Gene Transfer for X-Linked Severe Combined Immunodeficiency in Newly Diagnosed Infants (LVXSCID-ND)

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by St. Jude Children's Research Hospital
Sponsor:
Collaborators:
Assisi Foundation
Information provided by (Responsible Party):
St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier:
NCT01512888
First received: January 13, 2012
Last updated: June 30, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Severe Combined Immunodeficiency Disease, X-linked
Genetic: CL20-4i-EF/a-hyc-OPT
Drug: Busulfan
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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 Transduce Autologous CD34+ Hematopoietic Cells

Resource links provided by NLM:


Further study details as provided by St. Jude Children's Research Hospital:

Primary Outcome Measures:
  • Number of patients successfully infused with the CD34+ Cells. (Phase I) [ Time Frame: 16 Weeks from enrollment ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    Number of patients with effective lentiviral gene transfer for inducing significant T-cell reconstitution.


Secondary Outcome Measures:
  • Pharmacokinetic variables of busulfan [ Time Frame: Days -3 and -2 prior to therapy, and at hours 3, 3.25, 6, 8, 11, 18, and 24 after start of infusion. ] [ Designated as safety issue: No ]
    This outcome will not be analyzed for participants <3kg, For participants ≥3 to <6 kg, evaluation will be limited to pre-therapy and at hours 3, 3.25, 8, and 24 to comply with institutional requirements regarding maximum blood draw volume and sample collection times.

  • Pre-busulfan metabolomics of busulfan [ Time Frame: Day -4 prior to therapy ] [ Designated as safety issue: No ]
  • Change in pre-graft metabolomics of busulfan [ Time Frame: Day 0 immediately prior to therapy and approximately 72 hours after the first dose of busulfan ] [ Designated as safety issue: No ]

Estimated Enrollment: 28
Study Start Date: February 2012
Estimated Study Completion Date: February 2029
Estimated Primary Completion Date: February 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment

Participants will undergo a bone marrow harvest in the operating room to obtain bone marrow cells. These cells will undergo vector transduction with the lentiviral vector that contains a normal copy of the γc gene gene (CL20-4i-EF/a-hyc-OPT) and then the transduced cells be reinfused back into the patient. Participants will receive a conditioning regimen of busulfan.

Intervention: CL20-4i-EF/a-hyc-OPT

Genetic: CL20-4i-EF/a-hyc-OPT
Participants will undergo infusion with autologous CD34+ bone marrow cells transduced with a lentiviral vector that contains a normal copy of the human γc gene.
Other Names:
  • self inactivating lentiviral vector
  • IND 14570
Drug: Busulfan
Given intravenously (IV).
Other Name: Busulfex®

Detailed Description:

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. Patients who do not show evidence for early T-cell reconstitution by 16 (+ 1) weeks after cell infusion will be considered an early failure and offered an allogeneic transplant. For all other patients, 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 obtaining and infusing at least 3 million CD34+ cells per kilogram of body weight in SCID-X1 infants.

Primary Objective 2: Assess the safety of the study procedure and assess for early evidence of significant T-cell reconstitution at 16 (± 1) weeks as defined by no grade 3 or greater adverse events that are directly related to the gene transfer procedure AND the presence of at least one of the following: 1) greater than 500 T-cell receptor excision circles (TRECs) per µg of DNA OR 2) the development of T-cell proliferative responses to phytohemagglutinin (PHA) that are > 25 % of the value seen in normal controls OR 3) greater than 150 cells/ul CD3+ T-cells in the peripheral blood.

Primary Objective 3: 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:

  • Greater than 1000 copies of T-cell receptor excision circles (TRECs) per µg of DNA from peripheral blood mononuclear cells
  • the development of T-cell proliferative responses to phytohemagglutinin (PHA) that are > 50% the value seen in normal controls
  • ≥ 300 cells/ul CD3+ T-cells in the peripheral blood
  Eligibility

Ages Eligible for Study:   up to 12 Months
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • A clinical diagnosis of SCID-X1 documented in the medical record.
  • A proven mutation in the common gamma chain gene as defined by direct sequencing of patient DNA
  • Age newborn to < 1 year of age at the time of enrollment.
  • Less than 12 % of circulating lymphocytes are CD3+ T-cells by flow cytometry

Exclusion Criteria:

  • Availability of a HLA matched sibling for allogeneic transplantation
  • Prior therapy with allogeneic stem cell transplantation
  • Positive for HIV infection by genome PCR
  • Presence of a medical condition indicating that survival will be less than 16 weeks such as the requirement for mechanical ventilation, severe failure of a major organ system, or evidence of a serious, progressive infection that is refractory to medical therapy.
  • The presence of any medical contraindications to general anesthesia and bone marrow harvest by aspiration
  • A social situation indicating that the family may not be able to comply with protocol procedures and recommended medical care.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01512888

Contacts
Contact: Brian Sorrentino, MD 1-866-278-5833 info@stjude.org

Locations
United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Brian Sorrentino, MD    866-278-5833    info@stjude.org   
Principal Investigator: Brian Sorrentino, MD         
Sub-Investigator: Brandon Triplett, MD         
United States, Washington
Fred Hutchinson Cancer Research Center Not yet recruiting
Seattle, Washington, United States, 98109
Contact: Lauri M. Burroughs, MD    206-667-2396    lburroug@fhcrc.org   
Principal Investigator: Lauri M. Burroughs, MD         
Seattle Children's Research Institute Not yet recruiting
Seattle, Washington, United States, 98101
Contact: David J. Rawlings, MD    206-987-7450      
Principal Investigator: Andrew M. Scharenberg, MD         
Principal Investigator: David J. Rawlings, MD         
Sponsors and Collaborators
St. Jude Children's Research Hospital
Assisi Foundation
Investigators
Principal Investigator: Brian Sorrentino, MD St. Jude Children's Research Hospital
  More Information

Additional Information:
No publications provided

Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT01512888     History of Changes
Other Study ID Numbers: LVXSCID-ND, P01HL053749
Study First Received: January 13, 2012
Last Updated: June 30, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board
United States: Federal Government

Keywords provided by St. Jude Children's Research Hospital:
immunodeficiency
gene transfer
lentiviral vector
autologous CD34+ hematopoietic cells

Additional relevant MeSH terms:
Severe Combined Immunodeficiency
Immunologic Deficiency Syndromes
X-Linked Combined Immunodeficiency Diseases
Immune System Diseases
Infant, Newborn, Diseases
DNA Repair-Deficiency Disorders
Metabolic Diseases
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Busulfan
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Therapeutic Uses
Myeloablative Agonists

ClinicalTrials.gov processed this record on July 22, 2014