Biological Therapy in Treating Women With Stage IV Breast Cancer

Barbara Ann Karmanos Cancer Institute

Status and phase: Completed; Phase 1

Conditions: Breast Cancer

Treatments: Biological: therapeutic autologous lymphocytes; Biological: Aldesleukin; Biological: Sargramostim

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00027807

WSU-010307M1F (Other Identifier)

P30CA022453 (U.S. NIH Grant/Contract)

RWMC-0635146

CDR0000069072

WSU-0312004412 (Other Identifier)

2006-130 (Other Identifier)

Details and patient eligibility

About

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.

Full description

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)

Enrollment: 6 patients

Sex: Female

Ages: 18 to 120 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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6 participants in 1 patient group

Aldesleukin, Sargramostim & therapeutic autologous lymphocytes

Experimental group

Description:

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.

Treatment:

Biological: Sargramostim

Biological: Aldesleukin

Biological: therapeutic autologous lymphocytes