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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT02581137
First received: October 19, 2015
Last updated: September 12, 2017
Last verified: September 2017
  Purpose
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.

Condition Intervention Phase
Erythroplakia Hyperplasia Mild Dysplasia Moderate Dysplasia Oral Cavity Carcinoma Oral Leukoplakia Severe Dysplasia Other: Laboratory Biomarker Analysis Drug: Metformin Hydrochloride Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: M4OC-Prevent: Metformin for Oral Cancer Prevention

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Change in clinical response of oral premalignant lesions [ Time Frame: Baseline to up to 14 weeks ]
    Clinical response will be categorized into complete response (CR), partial response (PR), no change or progressive disease. A participant with CR or PR is considered as a respondent. A one-sided one-sample binomial exact test at a significance level of 5% will be performed to see if the clinical response rate is greater than 30% (poor treatment).


Secondary Outcome Measures:
  • Change in histologic response [ Time Frame: Baseline to up to 14 weeks ]
    The histologic response rate will be calculated and a one-sided 95% confidence interval based on the exact method will be derived.

  • Change in measurements of metformin hydrochloride concentrations in serum and saliva [ Time Frame: Baseline to up to 14 weeks ]
    Nonparametric methods, e.g. signed rank test, will be performed to evaluate each of the changes in tissue, serum, and saliva markers.

  • Change in serum and saliva inflammatory and angiogenic cytokines [ Time Frame: Baseline to up to 14 weeks ]
    Nonparametric methods, e.g. signed rank test, will be performed to evaluate each of the changes in tissue, serum, and saliva markers.

  • Change in serum metabolic markers [ Time Frame: Baseline to up to 14 weeks ]
    Nonparametric methods, e.g. signed rank test, will be performed to evaluate each of the changes in tissue, serum, and saliva markers.

  • Changes in cell proliferation and its molecular targets [ Time Frame: Baseline to up to 14 weeks ]
    Nonparametric methods, e.g. signed rank test, will be performed to evaluate each of the changes in tissue, serum, and saliva markers.

  • Changes in frequent dysregulated molecular mechanisms and OCT expression [ Time Frame: Baseline to up to 14 weeks ]
    Nonparametric methods, e.g. signed rank test, will be performed to evaluate each of the changes in tissue, serum, and saliva markers. A univariate logistic regression model with the clinical response as the outcome variable will be fitted to explore if any of the expression of frequent dysregulated mechanisms and OCT3 level are associated with the clinical response to metformin hydrochloride.

  • Impact of genomic alterations on the biological and biochemical consequences and clinical response to metformin hydrochloride [ Time Frame: Up to 14 weeks ]
    Nonparametric methods, e.g. signed rank test, will be performed to evaluate each of the changes in tissue, serum, and saliva markers. A univariate logistic regression model with the clinical response as the outcome variable will be fitted to explore if any genomic alterations are associated with the clinical response to metformin hydrochloride.


Estimated Enrollment: 26
Actual Study Start Date: June 10, 2016
Estimated Primary Completion Date: October 31, 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Prevention (extended-release metformin hydrochloride)
Patients receive extended-release metformin hydrochloride PO QD for 2 weeks and then BID for 10-12 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Metformin Hydrochloride
Given PO
Other Names:
  • Cidophage
  • Dimefor
  • Glifage
  • Glucoformin
  • Glucophage
  • Glucophage ER
  • Metformin HCl
  • Riomet
  • Siofor

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).

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

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02581137

Locations
United States, California
University of California San Diego
San Diego, California, United States, 92103
United States, Minnesota
University of Minnesota/Masonic Cancer Center
Minneapolis, Minnesota, United States, 55455
Canada, British Columbia
BC Cancer Research Centre
Vancouver, British Columbia, Canada, V5Z 1L3
University of British Columbia Hospital
Vancouver, British Columbia, Canada, V6T 2B5
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Scott Lippman The University of Arizona Medical Center-University Campus
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02581137     History of Changes
Other Study ID Numbers: NCI-2015-01733
NCI-2015-01733 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
N01-CN-2012-00031
HHSN2612012000311
1510157567 ( Other Identifier: The University of Arizona Medical Center-University Campus )
UAZ2015-05-02 ( Other Identifier: DCP )
N01CN00031 ( U.S. NIH Grant/Contract )
P30CA023074 ( U.S. NIH Grant/Contract )
Study First Received: October 19, 2015
Last Updated: September 12, 2017

Additional relevant MeSH terms:
Hyperplasia
Mouth Neoplasms
Leukoplakia
Leukoplakia, Oral
Erythroplasia
Pathologic Processes
Head and Neck Neoplasms
Neoplasms by Site
Neoplasms
Mouth Diseases
Stomatognathic Diseases
Precancerous Conditions
Pathological Conditions, Anatomical
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 21, 2017