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

• Sponsor: University of Washington (Other)
• Overall Status: Completed
• CT.gov ID: NCT00425672
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 15
• Location: 1
• Arm: 1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Male Breast Cancer; Recurrent Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer	Biological: ONTAK; Other: flow cytometry; Other: immunohistochemistry staining method; Other: enzyme-linked immunosorbent assay; Other: laboratory biomarker analysis; Genetic: protein expression analysis	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To evaluate the safety of ONTAK infusion in patients with advanced refractory breast cancer.

2. To evaluate the effect of ONTAK administration on peripheral blood T-regulatory cells.

SECONDARY OBJECTIVES:

1. 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.

2. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I-II Study of Denileukin Diftitox (ONTAK®) in Patients With Advanced Refractory Breast Cancer
• Actual Study Start Date: Sep 1, 2005
• Actual Primary Completion Date: Apr 1, 2010

Arms and Interventions

Arm

Intervention/Treatment

Experimental: 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.

Biological: ONTAK; Given IV; Other Names: DAB389 interleukin-2 DAB389 interleukin-2 immunotoxin DAB389-IL2 DAB389IL-2 denileukin diftitox DAB389IL2 DABIL2 ; Other: flow cytometry; Correlative studies; Other: immunohistochemistry staining method; Correlative studies; Other Names: immunohistochemistry ; Other: enzyme-linked immunosorbent assay; Correlative studies; Other Names: ELISA ; Other: laboratory biomarker analysis; Correlative studies; Genetic: protein expression analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

2. 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.

3. Presence of Endogenous Tumor-specific Immunity [21 days after cycle 6]

   Evaluate the effect of ONTAK on endogenous tumor specific immunity

4. 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington	United States	98109

Sponsors and Collaborators

• University of Washington
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Lupe Salazar, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mary (Nora) Disis, Principal Investigator, University of Washington
• ClinicalTrials.gov Identifier: NCT00425672
• Other Study ID Numbers: 6308 (FH/UWCC ID); NCI-2010-00800; 127; NCT00364208
• First Posted: Jan 23, 2007
• Last Update Posted: Dec 5, 2018
• Last Verified: Nov 1, 2018

• Additional relevant MeSH terms: Breast Neoplasms; Breast Neoplasms, Male; Interleukin-2; Denileukin diftitox; Immunotoxins

Study Results

Participant Flow

Arm/Group Title	ONTAK
Arm/Group Description	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
Period Title: Overall Study
STARTED	15
COMPLETED	14
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Arm I
Arm/Group Description	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
Overall Participants	15
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	13 86.7%
>=65 years	2 13.3%
Sex: Female, Male (Count of Participants)
Female	15 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 6.7%
Not Hispanic or Latino	14 93.3%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 6.7%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 6.7%
White	13 86.7%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	15 100%

Outcome Measures

1. Primary Outcome

Title	Safety Evaluated by Collecting Study Related Toxicity as Assessed by CTCAE v3.0
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I
Arm/Group Description	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
Measure Participants	15
Count of Participants [Participants]	15 100%

2. Primary Outcome

Title	Efficacy of ONTAK in Depleting T-regulatory Cells as a Decrease in Peripheral Blood Tregs Using Flow Cytometry
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Arm I
Arm/Group Description	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
Measure Participants	14
Count of Participants [Participants]	4 26.7%

3. Secondary Outcome

Title	Incidence of Interleukin-2 (IL-2) and IL-2 Receptor (IL-2R) Expression in Tumor Samples by Immunohistochemical (IHC) Analysis
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I
Arm/Group Description	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
Measure Participants	14
YES	8 53.3%
NO	6 40%

4. Secondary Outcome

Title	Presence of Circulating sIL-2R in the Peripheral Blood
Description	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

Outcome Measure Data

Analysis Population Description

4/14 patients had peripheral blood available before and after ONTAK treatment.

Arm/Group Title	Arm I
Arm/Group Description	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
Measure Participants	14
Pre ONTAK Treatment	4.8
6 Weeks Post ONTAK Treatment	8.1
12-16 Weeks Post ONTAK Treatment	34.8
18-23 Weeks Post ONTAK Treatment	17.7

5. Secondary Outcome

Title	Presence of Endogenous Tumor-specific Immunity
Description	Evaluate the effect of ONTAK on endogenous tumor specific immunity
Time Frame	21 days after cycle 6

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I
Arm/Group Description	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
Measure Participants	14
Count of Participants [Participants]	10 66.7%

6. Secondary Outcome

Title	Anti-tumor Effects of ONTAK Determined by Tumor Response and Progression
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I
Arm/Group Description	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
Measure Participants	15
Complete Response (CR)	0 0%
Partial Response (PR)	0 0%
Progressive Disease (PD)	10 66.7%
Stable Disease (SD)	4 26.7%

Adverse Events

Arm/Group Title	Arm I
Arm/Group Description	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
All Cause Mortality
	Arm I
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Arm I
	Affected / at Risk (%)	# Events
Total	1/15 (6.7%)
Gastrointestinal disorders
Severe Nausea and Vomiting	1/15 (6.7%)	1
Other (Not Including Serious) Adverse Events
	Arm I
	Affected / at Risk (%)	# Events
Total	15/15 (100%)
Blood and lymphatic system disorders
Hemoglobin Abnormal	8/15 (53.3%)	18
Lymphopenia	4/15 (26.7%)	8
Platelets Abnormal	3/15 (20%)	6
Leukocytes Abnormal	2/15 (13.3%)	7
ANC/AGC Abnormal	2/15 (13.3%)	3
Blood and Lymphatic System Disorders - Other	1/15 (6.7%)	3
Blood and Lymphatic System Disorders - Other	1/15 (6.7%)	1
Blood and Lymphatic System Disorders - Other	1/15 (6.7%)	2
Cardiac disorders
Cardiac Arrhythmia	1/15 (6.7%)	2
Hypertension	1/15 (6.7%)	2
Ear and labyrinth disorders
Tinnitus	1/15 (6.7%)	1
Other - Ringing in Ear	1/15 (6.7%)	1
Eye disorders
Loss of Acuity Related to Illness	1/15 (6.7%)	1
Vitreous Detachment	1/15 (6.7%)	1
Vision Blurred - Vision	1/15 (6.7%)	1
Watery Eye	1/15 (6.7%)	1
Gastrointestinal disorders
Weight Gain	1/15 (6.7%)	2
Weight Loss	1/15 (6.7%)	1
Constipation	12/15 (80%)	26
Nausea	9/15 (60%)	22
Anorexia	9/15 (60%)	14
Vomiting	7/15 (46.7%)	10
Diarrhea	4/15 (26.7%)	5
Gastritis	2/15 (13.3%)	2
Abdomen NOS	2/15 (13.3%)	3
General disorders
Fatigue	12/15 (80%)	36
Rigors/Chills	11/15 (73.3%)	12
Fever	4/15 (26.7%)	5
Pain - Tightness in Shoulders Secondary to Benadryl IV	1/15 (6.7%)	1
Flu-Like Syndrome	5/15 (33.3%)	10
Infections and infestations
Infection - Toe	1/15 (6.7%)	1
Investigations
Allergic Reaction/Hypersensitivity	1/15 (6.7%)	1
AST Abnormal	14/15 (93.3%)	34
ALT Abnormal	14/15 (93.3%)	33
Alkaline Phosphatase Abnormal	6/15 (40%)	11
Hypoproteinemia	2/15 (13.3%)	7
Metabolism and nutrition disorders
Dehydration	1/15 (6.7%)	2
Hypocalcemia	12/15 (80%)	28
Hypoalbuminemia	11/15 (73.3%)	27
Hypokalemia	10/15 (66.7%)	31
Hyperglycemia	8/15 (53.3%)	21
Creatinine Abnormal	8/15 (53.3%)	19
Hypoglycemia	2/15 (13.3%)	4
Hyponatremia	1/15 (6.7%)	2
Alkalosis (metabolic or respiratory)	1/15 (6.7%)	1
Hyperbilirubinemia	1/15 (6.7%)	1
Chloride High	1/15 (6.7%)	5
Leg Cramps	1/15 (6.7%)	1
Musculoskeletal and connective tissue disorders
Muscle Weakness	1/15 (6.7%)	2
Myalgia	6/15 (40%)	8
Arthralgia	5/15 (33.3%)	6
Pain - Chest Wall	4/15 (26.7%)	4
Pain - Back	3/15 (20%)	7
Pain - Muscle	3/15 (20%)	3
Pain - Bone	2/15 (13.3%)	3
Extremity	1/15 (6.7%)	2
Pain - Arm	1/15 (6.7%)	1
Pain - Musculoskeletal - Extremity	1/15 (6.7%)	1
Pain - Rib	1/15 (6.7%)	1
Arthralgia	1/15 (6.7%)	1
Nervous system disorders
Taste Alteration (dysgeusia)	1/15 (6.7%)	1
Dizziness	4/15 (26.7%)	5
Neuropathy: Sensory	4/15 (26.7%)	4
Ataxia (incoordination)	1/15 (6.7%)	1
Neuropathy: Motor	1/15 (6.7%)	4
Headache	10/15 (66.7%)	18
Psychiatric disorders
Insomnia	10/15 (66.7%)	14
Mood Alteration	3/15 (20%)	3
Confusion	2/15 (13.3%)	2
Respiratory, thoracic and mediastinal disorders
Throat/Pharynx/Larynx	1/15 (6.7%)	1
Dyspnea (Shortness of Breath)	9/15 (60%)	11
Cough	8/15 (53.3%)	12
Rhinitis	2/15 (13.3%)	3
Pleural Effusion (non-malignant)	1/15 (6.7%)	1
Pulmonary Fibrosis (radiologic changes)	1/15 (6.7%)	1
Skin and subcutaneous tissue disorders
Rash/Desquamation	2/15 (13.3%)	2
Rash: Acne/Acneiform	1/15 (6.7%)	1
Vascular disorders
Hypotension	2/15 (13.3%)	4
Flushing	1/15 (6.7%)	1
Edema: Limb	4/15 (26.7%)	6
Acute Vascular Leak Syndrome	10/15 (66.7%)	19

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.