Clinical Trial: Gene Transfer for X-Linked Severe Combined Immunodeficiency in Newly Diagnosed Infants

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: A Pilot Feasibility Study of Gene Transfer for X-Linked Severe Combined Immunodeficiency in Newly Diagnosed Infants Using a Self-Inactivating Lentiviral Vector to Transduc

Brief Summary: SCID-X1 is a genetic disorder of blood cells caused by DNA changes in a gene that is required for the normal development of the human immune system. The purpose of this study is to determine if a new method, called lentiviral gene transfer, can be used to treat SCID-X1. This method involves transferring a normal copy of the common gamma chain gene into the participant's bone marrow stem cells. The investigators want to determine if the procedure is safe, whether it can be done according to the methods they have developed, and whether the procedure will provide a normal immune system for the patient. It is hoped that this type of gene transfer may offer a new way to treat children with SCID-X1 that do not have a brother or sister who can be used as a donor for stem cell transplantation.

Detailed Summary:

Bone marrow CD34+ cells will be obtained in the operating room, transduced with the lentiviral vector that contains a normal copy of the γc gene, and reinfused without any myeloreductive conditioning. Participants will be monitored for hematopoietic recovery from busulfan and for severe adverse events for 42 days. The primary endpoint assessing the efficacy of this approach will be T-cell immune reconstitution 52 weeks (+ 2) weeks after transplantation. Continued and detailed evaluation of all aspects of immune reconstitution, protocol-related toxicity, and retroviral integration sites will also be performed. This study will evaluate the first use of a SIN lentiviral vector for the treatment of SCID-X1 and may lead to a new form of therapy that could be applied to the majority of newly diagnosed patients.

OBJECTIVES

Assess the safety, feasibility and efficacy of lentiviral gene transfer in newly diagnosed SCID-X1 patients transplanted with autologous CD34+ cells that have been transduced with a self-inactivating lentiviral vector (CL20-i4-EF1α-hγc-OPT) expressing a γc gene.

Primary Objective 1: Evaluate the safety and feasibility of infusing at least 1 million transduced CD34+ cells per kilogram of body weight in SCID-X1 infants.

Primary Objective 2: Evaluate the efficacy of lentiviral gene transfer for inducing significant T-cell reconstitution 52 weeks (± 2 weeks) after transplantation. Significant reconstitution of T cells is defined as at least 2 of the following 3 criteria being present:

  • The development of T-cell proliferative responses to phytohemagglutinin (PHA) that are ≥ 50% the value seen in normal contr
    Sponsor: St. Jude Children's Research Hospital

    Current Primary Outcome:

    • Number of patients with adequate cell collection and processing [ Time Frame: Day 0 ]
      The number of patients who underwent no more than two bone marrow harvests and who had cryopreservation of at least 1.5 million CD34+ cells/kg as an unmodified backup graft and cryopreservation of at least 1.0 million cells/kg following vector transduction.
    • Number of patients with adequate neutrophil count recovery after busulfan conditioning [ Time Frame: Day 42 post gene transfer ]
      Adequate recovery is defined as absolute neutrophil count (ANC) >500 cells/μl by day +42 unless the patient is neutropenic prior to busulfan administration.
    • Number of patients without Grade 3 adverse event (AE) [ Time Frame: 42 days post gene transfer ]
      The number of patients experiencing no directly related grade 4 or greater adverse event.
    • Number of patients with successful reconstitution [ Time Frame: 42 days post gene transfer ]
      Reconstitution with transduced cells defined as detection of vector-marked peripheral blood cells by real time PCR at or above 0.02% VCN in total WBC.
    • Number of patients with treatment failure [ Time Frame: 42 days post gene transfer ]
      Treatment failure will be defined as lack of adequate cell collection and processing, lack of neutrophil count recovery by day +42, occurrence of grade 4 or greater toxicities by day +42, and/or lack of detection of >0.02% transduced cells in peripheral blood by day +42 post gene transfer

      Original Primary Outcome:

      • Number of patients successfully infused with the CD34+ Cells. (Phase I) [ Time Frame: 16 Weeks from enrollment ]
        The number of patients who were successfully infused with at least 3 million CD34+ cells per kilogram of body weight.
      • Number of patients with early T-Cell reconstitution without Grade 3 AE (Phase I) [ Time Frame: 16 Weeks from enrollment ]
        The number of patients meeting the following criteria: No directly related grade 3 or greater adverse events and the presence of at least one marker of early T-cell reconstitution.
      • The number of patients with effective Lentiviral Gene Transfer (Phase II) [ Time Frame: 52 Weeks from enrollment ]
        Number of patients with effective lentiviral gene transfer for inducing significant T-cell reconstitution.


      Current Secondary Outcome:

      Original Secondary Outcome:

      Information By: St. Jude Children's Research Hospital

      Dates:
      Date Received: January 13, 2012
      Date Started: August 17, 2016
      Date Completion: August 31, 2034
      Last Updated: April 11, 2017
      Last Verified: March 2017