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 Cancer

Location:

Rochester, Minn.

Trial status:

Open for Enrollment

Why is this study being done?

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.

Who is eligible to participate?

Inclusion Criteria: - ELIGIBILITY CRITERIA FOR PRE-REGISTRATION - A reasonable suspicion of ovarian cancer by the treating oncologist is required, evidenced by abdominal carcinomatosis, omental caking, pleural effusions or ascites AND an elevated CA125 > 250 OR CA125:carcinoembryonic antigen (CEA) ratio > 25 OR CA125 =< 250 with no evidence of gastrointestinal (GI) cancer - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< upper normal institutional limits (except for patients with Gilbert's disease who are eligible despite elevated serum bilirubin level) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.0 × institutional upper limit of normal - Creatinine =< institutional upper limit of normal (ULN) OR creatinine clearance >= 60 mL/min/1.73 m^2 - Blood glucose =< 126 mg/dL fasting or =< 140 mg/dL nonfasting - Signed written pre-registration informed consent document - ELIGIBILITY CRITERIA FOR REGISTRATION: subjects must have histologically confirmed carcinoma consistent with ovarian, fallopian tube, or primary peritoneal carcinoma (any of these three are referred to in this protocol as "ovarian cancer [OvCA]" OR a cytological diagnosis of carcinoma); the following histologic subtypes are included: serous, endometrioid, undifferentiated, clear cell, mixed, transitional, malignant Brenner tumor or adenocarcinoma not otherwise specified (NOS); subjects eligible for this study may be in one of three surgical categories: status post primary debulking surgery; undergoing neoadjuvant chemotherapy at a site not participating in correlative tissue collection sub study OR undergoing neoadjuvant chemotherapy at a site participating in correlative tissue collection sub study - ELIGIBILITY CRITERIA FOR REGISTRATION: subjects undergoing primary debulking surgery must have stage III or IV disease and have undergone surgery to include, at a minimum, removal of the uterus, ovaries and fallopian tubes; these patients may be optimally debulked (less than 1 cm residual disease) but must have grossly visible macroscopic residual disease OR be suboptimally debulked - ELIGIBILITY CRITERIA FOR REGISTRATION: subjects for whom neoadjuvant chemotherapy followed by interval cytoreductive surgery is planned must have fine needle aspirate (FNA) or other cytology showing adenocarcinoma OR core biopsies OR surgically directed biopsies showing adenocarcinoma AND CA125 over 250 OR CA125:CEA ratio > 25 OR CA =< 250 with no evidence of GI cancer; they should have presumed stage III or IV disease, generally based on abdominal carcinomatosis, omental caking, pleural effusions or ascites - ELIGIBILITY CRITERIA FOR REGISTRATION: the subject and her physician must agree to six cycles of one of the standard of care regimens allowed on this protocol; these regimens (starting dosage) include: - IV paclitaxel 175 mg/m^2 and carboplatin area under the curve (AUC) 5-6 every 21 days - IV docetaxel 75 mg/m^2 and carboplatin AUC 5-6 every 21 days - IV paclitaxel 80 mg/m^2 day 1, 8, and 15 and carboplatin AUC 5-6 day 1 every 21 days - Use of granulocyte colony stimulating factor is permitted, but additional chemotherapy agents (e.g. gemcitabine) or biologic agents (e.g. bevacizumab) are not; dose modifications for patients over age 70 are allowable as outlined in the protocol - ELIGIBILITY CRITERIA FOR REGISTRATION: ECOG performance status =< 2 - ELIGIBILITY CRITERIA FOR REGISTRATION: Leukocytes >= 3,000/mcL - ELIGIBILITY CRITERIA FOR REGISTRATION: absolute neutrophil count >= 1,500/mcL - ELIGIBILITY CRITERIA FOR REGISTRATION: platelets >= 100,000/mcL - ELIGIBILITY CRITERIA FOR REGISTRATION: total bilirubin =< upper normal institutional limits (except for patients with Gilbert's disease who are eligible despite elevated serum bilirubin level) - ELIGIBILITY CRITERIA FOR REGISTRATION: AST(SGOT)/ALT(SGPT) =< 2.0 × institutional upper limit of normal - ELIGIBILITY CRITERIA FOR REGISTRATION: creatinine =< OR institutional ULN OR creatinine clearance >= 60 mL/min/1.73 m^2 - ELIGIBILITY CRITERIA FOR REGISTRATION: blood glucose =< 126 mg/dL fasting or =< 140 mg/dL nonfasting - ELIGIBILITY CRITERIA FOR REGISTRATION: women of child-bearing potential must agree to use an effective method of birth control on trial, as the safety of metformin in pregnancy has not been established; an effective method of birth control includes surgical sterilization of woman or her partner, abstinence, or two barrier methods (e.g. condom plus diaphragm); hormonal methods of birth control are not permitted on this study - ELIGIBILITY CRITERIA FOR REGISTRATION: ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - EXCLUSION CRITERIA FOR PRE-REGISTRATION - Subjects with known diabetes and those taking metformin, sulfonylureas, thiazolidinediones or insulin for any reason - Patients who are receiving any other investigational agents - Subjects with comorbidities that would limit their two year survival for reasons other than ovarian cancer - Concurrent active invasive malignancy or one previously diagnosed with a greater than 30% chance of recurrence in the next two years - History of allergic reactions attributed to compounds of similar chemical or biologic composition to metformin - Subjects must not have conditions associated with increased risk of metformin-associated lactic acidosis, including New York Heart Association class III or IV congestive heart failure, history of acidosis of any type, alcoholic liver disease, or habitual intake of 3 or more alcoholic beverages per day - Uncontrolled intercurrent illness including, but not limited to, ongoing or active major infection, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant or nursing women are excluded from this study - EXCLUSION CRITERIA FOR REGISTRATION: mucinous adenocarcinoma, borderline tumors - EXCLUSION CRITERIA FOR REGISTRATION: subjects who will undergo intraperitoneal chemotherapy - EXCLUSION CRITERIA FOR REGISTRATION: subjects receiving neoadjuvant chemotherapy for whom interval debulking surgery (assuming adequate response to therapy) is not planned - EXCLUSION CRITERIA FOR REGISTRATION: subjects receiving chemotherapy regimens not specified in the inclusion criteria - EXCLUSION CRITERIA FOR REGISTRATION: subjects should not be participating in other clinical trials of interventions designed to reduce risk of ovarian cancer recurrence or plan to receive off -protocol maintenance therapy (e.g. paclitaxel or bevacizumab) - EXCLUSION CRITERIA FOR REGISTRATION: subjects with known diabetes, fasting glucose over 126 mg/dL or random glucose over 140 mg/dL and those taking metformin, sulfonylureas, thiazolidenediones or insulin for any reason - EXCLUSION CRITERIA FOR REGISTRATION: patients who are receiving any other investigational agents - EXCLUSION CRITERIA FOR REGISTRATION: subjects with comorbidities which would lead to a clinical expectation that they will not survive two years for reasons other than ovarian cancer - EXCLUSION CRITERIA FOR REGISTRATION: concurrent active invasive malignancy or one previously diagnosed with a greater than 30% chance of recurrence in the next two years - EXCLUSION CRITERIA FOR REGISTRATION: history of allergic reactions attributed to compounds of similar chemical or biologic composition to metformin - EXCLUSION CRITERIA FOR REGISTRATION: subjects must not have conditions associated with increased risk of metformin-associated lactic acidosis, including New York Heart Association class III or IV congestive heart failure, history of acidosis of any type, alcoholic liver disease, or habitual intake of 3 or more alcoholic beverages per day - EXCLUSION CRITERIA FOR REGISTRATION: uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - EXCLUSION CRITERIA FOR REGISTRATION: pregnant or nursing women are excluded from this study

Last updated:

4/23/2014

NCT ID:

NCT02122185

IRB Number:

14-000924