Treating Patients With Advanced Solid Tumors, Breast Cancer or Recurrent Ovarian Cancer

OBJECTIVES:

- Determine the maximum tolerated dose, recommended phase II dose, and associated toxic
effects of BMS-247550 in patients with advanced solid tumors.

- Determine the pharmacokinetic and pharmacodynamic relationship of this treatment regimen
in these patients.

- Assess the extent of microtubule bundle and mitotic aster formation and cell cycle
kinetics in peripheral blood mononuclear cells in these patients treated with this
regimen.

- Determine any evidence of antitumor activity of this treatment regimen in these
patients.

- Evaluate the relationship between tumor response and the occurrence of mutation in the
class 1 isotype of B-tubulin and B-tubulin isotype distribution in patients with
advanced or recurrent solid tumors, ovarian cancer, or breast cancer treated with this
regimen.

- Investigate Multi-Drug Resistance Gene (MDR1), Multidrug Resistance-associated Protein
(MRP) Gene, and canalicular multispecific organic anion transporter 1(cMOAT) messenger
ribonucleic acid (mRNA) and protein expression as prognosticators of tumor response in
these patients treated with this regimen.

- Determine the relationship between stathmin expression and phosphorylation status as a
function of response in these patients treated with this regimen.

- Correlate the expression of proapoptotic (p53, bax, bad, and bid) and antiapoptotic
(survivin, inhibitors of apoptotic proteins, bcl-2, and bcl-x) proteins in tumor samples
and/or ascites with response and clinical outcome in these patients treated with this
regimen.

OUTLINE: This is a dose-escalation, multicenter study.

- Part I: Patients with advanced solid tumors receive BMS-247550 IV over 1 hour every 3
weeks. Treatment continues in the absence of disease progression or unacceptable
toxicity.

Cohorts of 3-6 patients receive escalating doses of BMS-247550 until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2
of 6 patients experience dose-limiting toxicity.

- Part II: Patients with ovarian, breast, or other cancer receive BMS-247550 as in the
part I portion of the study at the MTD. Treatment continues in the absence of disease
progression or unacceptable toxicity.

Patients are followed at 2 months.

PROJECTED ACCRUAL: Approximately 42-66 patients will be accrued for this study within 12-16
months.

Inclusion Criteria:

- Histologically or cytologically confirmed metastatic or unresectable solid malignancy
for which no standard or curative therapies exist or are no longer effective

- Metastatic, recurrent, or locally advanced breast, ovarian, or other cancer

- Hemoglobin at least 9.0 g/dL

- WBC at least 3,000/mm3

- Absolute neutrophil count at least 1,500/mm3

- Platelet count at least 100,000/mm3

- Bilirubin normal

- AST/ALT no greater than 3 times upper limit of normal

- Gilbert's syndrome allowed

- Creatinine no greater than 2 mg/dL

Exclusion Criteria:

- symptomatic congestive heart failure

- unstable angina pectoris

- cardiac arrhythmia

- grade 2 or greater clinical neuropathy

- prior allergy or hypersensitivity reaction (grade 2 or greater) to prior paclitaxel or
other therapy containing Cremophor EL

- allergy or intolerance to steroids, diphenhydramine, cimetidine, or ranitidine

- uncontrolled concurrent illness

- active infection

- pregnant or nursing

- other concurrent anticancer therapies or commercial agents

- other concurrent investigational agents

- other concurrent highly active antiretroviral therapy for HIV-positive patients