RECRUITING

Autologous Gene Therapy for Artemis-Deficient SCID

Conditions

Severe Combined Immunodeficiency Artemis-deficient Severe Combined Immunodeficiency gene therapy autologous stem cell transplant

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

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 24 newly diagnosed 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.

Official Title

A Phase I/II Safety and Efficacy Study of AProArt-CD34 in Artemis-Deficient Severe Combined Immunodeficiency in Newly Diagnosed Patients Using a Self-Inactivating Lentiviral Vector (AProArt) to Transduce Autologous CD34 Hematopoietic Cells

Quick Facts

Study Start:2018-05-31

Study Completion:2038-06

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT03538899

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:2 Months

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:CHILD, ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion Criteria
* ≥2.0 months of age at initiation of busulfan conditioning * Diagnosis of typical or leaky ART-SCID: * 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. * 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. * 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).	* 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.

Inclusion Criteria

Exclusion Criteria

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

* 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.

Contacts and Locations

Study Contact

Morton Cowan, MD

CONTACT

415-476-2188

Mort.Cowan@ucsf.edu

Jennifer Puck, MD

CONTACT

415 502-2090

Jennifer.Puck@ucsf.edu

Principal Investigator

Morton Cowan, MD

PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Study Locations (Sites)

University of California, San Francisco (UCSF) Children's Hospital

San Francisco, California, 94143

United States

Collaborators and Investigators

Sponsor: University of California, San Francisco

Morton Cowan, MD, PRINCIPAL_INVESTIGATOR, University of California, San Francisco

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2018-05-31

Study Completion Date2038-06

Study Record Updates

Study Start Date2018-05-31

Study Completion Date2038-06

Terms related to this study

Keywords Provided by Researchers

Artemis-deficient Severe Combined Immunodeficiency
gene therapy
autologous stem cell transplant

Additional Relevant MeSH Terms

Severe Combined Immunodeficiency