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

Study Overview
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Brief Summary
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RATIONALE: Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Imatinib mesylate may stop the growth of tumor cells by blocking the enzymes necessary for their growth and by stopping blood flow to the tumor. Giving trastuzumab together with imatinib mesylate may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of imatinib mesylate when given together with trastuzumab in treating patients with recurrent or metastatic HER2/neu-expressing (producing) cancer.

Detailed Description
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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.

Official Title
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Phase I of Trastuzumab and Imatinib Mesylate (Gleevec®, Formerly Known as STI-571) in Patients With Recurrent or Metastatic Her-2/Neu Expressing Cancer

Conditions
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Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Biological: trastuzumab
* Drug: imatinib mesylate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: trastuzumab|nan|
|Drug: imatinib mesylate|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) of imatinib mesylate given concurrently with trastuzumab (Herceptin®) as measured by CTC v 3.0 at course 1 |  |  | 
| Response as measured by RECIST criteria every 9 weeks |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Circulating tumor cells in blood as measured by Immunicom Cell PrepTM at baseline, every 3 weeks until week 9, and then with each disease re-evaluation |  |  | 
| Phosphorylation status of AKT, extracellular signal-regulated kinase (ERK), and KIT as measured by western blot and/or immunohistochemistry at baseline and week 9 |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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unspecified adult solid tumor, protocol specific