Paclitaxel and Carboplatin With or Without Metformin Hydrochloride in Treating Patients With Stage III, IV, or Recurrent Endometrial Cancer
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| ClinicalTrials.gov Identifier: NCT02065687 |
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Recruitment Status :
Active, not recruiting
First Posted : February 19, 2014
Results First Posted : January 12, 2021
Last Update Posted : September 30, 2021
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Sponsor:
Gynecologic Oncology Group
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
GOG Foundation ( Gynecologic Oncology Group )
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Endometrial Adenocarcinoma Endometrial Clear Cell Adenocarcinoma Endometrial Serous Adenocarcinoma Endometrial Undifferentiated Carcinoma Recurrent Uterine Corpus Carcinoma Stage III Uterine Corpus Cancer AJCC v7 Stage IIIA Uterine Corpus Cancer AJCC v7 Stage IIIB Uterine Corpus Cancer AJCC v7 Stage IIIC Uterine Corpus Cancer AJCC v7 Stage IV Uterine Corpus Cancer AJCC v7 Stage IVA Uterine Corpus Cancer AJCC v7 Stage IVB Uterine Corpus Cancer AJCC v7 | Drug: Carboplatin Other: Laboratory Biomarker Analysis Drug: Metformin Hydrochloride Drug: Paclitaxel Other: Placebo Administration Other: Quality-of-Life Assessment Other: Questionnaire Administration | Phase 2 Phase 3 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 469 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Double (Participant, Investigator) |
| Primary Purpose: | Treatment |
| Official Title: | 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 |
| Actual Study Start Date : | March 17, 2014 |
| Actual Primary Completion Date : | April 17, 2019 |
| Estimated Study Completion Date : | September 13, 2023 |
Resource links provided by the National Library of Medicine
| Arm | Intervention/treatment |
|---|---|
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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. |
Drug: Carboplatin
Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Drug: Metformin Hydrochloride Given PO
Other Names:
Drug: Paclitaxel Given IV
Other Names:
Other: Quality-of-Life Assessment Ancillary studies
Other Name: Quality of Life Assessment Other: Questionnaire Administration Ancillary studies |
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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. |
Drug: Carboplatin
Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Drug: Paclitaxel Given IV
Other Names:
Other: Placebo Administration Given PO Other: Quality-of-Life Assessment Ancillary studies
Other Name: Quality of Life Assessment Other: Questionnaire Administration Ancillary studies |
Primary Outcome Measures :
- 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 ]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.
- 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 ]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.
Secondary Outcome Measures :
- Proportion of Patients Responding to Therapy [ Time Frame: During study treatment, up to 5 years. ]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.
- 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 of response until disease progression, death, or date last seen among patients who responded.
- 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. ]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.
- 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 ]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.
- 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 ]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).
- 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.
Other Outcome Measures:
- 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.
- 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.
- 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.
- 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.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | Female |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
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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
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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.)
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- 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)
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02065687
Locations
Show 431 study locations
Sponsors and Collaborators
Gynecologic Oncology Group
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Victoria L Bae-Jump | NRG Oncology |
Study Documents (Full-Text)
Documents provided by GOG Foundation ( Gynecologic Oncology Group ):
Documents provided by GOG Foundation ( Gynecologic Oncology Group ):
Study Protocol and Statistical Analysis Plan [PDF] June 21, 2017
| Responsible Party: | Gynecologic Oncology Group |
| ClinicalTrials.gov Identifier: | NCT02065687 |
| Other Study ID Numbers: |
GOG-0286B NCI-2013-02284 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) s14-01068 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 ) |
| First Posted: | February 19, 2014 Key Record Dates |
| Results First Posted: | January 12, 2021 |
| Last Update Posted: | September 30, 2021 |
| Last Verified: | September 2021 |
Additional relevant MeSH terms:
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Carcinoma Adenocarcinoma Endometrial Neoplasms Cystadenocarcinoma, Serous Adenocarcinoma, Clear Cell Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Uterine Neoplasms Genital Neoplasms, Female Urogenital Neoplasms Neoplasms by Site Uterine Diseases Cystadenocarcinoma |
Neoplasms, Cystic, Mucinous, and Serous Metformin Paclitaxel Carboplatin Albumin-Bound Paclitaxel Antineoplastic Agents, Phytogenic Antineoplastic Agents Tubulin Modulators Antimitotic Agents Mitosis Modulators Molecular Mechanisms of Pharmacological Action Hypoglycemic Agents Physiological Effects of Drugs |