Hematopoietic Stem Cell Transplantation (HSCT) for Children With SCID Utilizing Alemtuzumab, Plerixafor & Filgrastim - Full Text View

Purpose

The goal of this study is to develop a novel approach to hematopoietic stem cell transplantation for children with Severe Combined Immunodeficiency Disease (SCID) that eliminates the use of toxic chemotherapy conditioning and maximizes the likelihood of T and B cell immune reconstitution. Rather than classic chemotherapeutic agents, the investigators will utilize a targeted stem cell mobilizer, plerixafor, in combination with alemtuzumab, a monoclonal antibody. Correlative scientific questions will include: 1) efficacy and characteristics of host stem cell mobilization; and 2) alemtuzumab pharmacokinetics in very young children.

Condition	Intervention	Phase
Severe Combined Immunodeficiency	Drug: Transplant Conditioning with Mobilization Only Drug: Transplant Conditioning with Mobilization and Alemtuzumab	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Hematopoietic Stem Cell Transplantation for Children With Severe Combined Immunodeficiency Disease Utilizing Alemtuzumab and Mobilization With Plerixafor & Filgrastim

Resource links provided by NLM:

Genetics Home Reference related topics: adenosine deaminase deficiency complement factor I deficiency purine nucleoside phosphorylase deficiency X-linked severe combined immunodeficiency ZAP70-related severe combined immunodeficiency

Drug Information available for: Plerixafor Filgrastim Lenograstim Granulocyte colony-stimulating factor Alemtuzumab

U.S. FDA Resources

Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:

Percent engraftment of donor B-cells in blood by STR testing [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
We will measure whether we are able to detect donor B-cells in the patient's blood after HSCT.

Secondary Outcome Measures:

Incidence of Acute GVHD [ Time Frame: 100 Days ] [ Designated as safety issue: Yes ]
Incidence of Chronic GVHD [ Time Frame: 2 Years ] [ Designated as safety issue: Yes ]
Percentage of patients who become independent from regular IVIG infusion [ Time Frame: 2 Years ] [ Designated as safety issue: No ]
Based on B-cell function assays from the patient's blood, we will be able to determine if patients are able to successfully discontinue IVIG infusions.
Percent engraftment of donor stem cells in bone marrow by STR testing [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
We will measure whether we are able to detect donor stem cells in the patient's bone marrow after HSCT.
Percent engraftment of donor T-cells in blood by STR testing [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
We will measure whether we are able to detect donor T-cells in the patient's blood after HSCT.

Estimated Enrollment:	7
Study Start Date:	August 2010
Estimated Study Completion Date:	September 2013
Estimated Primary Completion Date:	September 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: T-cell Graft Permissive SCID Patients with SCID with: i. NK- phenotype; ii. NK+ phenotype with 10/10 HLA-matched relative or unrelated donor; or iii. NK+ phenotype with maternal engraftment by STR analysis and undergoing haplocompatible HSCT from maternal donor	Drug: Transplant Conditioning with Mobilization Only Day -4: Filgrastim (G-CSF) 5 mcg/kg IV q12 hours; Day -3: Filgrastim (G-CSF) 5 mcg/kg IV q12 hours; Day -2: Filgrastim (G-CSF) 5 mcg/kg IV q12 hours; Day -1: Filgrastim (G-CSF) 5 mcg/kg IV q12 hours; Day 0: Plerixafor 240 mcg/kg subcutaneous 9-12 hours prior to transplant; Day 0 Transplant Other Name: Conditioning with Filgrastim and Plerixafor
Experimental: T-cell Graft Resistant SCID Patients with SCID with NK+ phenotype with HLA-mismatched donor	Drug: Transplant Conditioning with Mobilization and Alemtuzumab Day -7: Alemtuzumab 0.3 mg test dose then 0.3 mg/kg IV; Day -6: Alemtuzumab 0.3 mg/kg IV; Day -5: Alemtuzumab 0.3 mg/kg IV; Day -4: Filgrastim (G-CSF) 5 mcg/kg IV q12 hours; Day -3: Filgrastim (G-CSF) 5 mcg/kg IV q12 hours; Day -2: Filgrastim (G-CSF) 5 mcg/kg IV q12 hours; Day -1: Filgrastim (G-CSF) 5 mcg/kg IV q12 hours; Day 0: Plerixafor 240 mcg/kg subcutaneous 9-12 hours prior to transplant; Day 0: Transplant Other Name: Conditioning with Filgrastim, Plerixafor, and Alemtuzumab

Arms

Assigned Interventions

Experimental: T-cell Graft Permissive SCID

Patients with SCID with:

i. NK- phenotype; ii. NK+ phenotype with 10/10 HLA-matched relative or unrelated donor; or iii. NK+ phenotype with maternal engraftment by STR analysis and undergoing haplocompatible HSCT from maternal donor

Drug: Transplant Conditioning with Mobilization Only

Day -4: Filgrastim (G-CSF) 5 mcg/kg IV q12 hours; Day -3: Filgrastim (G-CSF) 5 mcg/kg IV q12 hours; Day -2: Filgrastim (G-CSF) 5 mcg/kg IV q12 hours; Day -1: Filgrastim (G-CSF) 5 mcg/kg IV q12 hours; Day 0: Plerixafor 240 mcg/kg subcutaneous 9-12 hours prior to transplant; Day 0 Transplant

Other Name: Conditioning with Filgrastim and Plerixafor

Experimental: T-cell Graft Resistant SCID

Patients with SCID with NK+ phenotype with HLA-mismatched donor

Drug: Transplant Conditioning with Mobilization and Alemtuzumab

Day -7: Alemtuzumab 0.3 mg test dose then 0.3 mg/kg IV; Day -6: Alemtuzumab 0.3 mg/kg IV; Day -5: Alemtuzumab 0.3 mg/kg IV; Day -4: Filgrastim (G-CSF) 5 mcg/kg IV q12 hours; Day -3: Filgrastim (G-CSF) 5 mcg/kg IV q12 hours; Day -2: Filgrastim (G-CSF) 5 mcg/kg IV q12 hours; Day -1: Filgrastim (G-CSF) 5 mcg/kg IV q12 hours; Day 0: Plerixafor 240 mcg/kg subcutaneous 9-12 hours prior to transplant; Day 0: Transplant

Other Name: Conditioning with Filgrastim, Plerixafor, and Alemtuzumab

Detailed Description:

The goal of this study is to develop an approach to hematopoietic stem cell transplantation for children with Severe Combined Immunodeficiency Disease (SCID) that eliminates the use of toxic chemotherapy conditioning and maximizes the likelihood of T and B cell immune reconstitution. SCID is a rare primary immunodeficiency disease in which there are multiple genotypes and phenotypes, and depending on various factors including the presence of B cell and NK cells, and the presence of maternal cells in the patient's circulation, there are numerous ways to approach a transplant. The major issues that must be addressed in any approach to transplantation for SCID are graft rejection and T and B cell immune reconstitution. Depending on the specific SCID diagnosis, the phenotype, and the presence of maternal engraftment at diagnosis, we will evaluate two transplant approaches that will attempt to optimize the engraftment of donor HSC and the likelihood of T and B cell reconstitution while eliminating the use of toxic chemotherapy conditioning.

Primary Objective: To determine if the administration of plerixafor & filgrastim (G-CSF) prior to stem cell infusion results in increased donor stem cell occupancy of available bone marrow niches and B-cell engraftment in patients with SCID.
Secondary Objectives:

i. To determine if NK cell depletion with Alemtuzumab will overcome NK-mediated graft resistance in haplocompatible transplants for NK+ SCID.

ii. To determine the optimal dosing of Alemtuzumab in very young children. iii. To determine the immunophenotypic characteristics of CD34+ cells mobilized and engrafted in patients receiving plerixafor & filgrastim prior to HCT.

iv. To determine the thymic output, as measured by T-cell receptor excision circles, in patients receiving haplocompatible transplants & boosts.

Eligibility

Ages Eligible for Study:	up to 3 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Patients with classic SCID phenotype (<400 CD3/ul or maternally engrafted and <10% of normal PHA lymphoproliferative response). Genotypic identification is preferable, but not required.
Patients must have an acceptable stem cell donor (HLA matched relative, 9 or 10/10 HLA-matched unrelated, or haplocompatible relative).

Exclusion Criteria:

Patients with "leaky" SCID syndromes, Omenn's Syndrome, reticular dysgenesis, ADA deficiency
Lansky score <60%
Patient with expected survival <4 weeks (including disseminated CMV infection involving lungs and/or CNS)

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01182675

Locations

United States, California
UCSF Benioff Children's Hospital
San Francisco, California, United States, 94143

Sponsors and Collaborators

University of California, San Francisco

Investigators

Principal Investigator:

Christopher C Dvorak, M.D.

University of California, San Francisco

More Information

Additional Information:

UCSF Blood Marrow Transplant Program Website This link exits the ClinicalTrials.gov site

Publications:

Dvorak CC, Hung GY, Horn B, Dunn E, Oon CY, Cowan MJ. Megadose CD34(+) cell grafts improve recovery of T cell engraftment but not B cell immunity in patients with severe combined immunodeficiency disease undergoing haplocompatible nonmyeloablative transplantation. Biol Blood Marrow Transplant. 2008 Oct;14(10):1125-33.

Dvorak CC, Cowan MJ. Radiosensitive severe combined immunodeficiency disease. Immunol Allergy Clin North Am. 2010 Feb;30(1):125-42.

Dvorak CC, Cowan MJ. Hematopoietic stem cell transplantation for primary immunodeficiency disease. Bone Marrow Transplant. 2008 Jan;41(2):119-26. Epub 2007 Oct 29. Review.

Responsible Party:	Christopher Dvorak, Assistant Professor, University of California, San Francisco
ClinicalTrials.gov Identifier:	NCT01182675 History of Changes
Other Study ID Numbers:	NCT01000701
Study First Received:	August 9, 2010
Last Updated:	May 16, 2013
Health Authority:	United States: Institutional Review Board

Keywords provided by University of California, San Francisco:

SCID
Transplant
Alemtuzumab
Plerixafor

Additional relevant MeSH terms:

Immunologic Deficiency Syndromes
Severe Combined Immunodeficiency
Immune System Diseases
Infant, Newborn, Diseases
DNA Repair-Deficiency Disorders
Metabolic Diseases
Lenograstim
Campath 1G
Antibodies, Neoplasm
JM 3100
Alemtuzumab

Adjuvants, Immunologic
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Antineoplastic Agents
Immunosuppressive Agents

ClinicalTrials.gov processed this record on May 23, 2013