Phase II Study of the Efficacy and Toxicity of Ontak(Registered Trademark) (Denileukin Diftitox) in the Therapy of Adult T-Cell Leukemia

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT00117845
• Collaborator: (none)
• Enrollment: 17
• Location: 1
• Arm: 1
• Actual Duration (Months): 95.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Adult T-cell leukemia (ATL) is and aggressive characterized by the presence of cluster of differentiation 4 (CD4)/cluster of differentiation 25 (CD25)-expressing T cells (interleukin-2 [IL-2]R expressing) in the peripheral blood and in lymphoid and other tissues. Denileukin diftitox (Ontak(Registered Trademark)) is a genetically engineered fusion protein that targets IL-2-expressing malignancies. Denileukin diftitox interacts with the IL-2R on the cell surface, is internalized via endocytosis, and inhibits cellular protein synthesis, resulting in cell death within hours to days. The objectives of this study are to determine the clinical response to Denileukin diftitox of patients with adult T-cell leukemia (ATL) and the safety of Denileukin diftitox in those patients.

Eligible participants must be 18 years of age or older with chronic, lymphomatous and acute forms of ATL, and must be infected with human T-cell lymphotropic virus type I (HTLV1).

Patients will be treated with 9 mcg/kg/d of Denileukin diftitox intravenously for 5 days every 2 weeks. Tumor response will be evaluated after two cycles of treatment. Stable or responding patients will continue treatment for a total of 12 months, with evaluations every four cycles of treatment. Patients will be treated for two cycles beyond a complete remission. The trial uses an optimal two-stage design targeting for a true response proportion of more than 30 percent. Nine patients will be treated initially, with expansion to 29 patients if a response is seen in 1 of the initial 9 patients treated. Treatment will be discontinued if a patient experiences serious side effects.

A potential benefit is that a patient may undergo partial or complete remission. The research may not directly benefit participants, but the results may aid in the treatment of others.

Condition or Disease	Intervention/Treatment	Phase
Leukemia, Adult T-Cell	Biological: Denileukin diftitox (Ontak)	Phase 2

Detailed Description

Background:

Adult T-Cell Leukemia is a lymphoproliferative disorder characterized by the presence of CD4/CD25 expressing T cells (IL-2R expressing) in the peripheral blood, in lymphoid and other tissues.

Denileukin diftitox is a genetically engineered fusion protein combining the enzymatically active domains of diphtheria toxin (DT) and the full length sequence of interleukin-2 (IL-2) that targets IL-2 expressing malignancies.

Denileukin diftitox interacts with the IL-2 R on the cell surface, is internalized via endocytosis, and inhibits cellular protein synthesis resulting in cell death within hours to days.

Objective:

Determine the clinical response to Denileukin diftitox (Ontak) of patients with adult T-cell leukemia (ATL).

Define the safety of Denileukin diftitox in patients who have ATL.

Eligibility:

Patients with chronic, lymphomatous and acute forms of ATL.

Patients must be human T-cell lymphotropic virus type I (HTLV1) positive.

Design:

Patients will be treated with 9mcg/kg/d of Denileukin diftitox for five days, on an every two week schedule.

Tumor response will be evaluated after two cycles of treatment. Stable or responding patients will continue treatment with evaluations every four cycles of treatment. Patients will be treated for two cycles beyond a complete remission.

The trial uses an optimal 2 stage design targeting for a true response proportion greater than 30%. Nine patients will be treated initially with expansion to 29 patients if a response is seen in one of the initial nine patients treated. If no response is seen at the 9 mcg/kg/d dose an additional 9 patients will be treated at a dose of 18 mcg/kg/d with expansion to 29 patients at this dose level if a response is seen. A stopping rule for excessive toxicity will be incorporated.

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of the Efficacy and Toxicity of Ontak (Denileukin Diftitox) in the Therapy of Adult T-Cell Leukemia
• Actual Study Start Date: Jul 11, 2005
• Actual Primary Completion Date: Dec 31, 2011
• Actual Study Completion Date: Jun 30, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Denileukin Diftitox in ATL Denileukin Diftitox in adult T-cell leukemia (ATL) Patients will be treated with Denileukin Diftitox 9 mcg/kg/d intravenously for 5 days every 2 weeks.	Biological: Denileukin diftitox (Ontak); Patients will be treated with Denileukin Diftitox 9 mcg/kg/d intravenously for 5 days every 2 weeks.

Outcome Measures

Primary Outcome Measures

1. Response Rate [up to 12 months]

   Response rate is based on the number of patients who achieve either a complete response (CR) or partial response (PR) to therapy. Complete response is complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease related symptoms if present before therapy and normalization of those biochemical abnormalities (for example LDH) definitely assignable to the lymphoma. Partial response is reduction by >=50% of leukemia cell count or >=50% reduction is the size of all measurable lesions, and no increase in size of any measurable or evaluable lesion or appearance of new lesion.

Secondary Outcome Measures

1. Number of Participants With Serious and Non-Serious Adverse Events [Date treatment consent signed to date off study, approximately 72 months]

   Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v3.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• INCLUSION CRITERIA:

Patients must have serum antibodies directed to human T-lymphotropic virus type 1 (HTLV-I).

All patients must have a histologically confirmed diagnosis of adult T-cell leukemia/lymphoma and more than 10% of the malignant cells must express cluster of differentiation 25 (CD25).

All stages of Tac-expressing adult T cell leukemia except smoldering are eligible: patients with chronic, lymphomatous or acute adult T-cell leukemia (ATL) are eligible. (See appendix 2 for characteristics of patients with the various stages of ATL)

Patients must have measurable disease. All patients with greater than 10% abnormal (i.e. TAC homogenous strongly expressing) peripheral blood mononuclear cells (PBMC) in the peripheral blood will be deemed to have measurable disease.

The patient must have a granulocyte count of at least 1000/mm^{3 and a platelet count of greater than or equal to 50,000/mm}3.

Patients must have a creatinine of less than 2.0 mg/dl.

Omission of cytotoxic chemotherapy for ATL for 3 weeks prior to entry into the trial is required. However, patients receiving corticosteroids will be eligible.

Patients must have a life expectancy of greater than 2 months.

Eligible patients must be greater than or equal to 18 years old. There is no upper age limit.

Patients must have serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) value less than or equal to 2.5 times the upper limit of normal and bilirubin less than or equal to 3.0/dl. If a liver function test is judged to be elevated due to the underlying ATL, this parameter will be considered an unevaluable parameter for toxicity determinations.

Patients must have a serum albumin greater than or equal to 2.5 g/dl

Patients must be able to understand and sign an Informed Consent form.

All patients must use adequate contraception during participation in this trial and for three months after completing therapy.

EXCLUSION CRITERIA:

Patients with symptomatic leukemic meningitis will be excluded. However, patients that have both ATL and another HTLV-I-associated disease, tropical spastic paraparesis (TSP), will be included.

Pregnant and nursing patients are not eligible for the study.

Human immunodeficiency virus (HIV) positive patients are excluded from the study. Denileukin diftitox may produce a different pattern of toxicities in immunocompromised individuals.

Patients with Smoldering ATL are excluded.

Patients with serious intercurrent illnesses, past history of a myocardial infarction within 6 months or severe coronary artery disease

Patients who previously received Denileukin diftitox are ineligible.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Thomas A Waldmann, M.D., National Cancer Institute (NCI)

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 10, 2014
• Informed Consent Form - Jun 13, 2011

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci U S A. 1980 Dec;77(12):7415-9.
• Uchiyama T, Yodoi J, Sagawa K, Takatsuki K, Uchino H. Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood. 1977 Sep;50(3):481-92.
• Yates AD, Morgan WT, Watkins WM. Linkage-specific alpha-D-galactosidases from Trichomonas foetus: characterisation of the blood-group B-destroying enzyme as a 1, 3-alpha-galactosidase and the blood-group P1-destroying enzyme as a 1, 4-alpha-galactosidase. FEBS Lett. 1975 Dec 15;60(2):281-5.

• Responsible Party: Thomas Waldmann, M.D., Principal Investigator, National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00117845
• Other Study ID Numbers: 050185; 05-C-0185; NCT00138190
• First Posted: Jul 8, 2005
• Last Update Posted: Nov 19, 2019
• Last Verified: Nov 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Thomas Waldmann, M.D., Principal Investigator, National Cancer Institute (NCI): Denileukin Diftitox (Ontak); Recombinant Immunotoxin; Human T-Cell Lymphotropic Virus (HTLV1); CD25 Positive; IL-2R; ATL; Ontak; Adult T-Cell Leukemia; Lymphoproliferative Disorders
• Additional relevant MeSH terms: Leukemia; Leukemia, T-Cell; Leukemia-Lymphoma, Adult T-Cell; Denileukin diftitox

Study Results

Participant Flow

Arm/Group Title	Denileukin Diftitox in ATL
Arm/Group Description	Denileukin Diftitox in adult T-cell leukemia (ATL) Patients will be treated with Denileukin Diftitox 9 mcg/kg/d intravenously for 5 days every 2 weeks.
Period Title: Overall Study
STARTED	17
COMPLETED	16
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Denileukin Diftitox in ATL
Arm/Group Description	Denileukin Diftitox in adult T-cell leukemia (ATL) Patients will be treated with Denileukin Diftitox 9 mcg/kg/d intravenously for 5 days every 2 weeks.
Overall Participants	17
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	15 88.2%
>=65 years	2 11.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.46 (11.64)
Sex: Female, Male (Count of Participants)
Female	9 52.9%
Male	8 47.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	17 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 5.9%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	16 94.1%
White	0 0%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	17 100%

Outcome Measures

1. Primary Outcome

Title	Response Rate
Description	Response rate is based on the number of patients who achieve either a complete response (CR) or partial response (PR) to therapy. Complete response is complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease related symptoms if present before therapy and normalization of those biochemical abnormalities (for example LDH) definitely assignable to the lymphoma. Partial response is reduction by >=50% of leukemia cell count or >=50% reduction is the size of all measurable lesions, and no increase in size of any measurable or evaluable lesion or appearance of new lesion.
Time Frame	up to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Denileukin Diftitox in ATL
Arm/Group Description	Denileukin Diftitox in adult T-cell leukemia (ATL) Patients will be treated with Denileukin Diftitox 9 mcg/kg/d intravenously for 5 days every 2 weeks.
Measure Participants	17
Complete Response	0 0%
Partial Response	0 0%

2. Secondary Outcome

Title	Number of Participants With Serious and Non-Serious Adverse Events
Description	Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v3.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Time Frame	Date treatment consent signed to date off study, approximately 72 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Denileukin Diftitox in ATL
Arm/Group Description	Denileukin Diftitox in adult T-cell leukemia (ATL) Patients will be treated with Denileukin Diftitox 9 mcg/kg/d intravenously for 5 days every 2 weeks.
Measure Participants	17
Count of Participants [Participants]	17 100%

Adverse Events

Time Frame	Date treatment consent signed to date off study, approximately 72 months.
Arm/Group Title	Denileukin Diftitox in ATL
Arm/Group Description	Denileukin Diftitox in adult T-cell leukemia (ATL) Patients will be treated with Denileukin Diftitox 9 mcg/kg/d intravenously for 5 days every 2 weeks.
All Cause Mortality
	Denileukin Diftitox in ATL
	Affected / at Risk (%)	# Events
Total	0/17 (0%)
Serious Adverse Events
	Denileukin Diftitox in ATL
	Affected / at Risk (%)	# Events
Total	5/17 (29.4%)
Cardiac disorders
Hypotension	1/17 (5.9%)	1
Gastrointestinal disorders
Dehydration	1/17 (5.9%)	1
Perforation, GI::Duodenum	1/17 (5.9%)	1
General disorders
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	1/17 (5.9%)	1
Rigors/chills	1/17 (5.9%)	1
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever)	1/17 (5.9%)	1
Infections and infestations
Infection (documented clinically or microbiologically)	1/17 (5.9%)	1
Metabolism and nutrition disorders
ALT, SGPT (serum glutamic pyruvic transaminase)	1/17 (5.9%)	1
AST, SGOT(serum glutamic oxaloacetic transaminase)	1/17 (5.9%)	1
Alkaline phosphatase	1/17 (5.9%)	1
Respiratory, thoracic and mediastinal disorders
Obstruction/stenosis of airway::Larynx	1/17 (5.9%)	1
Vascular disorders
Thrombosis/thrombus/embolism	1/17 (5.9%)	1
Other (Not Including Serious) Adverse Events
	Denileukin Diftitox in ATL
	Affected / at Risk (%)	# Events
Total	17/17 (100%)
Blood and lymphatic system disorders
Edema: limb	6/17 (35.3%)	6
Hemoglobin	14/17 (82.4%)	44
Leukocytes (total WBC)	8/17 (47.1%)	19
Lymphopenia	14/17 (82.4%)	56
Neutrophils/granulocytes (ANC/AGC)	9/17 (52.9%)	17
PTT (Partial Thromboplastin Time)	7/17 (41.2%)	9
Platelets	9/17 (52.9%)	13
Prothrombin time (PT)	1/17 (5.9%)	1
Cardiac disorders
Cardiac troponin I (cTnT)	1/17 (5.9%)	1
Hypertension	1/17 (5.9%)	1
Hypotension	4/17 (23.5%)	8
Palpitations	1/17 (5.9%)	1
Supraventricular and nodal arrhythmia::Sinus bradycardia	1/17 (5.9%)	2
Supraventricular and nodal arrhythmia::Sinus tachycardia	7/17 (41.2%)	11
Supraventricular and nodal arrhythmia::Supraventricular tachycardia	1/17 (5.9%)	1
Gastrointestinal disorders
Anorexia	4/17 (23.5%)	4
Colitis	1/17 (5.9%)	1
Dehydration	1/17 (5.9%)	1
Diarrhea	1/17 (5.9%)	3
Heartburn/dyspepsia	2/17 (11.8%)	2
Mucositis/stomatitis (clinical exam)::Oral cavity	1/17 (5.9%)	1
Nausea	6/17 (35.3%)	6
Pain::Abdomen NOS	1/17 (5.9%)	3
Vomiting	7/17 (41.2%)	9
General disorders
Fatigue (asthenia, lethargy, malaise)	5/17 (29.4%)	6
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	9/17 (52.9%)	27
Insomnia	1/17 (5.9%)	1
Pain - Other (Specify, Rt lumbar radiculopathy)	1/17 (5.9%)	1
Pain::Tumor pain	1/17 (5.9%)	1
Rigors/chills	7/17 (41.2%)	10
Weight gain	2/17 (11.8%)	2
Weight loss	2/17 (11.8%)	2
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever)	2/17 (11.8%)	2
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	1/17 (5.9%)	1
Infections and infestations
Febrile neutropenia	1/17 (5.9%)	1
Infection	1/17 (5.9%)	2
Infection	1/17 (5.9%)	2
Infection	1/17 (5.9%)	1
Infection	1/17 (5.9%)	3
Infection - Other (Specify, infection with neutropenia)	1/17 (5.9%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils::Blood	2/17 (11.8%)	2
Infection with normal ANC or Grade 1 or 2 neutrophils::Colon	1/17 (5.9%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils::Eye NOS	1/17 (5.9%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils::Skin (cellulitis)	1/17 (5.9%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils::Urinary tract NOS	2/17 (11.8%)	3
Metabolism and nutrition disorders
ALT, SGPT (serum glutamic pyruvic transaminase)	10/17 (58.8%)	39
AST, SGOT(serum glutamic oxaloacetic transaminase)	12/17 (70.6%)	48
Albumin, serum-low (hypoalbuminemia)	12/17 (70.6%)	36
Alkaline phosphatase	9/17 (52.9%)	20
Amylase	2/17 (11.8%)	6
Bicarbonate, serum-low	3/17 (17.6%)	4
Bilirubin (hyperbilirubinemia)	4/17 (23.5%)	16
CPK (creatine phosphokinase)	1/17 (5.9%)	1
Calcium, serum-high (hypercalcemia)	8/17 (47.1%)	9
Calcium, serum-low (hypocalcemia)	4/17 (23.5%)	5
Creatinine	4/17 (23.5%)	6
GGT (gamma-Glutamyl transpeptidase)	2/17 (11.8%)	2
Glucose, serum-low (hyperglycemia)	5/17 (29.4%)	8
Glucose, serum-low (hypoglycemia)	2/17 (11.8%)	4
Lipase	1/17 (5.9%)	1
Magnesium, serum-high (hypermagnesemia)	4/17 (23.5%)	5
Magnesium, serum-low (hypomagnesemia)	6/17 (35.3%)	10
Metabolic/Laboratory - Other (Specify, hypokalemia)	1/17 (5.9%)	1
Phosphate, serum-low (hypophosphatemia)	5/17 (29.4%)	11
Potassium, serum-high (hyperkalemia)	3/17 (17.6%)	3
Potassium, serum-low (hypokalemia)	2/17 (11.8%)	2
Proteinuria	4/17 (23.5%)	6
Sodium, serum-high (hypernatremia)	3/17 (17.6%)	4
Sodium, serum-low (hyponatremia)	8/17 (47.1%)	14
Uric acid, serum-high (hyperuricemia)	4/17 (23.5%)	8
Musculoskeletal and connective tissue disorders
Pain::Back	1/17 (5.9%)	1
Pain::Extremity-limb	1/17 (5.9%)	1
Pain::Joint	3/17 (17.6%)	3
Pain::Neck	1/17 (5.9%)	1
Nervous system disorders
Confusion	2/17 (11.8%)	2
Dizziness	3/17 (17.6%)	3
Mood alteration::Anxiety	2/17 (11.8%)	2
Neuropathy: cranial::CN I Smell	1/17 (5.9%)	1
Neuropathy: sensory	1/17 (5.9%)	1
Pain::Head/headache	7/17 (41.2%)	9
Tremor	1/17 (5.9%)	1
Respiratory, thoracic and mediastinal disorders
Cough	3/17 (17.6%)	5
Dyspnea	1/17 (5.9%)	1
Hypoxia	1/17 (5.9%)	2
Nasal cavity/paranasal sinus reactions	2/17 (11.8%)	2
Pain::Chest/thorax NOS	1/17 (5.9%)	3
Pain::Larynx	1/17 (5.9%)	1
Pneumonitis/pulmonary infiltrates	1/17 (5.9%)	3
Pulmonary/Upper Respiratory - Other (Specify,)	1/17 (5.9%)	1
Skin and subcutaneous tissue disorders
Pruritus/itching	2/17 (11.8%)	2
Rash/desquamation	4/17 (23.5%)	4
Sweating (diaphoresis)	1/17 (5.9%)	1
Vascular disorders
Acute vascular leak syndrome	3/17 (17.6%)	3
Thrombosis/thrombus/embolism	1/17 (5.9%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.