This randomized phase II trial studies how well metformin hydrochloride and combination chemotherapy works in treating patients with stage III-IV ovarian, fallopian tube, or primary peritoneal cancer. Drugs used in chemotherapy, such as carboplatin, paclitaxel and docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Metformin hydrochloride may help carboplatin, paclitaxel and docetaxel work better by making tumor cells more sensitive to the drugs. Studying samples of blood and tissue in the laboratory from patients receiving metformin hydrochloride may help doctors learn more about the effects of metformin hydrochloride on cells. It may also help doctors understand how well patients respond to treatment. Giving metformin hydrochloride together with combination chemotherapy may kill more tumor cells.
PRIMARY OBJECTIVES: I. To determine if the addition of metformin to standard adjuvant or neoadjuvant chemotherapy plus extended metformin (metformin hydrochloride) beyond standard chemotherapy increases progression free survival when compared to 6 cycles of standard chemotherapy alone in non-diabetic subjects with stage III (with any gross residual disease) or stage IV ovarian, primary peritoneal, or fallopian tube carcinoma. SECONDARY OBJECTIVES: I. To determine whether the addition of metformin to standard chemotherapy plus extended metformin beyond standard chemotherapy increases the time to biochemical progression when compared to chemotherapy alone. II. To compare biochemical (cancer antigen \[CA\]-125) response rates in the two arms. III. To describe and compare toxicities in the two arms. IV. To compare overall survival in both arms. TERTIARY OBJECTIVES: I. To elucidate metformin's molecular mechanism of action in ovarian, fallopian tube or primary peritoneal cancer by: determining whether metformin's anti-cancer effects are mediated by systemic metabolic changes, a direct effect on tumor cells, or both, and testing the metabolic and proteomic alterations induced in biospecimens from non-diabetic patients prospectively treated with standard chemotherapy in conjunction with metformin compared to placebo. OUTLINE: Patients receive a standard chemotherapy regimen at the discretion of the treating physician. Regimens include either paclitaxel intravenously (IV) over 2-3 hours and carboplatin IV over 30-60 minutes on day 1; docetaxel IV over 1 hour on and carboplatin IV over 30-60 minutes on day 1; or paclitaxel IV over 1 hour on days 1, 8, and 15, and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for up to 6 courses. Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive metformin hydrochloride orally (PO) twice daily (BID) and standard chemotherapy regimen as above for 6 courses. Treatment for metformin hydrochloride continues for up to 2 years in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive placebo PO BID and standard chemotherapy regimen as above for 6 courses. Treatment for placebo continues for up to 2 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 2 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
110
Given PO
Given PO
Participants will received standard chemotherapy (6-8 cycles). Specific regimen to be given is at the discretion of their treating physician.
University of Alabama
Birmingham, Alabama, United States
Mitchell Cancer Institute - University of South Alabama
Mobile, Alabama, United States
City of Hope
Duarte, California, United States
NCH Medical Group- Northwest Community Hospital
Arlington Heights, Illinois, United States
Rush University Medical Center
Chicago, Illinois, United States
University of Chicago
Chicago, Illinois, United States
Decatur Memorial Hospital
Decatur, Illinois, United States
NorthShore University HealthSystem
Evanston, Illinois, United States
Ingalls Memorial Hospital
Harvey, Illinois, United States
Mayo Clinic
Rochester, Minnesota, United States
Progression free survival (PFS) evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 and Gynecological Cancer Intergroup (GCIG) criteria
Kaplan-Meier curves will be generated and the metformin and placebo groups compared using a logrank test stratified by initial treatment (primary debulking surgery or neoadjuvant therapy). A one-sided alpha level of 0.15 will be used to determine statistical significance. Median PFS and associated 90% confidence interval will be estimated using the method described in Brookmeyer and Crowley. A Cox regression model will also be fit to assess and adjust for the effects of the stratification factor and other baseline covariates (for example, age, ECOG performance status).
Time frame: Time from randomization until disease progression or death from any cause, assessed up to 2 years
Time to biochemical (CA-125) progression using GCIG criteria
Analyzed using Kaplan-Meier curves, stratified logrank test, and Cox regression modeling. CA-125 response rates in the subgroup of patients with elevated CA-125 at entry (i.e., \> institutional ULN) will be compared between the two treatment arms using a chi-square test.
Time frame: Up to 2 years
Overall survival
Analyzed using Kaplan-Meier curves, stratified logrank test, and Cox regression modeling.
Time frame: Up to 2 years
Incidence of adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Adverse events will be summarized by type, grade, and attribution. Treatment group comparisons will be performed using chi-square or Fisher's exact test.
Time frame: Up to 2 years
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