Phase I Study of Intravenous BMS-214662 FTI (NSC# 710086) and Herceptin (NSC# 688097) Weekly in Patients With Advanced Malignancies
Phase I Study of Intravenous BMS-214662 FTI (NSC# 710086) and Herceptin (NSC# 688097) Weekly in Patients With Advanced Malignancies
Phase I trial to study the effectiveness of BMS-214662 plus trastuzumab in treating patients who have advanced solid tumors. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Combining monoclonal antibody therapy with chemotherapy may kill more tumor cells
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
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