Ixabepilone in Treating Patients With Recurrent or Persistent Leiomyosarcoma of the Uterus Previously Treated With Chemotherapy

Study Overview
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Brief Summary
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This phase II trial is studying the side effects and how well ixabepilone works in treating patients with recurrent or persistent leiomyosarcoma of the uterus previously treated with chemotherapy. Drugs used in chemotherapy, such as ixabepilone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the response rate (complete and partial responses by RECIST 1.1) of ixabepilone in patients with recurrent or persistent leiomyosarcoma of the uterus who have failed one previous chemotherapy regimen. II. To determine the nature and degree of toxicity of ixabepilone as assessed by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4 in this cohort of patients. SECONDARY OBJECTIVES: I. To determine the duration of progression-free survival (PFS) and overall survival (OS). II. To determine the level of beta-III tubulin expression measured by IHC in women with leiomyosarcoma. III. To determine if beta-III tubulin expression as measured by IHC predicts response to ixabepilone in women with leiomyosarcoma. OUTLINE: Patients receive ixabepilone intravenously (IV) over 3 hours on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Official Title
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A Phase II Evaluation of Ixabepilone (NSC #710428) in the Treatment of Recurrent or Persistent Leiomyosarcoma of the Uterus

Conditions
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Recurrent Uterine Corpus Sarcoma, Uterine Corpus Leiomyosarcoma

Intervention / Treatment
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* Drug: Ixabepilone
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed uterine leiomyosarcoma Persistent or recurrent disease that is refractory to curative or established treatments Histologic confirmation of the original primary tumor is required Measurable disease defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) Each lesion must be ≥ 10 mm by CT scan, MRI, or caliper measurement by clinical exam OR ≥ 20 mm by chest x-ray Lymph nodes must be ≥ 15 mm in short axis by CT scan or MRI Must have ≥ 1 target lesion to assess response Tumors within a previously irradiated field will be designated as non-target lesions unless progression is documented or a biopsy is obtained to confirm persistence ≥ 90 days following completion of radiotherapy Not eligible for a higher priority GOG protocol, if one exists Must have had 1 prior cytotoxic regimen that included a taxane regimen for management of leiomyosarcoma Single-agent or multi-agent therapy allowed Patients who did not receive prior therapy with a taxane (e.g., docetaxel) must receive a second regimen that includes a taxane No known brain metastases GOG performance status 0-2 Life expectancy > 6 months ANC ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Creatinine ≤ 1.5 times upper limit of normal (ULN) Bilirubin ≤ 1.5 times ULN AST ≤ 3 times ULN Alkaline phosphatase ≤ 2.5 times ULN Peripheral neuropathy (sensory or mother) ≤ grade 1 Negative pregnancy test Not pregnant or nursing Fertile patients must use effective contraception prior to and for the duration of study participation Free of active infection requiring antibiotics Uncomplicated urinary tract infection allowed No other invasive malignancy except non-melanoma skin cancer or curatively treated localized cancer of the breast, head and neck, or skin that was completed more than 3 years ago and the patient remains free of recurrence or metastatic disease No history of a severe hypersensitivity reaction to agents containing Cremophor EL or its derivatives (e.g., polyoxyethylated castor oil) No uncontrolled intercurrent illness including, but not limited to, any of the following: Ongoing or active infection Symptomatic congestive heart failure Unstable angina Cardiac arrhythmia Psychiatric illness and/or social situations that would limit compliance with study requirements No concurrent amifostine or other protective agents Recovered from effects of recent surgery, radiotherapy, or chemotherapy At least 1 week since prior hormonal therapy Hormonal therapy (cytotoxic or non-cytotoxic) not counted as prior regimen At least 3 weeks since any other prior therapy directed to the malignant tumor, including immunologic agents At least 4 weeks since prior radiation therapy One prior non-cytotoxic (biologic or cytostatic) regimen, administered as part of the previous cytotoxic regimen or in addition to it, allowed Non-cytotoxic agents include, but are not limited to, the following: Monoclonal antibodies Cytokines Small-molecule inhibitors of signal transduction More than 3 years since radiotherapy for localized cancer of the breast, head and neck, or skin provided patient remains free of recurrence or metastatic disease No prior ixabepilone No prior chemotherapy for any abdominal or pelvic tumor other than for the treatment of uterine leiomyosarcoma within the past 3 years Prior chemotherapy for localized breast cancer allowed provided it was completed more than 3 years ago and patient remains free of recurrent or metastatic disease No other concurrent investigational agents No concurrent strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, voriconazole, or grapefruit juice) or CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifampicin, rifabutin, phenobarbital, or St. John wort) No concurrent combination antiretroviral therapy for HIV-positive patients

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (ixabepilone)<br>Patients receive ixabepilone IV over 3 hours on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: Ixabepilone<br>* Given IV<br>* Other names: BMS-247550;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Response | Complete and Partial Tumor Response by RECIST 1.1. RECIST 1.1 defines complete response as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm and the disappearance of all non-target lesions and normalization of tumor marker level. 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. Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. These patients will have their response classified according to the definitions stated above. Complete and partial responses are included in the objective tumor response rate. | Every other cycle for the first 6 months; then every 3 months thereafter; up to 5 years. | 
| Frequency and Severity of Adverse Events as Assessed by NCI CTCAE v. 4.0 |  | Every cycle until completion of study treatment up to 30 days after stopping study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression-free survival (PFS) was defined as the period from study entry until disease progression, death, or the last date of contact. Progression was based on RECIST 1.1. RECIST 1.1 defines progressive disease as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions or unequivocal progression of non-target lesions is also considered progression. | From study entry to disease progression, death or date of last contact, whichever occurs first, up to 5 years of follow-up. | 
| Overall Survival | Overall survival is defined as the duration of time from study entry to time of death or the date of last contact. | From study entry to death or last contact, up to 5 years of follow-up. |