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

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.

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