Male Breast Cancer, Recurrent Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer
Conditions
Brief summary
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
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.
Interventions
BIOLOGICALONTAK
Given IV
OTHERflow cytometry
Correlative studies
OTHERimmunohistochemistry staining method
Correlative studies
OTHERenzyme-linked immunosorbent assay
Correlative studies
OTHERlaboratory biomarker analysis
Correlative studies
GENETICprotein expression analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
University of Washington
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety Evaluated by Collecting Study Related Toxicity as Assessed by CTCAE v3.0 | 7 Days after last dose of ONTAK | 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. |
| Efficacy of ONTAK in Depleting T-regulatory Cells as a Decrease in Peripheral Blood Tregs Using Flow Cytometry | 21 days after cycle 6 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Interleukin-2 (IL-2) and IL-2 Receptor (IL-2R) Expression in Tumor Samples by Immunohistochemical (IHC) Analysis | 21 days after cycle 6 | 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. |
| Presence of Circulating sIL-2R in the Peripheral Blood | 21 days after cycle 6 | Evaluate levels of circulating sIL-2R (pg/ml) in the peripheral blood assessed before and after ONTAK therapy. Changes from baseline will be tabulated. |
| Presence of Endogenous Tumor-specific Immunity | 21 days after cycle 6 | Evaluate the effect of ONTAK on endogenous tumor specific immunity |
| Anti-tumor Effects of ONTAK Determined by Tumor Response and Progression | 21 days after cycle 6 | 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). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I 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.
ONTAK: Given IV
flow cytometry: Correlative studies
immunohistochemistry staining method: Correlative studies
enzyme-linked immunosorbent assay: Correlative studies
laboratory biomarker analysis: Correlative studies
protein expression analysis: Correlative studies | 15 |
| Total | 15 |
Baseline characteristics
| Characteristic | Arm I |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 13 Participants |
| Region of Enrollment United States | 15 Participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 15 / 15 |
| serious Total, serious adverse events | 1 / 15 |
Outcome results
Primary
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.
Time frame: 21 days after cycle 6
Population: 14 patients equals patients that had repeat blood draws taken but did not complete the treatment except for 4 patients who completed the study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Efficacy of ONTAK in Depleting T-regulatory Cells as a Decrease in Peripheral Blood Tregs Using Flow Cytometry | 4 Participants |
Primary
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.
Time frame: 7 Days after last dose of ONTAK
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Safety Evaluated by Collecting Study Related Toxicity as Assessed by CTCAE v3.0 | 15 Participants |
Secondary
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).
Time frame: 21 days after cycle 6
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I | Anti-tumor Effects of ONTAK Determined by Tumor Response and Progression | Complete Response (CR) | 0 Participants |
| Arm I | Anti-tumor Effects of ONTAK Determined by Tumor Response and Progression | Partial Response (PR) | 0 Participants |
| Arm I | Anti-tumor Effects of ONTAK Determined by Tumor Response and Progression | Progressive Disease (PD) | 10 Participants |
| Arm I | Anti-tumor Effects of ONTAK Determined by Tumor Response and Progression | Stable Disease (SD) | 4 Participants |
Secondary
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.
Time frame: 21 days after cycle 6
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I | Incidence of Interleukin-2 (IL-2) and IL-2 Receptor (IL-2R) Expression in Tumor Samples by Immunohistochemical (IHC) Analysis | YES | 8 Participants |
| Arm I | Incidence of Interleukin-2 (IL-2) and IL-2 Receptor (IL-2R) Expression in Tumor Samples by Immunohistochemical (IHC) Analysis | NO | 6 Participants |
Secondary
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.
Time frame: 21 days after cycle 6
Population: 4/14 patients had peripheral blood available before and after ONTAK treatment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm I | Presence of Circulating sIL-2R in the Peripheral Blood | Pre ONTAK Treatment | 4.8 pg/ml |
| Arm I | Presence of Circulating sIL-2R in the Peripheral Blood | 6 Weeks Post ONTAK Treatment | 8.1 pg/ml |
| Arm I | Presence of Circulating sIL-2R in the Peripheral Blood | 12-16 Weeks Post ONTAK Treatment | 34.8 pg/ml |
| Arm I | Presence of Circulating sIL-2R in the Peripheral Blood | 18-23 Weeks Post ONTAK Treatment | 17.7 pg/ml |
Secondary
Presence of Endogenous Tumor-specific Immunity
Evaluate the effect of ONTAK on endogenous tumor specific immunity
Time frame: 21 days after cycle 6
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Presence of Endogenous Tumor-specific Immunity | 10 Participants |