Ixabepilone to Treat Cervical Cancer

Background

- Ixabepilone (Ixempra (Trademark), BMS-247550, NSC 710428) is a semi-synthetic analog of
the natural product epothilone B.

- The epothilones are a novel class of non-taxane microtubule-stabilizing agents obtained
from the fermentation of the cellulose degrading myxobacteria, Sorangium cellulosum.

- Ixabepilone is active against cancer models that are naturally insensitive to
paclitaxel or have developed resistance to paclitaxel, both in-vitro and in-vivo.

Objectives

Primary-

- Establish the efficacy of the investigational agent ixabepilone in patients with cervical
carcinoma when administered as a daily one-hour infusion on days 1 to 5 every three weeks,
as measured by overall response (PR+CR).

Secondary-

- Assess pharmacodynamic endpoints to determine the extent of tubulin polymerization and
whether or not there has been activation of cellular death pathways distal to the
target.

- Estimate progression-free survival and duration of response.

Eligibility

- Age greater than 18

- Histologic or cytologic confirmation of cervical carcinoma; either squamous cell or
non-squamous consisting of cervical adenocarcinoma, cervical adenosquamous carcinoma or
cervical carcinoma, non-squamous type.

Design

- Phase II study, open, non-randomized

- Ixabepilone will be administered at a dose of 6mg/m(2) daily on days 1 through 5, every
three weeks.

- Restaging will be done every two cycles using RECIST

- Planned maximum enrollment 76 persons

- INCLUSION CRITERIA:

Patients must fulfill all of the following criteria to be eligible for study admission:

1. Age greater than or equal to 18 years.

2. Histologic or cytologic confirmation of cervical carcinoma, squamous or non-squamous.
Within the non-squamous cohort is adenocarcinoma and adenosquamous as well as
non-squamous (not otherwise specified).

3. Subjects with unresectable recurrent cervical cancer are eligible.

4. Measurable disease that can be assessed using RECIST criteria.

5. Performance Status ECOG 0-2.

6. Life expectancy of 3 months or greater.

7. Suitable candidate for receiving planned therapy as evidenced by screening laboratory
assessments of hematologic, renal, hepatic, and metabolic functions: platelet count
greater than or equal to 75,000/mm(3), absolute granulocyte count (AGC) greater than
or equal to 1,000/mm(3), serum creatinine less than or equal to 1.6 or a measured
creatinine clearance greater than or equal to 40 ml/min, SGPT and SGOT less than or
equal to 2.5 times the NL, and total bilirubin less than or equal to 1.5 times the NL
(in patients with clinical evidence of Gilberts' disease, less than or equal to 3
times the NL).

Note: A diagnosis of Gilbert's disease will be made in the presence of (1)
unconjugated hyperbilirubinemia noted on several occasions; (2) normal results from
CBC count, reticulocyte count, and blood smear; (3) normal liver function test
results; and (4) an absence of other disease processes that can explain the
unconjugated hyperbilirubinemia.

8. Greater than or equal to 4 weeks from prior radiation, intravenous chemotherapy or
immunotherapy; greater than or equal to 6 weeks from prior nitrosourea; greater than
or equal to 2 weeks from a prior phase 0 study .

9. No serious intercurrent medical illness.

10. The ability to understand and willingness to sign a written informed consent form,
and to comply with the protocol.

11. Prior therapy with cisplatin or carboplatin is required.

EXCLUSION CRITERIA:

Patients with any of the following will be excluded from study entry:

1. Pregnant or nursing women are not eligible; neither are women of childbearing
potential unless using effective contraception as determined by the patient's
physician.

2. Patients with a history of CNS metastases, because symptoms/signs of progressive
disease may be confused with drug-related toxicities, unless control has been
achieved with either radiation or surgical resection at least three months prior to
enrollment on study.

3. Patients who are poor medical risk because of other non malignant systemic disease or
active, uncontrolled infection.

4. HIV positive patients will be considered for eligibility, as long as they are not
receiving antiretroviral drugs with strong CYP3A4 inhibitory activity.

5. Prior craniospinal radiation, or total body irradiation (TBI).

6. Patients receiving other investigational drugs, or strong CYP3A3 inhibitors (see
Section 3.6 for details) that cannot be discontinued or substituted.

7. CTCAE Grade 2 or greater motor or sensory neuropathy.

8. Known prior severe hypersensitivity reactions to agents containing Cremophor
(Trademark) EL.

9. Women with localized disease who are potentially curable through surgical resection.