ONTAK® in Treating Patients With Advanced Breast Cancer That Did Not Respond to Previous Treatment

Study Overview
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Brief Summary
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RATIONALE: ONTAK may be able to help reduce the type of cells that prevent other types of immune cells from attacking the breast cancer cells. PURPOSE: This phase I/II trial is studying the safety of ONTAK and its possible side effects to see how well it works in treating patients with advanced breast cancer that did not respond to previous treatment.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the safety of ONTAK infusion in patients with advanced refractory breast cancer. II. To evaluate the effect of ONTAK administration on peripheral blood T-regulatory cells. SECONDARY OBJECTIVES: I. To evaluate the incidence of IL-2R expression in tumor samples and investigate the correlation of tumor IL-2R expression and tumor response to ONTAK therapy. II. To evaluate levels of circulating sIL-2R before and after ONTAK therapy. III. To evaluate the effect of ONTAK on endogenous tumor specific immunity. IV. To evaluate the potential anti-tumor effects of ONTAK in patients with advanced refractory breast cancer. OUTLINE: Patients receive ONTAK IV over 1 hour on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 1 year.

Official Title
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Phase I-II Study of Denileukin Diftitox (ONTAK®) in Patients With Advanced Refractory Breast Cancer

Conditions
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Male Breast Cancer, Recurrent Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer

Intervention / Treatment
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* Biological: ONTAK
* Other: flow cytometry
* Other: immunohistochemistry staining method
* Other: enzyme-linked immunosorbent assay
* Other: laboratory biomarker analysis
* Genetic: protein expression analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with advanced stage refractory breast cancer Progressive or relapsed disease following standard therapy Patients must have measurable disease that can include, but is not limited to bone; specifically, patients must have measurable extraskeletal disease that can be accurately measured in at least one dimension as >= 20 mm with conventional CT techniques or >= 10 mm with spiral CT scan; measurable (bi-dimensional) chest wall disease will also be allowed Patients must be at least 14 days out from last cytotoxic chemotherapy; patients on bisphosphonates are eligible White blood cell count (WBC) > 3.0 THOU/ul ANC > 1.0 THOU/ul Platelets >= 100 THOU/ul Serum creatinine =< 2.0 mg/dL or creatinine clearance (calculated) >= 60 ml/min ALT/AST =< 2.0 x upper limit of normal Total bilirubin =< 1.5 x upper limit of normal Albumin >= 3.0 g/dL Subjects must have a Performance Status Score (ECOG Scale) =< 2 Subjects must have recovered from major infections and/or surgical procedures and, in the opinion of the investigator, not have a significant active concurrent medical illness precluding protocol treatment Men and women of reproductive ability must agree to contraceptive use during the study and for 1month after ONTAK treatment is discontinued Exclusion Criteria: Prior treatment with ONTAK (DAB389 IL-2) or DAB486 IL-2 Known history of hypersensitivity to diphtheria toxin or IL-2 Active autoimmune disease Known history of pulmonary disease except controlled asthma History of or pre-existing, cardiovascular disease as defined by New York Heart Association (NYHA) Class III-IV categorization Pregnant or breast-feeding women

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Arm I<br>Patients receive ONTAK IV over 1 hour on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. | Biological: ONTAK<br>* Given IV<br>* Other names: DABIL2;Other: flow cytometry<br>* Correlative studies<br>Other: immunohistochemistry staining method<br>* Correlative studies<br>* Other names: immunohistochemistry;Other: enzyme-linked immunosorbent assay<br>* Correlative studies<br>* Other names: ELISA;Other: laboratory biomarker analysis<br>* Correlative studies<br>Genetic: protein expression analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Evaluated by Collecting Study Related Toxicity as Assessed by CTCAE v3.0 | Subjects are monitored for the development of end organ damage by assessing adverse events with serum chemistries, liver function studies, serum albumin, complete blood counts, symptom assessment, and physical exams performed at every cycle until 3 weeks after the final dose of ONTAK. All adverse events for all systems are graded on a scale of 1-5 using CTCAE v3.0. | 7 Days after last dose of ONTAK | 
| Efficacy of ONTAK in Depleting T-regulatory Cells as a Decrease in Peripheral Blood Tregs Using Flow Cytometry | The efficacy of ONTAK in depleting Tregs will be defined as a decrease in peripheral blood Tregs by 25% of each individual subject's baseline. All subjects will undergo blood draws at baseline and post ONTAK infusions at designated time points. Tregs from the peripheral blood will be quantitated using flow cytometry. | 21 days after cycle 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Interleukin-2 (IL-2) and IL-2 Receptor (IL-2R) Expression in Tumor Samples by Immunohistochemical (IHC) Analysis | The incidence of IL-2 expression and its receptor complex, IL-2R in tumor samples will be evaluated by IHC analysis. Tumor sections will be interpreted as either positive or negative. | 21 days after cycle 6 | 
| Presence of Circulating sIL-2R in the Peripheral Blood | Evaluate levels of circulating sIL-2R (pg/ml) in the peripheral blood assessed before and after ONTAK therapy. Changes from baseline will be tabulated. | 21 days after cycle 6 | 
| Presence of Endogenous Tumor-specific Immunity | Evaluate the effect of ONTAK on endogenous tumor specific immunity | 21 days after cycle 6 | 
| Anti-tumor Effects of ONTAK Determined by Tumor Response and Progression | Anti-tumor effects of ONTAK will be determined by evaluating tumor response and progression per RECIST. An objective response to ONTAK will be defined as achieving a CR or PR. Analysis of the data will include determination of complete (CR) and partial response (PR) rates, as well as stable (SD) and progressive disease (PD). | 21 days after cycle 6 |