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Paclitaxel and Carboplatin With or Without Metformin Hydrochloride in Treating Patients With Stage III, IV, or Recurrent Endometrial Cancer

This study is currently recruiting participants.
Verified August 2017 by Gynecologic Oncology Group
Sponsor:
ClinicalTrials.gov Identifier:
NCT02065687
First Posted: February 19, 2014
Last Update Posted: August 23, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Gynecologic Oncology Group
February 14, 2014
February 19, 2014
August 23, 2017
March 17, 2014
September 1, 2019   (Final data collection date for primary outcome measure)
  • Overall survival (OS) (Phase II and III) [ Time Frame: From date of study entry to time of death or the date of last contact, assessed up to 5 years ]
    OS will be measured.
  • Progression-free survival (PFS) (Phase II) [ Time Frame: From date of study entry to time of progression or death, whichever occurs first, assessed up to 5 years ]
    PFS will be measured.
  • Progression-free survival (Phase II) [ Time Frame: From date of study entry to time of progression or death, whichever occurs first, assessed up to 5 years ]
  • Overall survival (Phase II and III) [ Time Frame: From date of study entry to time of death or the date of last contact, assessed up to 5 years ]
Complete list of historical versions of study NCT02065687 on ClinicalTrials.gov Archive Site
  • Duration of response by treatment [ Time Frame: From the date of response to disease progression, death, or date last seen assessed up to 5 years ]
    Duration will be characterized by treatment using Kaplan-Meier curves and quartile estimates.
  • Incidence of adverse events as assessed by Common Terminology Criteria for Adverse Events version 4 within each arm [ Time Frame: Up to 5 years ]
    Toxicities will be assessed by organ or organ system. For each category of toxicity, each patient will be evaluated by the worst grade experienced during the course of therapy. Data will be summarized by frequency and severity according to the regimen administered. Comparisons between regimens will be examined through exact Chi-Square methods by breaking the severity of the worst toxicities experienced by each patient into severe versus not severe (or into groups of none to mild, moderate, and severe or worse).
  • Level of obesity [ Time Frame: Up to 5 years ]
    Obesity will be quantitative assessed by body mass index (BMI) and will be assessed for its predictive and prognostic significance. The interaction between BMI and metformin treatment will be examined with an interaction term in a Cox proportional hazards model.
  • Overall survival (OS) (Phase II) [ Time Frame: From date of study entry to time of death or the date of last contact, assessed up to 26 months, assessed up to 6 years ]
    OS will be measured.
  • Progression free survival (PFS) (Phase III) [ Time Frame: From date of study entry to time of progression or death, whichever occurs first, assessed up to 5 years ]
    PFS will be measured.
  • Proportion of patients responding to therapy [ Time Frame: Up to 5 years ]
    Assessed using a 95% confidence interval.
  • Proportion of patients responding to therapy [ Time Frame: Up to 5 years ]
    Assessed using a 95% confidence interval (CI).
  • Duration of response by treatment [ Time Frame: From the date of response to disease progression, death, or date last seen assessed up to 5 years ]
    Duration will be characterized by treatment using Kaplan-Meier curves and quartile estimates.
  • Overall survival (Phase II) [ Time Frame: From date of study entry to time of death or the date of last contact, assessed up to 26 months, assessed up to 6 years ]
  • PFS (Phase III) [ Time Frame: From date of study entry to time of progression or death, whichever occurs first, assessed up to 5 years ]
  • Incidence of adverse events as assessed by CTCAE v4 within each arm [ Time Frame: Up to 5 years ]
    Toxicities will be assessed by organ or organ system. For each category of toxicity, each patient will be evaluated by the worst grade experienced during the course of therapy. Data will be summarized by frequency and severity according to the regimen administered. Comparisons between regimens will be examined through exact Chi-Square methods by breaking the severity of the worst toxicities experienced by each patient into severe versus not severe (or into groups of none to mild, moderate, and severe or worse).
  • Level of obesity [ Time Frame: Up to 5 years ]
    Obesity will be quantitative assessed by BMI and will be assessed for its predictive and prognostic significance. The interaction between BMI and metformin treatment will be examined with an interaction term in a Cox proportional hazards model.
  • Expression of MATE 2 [ Time Frame: Up to 5 years ]
    Expression will be examined by immunohistochemistry with intensity of staining and the percentage of cells staining positive. From these statistics, an H-score will be calculated. Expression will be further dichotomized as high expression and low expression at the median to maximize the power of the study.
  • Incidence of PIK3 mutations/amplifications [ Time Frame: Up to 5 years ]
    PIK3CA mutations/amplifications and PIK3R1/PIK3R2 mutations will be examined for prognostic and predictive significance.
  • Levels of key targets of the metformin/mTOR signaling pathway [ Time Frame: Up to 5 years ]
    Levels before and after treatment will be assessed for their predictive and prognostic significance.
  • Metabolic factor levels [ Time Frame: Up to 5 years ]
    Hip-to-waist ratio, diabetes status, hemoglobin A1c, fasting insulin glucose levels, and homeostatic model assessment scores will be assessed for their predictive and prognostic significance. Variables will be analyzed as continuous covariates (or as appropriate with transformations such as the logarithm) with Cox models or logistic regression.
  • Metabolic factor levels [ Time Frame: Up to 5 years ]
    Hip-to-waist ratio, diabetes status, HgBA1C, fasting insulin glucose levels, and HOMA scores will be assessed for their predictive and prognostic significance. Variables will be analyzed as continuous covariates (or as appropriate with transformations such as the logarithm) with Cox models or logistic regression.
  • Levels of metformin transporter proteins [ Time Frame: Up to 5 years ]
    Metformin transporter proteins include OCT 1-3, MATE 1/2 and PMAT. Levels before and after treatment will be assessed for their predictive and prognostic significance.
  • Levels of key targets of the metformin/mTOR signaling pathway [ Time Frame: Up to 5 years ]
    Levels before and after treatment will be assessed for their predictive and prognostic significance.
  • Incidence of PIK3 mutations/amplifications [ Time Frame: Up to 5 years ]
    PIK3CA mutations/amplifications and PIK3R1/PIK3R2 mutations will be examined for prognostic and predictive significance.
 
Paclitaxel and Carboplatin With or Without Metformin Hydrochloride in Treating Patients With Stage III, IV, or Recurrent Endometrial Cancer
A Randomized Phase II/III Study of Paclitaxel/Carboplatin/Metformin (NSC#91485) Versus Paclitaxel/Carboplatin/Placebo as Initial Therapy for Measurable Stage III or IVA, Stage IVB, or Recurrent Endometrial Cancer
This randomized phase II/III trial studies how well paclitaxel, carboplatin, and metformin hydrochloride works and compares it to paclitaxel, carboplatin, and placebo in treating patients with endometrial cancer that is stage III, IV, or has come back. Drugs used in chemotherapy, such as paclitaxel and carboplatin, 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 paclitaxel and carboplatin work better by making cancer cells more sensitive to the drugs. It is not yet known whether paclitaxel and carboplatin is more effective with or without metformin hydrochloride in treating endometrial cancer.

PRIMARY OBJECTIVES:

I. To determine if the addition of metformin (metformin hydrochloride) to the standard regimen of carboplatin and paclitaxel prolongs progression-free survival (PFS) in women with advanced or recurrent endometrial cancer. (Phase II) II. To determine if the addition of metformin to the standard regimen of carboplatin and paclitaxel prolongs overall survival (OS) in the same population if a phase III study is conducted. Both clinical trials (Phase II and III) will utilize OS as a primary endpoint if a phase III trial is opened.

SECONDARY OBJECTIVES:

I. To estimate the proportion of patients with objective response (response rate [RR]) in the population of patients with measurable disease by treatment.

II. To estimate the duration of response in the population of patients with measurable disease who respond by treatment.

III. To estimate overall survival (OS) and relative hazards of death for each treatment arm if the study stops after the phase II trial is completed. If the study continues with a phase III clinical trial, then PFS will be a secondary endpoint.

IV. To determine the nature, frequency and degree of toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) for each treatment arm.

V. To estimate possible differences in RR, PFS, OS, and toxicity rates for the treatment regimens by the patient's level of obesity.

TERTIARY OBJECTIVES:

I. To test whether PIK3CA mutations/amplifications, PTEN mutations or PIK3R1/PIK3R2 mutations have a lower hazard of progression or death (PFS endpoint) among patients who are treated with metformin.

II. To test whether higher expression of MATE 2 is associated with a lower hazard of progression or death (PFS endpoint) among patients who are treated with metformin.

III. To explore the association of metabolic factors (i.e. body mass index [BMI], hip-to-waist ratio, diabetes status, hemoglobin A1c [HgbA1C], fasting insulin and glucose levels, homeostatic model assessment [HOMA] scores) with treatment response to metformin/paclitaxel/carboplatin, PFS, and OS.

IV. To test whether genomic profiles (i.e. PIK3CA mutations/amplifications, PTEN mutations or PIK3R1/PIK3R2 mutations) differ between the tumors of obese and non-obese endometrial cancer (EC) patients.

V. To correlate expression of key targets of the insulin/IGF-1/mTOR signaling pathway (p-IGF1R, p-S6 and p-4EBP-1) with treatment response to metformin/paclitaxel/carboplatin, PFS, OS and obesity status.

VI. To determine if the genetic variants of the metformin transporters correspond with treatment response to metformin/paclitaxel/carboplatin, PFS and OS.

VII. To estimate differences in physical functioning, physical activity, and fatigue between treatment arms.

VIII. To explore the association between metabolic factors (i.e., BMI, hip-to-waist ratio, diabetes status, HgbA1C, fasting insulin and glucose levels, HOMA scores) and physical functioning, physical activity, and fatigue.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive paclitaxel intravenously (IV) over 3 hours on day 1, carboplatin IV over 30 minutes on day 1, and metformin hydrochloride orally (PO) twice daily (BID) (approximately 10-12 hours apart) on days 1-21 (once daily [QD] in course 1). Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance therapy comprising metformin hydrochloride PO BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive paclitaxel IV and carboplatin IV as in Arm I. Patients also receive placebo PO BID (approximately 10-12 hours apart) on days 1-21 (QD in course 1). Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance therapy comprising placebo PO BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

In both arms, patients who achieve stable disease (SD) or partial response (PR) and still have measurable disease at the completion of course 6 may continue to receive paclitaxel IV and carboplatin IV (with metformin hydrochloride or placebo) for an additional 4 courses at the discretion of the treating investigator.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Interventional
Phase 2
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
  • Endometrial Adenocarcinoma
  • Endometrial Clear Cell Adenocarcinoma
  • Endometrial Serous Adenocarcinoma
  • Endometrial Undifferentiated Carcinoma
  • Recurrent Uterine Corpus Carcinoma
  • Stage III Uterine Corpus Cancer
  • Stage IIIA Uterine Corpus Cancer
  • Stage IIIB Uterine Corpus Cancer
  • Stage IIIC Uterine Corpus Cancer
  • Stage IV Uterine Corpus Cancer
  • Stage IVA Uterine Corpus Cancer
  • Stage IVB Uterine Corpus Cancer
  • Drug: Carboplatin
    Given IV
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Metformin Hydrochloride
    Given PO
  • Drug: Paclitaxel
    Given IV
  • Other: Placebo
    Given PO
    Other Names:
    • placebo therapy
    • PLCB
    • sham therapy
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other Name: Quality of Life Assessment
  • Other: Questionnaire Administration
    Ancillary studies
  • Experimental: Arm I (paclitaxel, carboplatin, metformin hydrochloride)

    Patients receive paclitaxel IV over 3 hours on day 1, carboplatin IV over 30 minutes on day 1, and metformin hydrochloride PO BID (approximately every 10-12 hours apart) on days 1-21 (QD in course 1). Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance therapy comprising metformin hydrochloride PO BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

    In both arms, patients who achieve SD or PR and still have measurable disease at the completion of course 6 may continue to receive paclitaxel IV and carboplatin IV (with metformin hydrochloride or placebo) for an additional 4 courses at the discretion of the treating investigator.

    Interventions:
    • Drug: Carboplatin
    • Other: Laboratory Biomarker Analysis
    • Drug: Metformin Hydrochloride
    • Drug: Paclitaxel
    • Other: Quality-of-Life Assessment
    • Other: Questionnaire Administration
  • Active Comparator: Arm II (paclitaxel, carboplatin, placebo)

    Patients receive paclitaxel IV and carboplatin IV as in Arm I. Patients also receive placebo PO BID (approximately every 10-12 hours apart) on days 1-21 (QD in course 1). Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance therapy comprising placebo PO BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

    In both arms, patients who achieve SD or PR and still have measurable disease at the completion of course 6 may continue to receive paclitaxel IV and carboplatin IV (with metformin hydrochloride or placebo) for an additional 4 courses at the discretion of the treating investigator.

    Interventions:
    • Drug: Carboplatin
    • Other: Laboratory Biomarker Analysis
    • Drug: Paclitaxel
    • Other: Placebo
    • Other: Quality-of-Life Assessment
    • Other: Questionnaire Administration
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
540
Not Provided
September 1, 2019   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • Patients must have measurable stage III, measurable stage IVA, stage IVB (with or without measurable disease) or recurrent (with or without measurable disease) endometrial carcinoma

    • Histologic confirmation of the original primary tumor is required; patients with the following histologic epithelial cell types are eligible:

      • Endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified (N.O.S.)
  • Measurable disease is defined by Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1); measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded); each lesion must be >= 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or >= 20 mm when measured by chest x-ray; lymph nodes must be >= 15 mm in short axis when measured by CT or MRI
  • Patients must have a Gynecologic Oncology Group (GOG) performance status of 0, 1, or 2
  • Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl
  • Platelets greater than or equal to 100,000/mcl
  • Creatinine less than 1.4 mg/dl
  • Bilirubin less than or equal to 1.5 x institutional/laboratory upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 3 x ULN
  • Alkaline phosphatase less than or equal to 2.5 x ULN
  • Patients must NOT have received prior chemotherapy or targeted therapy, including chemotherapy used for radiation sensitization for treatment of endometrial carcinoma
  • Patients may have received prior radiation therapy for treatment of endometrial carcinoma; prior radiation therapy may have included pelvic radiation therapy, extended field pelvic/para-aortic radiation therapy, and/or intravaginal brachytherapy; all radiation therapy must be completed at least 4 weeks prior to the first date of study therapy
  • Patients may have received prior hormonal therapy for treatment of endometrial carcinoma; all hormonal therapy must be discontinued at least one week prior to the first date of study therapy
  • Patients must be able to swallow and retain orally-administered medication
  • Patients must have signed an approved informed consent and authorization permitting release of personal health information; individuals with impaired decision-making capacity are not eligible to participate on the study

Exclusion Criteria:

  • Patients must NOT be taking metformin or have been on metformin in the past 6 months
  • Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer are excluded if there is any evidence of other malignancy being present within the last three years
  • 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
  • Patients who are pregnant or nursing; if patients are of reproductive age and have not undergone hysterectomy, they must use an effective contraceptive method for the duration of this study
  • Any condition associated with increased risk of metformin-associated lactic acidosis; (e.g. congestive heart failure defined as New York Heart Association [NYHA] class III or IV functional status, history of acidosis of any type; habitual intake of 3 or more alcoholic beverages per day)
Sexes Eligible for Study: Female
18 Years and older   (Adult, Senior)
No
United States
 
 
NCT02065687
GOG-0286B
NCI-2013-02284 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
GOG-0286B
GOG-0286B ( Other Identifier: NRG Oncology )
GOG-0286B ( Other Identifier: CTEP )
U10CA180830 ( U.S. NIH Grant/Contract )
U10CA180868 ( U.S. NIH Grant/Contract )
U10CA027469 ( U.S. NIH Grant/Contract )
No
Not Provided
Not Provided
Gynecologic Oncology Group
Gynecologic Oncology Group
National Cancer Institute (NCI)
Principal Investigator: Victoria Bae-Jump NRG Oncology
Gynecologic Oncology Group
August 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP