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

NCT ID: NCT01182675

Last Updated: 2018-07-31

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 7 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-08-31
• Study Completion Date: 2013-09-30

Brief Summary

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.

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.

1. 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.

2. 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.

Conditions

Severe Combined Immunodeficiency

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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 Intervention: Transplant Conditioning with Mobilization Only

Group Type: EXPERIMENTAL

Transplant Conditioning with Mobilization Only

Intervention Type: DRUG

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

T-cell Graft Resistant SCID

Patients with SCID with NK+ phenotype with HLA-mismatched donor Intervention: Transplant Conditioning with Mobilization and Alemtuzumab

Group Type: EXPERIMENTAL

Transplant Conditioning with Mobilization and Alemtuzumab

Intervention Type: DRUG

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

Interventions

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

Intervention Type: 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

Intervention Type: DRUG

Other Intervention Names

Conditioning with Filgrastim and Plerixafor; Conditioning with Filgrastim, Plerixafor, and Alemtuzumab

Eligibility 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)

• Maximum Eligible Age: 3 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of California, San Francisco

OTHER

Sponsor Role: lead

Responsible Party

Christopher Dvorak

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Christopher C Dvorak, M.D.

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Locations

UCSF Benioff Children's Hospital

San Francisco, California, United States

Countries

United States

References

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):1125-1133. doi: 10.1016/j.bbmt.2008.07.008.

Reference Type: BACKGROUND

PMID: 18804042 (View on PubMed)

Dvorak CC, Cowan MJ. Radiosensitive severe combined immunodeficiency disease. Immunol Allergy Clin North Am. 2010 Feb;30(1):125-42. doi: 10.1016/j.iac.2009.10.004.

Reference Type: BACKGROUND

PMID: 20113890 (View on PubMed)

Dvorak CC, Cowan MJ. Hematopoietic stem cell transplantation for primary immunodeficiency disease. Bone Marrow Transplant. 2008 Jan;41(2):119-26. doi: 10.1038/sj.bmt.1705890. Epub 2007 Oct 29.

Reference Type: BACKGROUND

PMID: 17968328 (View on PubMed)

Other Identifiers

UCSF10-00701

Identifier Type: -

Identifier Source: org_study_id