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NCT02065687 · CITED IN SOURCE DOCUMENTS

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

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase
PHASE2, PHASE3
Status at capture
UNKNOWN
Registry last update
2021-09-30

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Progression-free Survival (PFS) (Phase II)

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outcome · POSTED

Overall Survival (OS) (Phase II and III)

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outcome · POSTED

Proportion of Patients Responding to Therapy

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outcome · POSTED

Duration of Response by Treatment

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outcome · POSTED

Overall Survival (OS) (Phase II)

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outcome · POSTED

Progression Free Survival (PFS) (Phase III)

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outcome · POSTED

Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4

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outcome · POSTED

Level of Obesity

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outcome · NOT POSTED

Metabolic Factor Levels

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outcome · NOT POSTED

Incidence of PIK3 Mutations/Amplifications

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outcome · NOT POSTED

Expression of MATE 2

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outcome · NOT POSTED

Levels of Key Targets of the Metformin/mTOR Signaling Pathway

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part
eligibility Criteria
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)
healthy Volunteers
false
minimum Age
18 Years
sex
FEMALE
std Ages
  1. ADULT
  2. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. description
    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.
    intervention Names
    1. Drug: Carboplatin
    2. Other: Laboratory Biomarker Analysis
    3. Drug: Metformin Hydrochloride
    4. Drug: Paclitaxel
    5. Other: Quality-of-Life Assessment
    6. Other: Questionnaire Administration
    label
    Arm I (paclitaxel, carboplatin, metformin hydrochloride)
    type
    EXPERIMENTAL
  2. description
    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.
    intervention Names
    1. Drug: Carboplatin
    2. Other: Laboratory Biomarker Analysis
    3. Drug: Paclitaxel
    4. Other: Placebo Administration
    5. Other: Quality-of-Life Assessment
    6. Other: Questionnaire Administration
    label
    Arm II (paclitaxel, carboplatin, placebo)
    type
    ACTIVE_COMPARATOR
interventions
  1. arm Group Labels
    1. Arm I (paclitaxel, carboplatin, metformin hydrochloride)
    2. Arm II (paclitaxel, carboplatin, placebo)
    description
    Given IV
    name
    Carboplatin
    other Names
    1. Blastocarb
    2. Carboplat
    3. Carboplatin Hexal
    4. Carboplatino
    5. Carboplatinum
    6. Carbosin
    7. Carbosol
    8. Carbotec
    9. CBDCA
    10. Displata
    11. Ercar
    12. JM-8
    type
    DRUG
  2. arm Group Labels
    1. Arm I (paclitaxel, carboplatin, metformin hydrochloride)
    2. Arm II (paclitaxel, carboplatin, placebo)
    description
    Correlative studies
    name
    Laboratory Biomarker Analysis
    type
    OTHER
  3. arm Group Labels
    1. Arm I (paclitaxel, carboplatin, metformin hydrochloride)
    description
    Given PO
    name
    Metformin Hydrochloride
    other Names
    1. APO-Metformin
    2. Cidophage
    3. Dimefor
    4. Glifage
    5. Glucoformin
    6. Glucophage
    7. Glucophage ER
    8. Metformin HCl
    9. Riomet
    10. Siofor
    type
    DRUG
  4. arm Group Labels
    1. Arm I (paclitaxel, carboplatin, metformin hydrochloride)
    2. Arm II (paclitaxel, carboplatin, placebo)
    description
    Given IV
    name
    Paclitaxel
    other Names
    1. Anzatax
    2. Asotax
    3. Bristaxol
    4. Praxel
    5. Taxol
    6. Taxol Konzentrat
    type
    DRUG
  5. arm Group Labels
    1. Arm II (paclitaxel, carboplatin, placebo)
    description
    Given PO
    name
    Placebo Administration
    type
    OTHER
  6. arm Group Labels
    1. Arm I (paclitaxel, carboplatin, metformin hydrochloride)
    2. Arm II (paclitaxel, carboplatin, placebo)
    description
    Ancillary studies
    name
    Quality-of-Life Assessment
    other Names
    1. Quality of Life Assessment
    type
    OTHER
  7. arm Group Labels
    1. Arm I (paclitaxel, carboplatin, metformin hydrochloride)
    2. Arm II (paclitaxel, carboplatin, placebo)
    description
    Ancillary studies
    name
    Questionnaire Administration
    type
    OTHER
Study design
allocation
RANDOMIZED
intervention Model
PARALLEL
masking Info
masking
DOUBLE
who Masked
  1. PARTICIPANT
  2. INVESTIGATOR
primary Purpose
TREATMENT
Enrollment
count
469
type
ACTUAL
Registered outcome plans (not posted results)
other Outcomes
  1. description
    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.
    measure
    Metabolic Factor Levels
    time Frame
    Up to 5 years
  2. description
    PIK3CA mutations/amplifications and PIK3R1/PIK3R2 mutations will be examined for prognostic and predictive significance.
    measure
    Incidence of PIK3 Mutations/Amplifications
    time Frame
    Up to 5 years
  3. description
    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.
    measure
    Expression of MATE 2
    time Frame
    Up to 5 years
  4. description
    Levels before and after treatment will be assessed for their predictive and prognostic significance.
    measure
    Levels of Key Targets of the Metformin/mTOR Signaling Pathway
    time Frame
    Up to 5 years
primary Outcomes
  1. description
    Time until disease progression, death, or date of last contact. This study was originally designed as a phase II/III study. It passed the phase 2 threshold and started the phase 3; however, a phase 3 interim analysis stopped the trial for futility. Therefore, data available for Phase III may be identical to data reported for Phase II or Phase II/III combined.
    measure
    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
  2. description
    The observed length of life from randomization into the study to death or the date of last contact. This study was originally designed as a phase II/III study. It passed the phase 2 threshold and started the phase 3; however, a phase 3 interim analysis stopped the trial for futility. Therefore, data available for Phase III may be identical to data reported for Phase II or Phase II/III combined.
    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
secondary Outcomes
  1. description
    The proportion of patients who had a response (complete or partial) by RECIST 1.1. Measurable disease is defined by 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 CT, 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.
    measure
    Proportion of Patients Responding to Therapy
    time Frame
    During study treatment, up to 5 years.
  2. description
    Duration of response until disease progression, death, or date last seen among patients who responded.
    measure
    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
  3. description
    The observed length of life from randomization into the study to death or the date of last contact. For response, only those patients who had measurable disease were included in an analysis of response. Non-measurable patients are included in the ITT analysis. This study was originally designed as a phase II/III study. It passed the phase 2 threshold and started the phase 3; however, a phase 3 interim analysis stopped the trial for futility. Therefore, data available for Phase III may be identical to data reported for Phase II or Phase II/III combined.
    measure
    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 5 years.
  4. description
    Time until disease progression, death, or date of last contact. For response, only those patients who had measurable disease were included in an analysis of response. Non-measurable patients are included in the ITT analysis. This study was originally designed as a phase II/III study. It passed the phase 2 threshold and started the phase 3; however, a phase 3 interim analysis stopped the trial for futility. Therefore, data available for Phase III may be identical to data reported for Phase II or Phase II/III combined.
    measure
    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
  5. description
    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. The number of patients with a grade three or greater adverse event will be reported (by system organ class).
    measure
    Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4
    time Frame
    Up to 5 years
  6. description
    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.
    measure
    Level of Obesity
    time Frame
    Up to 5 years
Full study description
brief Summary
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.
detailed Description
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 patients' 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.
Source references
Source notices and limitations
    Discovery and provenance
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        ent-list"><ol id="_724"><li> Paclitaxel and carboplatin with or without metformin in stages III, IV, and recurrent endometrial cancer (<a href="/clinicaltrials/NCT02065687">GOG-0286B</a> [NCT02065687]). </li><li>PI3K/mTOR inhibitor in recurrent or persistent endometrial cancer (<a href="/clinicaltrials/NCT02549989">15-079</a> [NC
        end
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        Paclitaxel and carboplatin with or without metformin in stages III, IV, and recurrent endometrial cancer (<a href="/clinicaltrials/NCT02065687">GOG-0286B</a> [NCT02065687]). </li><li>PI3K/mTOR inhibitor in recurrent or persistent endometrial cancer (<a href="/clinicaltrials/NCT02549989">15-079</a> [NCT02549989]).</li><li> Everol
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      source update dates
      1. context
        Updated: May 14, 2025
        datetime
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        display
        May 14, 2025

    Preserved source evidence · Not medical advice