Clinical Trial: Metformin Hydrochloride and Combination Chemotherapy in Treating Patients With Stage III-IV Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: A Randomized Placebo Controlled Phase II Trial of Metformin in Conjunction With Chemotherapy Followed by Metformin Maintenance Therapy in Advanced Stage Ovarian, Fallopian Tube and Primary Peritoneal

Brief Summary: 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.

Detailed Summary:

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 an
Sponsor: University of Chicago

Current Primary Outcome: Progression free survival (PFS) evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 and Gynecological Cancer Intergroup (GCIG) criteria [ Time Frame: Time from randomization until disease progression or death from any cause, assessed up to 2 years ]

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).


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Time to biochemical (CA-125) progression using GCIG criteria [ Time Frame: Up to 2 years ]
    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 to radiological progression using the RECIST v1.1 and GCIG criteria [ Time Frame: Up to 2 years ]
    Analyzed using Kaplan-Meier curves, stratified logrank test, and Cox regression modeling.
  • Time to death [ Time Frame: Up to 2 years ]
    Analyzed using Kaplan-Meier curves, stratified logrank test, and Cox regression modeling.
  • Overall survival [ Time Frame: Up to 2 years ]
    Analyzed using Kaplan-Meier curves, stratified logrank test, and Cox regression modeling.
  • Incidence of adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 2 years ]
    Adverse events will be summarized by type, grade, and attribution. Treatment group comparisons will be performed using chi-square or Fisher's exact test.
  • Changes in levels of serum markers (e.g., insulin, C-reactive protein, glucose, HOMA score) [ Time Frame: Baseline up to 1 month post-treatment ]
    Measured on a continuous scale and log2 transformed for analysis as appropriate. Statistical blocking factors will be used to adjust for serum assay batch effects if needed. Linear mixed effects models will be used to test for changes, and to test whether these changes differ between those with and without metformin. Assumptions will be verified and non-parametric tests used if needed.
  • Changes in levels of serum markers (e.g., insulin, C-reactive protein, glucose, HOMA score) [ Time Frame: Baseline up to 1 year post-treatment ]
    Measured on a continuous scale and log2 transformed for analysis as appropriate. Statistical blocking factors will be used to adjust for serum assay batch effects if needed. Linear mixed effects models will be used to test for changes, and to test whether these changes differ between those with and without metformin. Assumptions will be verified and non-parametric tests used if needed.
  • Percentage of stained cells as assessed by the H-score via tissue microarray [ Time Frame: Up to 2 years ]
    Associations with stage and grade will be assessed via linear models. Associations with PFS and overall survival, and whether these associations are modified by metformin hydrochloride, will be assessed via Kaplan Meier and Cox regression methods in an exploratory fashion. Assumptions will be verified and non-parametric tests used if needed.
  • Changes in peptide and protein levels via mass spectrometry and high-performance liquid chromatography [ Time Frame: Baseline to up to 2 years ]
    Mixed effects models will be utilized to assess paired changes, and need for body mass index as a covariate will be assessed. False discovery rates will be computed to assess significance. Model-based normalization strategies will be utilized if needed. Hierarchical cluster analysis will be used to understand relationships in the data and pathway analysis will be performed using String Analysis.
  • Median PFS evaluated using the RECIST v1.1 and GCIG criteria [ Time Frame: 12 months ]
    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).


Original Secondary Outcome: Same as current

Information By: University of Chicago

Dates:
Date Received: April 22, 2014
Date Started: June 2014
Date Completion:
Last Updated: November 28, 2016
Last Verified: November 2016