Lentiviral Gene Transfer for Treatment of Children Older Than Two Years of Age With X-Linked Severe Combined Immunodeficiency (XSCID)

NCT01306019 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: 11000711-I-0007
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase I/II non-randomized clinical trial of ex vivo hematopoietic stem cell (HSC) gene transfer treatment for X-linked severe combined immunodeficiency (XSCID, also known as SCID-X1) using a self-inactivating lentiviral vector incorporating additional features to improve safety and performance. The study will treat 35 patients with XSCID who are between 2 and 50 years of age and who have clinically significant impairment of immunity. Patients will receive a total busulfan dose of approximately 6 mg/kg/body weight (target busulfan Area Under Curve is 4500 min\*micromol/L/day) delivered as 3mg/kg body weight on day 1 and dose adjusted on day 2 (if busulfan AUC result is available) to achieve the target dose, to condition their bone marrow, and this will be followed by a single infusion of autologous transduced CD34+HSC. Patients will then be followed to evaluate engraftment, expansion, and function of gene corrected lymphocytes that arise from the transplant; to evaluate improvement in laboratory measures of immune function; to evaluate any clinical benefit that accrues from the treatment; and to evaluate the safety of this treatment. The primary endpoint of the study with respect to these outcomes will be at 2 years, though data relevant to these measures will be collected at intervals throughout the study and during the longer follow-up period of at least 15 years recommended by the Food and Drug Administration (FDA) Guidance "Long Term Follow-Up After Administration of Human Gene Therapy Products" https://www.fda.gov/media/113768/download for patients participating in gene transfer clinical trials. XSCID results from defects in the IL2RGgene encoding the common gamma chain (yc) shared by receptors for Interleukin 2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21. At birth XSCID patients generally lack or have a severe deficiency of T-lymphocytes and NK cells, while their B- lymphocytes are normal in number but are severely deficient in function, failing to make essential antibodies. The severe deficiency form of XSCID is fatal in infancy without intervention to restore some level of immune function. The best current therapy is a T-lymphocyte-depleted bone marrow transplant from an HLA tissue typing matched sibling, and with this type of donor it is not required to administer chemotherapy or radiation conditioning of the patient's marrow to achieve excellent engraftment and immune correction of an XSCID patient. However, the great majority of patients with XSCID lack a matched sibling donor, and in these patients the standard of care is to perform a transplant of T- lymphocyte depleted bone marrow from a parent. This type of transplant is called haploidentical because in general a parent will be only half- matched by HLA tissue typing to the affected child. Whether or not any conditioning is used, haploidentical transplant for XSCID has a significantly poorer prognosis than a matched sibling donor transplant. Following haploidentical transplant, XSCID patients are observed to achieve a wide range of partial immune reconstitution and that reconstitution can wane over time in some patients. That subset of XSCID patients who either fail to engraft, fail to achieve adequate immune reconstitution, or lose immune function over time suffer from recurrent viral, bacterial and fungal infections, problems with allo- or autoimmunity, impaired pulmonary function and/or significant growth failure. We propose to offer gene transfer treatment to XSCID patients\^3 \>= 2 years of age who have clinically significant defects of immunity despite prior haploidentical hematopoietic stem cell transplant, and who lack an HLA-matched sibling donor. Our current gene transfer treatment protocol can be regarded as a salvage/rescue protocol. Prior successful retroviral gene transfer treatment instead of bone marrow transplant (BMT) in Paris and London for 20 infants with XSCID has provided proof of principle for efficacy. However, a major safety concern is the occurrence of 5 cases of leukemia at 3-5 years after treatment triggered in part by vector insertional mutagenesis activation of LMO2 and other DNA regulatory genes by the strong enhancer present in the long-terminal repeat (LTR) of the Moloney Leukemia Virus (MLV)- based vector. Furthermore, previous studies of gene transfer treatment of older XSCID patients with MLV- based vectors demonstrated the additional problem of failure of adequate expansion of gene corrected T- lymphocytes to the very high levels seen in infants. To reduce or eliminate this leukemia risk, and possibly enhance performance sufficiently to achieve benefit in older XSCID patients, we have generated a lentivector with improved safety and performance features. We have generated a self-inactivating (SIN) lentiviral vector that is devoid of all viral transcription elements; that contains a short form of the human elongation factor 1a (EF1a) internal promoter to expres......

Conditions

X-linked Severe Combined Immunodeficiency (XSCID)

Keywords

T cell, B cell, NK cell; Gene Transfer; Peripheral Blood Stem Cells; Common Gamma Chain (gamma c); Immune Reconstitution

Outcome Measures

Primary Outcomes (1)

• Early evidence for efficacy will be defined by appearance and expansion in the circulation of autologous transduced T-lymphocytes with functional gmama-c and improved laboratory measures of immune function in the interim evaluation of these para...

  successful, partial successful or failure

  1 year

Secondary Outcomes (1)

• evidence for efficacy at 2 years after treatment will include these same laboratory parameters measured at the 2 year time point plus evidence for clinical benefit

  2 years

Study Arms (2)

cohort a

OTHER

First 8 Patients Treated

Biological: Ex vivo culture and transduction of the patient's autologous CD34+ HSC with lentivirus vector VSV-G pseudotyped CL20- 4i-EF1alpha-hgammac-OPT vector; Drug: Busulfan; Drug: Palifermin

cohort b

OTHER

Patients 9 and Beyond

Biological: Ex vivo culture and transduction of the patient's autologous CD34+ HSC with lentivirus vector VSV-G pseudotyped CL20- 4i-EF1alpha-hgammac-OPT vector; Drug: Busulfan; Drug: Palifermin

Interventions

Busulfan DRUG

3mg/kg per day with drug levels obtained on Day -3. Busulfan dose on day -2 will be adjusted (if busulfan AUC result is available) to achieve targeted busulfan AUC 4500 min\*umol/L/day. If the result is not available in time to adjust, then proceed to give the standard 3mg/kg on the second day

cohort a; cohort b

Palifermin DRUG

Mucositis prophylaxis commenced- Infusion of keratinocyte growth factor (palifermin) at 60 mcg/kg/day before (Days -6 to Day -4) administration of busulfan and (Days +1 to +3) post-busulfan administration

cohort a; cohort b

Ex vivo culture and transduction of the patient's autologous CD34+ HSC with lentivirus vector VSV-G pseudotyped CL20- 4i-EF1alpha-hgammac-OPT vector BIOLOGICAL

Transduced cell product administered intravenously over approximately 30 minutes by authorized licensed personnel consistent with NIH Clinical Center Department of Transfusion Medicine's standard operating procedures for cellular products.

cohort a; cohort b

Eligibility Criteria

• Age: 2 Years - 50 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• A proven mutation in the common gamma chain gene as defined by direct sequencing of patient DNA
• No available HLA matched sibling donor as determined before enrollment. (HLA typing will be performed prior to enrollment)
• Must be between 2 and 50 years of age and weigh greater than or equal to 10 kg
• If previously transplanted, must be greater than or equal to 18 months post HSCT
• Expected survival of at least 120 days.
• Participants of reproductive potential must agree to consistently use highly effective contraception throughout study participation and for at least 2 years post-treatment. Acceptable forms of contraception are:
• For males: Condoms or other contraception with partner.
• Documented to be negative for HIV infection by genome 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 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: (greater than or equal to 1 must be present)
• I. CD4+ lymphocytes: absolute number less than or equal to 50 percent of the lower limit of normal (LLN)
• II. CD4+ CD45RA+ lymphocytes: absolute number less than or equal to 50 percent of the LLN OR T-cell receptor excision circles (TRECs) less than or equal to 5 percent of normal for age.
• III. Memory B Cells: absolute number less than or equal to 50 percent of LLN

You may not qualify if:

• Any current or pre-existing hematologic malignancy
• 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)

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Publications (4)

• Howe SJ, Mansour MR, Schwarzwaelder K, Bartholomae C, Hubank M, Kempski H, Brugman MH, Pike-Overzet K, Chatters SJ, de Ridder D, Gilmour KC, Adams S, Thornhill SI, Parsley KL, Staal FJ, Gale RE, Linch DC, Bayford J, Brown L, Quaye M, Kinnon C, Ancliff P, Webb DK, Schmidt M, von Kalle C, Gaspar HB, Thrasher AJ. Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. J Clin Invest. 2008 Sep;118(9):3143-50. doi: 10.1172/JCI35798.

  PMID: 18688286 BACKGROUND

• Kang EM, Choi U, Theobald N, Linton G, Long Priel DA, Kuhns D, Malech HL. Retrovirus gene therapy for X-linked chronic granulomatous disease can achieve stable long-term correction of oxidase activity in peripheral blood neutrophils. Blood. 2010 Jan 28;115(4):783-91. doi: 10.1182/blood-2009-05-222760. Epub 2009 Dec 1.

  PMID: 19965657 BACKGROUND

• Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I, Vidaud M, Abel U, Dal-Cortivo L, Caccavelli L, Mahlaoui N, Kiermer V, Mittelstaedt D, Bellesme C, Lahlou N, Lefrere F, Blanche S, Audit M, Payen E, Leboulch P, l'Homme B, Bougneres P, Von Kalle C, Fischer A, Cavazzana-Calvo M, Aubourg P. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science. 2009 Nov 6;326(5954):818-23. doi: 10.1126/science.1171242.

  PMID: 19892975 BACKGROUND

• De Ravin SS, Liu S, Sweeney CL, Brault J, Whiting-Theobald N, Ma M, Liu T, Choi U, Lee J, O'Brien SA, Quackenbush P, Estwick T, Karra A, Docking E, Kwatemaa N, Guo S, Su L, Sun Z, Zhou S, Puck J, Cowan MJ, Notarangelo LD, Kang E, Malech HL, Wu X. Lentivector cryptic splicing mediates increase in CD34+ clones expressing truncated HMGA2 in human X-linked severe combined immunodeficiency. Nat Commun. 2022 Jun 28;13(1):3710. doi: 10.1038/s41467-022-31344-x.

  PMID: 35764638 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

X-Linked Combined Immunodeficiency Diseases

Interventions

Busulfan; Fibroblast Growth Factor 7

Condition Hierarchy (Ancestors)

Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Severe Combined Immunodeficiency; Primary Immunodeficiency Diseases; Infant, Newborn, Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Fibroblast Growth Factors; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Officials

• Suk S De Ravin, M.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Suk S De Ravin, M.D.

CONTACT

(301) 496-6772; sderavin@mail.nih.gov

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 26, 2011
• First Posted: March 1, 2011
• Study Start: September 25, 2012
• Primary Completion (Estimated): December 31, 2032
• Study Completion (Estimated): December 31, 2032
• Last Updated: May 1, 2026

Record last verified: 2025-11-06

Locations

US (1)