This trial is active, not recruiting.

Condition ada-scid
Treatment efs-ada transduced cd34+ cells from the bone marrow
Phase phase 1/phase 2
Sponsor Donald B. Kohn, M.D.
Collaborator National Institute of Allergy and Infectious Diseases (NIAID)
Start date May 2013
End date July 2018
Trial size 20 participants
Trial identifier NCT01852071, 0910-1006, 2P01HL073104, IND 15440, U01AI100801


In this current study, the investigators will determine whether using a lentiviral vector (based on HIV-1) will be more effective and safer at gene transfer to hematopoietic stem cells compared to previous gene transfer vectors based on murine (mouse) retroviruses for ADA-deficient SCID. The level of gene transfer in blood cells and immune function will be measured as endpoints.

United States No locations recruiting
Other countries No locations recruiting

Study Design

Endpoint classification safety study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Autologous transplantation of EFS-ADA transduced bone marrow CD34+ cells
efs-ada transduced cd34+ cells from the bone marrow
Eligible subjects will undergo bone marrow harvest under general anesthesia. The marrow will be processed to isolate CD34+ cells and transduced with the EFS-ADA lentiviral vector. If sufficient cells are obtained, the subjects will undergo marrow cytoreduction with busulfan (4 mg/kg). If the transduced CD34+ final cell product meets all release criteria, the cells will be infused intravenously. PEG-ADA enzyme replacement therapy will be discontinued at day +30. After discharge from the hospital, the subject will be seen for interval history and examination by either their home physician, the principal investigator or a clinical investigator and have blood drawn at months 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 18, 21, and 24.

Primary Outcomes

Assess safety by recording clinical toxicities.
time frame: 2 years
Assess safety by determining absence or presence of exposure to replication-competent lentivirus (RCL)
time frame: 2 years
Assess safety by evaluating the absence or development of monoclonal expansion or leukoproliferative complications from vector insertional effects
time frame: 2 years
Overall survival
time frame: 2 years
Event-free survival
time frame: 2 years

Secondary Outcomes

Determine the frequency of gene marking in peripheral blood cells
time frame: 2 years
Quantify clonal diversity of vector integrants
time frame: 2 Years
Quantify ADA enzyme activity in peripheral blood mononuclear cells
time frame: 2 years
Quantify total adenine nucleotides in erythrocytes
time frame: 2 years
Determine absolute lymphocytes on complete blood count
time frame: 2 years
Quantify the absolute numbers T, B, and NK lymphocytes
time frame: 2 years
Assess lymphocyte mitogenic proliferation
time frame: 2 years
Measure quantitative immunoglobulins by class
time frame: 2 years
Quantify specific antibody responses
time frame: 2 years
Assess T lymphocyte reconstitution
time frame: 2 years

Eligibility Criteria

Male or female participants at least 1 month old.

Inclusion Criteria: -Children ≥ 1.0 months of age with a diagnosis of ADA-deficient SCID based on A. Decreased ADA enzymatic activity in erythrocytes, leukocytes, skin fibroblasts, or in cultured fetal cells to levels consistent with ADA-deficient SCID as determined by reference laboratory or confirmed ADA gene mutation(s) known to cause disease , AND B. Evidence of severe combined immunodeficiency based on either: 1. Family history of first order relative with ADA deficiency and clinical and laboratory evidence of severe immunologic deficiency, OR 2. Evidence of severe immunologic deficiency in subject prior to institution of immune restorative therapy, based on 1. lymphopenia (absolute lymphocyte count <400 cells/mcL) OR absence or low number of T cells (absolute CD3+ count <300 cells/mcL) OR 2. severely decreased T lymphocyte blastogenic responses to phytohemagglutinin (either <10% of lower limit of normal controls for the diagnostic laboratory, <10% of the response of the normal control of the day, or stimulation index <10) - Ineligible for matched sibling allogeneic bone marrow transplantation: absence of a medically eligible HLA-identical sibling, with normal immune function, who may serve as an allogeneic bone marrow donor - Signed written informed consent according to guidelines of the IRB (UCLA Office of Human Research Protection Program and National Human Genome Research Institute (NHGRI) Institutional Review Board Exclusion Criteria: 1. Age ≤ 1.0 months Appropriate organ function as outlined below must be observed within 8 weeks of entering this trial. 2. Hematologic 1. Anemia (hemoglobin < 10.5 g/dl at < 2 years of age, or < 11.5 g/dl at > 2 years of age). 2. Neutropenia (absolute granulocyte count <500/mm3. 3. Thrombocytopenia (platelet count < 150,000/mm3, at any age). 4. INR or PT > 2X the upper limits of normal or PTT > 2.33X the upper limit of normal (patients with a correctable deficiency controlled on medication will not be excluded). 5. Cytogenetic abnormalities on peripheral blood or bone marrow or amniotic fluid (if available). 6. Prior allogeneic HSCT with cytoreductive conditioning 3. Infectious a. Evidence of active opportunistic infection or infection with HIV-1, hepatitis B, Hepatitis C, or parvovirus B 19 by DNA PCR within 30-90 days prior to bone marrow harvest. If other infection is present, it must be under control (e.g. stable or decreasing viral load) at the time of screening 4. Pulmonary 1. Resting O2 saturation by pulse oximetry < 95% on room air. 2. Chest x-ray indicating active or progressive pulmonary disease. 5. Cardiac 1. Abnormal electrocardiogram (EKG) indicating cardiac pathology. 2. Uncorrected congenital cardiac malformation with clinical symptomatology. 3. Active cardiac disease, including clinical evidence of congestive heart failure, cyanosis, hypotension. 4. Poor cardiac function as evidenced by LV ejection fraction < 40% on echocardiogram. 6. Neurologic 1. Significant neurologic abnormality by examination. 2. Uncontrolled seizure disorder. 7. Renal 1. Renal insufficiency: serum creatinine >= 1.2 mg/dl, or >= 3+ proteinuria. 2. Abnormal serum sodium, potassium, calcium, magnesium, phosphate at grade III or IV by Division of AIDS Toxicity Scale. 8. Hepatic/GI: 1. Serum transaminases > 5X the upper limit of normal (ULN). 2. Serum bilirubin > 2X ULN. 3. Serum glucose > 1.5x ULN. 4. Intractable severe diarrhea. 9. Oncologic 1. Evidence of active malignant disease other than dermatofibrosarcoma protuberans (DFSP) 2. Evidence of DFSP expected to require anti-neoplastic therapy within the 5 years following the infusion of genetically corrected cells 3. Evidence of DFSP expected to be life limiting within the 5 years following the infusion of genetically corrected cells 10. Known sensitivity to Busulfan 11. General 1. Expected survival < 6 months. 2. Pregnant. 3. Major congenital anomaly. 4. Ineligible for autologous HSCT by the criteria at the clinical site. 5. Other conditions which in the opinion of the principal investigator and/or co-investigators, contra-indicate the bone marrow harvest, the administration of busulfan, infusion of transduced cells or indicate the patient or patient's parents/primary caregivers inability to follow protocol.

Additional Information

Official title Autologous Transplantation of Bone Marrow CD34+ Stem/Progenitor Cells After Addition of a Normal Human ADA cDNA by the EFS-ADA Lentiviral Vector for Adenosine Deaminase (ADA)-Deficient Severe Combined Immunodeficiency (SCID)
Principal investigator Donald B Kohn, MD
Description The study will be open to twenty (20) infants and children diagnosed with ADA-deficient SCID who do not have a medically eligible, HLA-identical sibling donor for bone marrow transplantation. The EFS-ADA lentiviral vector with the human ADA cDNA will be used to transduce autologous CD34+ cells from the bone marrow of these subjects. The subjects will receive 4 mg/kg busulfan prior to re-infusion of their gene-modified cells. Safety is the primary endpoint. During the follow-up phase, the investigators will determine whether the cells can engraft and produce mature cells that contain and express the corrected ADA gene in the absence of PEG-ADA enzyme replacement therapy (ERT), which will be withheld at Day +30 following transplant. Efficacy studies to evaluate level of immune reconstitution will begin in the first year and will continue in the second year. This Phase I/II clinical trial will be performed at Mattel Children's Hospital, UCLA and at the Mark O. Hatfield Clinical Research Center, NIH.
Trial information was received from ClinicalTrials.gov and was last updated in August 2016.
Information provided to ClinicalTrials.gov by University of California, Los Angeles.