Trastuzumab and Imatinib Mesylate in Treating Patients With Recurrent or Metastatic HER2/Neu-Expressing Cancer

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of imatinib mesylate when administered with trastuzumab (Herceptin®) in patients with recurrent or metastatic HER2/neu-overexpressing cancer.
• Determine response in patients treated with this regimen.

Secondary

• Correlate the number of circulating tumor cells with radiographic imaging in patients treated with this regimen.

OUTLINE: This is a dose-escalation study of imatinib mesylate.

Patients receive trastuzumab (Herceptin®) IV over 90 minutes on day 1 and oral imatinib mesylate once or twice daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of imatinib mesylate 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.

PROJECTED ACCRUAL: Approximately 9-18 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed cancer that overexpresses HER2/neu, measured 3+ by immunohistochemistry or positive by fluorescence in situ hybridization

• Recurrent or metastatic disease
• Meets 1 of the following criteria for measurable or evaluable disease:

• Unidimensionally measurable disease at least 20 mm by conventional techniques OR at least 10 mm by spiral CT scan
• Evaluable disease, defined as a lesion on physical examination or imaging study that can be assessed as to changes in size but cannot be clearly measured in 1 dimension (e.g., pleural effusions, ascites, or bone disease)
• No carcinomatous meningitis or untreated/uncontrolled metastatic brain parenchymal disease

• Prior controlled brain parenchymal disease allowed provided at least 8 weeks since prior therapy AND no symptomatic progression off corticosteroids

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic

• ALT and AST ≤ 2.0 times upper limit of normal (ULN)
• Alkaline phosphatase ≤ 2.0 times ULN
• Bilirubin ≤ 1.3 mg/dL
• No known chronic liver disease (i.e., chronic active hepatitis or cirrhosis)

Renal

• Creatinine ≤ 2.0 mg/dL

Cardiovascular

• Ejection fraction ≥ lower limit of normal by MUGA
• No uncontrolled or significant cardiovascular disease
• No myocardial infarction within the past 6 months
• No ischemic heart disease requiring medication
• No congestive heart failure

Pulmonary

• No uncontrolled or significant pulmonary disease

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective barrier contraception during and for 3 months after study participation
• No active unresolved infection

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Prior trastuzumab (Herceptin®) allowed
• No concurrent filgrastim (G-CSF) or sargramostim (GM-CSF) to support blood counts
• No other concurrent anticancer biologic agents

Chemotherapy

• Prior chemotherapy for metastatic disease allowed
• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas) and recovered
• No concurrent anticancer chemotherapy

Endocrine therapy

• See Disease Characteristics

Radiotherapy

• At least 4 weeks since prior radiotherapy and recovered

Surgery

• More than 2 weeks since prior major surgery

Other

• At least 7 days since prior antibiotics
• No concurrent parenteral antibiotics
• No other concurrent anticancer agents
• No other concurrent investigational drugs
• No concurrent therapeutic anticoagulation with warfarin

• Concurrent mini-dose warfarin (1 mg/day) for prophylaxis of central venous catheter thrombosis allowed