Trastuzumab and Interleukin-2 in Treating Patients With Metastatic Breast Cancer

Study Overview
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Brief Summary
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Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Interleukin-2 may stimulate a person's white blood cells to kill breast cancer cells. Phase II trial to study the effectiveness of trastuzumab plus interleukin-2 in treating patients who have metastatic breast cancer that has not responded to previous trastuzumab therapy.

Detailed Description
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PRIMARY OBJECTIVES: I. To estimate the response rate and toxicity to low-dose IL-2 with intermediate-pulse dose interleukin 2 (IL-2) and trastuzumab in patients with uni-dimensional measurable metastatic breast cancer and human epidermal growth factor receptor 2 (HER2) positive (3+ overexpression by immunohistochemistry [IHC] method or positive by fluorescent in situ hybridization [FISH]) who either have had evidence of progressive disease while receiving a trastuzumab-containing regimen, or have had progressive disease within 12 months of receiving a trastuzumab-containing regimen. SECONDARY OBJECTIVES: I. To perform correlative immunologic assays to determine the degree of natural killer (NK) cell expansion in response to low-dose IL-2, and the effectiveness of patients' peripheral blood mononuclear cells (PBMC) in a standard antibody-dependent cell-mediated cytotoxicity (ADCC) assay directed against a HER2 target cell. II. To determine the pharmacokinetics of trastuzumab using an every 2-week schedule. III. To determine Fc-gamma receptor polymorphisms from study patients. OUTLINE: This is a multicenter study. Patients receive trastuzumab intravenously (IV) over 30-90 minutes on days 1 and 8 and aldesleukin subcutaneously (SC) on days 2-7 and 9-21. Beginning on day 22, patients receive trastuzumab IV over 30 minutes every 14 days. Patients also receive aldesleukin SC daily on days 1-14. Treatment continues for 1 year in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for at least 30 days. PROJECTED ACCRUAL: A total of 17-37 patients will be accrued for this study.

Official Title
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Phase II Trial of Anti-HER-2 Monoclonal Antibody Trastuzumab (Herceptin) in Combination With Low Dose Interleukin-2 (Proleukin) in Metastatic Breast Cancer Patients Who Have Previously Failed Trastuzumab

Conditions
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HER2-positive Breast Cancer, Male Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer

Intervention / Treatment
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* Biological: trastuzumab
* Biological: aldesleukin
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed breast cancer Primary and/or metastatic disease HER2 overexpression 3+ by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) Tumors with HER2 2+ overexpression by IHC allowed if confirmed by FISH Progressive disease during or within 12 months of receiving prior regimen containing trastuzumab (Herceptin) Unidimensionally measurable disease At least 20 mm by conventional techniques OR at least 10 mm by spiral CT scan The following are not considered measurable: Bone metastases Pleural or peritoneal effusion Ascites Leptomeningeal disease Lymphangitic disease Inflammatory breast cancer Cystic lesions CNS lesions CNS metastases allowed if all of the following conditions are met: Asymptomatic At least 3 months since prior surgery and/or cranial irradiation At least 3 weeks since prior steroids Hormone receptor status: Not specified Male or female Performance status - ECOG 0-2 Granulocyte count at least 1,000/mm^3 Platelet count at least 100,000/mm^3 Bilirubin no greater than 1.5 times upper limit of normal (ULN) SGOT and SGPT no greater than 2 times ULN (5 times ULN for liver metastases) Alkaline phosphatase no greater than 2 times ULN (5 times ULN for liver metastases) Creatinine no greater than 1.5 times ULN LVEF at least lower limit of normal by MUGA or echocardiogram No congestive heart failure or active ischemic heart disease Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No psychiatric illness, medical condition, or uncontrolled infection that would preclude study No underlying immunodeficiency (e.g., HIV or autoimmune disease) No other prior malignancy within the past 5 years except nonmelanoma skin cancer or carcinoma in situ of the cervix See Disease Characteristics Prior cumulative doxorubicin dose no greater than 360 mg/m^2 At least 3 weeks since prior chemotherapy No more than 2 prior chemotherapy regimens for metastatic disease No concurrent chemotherapy See Disease Characteristics At least 3 weeks since prior endocrine therapy No concurrent corticosteroids or dexamethasone Concurrent hormones allowed for conditions unrelated to disease (e.g., insulin for diabetes) See Disease Characteristics At least 3 weeks since prior radiotherapy No prior radiotherapy to study lesion, unless evidence of disease progression No concurrent palliative radiotherapy See Disease Characteristics At least 4 weeks since prior major surgery No concurrent immunosuppressive drugs
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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (trastuzumab and aldesleukin)<br>Patients receive trastuzumab IV over 30-90 minutes on days 1 and 8 and aldesleukin SC on days 2-7 and 9-21. Beginning on day 22, patients receive trastuzumab IV over 30 minutes every 14 days. Patients also receive aldesleukin SC daily on days 1-14. Treatment continues for 1 year in the absence of disease progression or unacceptable toxicity. | Biological: trastuzumab<br>* Given IV<br>Biological: aldesleukin<br>* Given SC<br>Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate using Response Evaluation Criteria in Solid Tumors (RECIST) |  | Up to 12 months | 
| Toxicity assessed using Common Toxicity Criteria (CTC) version 2.0 |  | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Degree of NK cell expansion |  | Up to 12 months | 
| Effectiveness of patients' PBMCs in a standard ADCC assay directed against HER2 target cells |  | Up to 12 months |