ACTOplus Met XR in Treating Patients With Stage I-IV Oral Cavity or Oropharynx Cancer Undergoing Definitive Treatment

PRIMARY OBJECTIVES:

I. To determine whether 14-21 days of treatment with ACTOplus met XR will result in a
decrease in proliferation index (Ki-67) expression in oral cavity/oropharyngeal tumor tissue
as compared to placebo.

SECONDARY OBJECTIVES:

I. Compare differences in proliferation index (Ki-67) expression from baseline to
post-exposure in visually normal appearing oral cavity/oropharyngeal tissue.

II. Compare immunohistochemical differences in the apoptosis biomarker cleaved caspase 3 from
baseline to post-exposure in oral cavity/oropharyngeal adjacent visually normal appearing
tissue and tumor tissue samples.

III. Compare immunohistochemical differences from baseline to post-exposure in oral
cavity/oropharyngeal tumor tissue samples with regard to cyclin D1, p21 and biguanide or PPAR
gamma associated pathway biomarkers; prospective biomarkers on the panel will include
phosphorylated (p)AKT, pAMPK, pS6 (metformin), and PPAR gamma.

IV. Compare immunohistochemical differences from baseline to post-exposure of oral
cavity/oropharyngeal tumor tissue samples with regard to tumor infiltrating immune cells
(effector CD8 [CD8+IFNg+]), regulatory CD4 T regulatory (Treg) (CD4+Foxp3+), tumor associated
myeloid cells (CD68), PD1 and PD-L1.

V. Compare and correlate pre- and post-ACTOplus met XR treatment human ribonucleic acid
(RNA)-sequencing (seq) gene analysis on total RNA samples from oral cavity/oropharyngeal
adjacent visually normal appearing tissue and tumor tissue pre-and post-study treatment.

VI. Determine human papillomavirus (HPV) status in pre-treatment tumor tissue using p16
immunohistochemistry.

VII. Compare pre- and post-study treatment positron emission tomography (PET)/computed
tomography (CT) scans to determine any change in tumor fluorodeoxyglucose (FDG)
uptake/metabolism.

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP I: Patients receive ACTOplus met XR orally (PO) once daily (QD) for 14-21 days in the
absence of disease progression or unacceptable toxicity. Patients may continue ACTOplus met
XR PO QD for a maximum of 25 days if end of treatment biopsy/surgical treatment is delayed
beyond day 22.

GROUP II: Patients receive placebo PO QD daily for 14-21 days.

Inclusion Criteria:

- Participant has a newly diagnosed, histologically confirmed, stage I-IV squamous cell
carcinoma or squamous cell carcinoma in situ of the oral cavity or oropharynx and will
be undergoing definitive surgical, radiotherapy, or chemoradiation treatment; patients
who are NOT candidates for localized treatment (surgery, radiation or chemoradiation)
with curative intent (i.e.patients with distant metastasis or contra-indication to
localized treatment) are not eligible OR

- Participant has a lesion in the oral cavity or oropharynx that is not yet biopsied but
is highly suspicious for cancer; (randomization will be placed on hold until the
presence of cancer is histologically confirmed, and a treatment plan is established;
if the presence of cancer is not confirmed, the participant will be considered a
screen failure)

- The participant's primary tumor is accessible to biopsy in the outpatient clinic
setting and the participant is willing to have baseline and end of study (day 15-26) 4
mm punch biopsies of tumor and adjacent visually normal appearing tissue for biomarker
analysis

- If the participant has a biopsy-confirmed cancer, the baseline biopsy to collect
tissue for biomarker analysis will be in addition to the pre-study diagnostic
biopsy

- If the participant is having surgical treatment, the end of study biopsies may be
collected at the time of surgery unless surgery is delayed beyond day 26

- If the participant is not having surgical treatment, the end of study biopsies
will be collected prior to initiation of non-surgical treatment

- Participant is able to complete a minimum of 14 days of study agent dosing prior to
initiation of definitive treatment for their cancer

- Participant is scheduled for an end of study biopsy within 22 days of starting study
agent and within 36 days of their study screening visit; (if the participant is
scheduled for surgical excision of the tumor and the surgery is delayed for any reason
after the participant has started taking the study agent, study agent dosing may be
extended up to a maximum of 25 days without compromising the evaluability of the end
of study biomarkers)

- Eastern Cooperative Oncology Group (ECOG) performance status = 0 or 1

- Life expectancy is > 6 months

- Body mass index (BMI) is >= 18.5

- Hemoglobin >= 10 g/dl

- White blood cells >= 3,000/microliter

- Platelets >= 100,000/microliter

- Total bilirubin =< 1.2 x institutional upper limit of normal

- With the exception of candidates with a diagnosis of Gilbert's disease in which
case the total bilirubin may extend up to 1.5 x institutional upper limit of
normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =<
1.2 x institutional upper limit of normal

- Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.2 x
institutional upper limit of normal

- Glucose, serum < 200 mg/dL

- Estimated glomerular filtration rate (eGFR) > 45 mL/min (if eGFR is not included on
the clinical lab report, the chronic kidney disease epidemiology [CKD-EPI] creatinine
calculator may be used)

- Participant is able to swallow a tablet whole

- Participant is willing and able to participate for the duration of the study

- Participant of childbearing 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 their study
participation; (should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her study physician immediately)

- NOTE: participants should not start hormonal therapy for the purpose of meeting
the eligibility criteria for this protocol

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Participant has received or will receive some form of treatment for their cancer prior
to completing a minimum of 14 days of study agent dosing; (a biopsy is not considered
a form of treatment)

- Participant has a concurrent diagnosis of type I or type II diabetes that is being
treated with insulin or an oral 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 or multidrug and toxin extrusion
[MATE] inhibitor (e.g. amiloride [Midamor]; cimetidine [Tagamet]; digoxin [Lanoxin,
Digitek, Digox]; dolutegravir [Tivicay]; morphine [Roxanol, Duramorph, Kadian, MS
Contin]; procainamide [Pronestyl, Procanbid]; quinidine [Quinidex, Cardioquin, Quin-G,
Quinora]; quinine [Qualaquin, Quinamm, Quiphile]; ranitidine [Zantac, Deprizine,
Gabitidine]; ranolazine [Ranexa]; triamterene [Dyrenium)] trimethoprim [Proloprim,
Trimpex, Primsol]; vancomycin [Vancocin, Vancoled]; or vandetanib [Calpresa])

- Participants is taking another investigational agent

- Participant has a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to ACTOplus Met XR

- Participant has a contraindication to biopsy

- Participants with a history of congestive heart failure or New York Heart Association
(NYHA) class III or IV functional status are excluded

- Participant has a history of liver disease

- Participant has > Common Terminology Criteria for 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)

- Participant has a history of hypoglycemia

- Participant is an active alcoholic or consumes excessive amounts of alcohol per the
following definitions:

- Female: More than 3 drinks on any day or a total of more than seven drinks in a
week

- Male: More than 4 drinks on any day or a total of more than 14 drinks in a week

- 1 drink =

- Beer: 12 oz. (1 standard size can or bottle)

- Wine: 5 oz. (one standard glass)

- Spirits: 6 oz. (one mixed drink or one 1.5 fluid oz. shot)

- Participant has a history of macular edema

- Participant has a history of bladder cancer (including in situ bladder cancer)

- Participant has a 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

- Participant is pregnant, breast feeding or planning to become pregnant; (all
participants of childbearing potential regardless of method of birth control must have
a negative pregnancy test at baseline; a woman is considered not to be of childbearing
potential is she has had a hysterectomy, bilateral oophorectomy, or if she is > 55
years of age with >= 2 years of amenorrhea)

- Breastfeeding should be discontinued if the mother is treated with ACTOplus met
XR