Clinical trial NCT02581137: Metformin Hydrochloride in Preventing Oral Cancer in Patients With an Oral Premalignant Lesion
Official title: M4OC-Prevent: Metformin for Oral Cancer Prevention
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Erythroplakia
Hyperplasia
Oral Cavity Carcinoma
Oral Leukoplakia
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2015-10-20
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: 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.

Detailed 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

Primary outcomes:
measure: Clinical Response to Metformin Intervention
timeFrame: Baseline to up to 14 weeks
Secondary outcomes:
measure: Histologic Response to Metformin Intervention
timeFrame: Baseline to up to 14 weeks
measure: Changes in Cell Proliferation and Its Molecular Targets
timeFrame: Baseline to up to 14 weeks
measure: Changes in Frequent Dysregulated Molecular Mechanisms and OCT Expression
timeFrame: Baseline to up to 14 weeks
measure: Impact of Genomic Alterations on the Biological and Biochemical Consequences and Clinical Response to Metformin Hydrochloride
timeFrame: Up to 14 weeks
measure: Change in Measurements of Metformin Hydrochloride Concentrations in Serum and Saliva
timeFrame: Baseline to up to 14 weeks
measure: Change in Serum Metabolic Markers
timeFrame: Baseline to up to 14 weeks
measure: Change in Serum and Saliva Inflammatory and Angiogenic Cytokines
timeFrame: Baseline to up to 14 weeks
Other outcomes:
measure: Change in Saliva Microbiome Analyzed Using Flow Cytometry
timeFrame: Baseline to up to 14 weeks
measure: Microbiome Signatures Correlated With Treatment Response
timeFrame: Baseline to up to 14 weeks
Locations:
city: San Diego
country: United States
facility: UC San Diego Medical Center - Hillcrest
state: California
city: Minneapolis
country: United States
facility: University of Minnesota/Masonic Cancer Center
state: Minnesota
city: Vancouver
country: Canada
facility: BC Cancer Research Centre
state: British Columbia
city: Vancouver
country: Canada
facility: University of British Columbia Hospital
state: British Columbia
Study officials:
affiliation: The University of Arizona Medical Center-University Campus
name: Scott M Lippman
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gutkind JS, Molinolo AA, Wu X, Wang Z, Nachmanson D, Harismendy O, Alexandrov LB, Wuertz BR, Ondrey FG, Laronde D, Rock LD, Rosin M, Coffey C, Butler VD, Bengtson L, Hsu CH, Bauman JE, Hewitt SM, Cohen EE, Chow HS, Lippman SM, Szabo E. Inhibition of mTOR signaling and clinical activity of metformin in oral premalignant lesions. JCI Insight. 2021 Sep 8;6(17):e147096. doi: 10.1172/jci.insight.147096.