Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

This randomized phase II trial is studying giving paclitaxel and carboplatin together with bevacizumab to see how well it works compared with giving paclitaxel and carboplatin together with temsirolimus or giving ixabepilone and carboplatin together with bevacizumab 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, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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

Further Study Information

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 CTCAE v3.0 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. To 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.

II. To explore the relationship among the various biomarkers by histologic subtype and treatment.

III. To 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 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.

Eligibility Criteria

Inclusion Criteria:

• Histologically confirmed endometrial carcinoma, including any of the following epithelial cell types:

• Endometrioid adenocarcinoma

• Serous adenocarcinoma

• Undifferentiated carcinoma

• Clear cell adenocarcinoma

• Mixed epithelial carcinoma

• Adenocarcinoma not otherwise specified

• Mucinous adenocarcinoma

• Squamous cell carcinoma

• Transitional cell carcinoma

• Stage III, IVA-B, or recurrent disease

• Refractory to curative or established therapy

• Measurable disease*, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by chest x-ray or ≥ 10 mm by CT scan, MRI, or caliper measurement by clinical exam

• Lymph nodes must be ≥ 15 mm in short axis by CT scan or MRI

• No history or evidence of CNS disease, including primary brain tumor, seizures not controlled with standard medical therapy, or any brain metastases

• Not eligible for a higher priority GOG protocol (any active GOG phase III protocol or rare tumor protocol), if one exists

• GOG performance status 0-2

• ANC ≥ 1,500/mm³

• Platelets ≥ 100,000/mm³

• Creatinine ≤ 1.5 times upper limit of normal (ULN)

• Bilirubin ≤ 1.5 times ULN

• SGOT and SGPT ≤ 2.5 times ULN

• Alkaline phosphatase ≤ 2.5 times ULN

• Urine protein:creatinine ratio < 1.0 g OR < 1,000 mg by 24-hour urine collection

• INR and PTT ≤ 1.5 times ULN

• Fasting cholesterol < 300 mg/dL

• Fasting triglycerides ≤ 2.5 times ULN

• Not pregnant or nursing

• Negative pregnancy test

• No other invasive malignancies within the past 3 years, except nonmelanoma skin cancer

• No serious, non-healing wound, ulcer, or bone fracture, including history of abdominal/pelvic fistula, gastrointestinal perforation, or intraabdominal abscess within the past 3 months

• No uncorrected underlying lesions that caused the fistula or perforation

• No active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels

• No clinically significant cardiovascular disease, including any of the following:

• Uncontrolled hypertension, defined as systolic BP > 150 mm Hg or diastolic BP > 90 mm Hg

• Myocardial infarction or unstable angina within the past 6 months

• NYHA class II-IV congestive heart failure

• History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation), or cardiac arrhythmias requiring anti-arrhythmic medications

• Atrial fibrillation that is well controlled with anti-arrhythmic medication allowed

• Peripheral vascular disease ≥ CTCAE grade 2

• History of cerebrovascular accident (stroke), transient ischemic attack, or subarachnoid hemorrhage within the past 6 months

• Aortic aneurysm and/or history of aortic dissection

• No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies

• No significant traumatic injury within the past 28 days

• No known history of interstitial pneumonitis

• No hypoxemia ≥ grade 2 by CTCAE v.3

• No dyspnea ≥ grade 2 by CTCAE v.3

• No uncontrolled diabetes or baseline hemoglobin A1C > 8%

• No peripheral neuropathy > grade 1 by CTCAE v.3

• At least 4 weeks since prior radiation therapy (RT) for treatment of endometrial carcinoma allowed, including pelvic RT, extended field pelvic/para-aortic RT, and/or intravaginal brachytherapy

• More than 3 years since prior RT to any portion of the abdominal cavity or pelvis, other than for the treatment of endometrial cancer

• More than 3 years since prior RT for localized cancer of the breast, head and neck, or skin and no metastatic or recurrent disease

• At least 1 week since prior hormonal therapy for treatment of endometrial carcinoma

• More than 28 days since prior and no concurrent major surgical procedure or open biopsy

• More than 7 days since prior minor surgical procedures, fine-needle aspirates, or core biopsies

• No prior chemotherapy or target therapy (e.g., bevacizumab or other VEGF pathway targeted therapy, temsirolimus, everolimus, ridaforolimus, sirolimus, or any other PI3K/AKT/mTor pathway targeted therapy), including chemotherapy used for radiation sensitization, for treatment of endometrial carcinoma

• More than 3 years since prior chemotherapy for any abdominal or pelvic tumor

• More than 3 years since prior adjuvant chemotherapy for localized breast cancer and no metastatic or recurrent disease

• No prior cancer treatment that contraindicates this protocol therapy

• No concurrent treatment with potent CYP3A4 inhibitors and agents that have CYP3A4 induction potential (arms II and III)

• No concurrent sunitinib malate during temsirolimus treatment (arm II)

• No concurrent amifostine or other protective agents

Trial Contact Information

Trial Lead Organizations/Sponsors

National Cancer Institute

Carol Aghajanian

Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00977574
Information obtained from ClinicalTrials.gov on February 05, 2013