Clinical trial NCT01852071: Autologous CD34+ Hematopoietic Stem Cells Transduced ex Vivo With Elongation Factor 1 Alpha Shortened (EFS) Lentiviral Vector Encoding for the Human ADA Gene
Official title: Autologous Transplantation of Bone Marrow CD34+ Stem/Progenitor Cells After Addition of a Normal Human ADA Complementary DNA (cDNA) by the EFS-ADA Lentiviral Vector for Severe Combined Immunodeficiency Due to Adenosine Deaminase Deficiency (ADA-SCID)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: ADA-SCID
Keywords: gene therapy
hematopoietic stem cell
ADA-SCID
lentiviral vector
Lead sponsor: University of California, Los Angeles
Sponsor class: OTHER
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
name: National Human Genome Research Institute (NHGRI)
name: National Heart, Lung, and Blood Institute (NHLBI)
name: Orchard Therapeutics
First posted: 2013-05-13
Enrollment: 46
Sex: ALL
Minimum age (years): 1
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The aim of this study is to assess the safety and efficacy of autologous transplantation of hematopoietic stem cells (CD34+ cells) from the bone marrow (BM) of ADA-deficient SCID infants and children following human ADA cDNA transfer by the EFS-ADA lentiviral vector. The level of gene transfer in blood cells and immune function will be measured as endpoints.

Detailed description: The study is open to twenty (20) infants and children diagnosed with ADA-deficient SCID who did not have a medically eligible, human leukocyte antigen (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 aim to determine whether the cells could engraft and produce mature cells that contain and express the corrected ADA gene in the absence of pegademase bovine (PEG-ADA) enzyme replacement therapy (ERT), which will be withheld at Day +30 following transplant. Efficacy studies to evaluate the level of immune reconstitution, will be performed in the first and second years of the study.

Eligibility criteria: 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 Institutional Review Board (IRB) (UCLA Office of Human Research Protection Program and National Human Genome Research Institute (NHGRI) IRB

Exclusion Criteria:

1. Age ≤ 1.0 months Appropriate organ function as outlined below must be observed within 60 days 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. International Normalised Ratio (INR) or Prothrombin Time (PT) \> 2 times the upper limits of normal or Partial Thromboplastin Time (PTT) \> 2.33 times 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 Hematopoietic Stem Cell Transplant (HSCT) with cytoreductive conditioning
3. Infectious

   a. Evidence of infection with HIV-1, hepatitis B, Hepatitis C, or parvovirus B 19 by DNA Polymerase Chain Reaction (PCR) within 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 \> 5 times the upper limit of normal (ULN).
   2. Serum bilirubin \> 2 times ULN.
   3. Serum glucose \> 1.5 times 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.

Primary outcomes:
measure: Overall Survival (OS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year)
timeFrame: 12 months
measure: Event-free Survival (EvFS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year)
timeFrame: 12 months
Secondary outcomes:
measure: OS of Subjects Treated With Investigational Medicinal Product (IMP) (2 Years)
timeFrame: 24 months
measure: EvFS of Subjects Treated With Investigational Medicinal Product (IMP) (2 Years)
timeFrame: 24 months
measure: Vector Copy Number (VCN) in Peripheral Blood (PB) Granulocytes.
timeFrame: 24 months
measure: VCN in Peripheral Blood Mononuclear Cells (PBMCs)
timeFrame: 24 months
measure: ADA Activity in Erythrocytes
timeFrame: 24 months
measure: Reduction in Deoxyadenosine Nucleotide (dAXP) in Erythrocytes
timeFrame: 24 months
measure: Change From Baseline in CD3+ T Cell Counts (2 Years)
timeFrame: 24 months
measure: Number of Single Integration Sites Representing >30% of the Total Integration Sites (2 Years)
timeFrame: 24 months
measure: Severe Infection Rate Excluding the First Three Months After Treatment
timeFrame: 24 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Mattel Children's Hospital, UCLA
state: California
city: Bethesda
country: United States
facility: Mark O. Hatfield Clinical Research Center, NIH
state: Maryland
Study officials:
affiliation: University of California, Los Angeles
name: Donald B Kohn, MD
role: PRINCIPAL_INVESTIGATOR
References:
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