Biological Therapy in Treating Women With Stage IV Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Biological therapies use different ways to stimulate the immune system and stop cancer cells from growing. Combining different types of biological therapies may kill more tumor cells. PURPOSE: Phase I/II trial to study the effectiveness of combining different biological therapies in treating women who have stage IV breast cancer.

Detailed Description
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OBJECTIVES: Determine the maximum tolerated dose of armed activated T cells given in combination with interleukin-2 and sargramostim (GM-CSF) in women with stage IV breast cancer. Determine the toxicity profile of this regimen in these patients. Determine the clinical response and overall and progression-free survival of patients treated with this regimen. OUTLINE: This is a dose-escalation study of armed activated T cells. Patients undergo peripheral blood mononuclear cell (PBMC) collection. The PBMCs are treated ex vivo with monoclonal antibody OKT3 to form armed activated T cells (ATC). The armed ATC are expanded for 14 days in interleukin-2 (IL-2). Patients receive armed ATC IV over 30 minutes twice weekly for 4 weeks. Patients also receive IL-2 subcutaneously (SC) once daily and sargramostim (GM-CSF) SC twice weekly beginning 3 days before the first infusion of armed ATC and continuing until 7 days after the last infusion of armed ATC. Cohorts of 3-6 patients receive escalating doses of armed ATC 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. Once the MTD is determined, additional patients are treated at that dose. Patients are followed at 1, 2, and 5 months and then every 6 months thereafter. PROJECTED ACCRUAL: A total of 15-30 patients will be accrued for the phase I portion of this study and a total of 18-33 patients will be accrued for the phase II portion of this study within 4-6 years. PLEASE NOTE: THIS STUDY WAS INTENDED TO BE A PHASE I/II STUDY, BUT NEVER MOVED FORWARD TO PHASE II. (4-22-09)

Official Title
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Treatment of Stage IV Breast Cancer With OKT3 x Herceptin Armed Activated T Cells, Low Dose IL-2, And GM-CSF (Phase I Only as of 4-22-09 as Per IRB Approval Date)

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: Aldesleukin
* Biological: Sargramostim
* Biological: therapeutic autologous lymphocytes


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Phase I: Histologically confirmed infiltrating ductal carcinoma of the breast Metastatic disease Clinically asymptomatic with non-life-threatening metastases allowed Measurable or evaluable disease by radiograph, CT scan, MRI, nuclear medicine bone scan, or physical examination No measurable disease allowed if tumor or metastasis has been removed or successfully treated prior to study No rapidly progressive symptomatic disease affecting major organ systems (e.g., lungs and liver) Stable or unstable disease for 3 months on hormonal therapy Stable or unstable disease for at least 1 month after chemotherapy No active brain metastases Brain metastases previously treated with definitive radiotherapy and/or surgical resection allowed Hormone receptor status: Estrogen and progesterone receptor status known Phase II: All Phase I criteria HER2/neu overexpression (2+ or 3+) by immunohistochemistry Prior trastuzumab (Herceptin) allowed if disease still overexpresses HER2/neu PATIENT CHARACTERISTICS: Age: 18 and over Sex: Female Menopausal status: Not specified Performance status: Karnofsky 70-100% OR ECOG 0-2 Life expectancy: At least 3 months Hematopoietic: Granulocyte count at least 1,500/mm^3 Platelet count at least 50,000/mm^3 Hemoglobin at least 8 g/dL Hepatic: Bilirubin less than 1.5 times normal SGOT less than 1.5 times normal Renal: Creatinine no greater than 1.8 mg/dL Creatinine clearance at least 60 mL/min BUN no greater than 1.5 times normal Cardiovascular: No myocardial infarction within the past year No prior myocardial infarction with coronary symptoms requiring medication and/or depressed left ventricular function (LVEF less than 50% by MUGA) No angina or coronary symptoms requiring medication and/or with depressed left ventricular function (LVEF less than 50% by MUGA) No congestive heart failure requiring medical management LVEF at least 50% at rest by MUGA No uncontrolled hypertension (i.e., systolic blood pressure [BP] ≥ 130 mm Hg or diastolic BP ≥ 80 mm Hg) Pulmonary: FEV1, DLCO, and FVC at least 50% predicted Other: Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception HIV negative No other serious medical or psychiatric illness that would preclude study participation No other prior or concurrent malignancy within the past 5 years except curatively treated squamous cell carcinoma in situ of the cervix, basal cell skin cancer, or any other curatively treated disease in complete remission PRIOR CONCURRENT THERAPY: Biologic therapy: See Disease Characteristics Prior trastuzumab allowed for phase I Chemotherapy: See Disease Characteristics At least 4 weeks since prior chemotherapy Endocrine therapy: See Disease Characteristics Concurrent hormonal therapy for breast cancer must continue during study No other concurrent hormonal therapy except steroids for adrenal failure, septic shock, or pulmonary toxicity or hormonal therapy for non-disease-related conditions (e.g., insulin for diabetes) Radiotherapy: See Disease Characteristics Surgery: See Disease Characteristics

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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Female

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: Aldesleukin, Sargramostim & therapeutic autologous lymphocytes<br>Peripheral blood mononuclear cells (PBMC) for the generation of ATC will be collected using 1 or 2 phereses to obtain 8-20 × 109 PBMC for T cell expansion. The PBMC will be activated with OKT3 and expanded in IL-2 to generate from 20-320 ×109 ATC during a maximum of 14 days of culture. Three patients will be treated at each dose level. The dose levels for each infusion are: 5, 10, 20, and 40 billion. Each patient will receive a total of 8 doses of armed ATC given twice weekly for 4 weeks. If the patients encounter toxicities related to armed ATC, the dose and administration will be modified as delineated per the protocol. The patients will also receive subcutaneous injections of IL-2 (3.0 × 105 IU/m2/day) starting 3 days before the 1st armed ATC infusion and ending 7 days after the last armed ATC infusion. GM-CSF (250μg/m2 twice per week) will given subcutaneously to start 3 days before the 1st armed ATC infusion and ending 7 days after the last dose of armed ATC. | Biological: Aldesleukin<br>* Subcutaneous injections of IL-2 (3.0 × 105 IU/m2/day) starting 3 days before the 1st armed ATC infusion and ending 7 days after the last armed ATC infusion.<br>* Other names: IL-2;Biological: Sargramostim<br>* GM-CSF Injections will be given SQ GM-CSF (250 μg/m2/twice weekly), to start 3 days before the first ATC infusion and ending 1 week after the last ATC infusion.<br>* Other names: Granulocyte-Macrophage Colony Stimulating Factor;Biological: therapeutic autologous lymphocytes<br>* The time for armed-ATC infusions will vary from patient to patient, but the dose of armed-ATC (up to 40 billion) will be given over 30 min.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose |  | The dose at which dose-limiting toxicity occurs is defined as that dose at which 2 or more of 6 patients at that dose level have their infusions stopped due to toxicities or receive less than 80% of the planned dose. | 
| Toxicity profile |  | Months 1, 2, 5 and 11, then every 6 months | 
| Clinical responses |  | Months: 1, 2, 5 and 11, then every 6 months | 
| Overall survival and progression-free survival |  | The interval from the beginning of immunotherapy to the time of death or for progression free survival it is defined as the interval from the beginning of immunotherapy to progression | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune changes |  | 1 (+ 7 days), 2 (+ 7 days), 5 months (+ 7 days), then every 6months (+ 7 days) (immune evaluations will also be performed after the 4th and 8th infusion of Her2Bi armed ATC and within 1week of the completion of HER2Bi armed ATC) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV breast cancer, recurrent breast cancer, ductal breast carcinoma