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

Status: Active

Description

This partially randomized phase II trial studies how well metformin hydrochloride and combination chemotherapy work 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.

Eligibility Criteria

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)
  • 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

Locations & Contacts

Alabama

Birmingham
University of Alabama at Birmingham Cancer Center
Status: Temporarily closed to accrual
Contact: Seiko Diane Yamada
Phone: 773-702-6721
Email: sdyamada@uchicago.edu
Mobile
USA Health Strada Patient Care Center
Status: Temporarily closed to accrual
Contact: Rodney Rocconi
Email: rocconi@health.southalabama.edu

Arizona

Scottsdale
Mayo Clinic in Arizona
Status: In review
Contact: Shana Clark
Phone: 480-342-6059
Email: clark.shana@mayo.edu

California

Duarte
City of Hope Comprehensive Cancer Center
Status: Approved
Contact: Mark T. Wakabayashi
Phone: 626-256-4673
Email: mwakabayashi@coh.org

Illinois

Arlington Heights
Northwest Community Hospital
Status: Temporarily closed to accrual
Contact: Josephine Mary Smudde
Email: jsmudde@nch.org
Chicago
Rush University Medical Center
Status: Temporarily closed to accrual
Contact: Summer B. Dewdney
Phone: 312-942-6300
Email: summer_dewdney@rush.edu
University of Chicago Comprehensive Cancer Center
Status: Active
Contact: Seiko Diane Yamada
Phone: 773-702-6721
Email: sdyamada@uchicago.edu
Decatur
Decatur Memorial Hospital
Status: Temporarily closed to accrual
Contact: James Lloyd Wade
Phone: 217-876-6600
Evanston
NorthShore University HealthSystem-Evanston Hospital
Status: Temporarily closed to accrual
Contact: Gustavo C. Rodriguez
Phone: 847-570-2639
Email: grodriguez@northshore.org
Harvey
Ingalls Memorial Hospital
Status: Temporarily closed to accrual
Contact: James A. Wallace
Phone: 708-339-4800
Email: James.Wallace@uchospitals.edu

Iowa

Iowa City
University of Iowa / Holden Comprehensive Cancer Center
Status: Temporarily closed to accrual
Contact: Sharon Stockman
Phone: 319-356-2015
Email: sharon-stockman@uiowa.edu

Minnesota

Rochester
Mayo Clinic
Status: Temporarily closed to accrual
Contact: Sean C. Dowdy
Phone: 507-266-0225
Email: dowdy.sean@mayo.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine if the addition of metformin (metformin hydrochloride) to standard adjuvant or neoadjuvant chemotherapy plus extended metformin 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.

EXPLORATORY 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 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 8 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 up to 8 courses. Treatment with 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 up to 8 courses. Treatment with 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 every 6 months for 2 years.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
University of Chicago Comprehensive Cancer Center

Principal Investigator
Seiko Diane Yamada

Trial IDs

Primary ID IRB13-1235
Secondary IDs NCI-2014-00860, UC IRB13-1235
Clinicaltrials.gov ID NCT02122185