Biological Therapy in Treating Women With Stage IV Breast Cancer

Breast Cancer Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00027807
• Other study ID #: CDR0000069072
• Secondary ID: P30CA0224532006-
• Status: Completed
• Phase: Phase 1
• First received: December 7, 2001
• Last updated: February 15, 2016
• Start date: October 2001
• Est. completion date: March 2013

Study information

• Verified date: February 2016
• Source: Barbara Ann Karmanos Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 6
• Est. completion date: March 2013
• Est. primary completion date: September 2010
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 120 Years

Eligibility

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

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

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.
• 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.
• 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.

Locations

Country	Name	City	State
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
Barbara Ann Karmanos Cancer Institute	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (4)

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

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.

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: — View Citation

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Yes
Primary	Toxicity profile		Months 1, 2, 5 and 11, then every 6 months	Yes
Primary	Clinical responses		Months: 1, 2, 5 and 11, then every 6 months	No
Primary	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	No
Secondary	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)	No