Interleukin-2 Treatment for Wiskott-Aldrich Syndrome - Full Text View

Sponsor:	Jordan Orange
Information provided by (Responsible Party):	Jordan Orange, Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier:	NCT00774358

Purpose

Context: Wiskott-Aldrich syndrome (WAS) is a fatal, devastating disease with ill-defined treatment modalities, which affects young boys. Classic WAS is characterized by a clinical triad of thrombocytopenia, eczema and severe, recurrent infections. Despite diagnostic and therapeutic advances most WAS patients die at less than 12 years of age due to infections, hemorrhage, malignancy or complications from treatments. WAS patients suffer from herpesvirus infections as a result of poor Natural Killer (NK) cell function (cytotoxicity). In the laboratory, the investigators have seen correction of WAS Natural Killer Cell (NK) function after treatment with Interleukin-2 (IL-2).

Objectives: Initiate a prospective clinical trial by treating WAS subjects with IL-2 and using safety as the primary endpoint. Restoration of NK cell cytotoxicity and effects on cytoskeletal dynamics are secondary endpoints. The investigators will also observe patient clinical status (eczema, infections, use of treatment dose antibiotics, food allergies, etc).

Study Design/Setting/Participants: This is a prospective clinical trial treating 9 WAS subjects in the Clinical Translational Research Center (CTRC) with IL-2.

Intervention: The investigators propose to subcutaneously administer 0.5 MU/m2 of IL-2 daily to WAS subjects for 5 days. Research treatment will be repeated 2 and 4 months later. Inter-patient dose escalation will be employed to 1 MU/m2 and/or 2 MU/m2 based on safety as the primary endpoint.

Study Measures: The investigators will observe safety and tolerability measures and perform assays on subject blood samples prior to and after research treatment to observe improvement in NK cell function.

Condition	Intervention	Phase
Wiskott-Aldrich Syndrome (WAS) X-linked Thrombocytopenia	Drug: Interleukin-2	Phase I

Study Type:	Interventional
Study Design:	Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Reinstituting Natural Killer Cell Cytotoxicity and Cytoskeletal Dynamics in Wiskott-Aldrich Syndrome With IL-2 Therapy

Resource links provided by NLM:

Genetics Home Reference related topics: complement factor I deficiency hemophilia MYH9-related disorder Wiskott-Aldrich syndrome Help Me Understand Genetics

MedlinePlus related topics: Eczema

Drug Information available for: Interleukin-2 Aldesleukin

U.S. FDA Resources

Further study details as provided by Children's Hospital of Philadelphia:

Primary Outcome Measures:

Safety and Tolerability [ Time Frame: One year ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Evaluate effects on cytoskeletal dynamics [ Time Frame: One year ] [ Designated as safety issue: No ]
Requirement for treatment dose antibiotics [ Time Frame: One year ] [ Designated as safety issue: No ]
Number and severity of infections [ Time Frame: One year ] [ Designated as safety issue: No ]
Eczema [ Time Frame: One year ] [ Designated as safety issue: No ]
Food allergies [ Time Frame: One year ] [ Designated as safety issue: No ]
NK cell cytotoxicity [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Estimated Enrollment:	9
Study Start Date:	October 2008
Estimated Study Completion Date:	October 2013
Estimated Primary Completion Date:	October 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Interleukin-2	Drug: Interleukin-2 We propose to subcutaneously administer 0.5 MU/m2 of IL-2 daily to WAS subjects for 5 days. Research treatment will be repeated 2 and 4 months later. Inter-patient dose escalation will be employed to 1 MU/m2 and/or 2 MU/m2 based on safety as the primary endpoint. Other Names: IL-2 Aldesleukin Proleukin

Detailed Description:

The Wiskott-Aldrich syndrome (WAS) is a fatal genetic disease of the immune system that results from a mutation of the WAS protein (WASp) gene. Immune cells that carry this mutation have a decreased ability to reorganize filamentous actin (F-actin) after activation. As a result there are a number of defective immunologic functions, some of which result in deficient host defense. The investigators have identified a pervasive deficit in natural killer (NK) cell cytotoxicity in WAS patients. WAS patients suffer from conditions that are hallmarks of NK cell deficiencies. These include severe herpesvirus infections and B cell malignancies. Our lab and others have also found that exposure of WAS subject NK cells to IL-2 in vitro restores NK cell function and allows for normal F-actin reorganization. Thus, the investigators propose a proof of principal clinical trial to treat WAS subjects with IL-2 to determine safety and efficacy of IL-2 in this population and if NK cell function is restored ex vivo. If IL-2 can circumvent a defective WASp to restore NK cell function, the investigators will propose a larger NIH funded efficacy trial of IL-2 in WAS. The investigators will also use the in vivo treatment of WAS subjects to forward our mechanistic studies of how IL-2 may facilitate F-actin reorganization in the absence of WASp function.

Eligibility

Ages Eligible for Study:	24 Months and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Age: Subjects age greater than 24 months
Weight: Subjects greater than 12.5 kilograms
Disease status: WAS classified as Grade 1-4
Informed Consent: Written informed consent of the subject (if an adult) or parental permission, and assent of the child subject provided justification is made for the inclusion of children in the study

Exclusion Criteria:

Prior or planned hematopoetic transplant
WAS classified as currently Grade 5 (autoimmune disease or malignancy)
Known previous reaction to IL-2
Subjects taking nephrotoxic, cytotoxic, cardiotoxic, or hepatotoxic medications (including medications for hypertension)
Subjects currently taking corticosteroids (not included here: topical and inhaled corticosteroids)
Subjects taking Interferon alpha
Use of any other investigational agent in the last 30 days
Women of childbearing potential not using contraception method(s), as well as women who are breastfeeding
Subjects with abnormal cardiac, hepatic and CNS function

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00774358

Contacts

Contact: Brenda Gwafila, RN	267-426-9639	gwafilab@email.chop.edu
Contact: Jordan Orange, MD PhD	267-426-5622	orange@mail.med.upenn.edu

Locations

United States, Pennsylvania
Children's Hospital of Philadelphia	Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Brenda Gwafila, RN 267-426-9639 gwafilab@email.chop.edu
Contact: Denise DePaul, RN 267-426-6845 depaul@email.chop.edu
Sub-Investigator: Kimberly Nichols, MD
Sub-Investigator: Paul R Gallagher, PhD
Sub-Investigator: Rushani Saltzman, MD
Sub-Investigator: Antonella Cianferoni, MD
Sub-Investigator: Michael Keller, MD
Sub-Investigator: Hillary Hernandez-Trujillo, MD
Sub-Investigator: Soma Jyonouchi, MD
Sub-Investigator: Lisa Forbes, MD
Hospital of the University of Pennsylvania	Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Brenda Gwafila, RN 267-426-9636 ext 69636 gwafilab@email.chop.edu
Contact: Denise DePaul, RN 267 426 6845 ext 66842 DePaul@email.chop.edu
Principal Investigator: Benjamin Soule, MD

Sponsors and Collaborators

Jordan Orange

Investigators

Principal Investigator:

Jordan S Orange, MD PhD

Children's Hospital of Philadelphia

More Information

Additional Information:

Please see Study Description at www.wastherapy.com This link exits the ClinicalTrials.gov site

PI website: www.orangelab.org This link exits the ClinicalTrials.gov site

Publications:

Azuma H, Sakata H, Saijyou M, Okuno A. Effect of interleukin 2 on intractable herpes virus infection and chronic eczematoid dermatitis in a patient with Wiskott-Aldrich syndrome. Eur J Pediatr. 1993 Dec;152(12):998-1000.

Pahwa R, Chatila T, Pahwa S, Paradise C, Day NK, Geha R, Schwartz SA, Slade H, Oyaizu N, Good RA. Recombinant interleukin 2 therapy in severe combined immunodeficiency disease. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5069-73.

Piscitelli SC, Wells MJ, Metcalf JA, Baseler M, Stevens R, Davey RT Jr. Pharmacokinetics and pharmacodynamics of subcutaneous interleukin-2 in HIV-infected patients. Pharmacotherapy. 1996 Sep-Oct;16(5):754-9.

Witzke O, Winterhagen T, Reinhardt W, Heemann U, Grosse-Wilde H, Kreuzfelder E, Roggendorf M, Philipp T. Comparison between subcutaneous and intravenous interleukin-2 treatment in HIV disease. J Intern Med. 1998 Sep;244(3):235-40.

Toren A, Nagler A, Rozenfeld-Granot G, Levanon M, Davidson J, Bielorai B, Kaplinsky C, Meitar D, Mandel M, Ackerstein A, Ballin A, Attias D, Biniaminov M, Rosenthal E, Brok-Simoni F, Rechavi G, Kaufmann Y. Amplification of immunological functions by subcutaneous injection of intermediate-high dose interleukin-2 for 2 years after autologous stem cell transplantation in children with stage IV neuroblastoma. Transplantation. 2000 Oct 15;70(7):1100-4.

Sundin DJ, Wolin MJ. Toxicity management in patients receiving low-dose aldesleukin therapy. Ann Pharmacother. 1998 Dec;32(12):1344-52. Review.

Starr SE, McFarland EJ, Muresan P, Fenton T, Pitt J, Douglas SD, Deveikis A, Levin MJ, Rathore MH; PACTG 299 Study Team. Phase I/II trial of intravenous recombinant interleukin-2 in HIV-infected children. AIDS. 2003 Oct 17;17(15):2181-9.

Gismondi A, Cifaldi L, Mazza C, Giliani S, Parolini S, Morrone S, Jacobelli J, Bandiera E, Notarangelo L, Santoni A. Impaired natural and CD16-mediated NK cell cytotoxicity in patients with WAS and XLT: ability of IL-2 to correct NK cell functional defect. Blood. 2004 Jul 15;104(2):436-43. Epub 2004 Mar 4.

Orange JS, Brodeur SR, Jain A, Bonilla FA, Schneider LC, Kretschmer R, Nurko S, Rasmussen WL, Köhler JR, Gellis SE, Ferguson BM, Strominger JL, Zonana J, Ramesh N, Ballas ZK, Geha RS. Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations. J Clin Invest. 2002 Jun;109(11):1501-9.

Responsible Party:	Jordan Orange, Jordan Orange, MD/PhD, Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier:	NCT00774358 History of Changes
Other Study ID Numbers:	2007-6-5354
Study First Received:	October 16, 2008
Last Updated:	January 23, 2012
Health Authority:	United States: Food and Drug Administration

Keywords provided by Children's Hospital of Philadelphia:

Primary Immunodeficiency

Additional relevant MeSH terms:

Thrombocytopenia
Wiskott-Aldrich Syndrome
Blood Platelet Disorders
Hematologic Diseases
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hemorrhagic Disorders
Lymphopenia
Leukopenia
Leukocyte Disorders
Genetic Diseases, Inborn
Genetic Diseases, X-Linked

Immunologic Deficiency Syndromes
Immune System Diseases
Interleukin-2
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents

ClinicalTrials.gov processed this record on February 09, 2012