This randomized phase II trial studies paclitaxel, carboplatin, and bevacizumab or paclitaxel, carboplatin, and temsirolimus or ixabepilone, carboplatin, and bevacizumab to see how well they work in treating patients with stage III, stage IV, or recurrent endometrial cancer. Drugs used in chemotherapy, such as paclitaxel, carboplatin, and ixabepilone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known which treatment regimen is most effective in treating patients with endometrial cancer.
PRIMARY OBJECTIVES: I. To estimate the hazard of progression or death of each of the three arms relative to that of historical controls in patients with advanced or recurrent endometrial cancer. SECONDARY OBJECTIVES: I. To determine the nature, frequency, and maximum degree of toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v)3.0 for each of the three arms. II. To estimate the distribution of the duration of overall survival for each of the three arms. III. To estimate the proportion of patients with measurable disease who have confirmed objective tumor responses by treatment. TERTIARY OBJECTIVES: I. Explore the associations between select biomarkers and progression-free survival as well as secondary measures of clinical outcome (overall survival, tumor response, or disease status if possible) in the context of histologic cell type and treatment. IA. Somatic mutations in phosphatase and tensin homolog (PTEN)/ phosphoinositide-3-kinase (PI3K) and RAS pathway members by Sequenom mutational profiling and targeted sequencing of candidate genes. IB. Microsatellite instability by analysis of five National Cancer Institute consensus microsatellite markers (BAT25, BAT26, D2S2123, D5S346, and D17S250) using the Applied Biosystems (ABI) Prism 3100 Genetic Analyzer. IC. Copy number alterations (gains or losses) by array comparative genomic hybridization (aCGH). ID. Tumor expression of PTEN and class III beta-tubulin using immunohistochemistry. IE. Concentration of vascular endothelial growth factor (VEGF) in pre-cycle 1 plasma using an enzyme-linked immunosorbent assay. II. Explore the relationship among the various biomarkers by histologic subtype and treatment. III. Explore which combination of biomarkers and clinical covariates optimally predicts responsiveness and resistance to the three treatment arms. OUTLINE: Patients are randomized to 1 of 3 treatment arms. ARM I: Patients receive paclitaxel intravenously (IV) over 3 hours, carboplatin IV over 30 minutes, and bevacizumab\* IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. NOTE: \*Patients undergoing treatment post-surgery (=\< 12 weeks) receive bevacizumab beginning on course 2. ARM II: Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 1 and temsirolimus\* IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive temsirolimus IV over 30 minutes on days 1, 8, and 15. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. NOTE: \*Patients undergoing treatment post-surgery (=\< 12 weeks) receive temsirolimus beginning on course 2. ARM III: Patients receive ixabepilone IV over 1 hour, carboplatin IV over 30 minutes, and bevacizumab\* IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. NOTE: \*Patients undergoing treatment post-surgery (=\< 12 weeks) receive bevacizumab beginning on course 2. After completion of study therapy, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
349
Given IV
Given IV
Given IV
Correlative studies
Given IV
Given IV
Saint Joseph's Hospital and Medical Center
Phoenix, Arizona, United States
Mayo Clinic in Arizona
Scottsdale, Arizona, United States
University of Arizona Cancer Center-North Campus
Tucson, Arizona, United States
Providence Saint Joseph Medical Center/Disney Family Cancer Center
Burbank, California, United States
John Muir Medical Center-Concord
Concord, California, United States
Number of Participants Who Progressed or Died by 25 Months From Enrollment
PFS (Progression free survival) is defined as the duration of time from date of study entry to time of progression or death, whichever occurs first. Patients with a status of alive, progression-free are censored at their date of last follow-up. To lessen the potential for bias in the progression evaluation times between treatment arms and historical controls, progression/death times will be grouped over 6 18-week time intervals. Progressions are carried forward to the end of the interval. All progressions or deaths occurring after the 6th 18-week interval are censored at 25 months for this analysis. Study NCT00977574
Time frame: at 25 months
Frequency and Severity of Toxicity as Assessed by CTCAE v3.0 for Each of the Three Arms.
Time frame: Median of 10 cycles of treatment plus 30 days
The Median Duration of Overall Survival for Each of the Three Arms.
Overall survival is defined as the duration of time from study entry to time of death or the date of last contact.
Time frame: Time from date of study entry to time of death or the date of last contact, assessed up to 5 years
The Proportion of Patients With Measurable Disease Who Have Confirmed Objective Tumor Responses by Treatment.
RECIST 1.1 was used to define objective tumor response. A complete response is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. A partial response is defined as At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. There can be no unequivocal progression of non-target lesions and no new lesions. Complete and partial responses are included in the objective tumor response rate. Confirmation of response was not required.
Time frame: Imaging was done every 3 cycles and at any other time clinically indicated. Imaging was required every 9 weeks until progression or initiation on non protocol therapy. After 2 years of protocol therapy or follow up, CT scan or MRI was every 3 months
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UC San Diego Moores Cancer Center
La Jolla, California, United States
UCLA / Jonsson Comprehensive Cancer Center
Los Angeles, California, United States
Palo Alto Medical Foundation-Gynecologic Oncology
Mountain View, California, United States
UC San Diego Medical Center - Hillcrest
San Diego, California, United States
San Diego VA Medical Center
San Diego, California, United States
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