OBJECTIVES:

• Determine the maximum tolerated dose and dose-limiting toxicity of BMS-214662 in patients with advanced solid tumors.
• Determine the safety of an appropriate dose of this drug for phase II studies.
• Determine the pharmacokinetics of this drug in these patients.
• Determine the extent and duration of farnesyltransferase inhibition in peripheral blood mononuclear cells and other relevant surrogate markers of pharmacological activity in patients treated with this drug.
• Determine any preliminary evidence of antitumor activity of this drug in these patients.
• Determine pharmacodynamic relationships for the pharmacological effect of this drug upon surrogate markers of activity and host toxicity in these patients.
• Compare the toxicity profiles for the 1-hour vs 24-hour IV infusions of this drug in these patients.

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

Single patient cohorts receive BMS-214662 IV over escalating periods of 2, 4, 8, 16, and 24 hours weekly for 3 weeks followed by 1 week of rest. If no patient experiences dose-limiting toxicity (DLT), dose escalation proceeds in the single patient cohorts.

Treatment repeats every 4 weeks for at least 2 courses in the absence of disease progression or unacceptable toxicity. Individual patient cohorts may increase their duration of BMS-214662 infusion in subsequent courses to the current duration safely reached.

Beginning with the infusion level at which DLT is first encountered by a single patient, cohorts of 3-6 patients receive escalating doses of BMS-214662 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 DLT. An additional cohort of 10 patients is treated at the MTD.

Patients are followed for at least 4 weeks.

PROJECTED ACCRUAL: A total of 20-40 patients will be accrued for this study within 9-12 months.

DISEASE CHARACTERISTICS:

• Diagnosis of metastatic or inoperable malignancy for which no known curative or survival-prolonging palliative therapy exists or which has failed these therapies
• No leukemia or primary CNS tumor
• No active brain metastases, including cerebral edema by CT scan or MRI, progression from prior imaging study, requirement for steroids, or clinical symptoms

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-1

Life expectancy:

• At least 2 months

Hematopoietic:

• Absolute neutrophil count at least 1,500/mm3
• Platelet count at least 100,000/mm3

Hepatic:

• SGOT/SGPT no greater than 2.5 times upper limit of normal (ULN)
• Bilirubin no greater than ULN

Renal:

• Creatinine no greater than ULN
• Creatinine clearance at least 50 mL/min
• No known pre-existing renal disease

Cardiovascular:

• No clinically significant atrial or ventricular arrhythmias
• No second- or third-degree heart block or prolonged QTc interval (greater than 450 ms)

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No uncontrolled serious medical or psychiatric illness

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• At least 4 weeks since prior chemotherapy

Endocrine therapy:

• See Disease Characteristics

Radiotherapy:

• At least 4 weeks since prior radiotherapy
• No concurrent radiotherapy

Surgery:

• At least 3 weeks since prior major surgery

Other:

• At least 7 days since prior substrates of cytochrome P450-3A4 (CYP3A4), including terfenadine, astemizole, triazolam, midazolam, cisapride, bepridil, rifabutin, simvastatin, lovastatin, and propafenone
• No substrates of CYP3A4 during and for at least 1 week after study
• No non-steroidal anti-inflammatory drugs or other potentially nephrotoxic medications for at least 2 days before, during, and for at least 2 days after study drug administration