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

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified April 2014 by University of Chicago
Sponsor:
Collaborator:
Information provided by (Responsible Party):
University of Chicago
ClinicalTrials.gov Identifier:
NCT02122185
First received: April 22, 2014
Last updated: April 23, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Brenner Tumor
Malignant Ascites
Malignant Pleural Effusion
Ovarian Clear Cell Cystadenocarcinoma
Ovarian Endometrioid Adenocarcinoma
Ovarian Mixed Epithelial Carcinoma
Ovarian Serous Cystadenocarcinoma
Ovarian Undifferentiated Adenocarcinoma
Recurrent Fallopian Tube Cancer
Recurrent Ovarian Epithelial Cancer
Recurrent Ovarian Germ Cell Tumor
Recurrent Primary Peritoneal Cavity Cancer
Stage IIIA Fallopian Tube Cancer
Stage IIIA Ovarian Epithelial Cancer
Stage IIIA Ovarian Germ Cell Tumor
Stage IIIA Primary Peritoneal Cavity Cancer
Stage IIIB Fallopian Tube Cancer
Stage IIIB Ovarian Epithelial Cancer
Stage IIIB Ovarian Germ Cell Tumor
Stage IIIB Primary Peritoneal Cavity Cancer
Stage IIIC Fallopian Tube Cancer
Stage IIIC Ovarian Epithelial Cancer
Stage IIIC Ovarian Germ Cell Tumor
Stage IIIC Primary Peritoneal Cavity Cancer
Stage IV Fallopian Tube Cancer
Stage IV Ovarian Epithelial Cancer
Stage IV Ovarian Germ Cell Tumor
Stage IV Primary Peritoneal Cavity Cancer
Drug: paclitaxel
Drug: carboplatin
Drug: docetaxel
Drug: metformin hydrochloride
Drug: placebo
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Investigator)
Primary Purpose: Treatment
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 Cancer

Resource links provided by NLM:


Further study details as provided by University of Chicago:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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).


Secondary Outcome Measures:
  • Time to biochemical (CA-125) progression using GCIG criteria [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Analyzed using Kaplan-Meier curves, stratified logrank test, and Cox regression modeling.

  • Time to death [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Analyzed using Kaplan-Meier curves, stratified logrank test, and Cox regression modeling.

  • Overall survival [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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).


Estimated Enrollment: 160
Study Start Date: June 2014
Estimated Primary Completion Date: February 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (combination chemotherapy, metformin hydrochloride)
Patients receive metformin hydrochloride PO 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.
Drug: paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • TAX
  • Taxol
Drug: carboplatin
Given IV
Other Names:
  • Carboplat
  • CBDCA
  • JM-8
  • Paraplat
  • Paraplatin
Drug: docetaxel
Given IV
Other Names:
  • RP 56976
  • Taxotere
  • TXT
Drug: metformin hydrochloride
Given PO
Other Name: Glucophage
Other: laboratory biomarker analysis
Correlative studies
Placebo Comparator: Arm II (combination chemotherapy, placebo)
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.
Drug: paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • TAX
  • Taxol
Drug: carboplatin
Given IV
Other Names:
  • Carboplat
  • CBDCA
  • JM-8
  • Paraplat
  • Paraplatin
Drug: docetaxel
Given IV
Other Names:
  • RP 56976
  • Taxotere
  • TXT
Drug: placebo
Given PO
Other Name: PLCB
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years to 77 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02122185

Locations
United States, Illinois
University of Chicago Not yet recruiting
Chicago, Illinois, United States, 60637
Contact: Seiko D. Yamada    773-702-6721    sdyamada@uchicago.edu   
Principal Investigator: Seiko D. Yamada         
NorthShore University HealthSystem Not yet recruiting
Evanston, Illinois, United States, 60201
Contact: Gustavo C. Rodriguez    847-570-2639    grodriguez@northshore.org   
Principal Investigator: Gustavo C. Rodriguez         
United States, Minnesota
Mayo Clinic Not yet recruiting
Rochester, Minnesota, United States, 55905
Contact: Sean C. Dowdy    507-266-0225    dowdy.sean@mayo.edu   
Principal Investigator: Sean C. Dowdy         
Sponsors and Collaborators
University of Chicago
Investigators
Principal Investigator: Seiko Yamada University of Chicago
  More Information

No publications provided

Responsible Party: University of Chicago
ClinicalTrials.gov Identifier: NCT02122185     History of Changes
Other Study ID Numbers: IRB13-1235, NCI-2014-00860, IRB13-1235, UC IRB13-1235, P30CA014599
Study First Received: April 22, 2014
Last Updated: April 23, 2014
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Adenocarcinoma
Brenner Tumor
Carcinoma
Carcinoma, Endometrioid
Cystadenocarcinoma
Cystadenocarcinoma, Serous
Fallopian Tube Neoplasms
Germinoma
Neoplasms
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Ovarian Neoplasms
Peritoneal Neoplasms
Pleural Effusion
Pleural Effusion, Malignant
Abdominal Neoplasms
Adnexal Diseases
Digestive System Diseases
Digestive System Neoplasms
Endocrine Gland Neoplasms
Endocrine System Diseases
Endometrial Neoplasms
Fallopian Tube Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Gonadal Disorders
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Connective and Soft Tissue
Neoplasms, Connective Tissue

ClinicalTrials.gov processed this record on October 23, 2014