Randomized Double Blind Placebo Controlled Trial of Barrett's Esophagus Chemoprevention With Metformin
Overview
- Phase
- Phase 2
- Intervention
- metformin hydrochloride
- Conditions
- Barrett Esophagus
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 93
- Locations
- 7
- Primary Endpoint
- Percent Change in Median pS6K1 Immunostaining Among Participants With Barrett Esophagus
- Status
- Completed
- Last Updated
- 11 years ago
Overview
Brief Summary
This randomized phase II trial studies how well metformin hydrochloride works in preventing esophageal cancer in patients with Barrett esophagus. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of metformin hydrochloride may keep esophageal cancer from forming.
Detailed Description
PRIMARY OBJECTIVES: I. To compare the percent change in the mean pS6K1 immunostaining from baseline in mucosal Barrett esophagus (BE) biopsies among patients assigned to 2,000 mg metformin hydrochloride once daily (QD) versus placebo as determined from Barrett mucosal biopsy samples obtained pre- and post-intervention. SECONDARY OBJECTIVES: I. To evaluate adverse events associated with the two intervention arms. TERTIARY OBJECTIVES: I. To assess the effects of metformin hydrochloride 2,000 mg QD versus placebo on the changes in pS6K1 using traditional IHC categories. II. To assess the effects of metformin hydrochloride 2,000 mg QD versus placebo on absolute change in pS6K1. III. To assess changes in serum markers (metformin hydrochloride, fasting insulin, HOMA-IR, IGF-1, IGF-2, IGFBP-1, IGFBP-3, fasting leptin, and fasting adiponectin) as determined from serum samples obtained pre- and post-intervention. IV. To assess changes in proliferation (Ki-67) and apoptosis (cleaved caspase 3) as determined from Barrett mucosal biopsy samples obtained pre- and post-intervention. V. To assess changes in molecular mediators of the insulin pathway (p-IRS-1, p-AKT\^Serine 473) as determined from Barrett mucosal biopsy samples obtained pre- and post-intervention. VI. To assess changes in relative activity of AMPK (phosphorylated AMPK/total AMPK ratio) and molecular mediators of AMP kinase (p-mTOR, pS6K1\^Serine 235) as determined from Barrett mucosal biopsy samples obtained pre- and post-intervention. VII. To assess changes in Programmed Cell Death 4 expression and miR-21 as determined from Barrett mucosal biopsy samples pre- and post-intervention. VIII. To establish a biospecimen repository archive for future correlative studies. OUTLINE: This is a multicenter study. Patients are stratified according to nonsteroidal anti-inflammatory drugs use (regular vs no regular), body mass index (≥ 30 kg/m² vs \< 30 kg/m²), gender (male vs female), and length of Barrett (2.00 to 4.99 cm vs ≥ 5.00 cm). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive extended-release metformin hydrochloride orally (PO) once daily (QD) on week 1, and twice daily (BID) on weeks 2-12 (every morning \[QAM\] and every evening \[QPM\] on week 3) in the absence of unacceptable toxicity or disease progression. Arm II: Patients receive extended-release placebo PO QD on week 1 and BID on weeks 2-12 (QAM and QPM on week 3) in the absence of unacceptable toxicity or disease progression. Blood, tissue, and mucosal tissue samples are collected at baseline and after completion of study treatment for pS6K1 analysis and other serum, mucosal, and molecular markers studies by IHC, ELISA, western blotting, and high-performance liquid chromatography (HPLC) methods. After completion of study treatment, patients are followed up for 30 days.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically confirmed diagnosis of Barrett esophagus, with no dysplasia, indeterminate for dysplasia, or low-grade dysplasia as defined by the presence of specialized columnar epithelium on histology and \>= 2 cm of involvement on endoscopy
- •Adequate Barrett mucosa, which is defined as \>= 1 out of 4 research samples (i.e., \>= 25%) with \>= 50% intestinal metaplasia in biopsies required to satisfy the endpoints of the study
- •No history of esophageal carcinoma or other cancer(s) (except for non-melanoma skin cancers)
- •No erosive esophagitis or ulcerative esophagitis, unless treatment with a proton pump inhibitor (PPI) results in healed erosions or ulcers prior to entry endoscopy
- •No history of high-grade dysplasia or cancer (confirmed locally by esophagogastroduodenoscopy \[EGD\] and Pathology reports)
- •No ulcer, plaque, nodule, stricture, or other luminal irregularity within the Barrett segment, unless clinical biopsy produces no evidence of high-grade dysplasia or cancer
- •ECOG performance status =\< 1
- •Hemoglobin \>= 10 g/dL
- •Leukocytes \>= 3,000/mL (\>= 2,500/mL for African-American participants)
- •Absolute neutrophil count \>= 1,500/mL (\>= 1,000/mL for African-American participants)
Exclusion Criteria
- Not provided
Arms & Interventions
Arm I
Patients receive extended-release metformin hydrochloride PO QD on week 1, and BID on weeks 2-12 (QAM QPM on week 3) in the absence of unacceptable toxicity or disease progression.
Intervention: metformin hydrochloride
Arm II
Patients receive extended-release placebo PO QD on week 1and BID on weeks 2-12 (QAM and QPM on week 3) in the absence of unacceptable toxicity or disease progression.
Intervention: placebo
Outcomes
Primary Outcomes
Percent Change in Median pS6K1 Immunostaining Among Participants With Barrett Esophagus
Time Frame: Baseline to 3 months
The percent change in pS6K1 was calculated as month 3 pS6k1 values minus baseline pS6k1 values, then divide by baseline pS6k1 values and multiply by 100.
Secondary Outcomes
- Overall Adverse Event Rates(Up to 30 days)