pregnancy test within 14 days of Day 1. A person who has had a hysterectomy, a bilateral oophorectomy, or if > 55 years of age with ≥ 2 years of amenorrhea is considered not to be of childbearing potential
• A concurrent diagnosis of Type I or Type II diabetes that is being treated with insulin or an antidiabetic agent. Participants whose Type II diabetes is controlled with diet and/or exercise alone are eligible provided they meet all other eligibility criteria
• Participant has taken any of the following medications within the past 3 months: * A thiazolidinedione [e.g. pioglitazone (Actos) or rosiglitazone (Avandia)], * A biguanide [e.g. metformin (Glucophage, Glumetza, Fortamet, Riomet) or proguanil (Paludrine)] * A combination drug containing one of the agents above (Brand names include: ACTOplus Met, Avandamet, Avandaryl, Duetact, Glucovance, Invokamet, Janumet, Jentadueto, Komboglyze, Metaglip, PrandiMet, Synjardy, Xigudo
• Participant is currently taking a strong CYP2C8 inhibitor [e.g. gemfibrozil (Lopid)]
• Participant is currently taking an enzyme inducer of CYP2C8 [carbamazepine (Carbatrol, Epitol, Equetro. Tegretol) cortisol (Hydrocortisone); dexamethasone (Decadron); phenobarbital (Luminal Sodium): phenytoin (Dilantin, Phenytek, Novaplus Phenytoin Sodium); primidone (Mysoline); rifampin (Rifadin, Rimactane); rifapentine (Priftin); secobarbital (Seconal)]
• Participant is currently taking topiramate (Topamax) commonly used in epilepsy or to prevent migraines or other carbonic anhydrase inhibitors [e.g. zonisamide (Zonegran); acetazolamide (Diamox Sequels); or dichlorphenamide (Keveyis, Daranide)]
• Participant is currently taking a cationic drug [e.g. amiloride (Midamor); cimetidine (Tagamet); digoxin (Lanoxin, Digitek, Digox); morphine (Roxanol, Duramorph, Kadian, MS Contin); procainamide (Pronestyl, Procanbid); quinidine (Quinidex, Cardioquin, Quin-G, Quinora); quinine (Qualaquin, Quinamm, Quiphile); ranitidine (Zantac, Deprizine, Gabitidine); triamterene (Dyrenium); trimethoprim (Proloprim, Trimpex, Primsol); or vancomycin (Vancocin, Vancoled).
• Participant is taking another investigational agent (not approved by the Food and Drug Administration [FDA] for any indication)
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to Actos or Metformin
• Any contraindication to biopsy – this study requires a 4 mm punch biopsy of a lesion and of nearby normal tissue prior to treatment and at the end of the 12 week treatment period
• A history of congestive heart failure or New York Heart Association (NYHA) Class III or IV functional status as thiazolidinediones, such as pioglitazone can cause or exacerbate congestive heart failure in some patients
• Participant has > Common Terminology Criteria in Adverse Events (CTCAE) Grade 1 limb edema (5 - 10% inter-limb discrepancy in volume or circumference at point of greatest visible difference; swelling or obscuration of anatomic architecture on close inspection)
• History of hypoglycemia
• History of bladder cancer, including in situ bladder cancer
• History of invasive cancer (other than non-melanoma skin cancer or cervical cancer in situ) active within 18 months prior to the baseline study visit. (Participants who have a history of cancer that was curatively treated without evidence of recurrence in the 18 months prior to the baseline study visit are considered eligible)
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements