A Phase I/II Trial of BMS-247550 for Treatment of Patients With Recurrent High-Grade Gliomas

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of BMS-247550 when administered to adults with
recurrent malignant gliomas, receiving (Group A) or not receiving (Group B) anticonvulsants
known to be metabolized by the P450 hepatic enzyme complex.

II. To describe the pharmacokinetics of this route of administration, measuring BMS-247550,
and determine the effects of hepatic enzyme inducing drugs, such as anticonvulsants, on the
pharmacokinetics.

III. To determine the response rate of adult patients with recurrent glioma to BMS-247550
administered at the MTD.

IV. To describe the toxicity associated with this regimen in adult patients with recurrent
malignant gliomas.

SECONDARY OBJECTIVES:

I. To determine the percent of patients with 6 month progression free survival, duration of
progression free survival and survival associated with this therapy in adult patients with
recurrent malignant gliomas.

OUTLINE: This is a phase I, dose-escalation, multicenter study followed by a phase II, safety
and efficacy, multicenter study. For phase I only, patients are stratified according to
cytochrome P450-inducing anticonvulsant use (yes vs no).

Phase I: Patients receive ixabepilone IV over 1 hour on days 1-5. Courses repeat every 3
weeks in the absence of disease progression or unacceptable toxicity.

Cohorts of 3 patients receive escalating doses of ixabepilone until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2
of 3 patients experience dose-limiting toxicity.

Phase II: Once the MTD is determined, additional patients receive ixabepilone as above at the
MTD.

Patients are followed every 2 months.

PROJECTED ACCRUAL: A minimum of 10-15 patients will be accrued for the phase I portion of
this study. A total of 22-33 patients will be accrued for the phase II portion of this study
within 4-6 months.

Inclusion Criteria:

- Patients must have histologically proven malignant glioma (anaplastic astrocytoma or
glioblastoma multiforme) which is progressive or recurrent following radiation therapy
+/- chemotherapy; patients with previous low grade glioma who progressed after
radiotherapy +/- chemotherapy and are biopsied and found to have a high grade glioma
are eligible

- Patients must have measurable progressive or recurrent malignant glioma by MRI or CT
imaging

- Patients must have recovered from severe toxicity of prior therapy; an interval of at
least 3 months must have elapsed since the completion of the most recent course of
radiation therapy while at least 3 weeks must have elapsed since the completion of a
non-nitrosourea containing chemotherapy regimen and at least 6 weeks since the
completion of a nitrosourea containing chemotherapy regimen

- Patients must have a Karnofsky performance status >= 60% (i.e. the patient must be
able to care for himself/herself with occasional help from others)

- Absolute neutrophil count >= 1500/mm^3

- Platelets >= 100,000/mm^3

- HgB > 9 g/dl

- Creatinine =< 1.5mg/dl

- Total Bilirubin =< 1.5mg/dl

- Transaminases =< 2.5 times above the upper limits of the institutional norm)

- Patients must be able to provide written informed consent

- Patients must have =< 2 prior chemotherapy regimens

- Patients with the potential for pregnancy or impregnating their partner must agree to
follow acceptable birth control methods to avoid conception; the anti-proliferative
activity of this experimental drug may be harmful to the developing fetus or nursing
infant; female patients of child-bearing potential must have a negative pregnancy test

- Patients must have no concurrent malignancy except curatively treated basal or
squamous cell carcinoma of the skin or carcinoma in situ of the cervix and breast;
patients with prior malignancies must be disease-free for >= five years

- Patients must be maintained on a stable corticosteroid regimen from the time of their
baseline scan until the start of treatment

- Patients must have a Mini Mental State Exam score of >= 15

Exclusion Criteria:

- Patients with serious concurrent infection or medical illness, which would jeopardize
the ability of the patient to receive the treatment outlined in this protocol with
reasonable safety

- Patients who are pregnant or breast-feeding

- Patients with more than 2 prior chemotherapy regimens

- Patients receiving concurrent investigational agents

- Patients receiving any of the following medications which are known to be moderate to
significant inhibitors of CYP3A4 are not eligible:

- Antibiotics: clarithromycin, erythromycin, troleandomycin

- Anti-HIV agents: delavirdine, nelfinavir, amprenavir, ritonavir, indinavir,
saquinavir, lopinavir

- Antifungals: itraconazole, ketoconazole, fluconazole (doses > 200mg/day),
voriconazole

- Antidepressants: nefazodone, fluvoxamine

- Calcium channel blockers: verapamil, diltiazem

- Miscellaneous: amiodarone NOTE: The above list of agents was provided by the
National Cancer Institute as moderate to significant inhibitors of CYP3A4 that
should not be administered with BMS; there may be other agents that have similar
activities on CYP3A4, however these are currently unspecified; if investigators
are concerned about a particular medication's inhibitory effect on CYP3A4, they
are encouraged to consult local pharmacy services for more information and to
contact the principal investigator to discuss the situation further