Metformin Hydrochloride in Preventing Oral Cancer in Patients With an Oral Premalignant Lesion

Sponsor: National Cancer Institute (NCI)

Sponsor score: 0

ClinicalTrials ID:NCT02581137

This phase IIa trial evaluates metformin hydrochloride's efficacy in treating oral premalignant lesions over 12-14 weeks. Primary focus is on clinical response, with secondary objectives examining histologic changes and biomarker effects. Eligible participants have specific lesion criteria and meet health benchmarks. Metformin is administered orally, with follow-up post-treatment.

Patient Parameters

Parameter	Options

Program Overview

This phase IIa trial studies how well metformin hydrochloride works in preventing oral cancer in patients with an oral premalignant lesion (oral leukoplakia or erythroplakia). Oral premalignant lesions look like red or whitish plaques or lesions in the mouth that do not rub off and can be associated with a higher risk of cancer. Metformin hydrochloride may help prevent oral cancer from forming in patients with an oral premalignant lesion.

Description

PRIMARY OBJECTIVES:

I. To determine the clinical response of oral premalignant lesions to 12-14 weeks of metformin (metformin hydrochloride) intervention.

SECONDARY OBJECTIVES:

I. Histologic response to metformin intervention in the target lesion. II. Tissue-based biomarkers: metformin effect on cell proliferation and its molecular targets in the target lesion and in the normal tissue (marker of cell proliferation, Ki67, molecular targets of metformin, including, in order of priority, phosphorylated ribosomal protein S6 kinase [pS6], phosphorylated v-akt murine thymoma viral oncogene homolog 1 [pAKT]S473, phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 [p4EBP], phosphorylated acetyl-CoA carboxylase alpha [pACC]).

III. Tissue-based biomarkers: expression of dysregulated molecular mechanisms and organic cation transporter 3 (OCT 3) in the target lesion and in the normal tissue, including, in order of priority, epidermal growth factor receptor (EGFR), phosphorylated (p)EGFR, tumor protein 53 (p53), phosphatase and tensin homolog (PTEN), phosphorylated mitogen-activated protein kinase 1 (pERK), cyclin-dependent kinase inhibitor 2A (p16), and OCT3.

IV. Tissue-based biomarkers: targeted analysis of cancer-associated genes in the target lesion and blood deoxyribonucleic acid (DNA).

V. Serum and saliva based biomarkers: metformin effect on serum metabolic markers (C-peptide, glycosylated hemoglobin [HbA1c]).

VI. Serum and saliva based biomarkers: metformin concentrations in serum and saliva.

VII Serum and saliva based biomarkers: metformin effect on serum and saliva inflammatory and angiogenic cytokines, including interleukin (IL)-6, IL-8, growth-related oncogene-1 (GRO-1), and vascular endothelial growth factor (VEGF).

EXPLORATORY OBJECTIVES:

I. To characterize changes in the saliva microbiome before and after metformin intervention, including both the absolute microbial load and taxonomic composition.

II. To evaluate the potential microbiome signatures that are correlated with treatment response.

OUTLINE:

Patients receive extended-release metformin hydrochloride orally (PO) once daily (QD) for 2 weeks and then twice daily (BID) for 10-12 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 2-4 weeks.

Eligibility Criteria

Inclusion Criteria

Participants with oral leukoplakia or erythroplakia with mild, moderate, or severe histologic dysplasia, or hyperplasia not associated with mechanical factors such as ill-fitted dentures
Measurable disease - minimum lesion size of 8 x 3 mm before initial biopsy
Karnofsky performance status >= 70%
Leukocytes >= 3,000/microliter
Absolute neutrophil count >= 1,000/microliter
Platelets >= 100,000/microliter
Total bilirubin =< 1.5 × institutional upper limit of normal (ULN)
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =<1.5 × institutional ULN
eGFR > 40 mL/min using the Cockcroft-Gault equation
Life expectancy > 3 months
Willing to use adequate contraception (barrier method, abstinence, subject has had a vasectomy or partner is using effective birth control or is postmenopausal) for the duration of study participation
Ability to take oral medication
Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

Patients with diabetes who are taking insulin or oral agents
History of diabetic ketoacidosis
Participants may not be receiving any other investigational agents within past 3 months
History of allergic reactions attributed to compounds of similar chemical composition to metformin or prior use of metformin within the last year
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, human immunodeficiency virus (HIV)-positive, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Oral carcinoma in situ
History of chronic alcohol use or abuse defined as any one of the following: a) average consumption of 3 or more alcohol containing beverages daily in the past 12 months; b) consumption of 7 or more alcoholic beverages within a 24 hour (hr) period in the past 12 months
Glycated hemoglobin (HbA1c) > 8%
Pregnancy or nursing women
Acute or chronic liver disease, evidence of hepatitis (infectious or autoimmune), cirrhosis or portal hypertension
History of renal disease
History of prior head and neck squamous cell carcinoma (HNSCC) unless curatively treated for >= 1 year
Have received chemotherapy and/or radiation for any malignancy (excluding non-melanoma skin cancer and cancers confined to organs with removal as only treatment) in the past 2 years; ongoing adjuvant hormonal therapy for breast cancer is allowed

Locations

FACILITY	ZIP	CITY	STATE
UC San Diego Medical Center - Hillcrest	92103	San Diego	California
University of Minnesota/Masonic Cancer Center	55455	Minneapolis	Minnesota

Get This Program In Your Inbox

You can sign up and apply your patients for this program.