ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 16 of 70 for:    "Severe Combined Immunodeficiency" OR "adenosine deaminase deficiency"

Autologous Gene Therapy for Artemis-Deficient SCID

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03538899
Recruitment Status : Recruiting
First Posted : May 28, 2018
Last Update Posted : June 11, 2018
Sponsor:
Information provided by (Responsible Party):
Morton Cowan, University of California, San Francisco

Brief Summary:
This study aims to determine if a new method can be used to treat Artemis-deficient Severe Combined Immunodeficiency (ART-SCID), a severe form of primary immunodeficiency caused by mutations in the DCLRE1C gene. This method involves transferring a normal copy of the DCLRE1C gene into stem cells of an affected patient. Participants will receive an infusion of stem cells transduced with a self-inactivating lentiviral vector that contains a normal copy of the DCLRE1C gene. Prior to the infusion they will receive sub-ablative, dose-targeted busulfan conditioning. The study will investigate if the procedure is safe, whether it can be done according to the methods described in the protocol, and whether the procedure will provide a normal immune system for the patient. A total of 15 patients will be enrolled at the University of California San Francisco in this single-site trial, and will be followed for 15 years post-infusion. It is hoped that this type of gene transfer may offer improved outcomes for ART-SCID patients who lack a brother or sister who can be used as a donor for stem cell transplantation or who have failed to develop a functioning immune system after a previous stem cell transplant.

Condition or disease Intervention/treatment Phase
Severe Combined Immunodeficiency Drug: AProArt Device: CliniMACS® CD34 Reagent System cell sorter device Drug: Busulfan Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Longitudinal study of autologous stem cell transplant of cells transduced with corrected DCLRE1C gene using a self-inactivating lentiviral vector (AProArt). The CliniMACS® CD34 Reagent System cell sorter device will be used to select CD 34 cells. Sub-ablative busulfan will be used for pre-transplant conditioning.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Feasibility Study of Gene Transfer for Artemis-Deficient Severe Combined Immunodeficiency (ART-SCID) Using a Self-Inactivating Lentiviral Vector (AProArt) to Transduce Autologous CD34 Hematopoietic Cells
Actual Study Start Date : May 31, 2018
Estimated Primary Completion Date : June 2038
Estimated Study Completion Date : June 2038


Arm Intervention/treatment
Experimental: Gene therapy (AProArt)
Gene Transfer for Artemis-Deficient Severe Combined Immunodeficiency (ART-SCID) Using a Self-Inactivating Lentiviral Vector (AProArt) to Transduce Autologous CD34 Hematopoietic Cells. The CliniMACS® CD34 Reagent System sorter device will be used to select CD34 cells. Patients will be conditioned with low dose busulfan prior to transplant.
Drug: AProArt
Participants will undergo infusion with autologous hematopoietic cells transduced with a lentiviral vector, AProArt, which contains the correct form of DCLRE1C complementary deoxyribonucleic acid DNA, after receiving sub-ablative, exposure-targeted busulfan conditioning.
Other Name: lentiviral gene therapy using AProArt

Device: CliniMACS® CD34 Reagent System cell sorter device
Processing of hematopoietic progenitor cells to select CD34 cells, using the CliniMACS® CD34 Reagent System, prior to infusion.

Drug: Busulfan
Busulfan is a cell cycle non-specific alkylating antineoplastic agent, in the class of alkyl sulfonates. Patients will receive low-dose busulfan conditioning targeted over 2 days to achieve a cumulative area under the curve (AUC) of 20 mg*hr/L.
Other Name: Busulfex




Primary Outcome Measures :
  1. Survival of patients with ART-SCID who receive self-inactivating (SIN) lentiviral vector (AProArt)-transduced CD34 cells through autologous stem cell transplant [ Time Frame: 2 years ]
    Patient survival status and (if applicable) cause of death will be recorded to assess overall survival.


Secondary Outcome Measures :
  1. Dose of AProArt transduced cells [ Time Frame: 1 month ]
    Number of AProArt-transduced CD34 cells infused per kg of body weight will be calculated, with a target of at least 2x10e6 transduced cells and up to 15x10e6 transduced cells per kilogram.

  2. Incidence of treatment emergent Adverse Events related to busulfan administration [ Time Frame: 42 days ]
    Treatment emergent adverse events will be measured using CTCAE version 4.0.

  3. Hematopoietic recovery in patients with ART-SCID who receive self-inactivating (SIN) lentiviral vector (AProArt)-transduced CD34 cells through autologous stem cell transplant. [ Time Frame: 1 year ]
    Patients will undergo blood tests to measure complete blood count and differential.

  4. Lymphocyte studies to measure immune system reconstitution in patients who have received AProArt lentiviral vector-transduced autologous CD34 hematopoietic stem cell transplant after low dose busulfan conditioning [ Time Frame: 2 years ]
    Patients will undergo blood tests to measure T, B, and NK cell numbers and function.

  5. Specific antibody titers to measure establishment of immune function in patients who have received AProArt lentiviral vector-transduced autologous CD34 hematopoietic stem cell transplant after low dose busulfan conditioning [ Time Frame: 2 years ]
    Patients will undergo blood tests to measure antibody production to tetanus toxoid as documented by achieving protective levels following immunization.

  6. Immunoglobulin levels to measure establishment of B cell immune function in patients who have received AProArt lentiviral vector-transduced autologous CD34 hematopoietic stem cell transplant after low dose busulfan conditioning [ Time Frame: 2 years ]
    Patients will undergo blood tests to measure levels of circulating immunoglobulins.

  7. Multilineage engraftment of AProArt lentiviral vector-transduced hematopoietic cells [ Time Frame: 2 years ]
    Engraftment will be measured by performing quantitative PCR assays to detect transduced cells in at least two of the following lineages: T, B, NK and granulocyte/myeloid.

  8. Incidence of Adverse Events related to autologous stem cell transplant of self-inactivating (SIN) lentiviral vector (AProArt)-transduced CD34 cells [ Time Frame: 2 years ]
    Adverse events will be measured using CTCAE version 4.0, including any oncogenic events.


Other Outcome Measures:
  1. Final area under the curve (AUC) of low dose busulfan exposure [ Time Frame: 42 days ]
    Final area under the curve (AUC) will be compared to the target cumulative AUC of 20±4 mg*hr/L.

  2. Repertoire diversity in ART-SCID recipients of gene therapy post-transplant. [ Time Frame: 2 years ]
    Measurement via spectratyping of the T cell receptor Vb rearranged receptors.

  3. Vector copy number sustained over time after infusion of transduced hematopoeitic stem cell transplant. [ Time Frame: 2 years ]
    Laboratory studies will measure the number of vector copies found in blood leukocyte populations, including granulocytes, T-cells, B-cells and NK cells. The cell populations will be isolated by gradient centrifugation followed by staining with monoclonal antibodies and flow sorting.

  4. Location of vector-integration sites for maintenance of a diverse insertion site repertoire [ Time Frame: 2 years ]
    From a mixed population of blood leukocytes, gradient isolated and flow-sorted components (T, B, myeloid, and NK cells), will have genomic DNA fragments amplified by linker-mediated PCR. Massively parallel sequencing will be performed and the junction host DNA sequences between the integrated vector and linkers will be mapped to the human genome using BLAST software. The genomic location of each insertion site will be determined, and number of cells with the same insertion site will be monitored.

  5. Incidence of long-term Adverse Events related to autologous stem cell transplant of self-inactivating (SIN) lentiviral vector (AProArt)-transduced CD34 cells. [ Time Frame: 15 years ]
    Adverse events will be measured using CTCAE V4.0

  6. Long term survival in ART-SCID patients who undergo autologous stem cell transplant of self-inactivating (SIN) lentiviral vector (AProArt)-transduced CD34 cells. [ Time Frame: 15 years ]
    Number of participants with immune system function as measured by T and B cell numbers and function.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   2 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • ≥2.0 months of age at initiation of busulfan conditioning
  • Diagnosis of typical or leaky ART-SCID:

Newly diagnosed ART-SCID patients must have:

  • Artemis deficiency; AND
  • CD3 count < 300 autologous cells/µL (typical ART-SCID) OR spontaneous maternal chimerism, OR CD3 count >300/µL but with restricted T cell receptor Vb diversity, defined as 18/24 or fewer polyclonal families.

AND - CD45 cell response to mitogens (PHA) < 50% of the lower limit of normal range for the lab (leaky ART-SCID).

Patients diagnosed with ART-SCID per the criteria above who have failed an allogeneic transplant (including an HLA matched sibling transplant) may participate if they meet the criteria below:

- Are at least 3 months post allogeneic hematopoeitic stem cell transplant without evidence of engraftment of allogeneic donor cells (excluding maternal cells)

OR are engrafted but have at least 2 of the following 4 conditions:

  • Declining CD3 donor chimerism with at least 3 evaluations separated by at least 1 month prior to time of enrollment OR < 5% overall donor chimerism in blood and marrow at ≥3 months post transplant.
  • Incompletely reconstituted T cell immunity at ≥6 months (1 of the following 2):

    • CD4 < 200/μL AND CD45 cell PHA < 50% of the lower limit of normal for lab;
    • CD4 CD45RA < 20% of total CD4 cells OR T cell receptor Vb diversity is restricted, defined as 18/24 or fewer polyclonal families.
    • No donor B cells OR lack of B cell function (immunoglobulin M isohemagglutinins < 1:8 (not blood type AB) AND immunoglobulin A (IgA) or IgM values below reference range for age AND if not receiving intravenous immunoglobulin (IVIG), no protective level of antibody to tetanus immunization x2).
    • Clinical manifestations consistent with persistent T and B cell immunodeficiency e.g., chronic infection including norovirus, cytomegalovirus, human herpes virus 6; OR acute or recurrent infection (e.g., PJP), bronchiectasis, chronic sinusitis.

AND

  • Have no prior exposure to high dose busulfan (≥10 mg/kg total dose or average cumulative exposure of ≥40 mg*hr/L). If the total cumulative AUC including previous busulfan exposure plus the dose to be administered in this protocol is predicted to be ≤60 mg*hr/L, then patient would be eligible providing other criteria are satisfied.
  • No medically eligible HLA-identical sibling with a normal immune system who could serve as an allogeneic bone marrow donor (applies to newly diagnosed patients only).

Written informed consent according to guidelines of the Institutional Review Board (IRB).

Exclusion Criteria:

  • Liver function tests (aspartate aminotransferase, alanine transaminase, gamma-glutamyl transferase) > three times the upper limit of normal for lab and/or total bilirubin >1.50 mg/dl at the time of planned initiation of busulfan conditioning.
  • Prior history of veno-occlusive disease (Sinusoidal obstruction syndrome) of the liver.
  • Medically eligible HLA-matched sibling (applies to newly diagnosed patients only).
  • Evidence of HIV infection by polymerase chain reaction or p24 antigen testing.
  • Unable to tolerate general anesthesia and/or marrow harvest or peripheral blood stem cell collection (apheresis) or insertion of central venous catheter.
  • Presence of a medical condition indicating that survival is predicted to be less than 4 months, 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.
  • Pregnancy
  • A social situation indicating that the family may not be able to comply with protocol procedures and recommended medical care and follow-up.
  • Other conditions which in the opinion of the Principal Investigator and/or co-investigators, contra-indicate the infusion of transduced cells or study participation.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03538899


Contacts
Contact: Morton Cowan, MD 415-476-2188 Mort.Cowan@ucsf.edu
Contact: Jennifer Puck, MD 415 502-2090 Jennifer.Puck@ucsf.edu

Locations
United States, California
University of California, San Francisco (UCSF) Children's Hospital Recruiting
San Francisco, California, United States, 94143
Sponsors and Collaborators
University of California, San Francisco
Investigators
Principal Investigator: Morton Cowan, MD University of California, San Francisco

Publications:
Blyth CR, Still HA. Still, Binomial Confidence Intervals. Journal of the American Statistical Association 78(381): 108-116, 1983.
Casella G. Refining binomial confidence intervals. Canadian Journal of Statistics 14(2): 113-129, 1986.

Responsible Party: Morton Cowan, Professor Emeritus, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03538899     History of Changes
Other Study ID Numbers: 17-22799
TR3-05535 ( Other Grant/Funding Number: California Institute of Regenerative Medicine )
CLIN1-08363 ( Other Grant/Funding Number: California Institute of Regenerative Medicine )
First Posted: May 28, 2018    Key Record Dates
Last Update Posted: June 11, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data that underlie the results reported in scientific journals (text, tables, figures, and appendices) after de-identification.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: Beginning 3 months and ending 5 years following article publication
Access Criteria: Researchers can submit a request for access to the study Steering Committee. If the proposal is determined to be methodologically sound, data requestors will need to sign a data access agreement prior to gaining access.

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: No
Pediatric Postmarket Surveillance of a Device Product: No

Keywords provided by Morton Cowan, University of California, San Francisco:
Artemis-deficient Severe Combined Immunodeficiency
gene therapy
autologous stem cell transplant

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