Clinical Trials /

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

NCT02122185

Description:

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.

Related Conditions:
  • Fallopian Tube Carcinoma
  • Ovarian Carcinoma
  • Primary Peritoneal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Metformin and Chemotherapy in Treating Patients With Stage III-IV Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
  • 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

Clinical Trial IDs

  • ORG STUDY ID: IRB13-1235
  • SECONDARY ID: NCI-2014-00860
  • SECONDARY ID: IRB13-1235
  • NCT ID: NCT02122185

Conditions

  • 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

Interventions

DrugSynonymsArms
metformin hydrochlorideGlucophageMetformin plus chemotherapy
placeboPLCBPlacebo plus chemotherapy
ChemotherapyMetformin plus chemotherapy

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Metformin plus chemotherapyExperimentalPatients receive metformin hydrochloride PO BID and standard chemotherapy for 6 -8 cycles. Treatment with metformin hydrochloride continues for up to 2 years in the absence of disease progression or unacceptable toxicity.
  • metformin hydrochloride
  • Chemotherapy
Placebo plus chemotherapyPlacebo ComparatorPatients receive placebo PO BID and standard chemotherapy for 6 -8 cycles. Treatment with placebo continues for up to 2 years in the absence of disease progression or unacceptable toxicity.
  • placebo
  • Chemotherapy

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

          -  Aged 18 years or older

          -  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:

          -  Histologically confirmed carcinoma consistent with ovarian, fallopian tube, or primary
             peritoneal carcinoma

          -  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

          -  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

          -  Subject and her physician must agree to six cycles or up to 8 cycles of one of the
             standard of care regimens allowed on this protocol; these regimens (starting dosage)
             include:

        If < 70 years old:

          -  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

        If 70 years or older:

          -  IV paclitaxel 135 mg/m^2 plus IV carboplatin AUC 5 plus optional G-CSF every 21 days

          -  IV paclitaxel 60 mg/m^2 day 1, 8, 15 plus IV carboplatin AUC 5 every 21 days (Day 15
             paclitaxel optional)

          -  IV paclitaxel 60 mg/m^2 plus IV carboplatin AUC 2 day 1, 8, and 15 every 21 days

               -  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)

               -  AST(SGOT)/ALT(SGPT) =< 2.0 × institutional upper limit of normal

               -  creatinine =< OR institutional ULN OR creatinine clearance >= 60 mL/min/1.73 m^2

               -  blood glucose =< 126 mg/dL fasting or =< 140 mg/dL nonfasting

               -  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

               -  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

        EXCLUSION CRITERIA FOR REGISTRATION:

          -  mucinous adenocarcinoma, borderline tumors

          -  subjects who will undergo intraperitoneal chemotherapy

          -  subjects receiving neoadjuvant chemotherapy for whom interval debulking surgery
             (assuming adequate response to therapy) is not planned

          -  subjects receiving chemotherapy regimens not specified in the inclusion criteria

          -  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)

          -  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

          -  patients who are receiving any other investigational agents

          -  subjects with comorbidities which would lead to a clinical expectation that they will
             not survive two years 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
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements

          -  pregnant or nursing women
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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

Measure:Time to biochemical (CA-125) progression using GCIG criteria
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:Overall survival
Time Frame:Up to 2 years
Safety Issue:
Description:Analyzed using Kaplan-Meier curves, stratified logrank test, and Cox regression modeling.
Measure: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
Safety Issue:
Description:Adverse events will be summarized by type, grade, and attribution. Treatment group comparisons will be performed using chi-square or Fisher's exact test.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Chicago

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