BMS-599626 in Treating Patients With Metastatic Solid Tumors

OBJECTIVES:

Primary

• Determine the maximum tolerated dose, biologically active dose, and recommended phase II dose(s) of BMS-599626 in patients with metastatic HER2/neu-overexpressing primary solid tumors.

Secondary

• Determine the safety and tolerability of this drug in these patients.
• Determine the pharmacokinetics of this drug in these patients.
• Determine the effect of this drug on biomarkers and predictive markers of HER1 and HER2 in skin and tumor in these patients.
• Evaluate tumor metabolic activity in response to this drug in these patients.
• Determine, preliminarily, evidence of anti-tumor activity of this drug in these patients.

OUTLINE: This is an open-label, dose-escalation, multicenter study.

Patients receive oral BMS-599626 once daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of BMS-599626 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, 20 patients are treated at that dose level.

PROJECTED ACCRUAL: Approximately 3-60 patients will be accrued for this study within 1 year.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed primary solid (i.e., non-hematologic) tumor

• Radiographic or tissue confirmation of metastatic disease

• Locally advanced disease allowed if no surgical or local therapeutic treatment exists
• HER2/neu overexpression (1+, 2+, or 3 +) by immunohistochemistry

• Tumors with HER2 gene amplification by fluorescence in situ hybridization analysis allowed
• Tumor paraffin tissue block OR 20-30 unstained slides from tumor tissue block must be available for biomarker and predictive marker analyses
• Disease progression during or after standard therapy OR no standard therapy exists
• Measurable or non-measurable disease

• Measurable disease is required for the expanded cohort treated at the maximum tolerated dose of the study drug
• No known brain metastasis

• Patients with controlled brain metastasis with no disease progression 60 days after prior therapy and no neurologic signs or symptoms are allowed

• Patients with signs or symptoms suggestive of brain metastasis are eligible provided that brain metastasis is ruled out by CT scan or MRI

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-1

Life expectancy

• At least 3 months

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 9.0 g/dL

Hepatic

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• ALT and AST ≤ 2.5 times ULN
• PT/PTT ≤ 1.5 times ULN
• INR ≤ 1.5 times ULN

Renal

• Creatinine ≤ 1.5 times ULN
• Calcium normal

Cardiovascular

• LVEF ≥ 45%
• Heart rate ≥ 50 beats/min on electrocardiogram
• No uncontrolled cardiovascular disease
• No myocardial infarction within the past 12 months
• No uncontrolled angina within the past 6 months
• No congestive heart failure within the past 6 months
• No prolonged QTc (> 450 msec) on electrocardiogram
• No diagnosed or suspected congenital long QT syndrome
• No history of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, or torsades de pointes)
• No history of second- or third-degree heart block

• Patients with pacemakers may be eligible
• No uncontrolled hypertension

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for at least 3 months after study participation
• Potassium normal
• Magnesium normal
• No medical condition that has a risk of causing torsades de pointes
• No active infection
• No serious uncontrolled medical disorder that would preclude study participation
• No dementia or altered mental status that would preclude giving informed consent
• No known allergy to BMS-599626 or related compound
• No prisoners or patients involuntarily incarcerated for treatment of either a psychiatric or physical (e.g., infectious disease) illness

PRIOR CONCURRENT THERAPY:

Biologic therapy

• At least 4 weeks since prior immunotherapy
• At least 2 weeks since prior targeted kinase inhibitor (e.g., trastuzumab [Herceptin^®])

Chemotherapy

• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas, mitomycin, or doxorubicin HCl liposome)

Endocrine therapy

• At least 2 weeks since prior anticancer hormonal therapy

Radiotherapy

• At least 4 weeks since prior radiotherapy

Surgery

• Not specified

Other

• Recovered from prior therapy
• Prior adjuvant or neoadjuvant therapy allowed
• No short-acting antacids (e.g., Maalox^® or TUMS^®) 8 hours before or 4 hours after study drug administration
• No recent anticancer therapy
• More than 4 weeks since prior investigational agents
• At least 5 days (or 5 half-lives) since prior drugs that cause torsades de pointes
• At least 48 hours since prior proton pump inhibitors (e.g., omeprazole or lansoprazole) or histamine H_2 antagonists (e.g., ranitidine, famotidine, or cimetidine)
• Concurrent low-dose coumadin allowed
• No other concurrent investigational agents
• No concurrent drugs that may cause torsades de pointes or QTc prolongation