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

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 (within 4 weeks of preregistration)
• Absolute neutrophil count >= 1,500/mcL (within 4 weeks of preregistration)
• Platelets >= 100,000/mcL (within 4 weeks of preregistration)
• Total bilirubin =< upper normal institutional limits (except for patients with Gilbert’s disease who are eligible despite elevated serum bilirubin level) (within 4 weeks of preregistration)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.0 x institutional upper limit of normal (within 4 weeks of preregistration)
• Creatinine =< institutional upper limit of normal (ULN) OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal (within 4 weeks of preregistration)
• Blood glucose =< 126 mg/dL fasting or =< 140 mg/dL nonfasting (within 4 weeks of preregistration)
• 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 6 cycles (a total of up to 8 cycles will be allowed) of one of the standard of care regimens allowed on this protocol; these regimens (starting dosage) include: * < 70 years of age: ** R1: IV paclitaxel 175 mg/m^2 and carboplatin area under the curve (AUC) 5-6 every 21 days ** R2: IV docetaxel 75 mg/m^2 and carboplatin AUC 5-6 every 21 days ** R3: IV paclitaxel 80 mg/m^2 day 1, 8, and 15 and carboplatin AUC 5-6 day 1 every 21 days * >= 70 years of age may (but not required to) choose one of the following alternative regimens: ** R4: IV paclitaxel 135 mg/m^2 plus IV carboplatin AUC 5 plus optional filgrastim (G-CSF) every 21 days ** R5: IV paclitaxel 60 mg/m^2 day 1, 8, and 15 plus IV carboplatin AUC 5 day 1 every 21 days (day 15 paclitaxel optional) ** R6: IV paclitaxel 60 mg/m^2 plus IV carboplatin AUC 2 day 1, 8, and 15 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 >= age 70 are allowable as indicated above; patients >= age 70 for whom the physician deems carboplatin AUC 5 to be unsafe may be treated with AUC 4
• ELIGIBILITY CRITERIA FOR REGISTRATION: ECOG performance status =< 2
• ELIGIBILITY CRITERIA FOR REGISTRATION: Leukocytes >= 3,000/mcL (within one week of registration if patient postop, otherwise within two weeks of registration)
• ELIGIBILITY CRITERIA FOR REGISTRATION: absolute neutrophil count >= 1,500/mcL (within one week of registration if patient postop, otherwise within two weeks of registration)
• ELIGIBILITY CRITERIA FOR REGISTRATION: platelets >= 100,000/mcL (within one week of registration if patient postop, otherwise within two weeks of registration)
• 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) (within one week of registration if patient postop, otherwise within two weeks of registration)
• ELIGIBILITY CRITERIA FOR REGISTRATION: AST(SGOT)/ALT(SGPT) =< 2.0 x institutional upper limit of normal (within one week of registration if patient postop, otherwise within two weeks of registration)
• ELIGIBILITY CRITERIA FOR REGISTRATION: creatinine =< institutional ULN OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal (within one week of registration if patient postop, otherwise within two weeks of registration)
• ELIGIBILITY CRITERIA FOR REGISTRATION: blood glucose =< 126 mg/dL fasting or =< 140 mg/dL nonfasting (within one week of registration if patient postop, otherwise within two weeks of registration)
• ELIGIBILITY CRITERIA FOR REGISTRATION: women of child-bearing potential must agree to use an effective method of birth control on trial; an effective method of birth control includes surgical sterilization of woman or her partner, abstinence, or two barrier methods (e.g. condom plus diaphragm); or hormonal methods of birth control (oral contraceptives or intrauterine device)
• 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). Use of olaparib in BRCA genetic mutation carriers per Food and Drug Administration (FDA) approval is allowable.
• 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, thiazolidinediones or insulin for any reason; either fasting OR random glucose may be used to determine eligibility
• 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