Autologous Gene Therapy for Artemis-Deficient SCID

• Register: ClinicalTrials.gov
• Last refreshed on: 19 February 2024
• Main ID: NCT03538899
• Date of registration: 03/05/2018
• Prospective Registration: Yes
• Primary sponsor: University of California, San Francisco
• Public title: Autologous Gene Therapy for Artemis-Deficient SCID
• Scientific 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
• Date of first enrolment: May 31, 2018
• Target sample size: 25
• Recruitment status: Recruiting
• URL: https://clinicaltrials.gov/ct2/show/NCT03538899
• Study type: Interventional
• Study design: Allocation: N/A. Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1/Phase 2

Countries of recruitment

United States

Contacts

• Name: Morton Cowan, MD

• Name: Morton Cowan, MD
• Affiliation: University of California, San Francisco

Key inclusion & exclusion 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.



Age minimum: 2 Months
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Severe Combined Immunodeficiency

Intervention(s)

Drug: AProArt

Drug: Busulfan

Device: CliniMACS® CD34 Reagent System cell sorter device

Primary Outcome(s)

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]

Secondary Outcome(s)

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]

Incidence of treatment emergent Adverse Events related to busulfan administration [Time Frame: 42 days]

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]

Dose of AProArt transduced cells [Time Frame: 1 month]

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]

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]

Incidence of Adverse Events related to autologous stem cell transplant of self-inactivating (SIN) lentiviral vector (AProArt)-transduced CD34 cells [Time Frame: 2 years]

Multilineage engraftment of AProArt lentiviral vector-transduced hematopoietic cells [Time Frame: 2 years]

Secondary ID(s)

CLIN1-08363

TR3-05535

17-22799

Source(s) of Monetary Support

Please refer to primary and secondary sponsors