Biological Therapy in Treating Women With Stage IV Breast Cancer

Sponsor

Barbara Ann Karmanos Cancer Institute (Other)

Overall Status

Completed

CT.gov ID

NCT00027807

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arm

137

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Biological: Aldesleukin Biological: Sargramostim Biological: therapeutic autologous lymphocytes	Phase 1

Detailed 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)

Study Design

Study Type:

Interventional

Actual Enrollment :

6 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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)

Study Start Date :

Oct 1, 2001

Actual Primary Completion Date :

Sep 1, 2010

Actual Study Completion Date :

Mar 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Aldesleukin, Sargramostim & therapeutic autologous lymphocytes 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 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. Other Names: Proleukin ® IL-2 Biological: Sargramostim 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. Other Names: LeukineTM GM-CSF Granulocyte-Macrophage Colony Stimulating Factor Biological: therapeutic autologous lymphocytes 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.

Arm

Intervention/Treatment

Experimental: Aldesleukin, Sargramostim & therapeutic autologous lymphocytes

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

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.

Other Names:

Proleukin ®

IL-2

Biological: Sargramostim

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.

Other Names:

LeukineTM

GM-CSF

Granulocyte-Macrophage Colony Stimulating Factor

Biological: therapeutic autologous lymphocytes

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.

Outcome Measures

Primary Outcome Measures

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

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)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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)