BMS-214662 Plus Trastuzumab in Treating Patients With Advanced Solid Tumors

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose and recommended phase II dose of BMS-214662 when combined with trastuzumab (Herceptin) in patients with advanced solid tumors.

II. Determine the dose-limiting toxic effects of this regimen in these patients.

SECONDARY OBJECTIVES:

I. Determine the pharmacokinetics of this regimen in these patients. Ii. Determine, in a preliminary manner, the antitumor activity of this regimen in these patients.

OUTLINE: This is a dose-escalation study of BMS-214662.

Patients receive BMS-214662 IV over 1 hour on days 2, 8, 15, and 22 and trastuzumab (Herceptin) IV over 30-90 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

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 6 patients experience dose-limiting toxicity. Once the MTD is determined, additional patients are accrued to receive treatment with BMS-214662 and trastuzumab at the recommended phase II dose.

PROJECTED ACCRUAL: A total of 3-28 patients will be accrued for this study.

Inclusion criteria

• Histologically or cytologically confirmed solid tumor that is unresponsive to currently available therapies or for which no known effective therapy exists
• Overexpressing HER-2-neu (2+ or 3+) by immunohistochemistry or fluorescent in situ hybridization
• Clinically or radiologically evaluable disease
• No carcinomatous meningitis or untreated/uncontrolled metastatic brain parenchymal disease

• At least 8 weeks since prior therapy for prior brain parenchymal disease and asymptomatic off corticosteroids
• Performance status - ECOG 0-2
• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Bilirubin no greater than 1.8 mg/dL
• ALT and AST no greater than 1.5 times upper limit of normal (ULN)
• Creatinine no greater than 1.5 times ULN
• No uncontrolled or significant cardiovascular disease
• No myocardial infarction within the past 6 months
• No prior clinically significant atrial or ventricular arrhythmias
• No prior second or third degree heart block
• No ischemic heart disease requiring medication
• No congestive heart failure
• Corrected QT interval no greater than 450 milliseconds by electrocardiogram
• Ejection fraction at least lower limit of normal by MUGA scan
• No uncontrolled or significant pulmonary disease
• No active unresolved infection
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after study
• At least 4 weeks since prior immunotherapy, including trastuzumab (Herceptin), and recovered
• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered
• No anthracyclines for at least 22 weeks after completion of study therapy
• No other concurrent chemotherapy
• Concurrent hormone replacement therapy allowed
• No other concurrent hormonal therapy
• At least 4 weeks since prior radiotherapy and recovered
• No prior radiotherapy to more than 25% of the bone marrow-containing skeleton
• No concurrent radiotherapy
• At least 4 weeks since prior investigational agents and recovered
• At least 7 days since prior known substrates of cytochrome P450-3A4 (CYP3A4)
• At least 7 days since prior parenteral antibiotics
• No concurrent substrates of CYP3A4
• No concurrent parenteral antibiotics
• No other concurrent experimental medications