PRIMARY OBJECTIVES:
I. To determine if the addition of metformin (metformin hydrochloride) to the standard regimen of carboplatin and paclitaxel prolongs progression-free survival (PFS) in women with advanced or recurrent endometrial cancer. (Phase II) II. To determine if the addition of metformin to the standard regimen of carboplatin and paclitaxel prolongs overall survival (OS) in the same population if a phase III study is conducted. Both clinical trials (Phase II and III) will utilize OS as a primary endpoint if a phase III trial is opened.
SECONDARY OBJECTIVES:
I. To estimate the proportion of patients with objective response (response rate \[RR\]) in the population of patients with measurable disease by treatment.
II. To estimate the duration of response in the population of patients with measurable disease who respond by treatment.
III. To estimate overall survival (OS) and relative hazards of death for each treatment arm if the study stops after the phase II trial is completed. If the study continues with a phase III clinical trial, then PFS will be a secondary endpoint.
IV. To determine the nature, frequency and degree of toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) for each treatment arm.
V. To estimate possible differences in RR, PFS, OS, and toxicity rates for the treatment regimens by the patients' level of obesity.
TERTIARY OBJECTIVES:
I. To test whether PIK3CA mutations/amplifications, PTEN mutations or PIK3R1/PIK3R2 mutations have a lower hazard of progression or death (PFS endpoint) among patients who are treated with metformin.
II. To test whether higher expression of MATE 2 is associated with a lower hazard of progression or death (PFS endpoint) among patients who are treated with metformin.
III. To explore the association of metabolic factors (i.e. body mass index \[BMI\], hip-to-waist ratio, diabetes status, hemoglobin A1c \[HgbA1C\], fasting insulin and glucose levels, homeostatic model assessment \[HOMA\] scores) with treatment response to metformin/paclitaxel/carboplatin, PFS, and OS.
IV. To test whether genomic profiles (i.e. PIK3CA mutations/amplifications, PTEN mutations or PIK3R1/PIK3R2 mutations) differ between the tumors of obese and non-obese endometrial cancer (EC) patients.
V. To correlate expression of key targets of the insulin/IGF-1/mTOR signaling pathway (p-IGF1R, p-S6 and p-4EBP-1) with treatment response to metformin/paclitaxel/carboplatin, PFS, OS and obesity status.
VI. To determine if the genetic variants of the metformin transporters correspond with treatment response to metformin/paclitaxel/carboplatin, PFS and OS.
VII. To estimate differences in physical functioning, physical activity, and fatigue between treatment arms.
VIII. To explore the association between metabolic factors (i.e., BMI, hip-to-waist ratio, diabetes status, HgbA1C, fasting insulin and glucose levels, HOMA scores) and physical functioning, physical activity, and fatigue.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive paclitaxel intravenously (IV) over 3 hours on day 1, carboplatin IV over 30 minutes on day 1, and metformin hydrochloride orally (PO) twice daily (BID) (approximately 10-12 hours apart) on days 1-21 (once daily \[QD\] in course 1). Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance therapy comprising metformin hydrochloride PO BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive paclitaxel IV and carboplatin IV as in Arm I. Patients also receive placebo PO BID (approximately 10-12 hours apart) on days 1-21 (QD in course 1). Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance therapy comprising placebo PO BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
In both arms, patients who achieve stable disease (SD) or partial response (PR) and still have measurable disease at the completion of course 6 may continue to receive paclitaxel IV and carboplatin IV (with metformin hydrochloride or placebo) for an additional 4 courses at the discretion of the treating investigator.
After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.
