Recruiting

Phase 1

Phase 2

Lentiviral Gene TransferLentiviral Gene Transfer for Treatment of Children Older Than 2 Years of Age With X-Linked Severe Combined Immunodeficiency

Sponsor:

National Institute of Allergy and Infectious Diseases (NIAID)

Code:

NCT03315078

Conditions

X-Linked Combined Immunodeficiency Diseases

Eligibility Criteria

Sex: All

Age: 2 - 40

Healthy Volunteers: Not accepted

Interventions

CD34+ HSCs transduced with the lentivirus vector, VSV-G pseudotyped CL20-4i-EF1α-hγc-OPT

Palifermin

Busulfan

Study Details

Brief summary:

The purpose of this study is to evaluate the safety and effectiveness of lentiviral gene transfer treatment at restoring immune function to participants with X-linked severe combined immunodeficiency (XSCID) who are 2 to 40 years of age, and have significant impairment of immunity.

Conditions

X-Linked Combined Immunodeficiency Diseases

Study ID

NCT03315078

Start date

Apr, 2012

Status verified date

Dec, 2019

Completion date

Dec, 2022

Anticipated

Primary completion date

Dec, 2022

Anticipated

Eligibility Criteria

Sex: All

Age: 2 - 40

Healthy Volunteers: Not accepted

Inclusion Criteria:

A proven mutation in the common gamma chain gene as defined by direct sequencing of patient DNA
Human leukocyte antigen (HLA) typing of the patient will have been performed before enrollment
No available HLA matched sibling donor as determined before enrollment.
Must be between 2 and 40 years of age and weigh 10 kg
If previously transplanted, must be 18 months post-hematopoietic stem cell transplant (HSCT)
Expected survival of at least 120 days.
Documented to be negative for HIV infection by genome polymerase chain reaction (PCR)
The patient must be judged by the primary evaluating physician to have a suitable family and social situation consistent with ability to comply with protocol procedures and the long-term follow-up requirements.
Medical lab data (historical) of severe B cell dysfunction (low or absent immunoglobulin G \[IgG\] levels, failed immune response to vaccines); OR demonstrated requirement for intravenous gamma globulin (IVIG) (significant drop over 3 to 6 weeks between peak and trough IgG levels).
Must be willing to have blood and tissue samples stored. IN ADDITION, patients must satisfy the following Laboratory Criteria AND Clinical Criteria:
Laboratory Criteria: (at least 1 must be present)

CD4+ lymphocytes: absolute number less than or equal to 50% of the lower limit of normal (LLN)
CD4+CD45RA+ lymphocytes: absolute number less than or equal to 50% of the LLN OR T-cell receptor excision circles (TRECs) less than or equal to 5% of normal for age.
Memory B Cells: absolute number less than or equal to 50% of LLN
Serum immunoglobulin M (IgM) less than normal for age
Natural killer (NK) cells: absolute number less than or equal to 50% of LLN
Lymphocyte proliferative response to each of 2 mitogens, phytohemagglutinin (PHA) and concanavalin A (ConA), is less than or equal to 25% compared with a normal control.
Molecular spectratype analysis- absent or very oligoclonal (1-3 dominant peaks) in greater than or equal to 6 of the 24 Vbeta T-cell receptor families.
Clinical Criteria: (at least 1 must be present)
i. Infections (not including molluscum, warts or mucocutaneous candidiasis; see vii and viii below): 3 significant new or chronic active infections during the 2 years preceding evaluation for enrollment, with each infection accounting for one criteria. Infections are defined as an objective sign of infection (fever greater than 38.3\^0C \[101\^0F\] or neutrophilia or pain/redness/swelling or radiologic/ultrasound imaging evidence or typical lesion or histology or new severe diarrhea or cough with sputum production). In addition to one or more of these signs/symptoms of possible infection, there also must be at least 1 of the following criteria as evidence of the attending physician's "intent to treat" a significant infection (a. and b.) or objective evidence for a specific pathogen causing the infection (c.)

a. Treatment (not prophylaxis) with systemic antibacterial, antifungal or antiviral antibiotics 14 days OR
b. Hospitalization of any duration for infection OR
c. Isolation of a bacteria, fungus, or virus from biopsy, skin lesion, blood, nasal washing, bronchoscopy, cerebrospinal fluid or stool likely to be an etiologic agent of infection
ii. Chronic pulmonary disease as defined by:

a. Bronchiectasis by x-ray computerized tomography OR
b. Pulmonary function test (PFT) evidence for restrictive or obstructive disease that is 60% of Predicted for Age OR
c. Pulse oximetry 94% in room air (if patient is too young to comply with performance of pulmonary function tests \[PFTs\]).
iii. Gastrointestinal enteropathy:

a. Diarrhea-watery stools 3 times per day (of at least 3 months duration that is not a result of infection as defined in criterion number i. above) OR
b. Endoscopic evidence (gross and histologic) for enteropathy (endoscopy will only be performed if medically indicated) OR
c. Other evidence of enteropathy or bacterial overgrowth syndrome: including malabsorption of fat soluble vitamin(s), abnormal D-xylose absorption, abnormal hydrogen breath test, evidence of protein losing enteropathy (for example increasingly high or frequent dosing of intravenous gamma globulin supplement required to maintain blood IgG level).
iv. Poor nutrition: Requires gastrostomy tube (G-tube) or intravenous feeding supplement to maintain weight or nutrition.
v. Auto- or allo-immunity: Examples must include objective physical findings that include, but are not limited to any one of alopecia, severe rashes, uveitis, joint pain with redness or swelling or limitation of movement that is not a result of infection, lupus-like lesions, and granulomas (Does not include auto- or allo-immune enteropathy which is criterion iii). Where possible and appropriate, diagnosis will be supported by histopathology or other diagnostic modality.
vi. Failure to grow in height: 3rd percentile for age
vii. Skin molluscum contagiosum OR warts (this criterion is satisfied if molluscum consists of 10 lesions or there are two or more lesions at each of two or more widely separated anatomic sites; or there are 3 warts at different anatomic sites at the same time; or the patient has both molluscum and warts)
viii. Mucocutaneous candidiasis (chronic oral thrush or candida esophagitis or candida intertriginous infection or candida nail infections; must be culture positive to satisfy this criterion)
ix. Hypogammaglobulinemia: requires regular IgG supplementation

Exclusion Criteria:

Any current or pre-existing hematologic malignancy
Current treatment with any chemotherapeutic agent (becomes eligible if not on treatment for at least 3 months)
Documented HIV-1 infection
Documented active Hepatitis B infection
Childhood malignancy (occurring before 18 years of age) in the patient or a first degree relative, or previously diagnosed known genotype of the subject conferring a predisposition to cancer (no DNA or other testing for cancer predisposition genes will be performed as part of the screen for this protocol)

Study Design

Enrollment

13 participants

Anticipated

Intervention Model

Single group

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: Gene-Modified CD34+ HSCs

Participants will receive palifermin on Days -6, -5, and -4 and then busulfan on Days -3 and -2. On Day 0, participants will undergo the gene transfer treatment with infusion of the gene-modified CD34+ HSCs. They will receive palifermin on Days 1, 2, and 3.

Interventions

CD34+ HSCs transduced with the lentivirus vector, VSV-G pseudotyped CL20-4i-EF1α-hγc-OPT

Administered by intravenous (IV) infusion

Palifermin

Administered by IV infusion at a dose of 60 mg/kg/day

Busulfan

Administered by IV infusion at a dose of approximately 3 mg/kg per day

Primary outcome measure

Level of autologous transduced T-lymphocytes with functional γc [ Time Frame: Measured through Year 2 ]
Incidence of serious side effects due to lentiviral gene transfer [ Time Frame: Measured through Year 15 ]
Distribution of integration sites of the lentiviral vector in reconstituted peripheral blood cells [ Time Frame: Measured through Year 15 ]

Central Contacts and Locations

Locations

Laboratory of Host Defenses (LHD), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)

Recruiting

Bethesda, Maryland, United States, 20892-1456

Contacts

Suk See DeRavin, M.D., Ph.D

301-496-6772

More Information

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Last update posted

Dec 4, 2019

Last verified

Dec, 2019

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-10. This information was provided to ClinicalTrials.gov by National Institute of Allergy and Infectious Diseases (NIAID) on 2019-12-04.