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

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ClinicalTrials.gov Identifier: NCT01306019
Recruitment Status : Recruiting
First Posted : March 1, 2011
Last Update Posted : June 10, 2024
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Brief Summary:

This is a non-randomized clinical trial using a lentiviral gene transfer vector (or lentivector, LV) to treat patients with X-linked severe combined immunodeficiency (XSCID) who have clinically significant impairment of immunity. We will collect the patient s own stem cells that will be transduced or exposed to the vector carrying a normal copy of the gene. The gene-corrected stem cells will be administered as a one-time infusion. Patients will receive a low-moderate dose of a chemotherapy drug called busulfan (6 mg/kilogram body weight) to allow engraftment of the stem cells. After the infusion, patients will be monitored to see if the treatment is safe and whether their immune system improves. Patients will be monitored for up to 15 years after treatment to assess immune function and the safety of the treatment.

XSCID is a genetic disease caused by defects in the common gamma chain, a protein found at the surface of immune cells called lymphocytes, and is necessary to their growth and function. XSCID patients cannot make T-lymphocytes necessary to fight infections, and their B-cells fail to make essential antibodies. Without normal T-and B-lymphocyte function, patients develop fatal infections in infancy unless they receive a bone marrow transplant from a healthy donor. The best type of transplant is from a tissue-matched healthy sibling, but most XSCID patients do not have a tissue-matched sibling and are treated with a transplant from a parent who is only half-matched by tissue typing. While a half-matched transplant from a parent can be lifesaving for an infant with XSCID, a subset of patients fail to achieve sufficient long-lasting restoration of immunity to prevent infections and other chronic problems.

Trials of gene transfer treatments using mouse retrovirus vectors for infants with XSCID have been performed and have shown this type of gene transfer can be an alternate approach for significantly restoring immunity to infants with XSCID. However, among the 18 infants with XSCID benefiting long-term from the gene transfer treatment, 5 developed T-lymphocyte leukemia and 1 died of this leukemia. When older children with XSCID were treated with gene transfer, the restoration of immunity was much less than seen in the infants. These observations of gene transfer treatments using mouse retrovirus vectors to treat infants and older patients with XSCID suggest that safer and more effective vectors were needed and that there also may be a need to give chemotherapy or another mode of conditioning to increase engraftment in the marrow of the gene-corrected blood stem cells. Our data and other published studies suggest that lentivectors derived from the human immunodeficiency virus and have the properties of our highly modified vector have a reduced interaction with nearby genes and therefore less of a tendency to activate genes that may lead to cancer formation. This type of lentivector may work better at getting into blood stem cells.

The study's purpose is to evaluate the safety and effectiveness of lentiviral gene transfer treatment in restoring immune function to 35 XSCID patients who are 2 to 40 years of age and have significant impairment of immunity. Early evidence for effectiveness will be defined by appearance and expansion in the circulation of the patient s gene-corrected T-lymphocytes with a functional >=c gene and improved laboratory measures of immune function. The primary endpoint for efficacy will be at 2 years after treatment and will include these laboratory parameters plus evidence for clinical benefit. Evidence for safety will focus on the maintenance of a diversity of gene-marked cells and no occurrence of abnormal patterns of production of blood cells or any leukemia or other cancer.

...


Condition or disease Intervention/treatment Phase
X-linked Severe Combined Immunodeficiency (XSCID) 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 Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Lentiviral Gene Transfer for Treatment of Children Older Than 2 Years of Age With X-Linked Severe Combined Immunodeficiency
Actual Study Start Date : September 25, 2012
Estimated Primary Completion Date : December 31, 2032
Estimated Study Completion Date : December 31, 2032


Arm Intervention/treatment
cohort a
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
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.

Drug: Busulfan
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

Drug: Palifermin
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 b
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
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.

Drug: Busulfan
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

Drug: Palifermin
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




Primary Outcome Measures :
  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... [ Time Frame: 1 year ]
    successful, partial successful or failure


Secondary Outcome Measures :
  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 [ Time Frame: 2 years ]
    maintenance of polyclonality of vector marking, the lack of emergence of a dominant gene marked clone in any hematopoietic lineage, and no occurrence of either hematologic dysplasia or any leukemia or other cancer resulting from the gene transfer



Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 40 Years   (Child, Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • 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 40 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 plus CD45RA+ lymphocytes: absolute number less than or equal to 50 percent of the LLN OR T-cell receptor excision circles (TRECs)squared less than or equal to 5 percent of normal for age.

iii. Memory B Cells: absolute numberless than or equal to 50percent of LLN

iv. Serum IgM<normal for age

v. NK cells: absolute number less than or equal to 50 percent of LLN

vi. Lymphocyte proliferative response to each of 2 mitogens, phytohemagglutinin (PHA) and concanavalin A (ConA), is squared 25 percent with a normal control.

vii. Molecular spectratype analysis- absent or very oligoclonal (1-3 dominant peaks) in greater than or equal to 6 of the 24 V- Beta T-cell receptor families.

Clinical Criteria: (greater than or equal to 1 must be present):

i Infections (not including molluscum, warts or mucocutaneous candidiasis; see vii and viii below):

Three 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 degrees C [101 degrees F] 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.)

-Treatment (not prophylaxis) with systemic antibacterial, antifungal or antiviral antibiotics greater than or equal to 14 days

OR

-Hospitalization of any duration for infection

OR

-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:

-Bronchiectasis by x-ray computerized tomography

OR

-Pulmonary function test (PFT) evidence for restrictive or obstructive disease that is 60 percent of Predicted for Age

OR

-Pulse oximetry 94 percent in room air (if patient is too young to comply with performance of PFTs).

iii Gastrointestinal enteropathy:

-Diarrhea-watery stools greater than or equal to 3 times per day (of at least 3 months duration that is not a result of infection as defined in criterion above)

OR

-Endoscopic evidence (gross and histologic) for enteropathy (endoscopy will only be performed if medically indicated)

OR

-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 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: less than or equal to 3 rd 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

INCLUSION OF VULNERABLE PARTICIPANTS:

  • Children: Children 2 years of age and older may enroll on this study because the condition under study affects children and the study holds the prospect for direct benefit.
  • Adults who lack capacity to consent to research participation: Adults who are unable to consent are eligible for enrollment in this protocol because patients with SCID-X1 may have serious complications affecting decision-making ability and because the study intervention might provide direct benefit. Similarly, enrolled participants who lose the ability to provide ongoing consent (either

temporarily or permanently) during study participation may continue in the study following NIH Human Research Protection Program (HRPP) Policy 403, Research with Subjects Lacking Capacity to Consent. The risks and benefits of participation for adults unable to consent should be identical to those described for less vulnerable patients.

-Pregnant and Lactating Women: Pregnant women are excluded from this study because IL2RG gene is located on the X-chromosome and only males are affected. There are no female patients wtith X-linked SCID.

EXCLUSION CRITERIA:

  • 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)

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): NCT01306019


Contacts
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Contact: Suk S De Ravin, M.D. (301) 496-6772 sderavin@mail.nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY dial 711    ccopr@nih.gov   
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
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Principal Investigator: Suk S De Ravin, M.D. National Institute of Allergy and Infectious Diseases (NIAID)
Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT01306019    
Other Study ID Numbers: 110007
11-I-0007
First Posted: March 1, 2011    Key Record Dates
Last Update Posted: June 10, 2024
Last Verified: March 7, 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: .The PI has yet to determine how IPD will be shared.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):
T cell, B cell, NK cell
Gene Transfer
Peripheral Blood Stem Cells
Common Gamma Chain (gamma c)
Immune Reconstitution
Additional relevant MeSH terms:
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Severe Combined Immunodeficiency
X-Linked Combined Immunodeficiency Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Primary Immunodeficiency Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
DNA Repair-Deficiency Disorders
Metabolic Diseases
Genetic Diseases, X-Linked
Busulfan
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Antineoplastic Agents
Myeloablative Agonists