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

Purpose

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	Intervention	Phase
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 Other: Laboratory Biomarker Analysis Drug: Metformin Hydrochloride Drug: Paclitaxel Other: Placebo Other: Quality-of-Life Assessment Other: Questionnaire Administration	Phase 2 Phase 3


Study Type:	Interventional
Study Design:	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

Resource links provided by NLM:

Drug Information available for: Metformin Metformin hydrochloride Paclitaxel Carboplatin

Genetic and Rare Diseases Information Center resources: Adenocarcinoma of the Appendix

U.S. FDA Resources

Further study details as provided by Gynecologic Oncology Group:

Primary Outcome Measures:

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.

Secondary Outcome Measures:

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.

Other Outcome Measures:

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.


Estimated Enrollment:	540
Actual Study Start Date:	March 17, 2014
Estimated Primary Completion Date:	September 1, 2019 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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: Laboratory Biomarker Analysis Correlative studies Drug: Metformin Hydrochloride Given PO Drug: Paclitaxel Given IV Other: Quality-of-Life Assessment Ancillary studies Other Name: Quality of Life Assessment Other: Questionnaire Administration Ancillary studies
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: Laboratory Biomarker Analysis Correlative studies 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

Arms

Assigned Interventions

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: Laboratory Biomarker Analysis

Correlative studies

Drug: Metformin Hydrochloride

Given PO

Drug: Paclitaxel

Given IV

Other: Quality-of-Life Assessment

Ancillary studies

Other Name: Quality of Life Assessment

Other: Questionnaire Administration

Ancillary studies

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: Laboratory Biomarker Analysis

Correlative studies

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

Show Detailed Description

Eligibility


Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	No

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)

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: NCT02065687

Show 407 Study Locations

Sponsors and Collaborators

Gynecologic Oncology Group

National Cancer Institute (NCI)

Investigators


Principal Investigator:	Victoria Bae-Jump	NRG Oncology

More Information


Responsible Party:	Gynecologic Oncology Group
ClinicalTrials.gov Identifier:	NCT02065687 History of Changes
Other Study ID Numbers:	GOG-0286B NCI-2013-02284 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) 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 )
Study First Received:	February 14, 2014
Last Updated:	August 22, 2017

Additional relevant MeSH terms:


Carcinoma Adenocarcinoma Endometrial Neoplasms Uterine Neoplasms Cystadenocarcinoma, Serous Adenocarcinoma, Clear Cell Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Genital Neoplasms, Female Urogenital Neoplasms Neoplasms by Site Uterine Diseases Genital Diseases, Female	Cystadenocarcinoma Neoplasms, Cystic, Mucinous, and Serous Paclitaxel Albumin-Bound Paclitaxel Carboplatin Metformin Antineoplastic Agents, Phytogenic Antineoplastic Agents Tubulin Modulators Antimitotic Agents Mitosis Modulators Molecular Mechanisms of Pharmacological Action Hypoglycemic Agents Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 19, 2017