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

Phase 2

Terminated

• Conditions: Severe Combined Immunodeficiency
• Interventions: Drug: Transplant Conditioning with Mobilization and Alemtuzumab; Drug: Transplant Conditioning with Mobilization Only

• Registration Number: NCT01182675
• Lead Sponsor: University of California, San Francisco

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.

Study Timeline

• Study Start: 2010-08
• Study First Submitted: 2010-08-09
• Study First Submitted QC: 2010-08-13
• Study First Posted: 2010-08-17
• Primary Completion: 2013-09
• Study Completion: 2013-09
• Results First Submitted: 2014-10-28
• Results First Submitted QC: 2014-11-06
• Results First Posted: 2014-11-10
• Status Verified: 2018-07
• Last Update Submitted: 2018-07-04
• Last Update Posted: 2018-07-31

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 7

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).

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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)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
T-cell Graft Resistant SCID	Transplant Conditioning with Mobilization and Alemtuzumab	Patients with SCID with NK+ phenotype with HLA-mismatched donor Intervention: Transplant Conditioning with Mobilization and Alemtuzumab
T-cell Graft Permissive SCID	Transplant Conditioning with Mobilization Only	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

Primary Outcome Measures

Name	Time	Method
Engraftment of Donor B-cells in Blood by STR Testing	1 Year	Number of participants in whom donor B cells were detected in the patient's blood after HSCT.

Secondary Outcome Measures

Name	Time	Method
Incidence of Acute GVHD	100 Days
Incidence of Chronic GVHD	2 Years
Percentage of Patients Who Become Independent From Regular IVIG Infusion	2 Years	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.
Number of Patients With Engraftment of Donor Stem Cells in Bone Marrow by STR Testing	1 Year	We will measure whether we are able to detect donor stem cells in the patient's bone marrow after HSCT.
Number of Patients Who Achieve Engraftment of Donor T-cells in Blood by STR Testing	1 Year	We will measure whether we are able to detect donor T-cells in the patient's blood after HSCT.

Trial Locations

Locations (1)

UCSF Benioff Children's Hospital; 🇺🇸 San Francisco, California, United States