Biological Therapy in Treating Women With Stage IV Breast Cancer

NCT ID: NCT00027807

Last Updated: 2016-02-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 6 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2001-10-31
• Study Completion Date: 2013-03-31

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.

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)

Conditions

Breast Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Aldesleukin

Intervention Type: BIOLOGICAL

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.

Sargramostim

Intervention Type: BIOLOGICAL

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.

therapeutic autologous lymphocytes

Intervention Type: BIOLOGICAL

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: BIOLOGICAL

Other Intervention Names

Proleukin ®; IL-2; LeukineTM; GM-CSF; Granulocyte-Macrophage Colony Stimulating Factor

Eligibility Criteria

Inclusion 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 120 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Barbara Ann Karmanos Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Lawrence Lum

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Lawrence G. Lum, MD, DSc

Role: STUDY_CHAIR

Barbara Ann Karmanos Cancer Institute

Locations

Barbara Ann Karmanos Cancer Institute

Detroit, Michigan, United States

Countries

United States

References

Lum LG, Rathore R, Colvin GA, et al.: Targeting HER2/neu tumor cells with anti-CD3 activated T cells: clinical trials and trafficking studies. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-719, 2003.

Reference Type: BACKGROUND

Grabert RC, Smith JA, Tiggs JC, et al.: Anti-CD3 activated T cells (ATC) armed with OKT3 x Herceptin Bispecific antibody (Her2Bi), survive and divide, and secrete cytokines and chemokines after multiple cycles of killing directed at Her2/neu+ (Her2) tumor targets. [Abstract] Proceedings of the 94th Annual Meeting of the American Association of Cancer Research 44: A-2872, 565, 2003.

Reference Type: RESULT

Sen M, Wankowski DM, Garlie NK, Siebenlist RE, Van Epps D, LeFever AV, Lum LG. Use of anti-CD3 x anti-HER2/neu bispecific antibody for redirecting cytotoxicity of activated T cells toward HER2/neu+ tumors. J Hematother Stem Cell Res. 2001 Apr;10(2):247-60. doi: 10.1089/15258160151134944.

Reference Type: RESULT

PMID: 11359672 (View on PubMed)

Lum LG, Thakur A, Al-Kadhimi Z, Colvin GA, Cummings FJ, Legare RD, Dizon DS, Kouttab N, Maizel A, Colaiace W, Liu Q, Rathore R. Targeted T-cell Therapy in Stage IV Breast Cancer: A Phase I Clinical Trial. Clin Cancer Res. 2015 May 15;21(10):2305-14. doi: 10.1158/1078-0432.CCR-14-2280. Epub 2015 Feb 16.

Reference Type: RESULT

PMID: 25688159 (View on PubMed)

Park JA, Santich BH, Xu H, Lum LG, Cheung NV. Potent ex vivo armed T cells using recombinant bispecific antibodies for adoptive immunotherapy with reduced cytokine release. J Immunother Cancer. 2021 May;9(5):e002222. doi: 10.1136/jitc-2020-002222.

Reference Type: DERIVED

PMID: 33986124 (View on PubMed)

Other Identifiers

P30CA022453

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2006-130

Identifier Type: OTHER

Identifier Source: secondary_id

RWMC-0635146

Identifier Type: -

Identifier Source: secondary_id

WSU-010307M1F

Identifier Type: OTHER

Identifier Source: secondary_id

WSU-0312004412

Identifier Type: OTHER

Identifier Source: secondary_id

CDR0000069072

Identifier Type: -

Identifier Source: org_study_id