Try the modernized beta website. Learn more about the modernization effort.
Working… Menu

Efficacy and Safety of the Cryopreserved Formulation of OTL-101 in Subjects With ADA-SCID

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02999984
Recruitment Status : Completed
First Posted : December 21, 2016
Last Update Posted : April 13, 2020
California Institute for Regenerative Medicine (CIRM)
University of California, Los Angeles
Information provided by (Responsible Party):
Orchard Therapeutics

Brief Summary:
This is a prospective, non-randomized, single-cohort, longitudinal, single-center, clinical study designed to assess the efficacy and safety of a cryopreserved formulation of OTL-101 (autologous CD34+ hematopoietic stem/progenitor cells transduced ex vivo with EFS (Elongation Factor 1α Short form) Lentiviral Vector (LV) encoding for the human ADA gene) administered to ADA-SCID subjects between the ages of 30 days and 17 years of age, who are not eligible for an Human Leukocyte Antigen (HLA) matched sibling/family donor and meeting the inclusion/exclusion criteria. The OTL-101 product is infused after a minimal interval of at least 24 hours following the completion of reduced intensity conditioning. For subjects who successfully receive the OTL-101 product, pegademase bovine (PEG-ADA) Enzyme Replacement Therapy (ERT) is discontinued at Day+30 (-3/+15) after the transplant. After their discharge from hospital, the subjects will be seen at regular intervals to review their history, perform examinations and draw blood samples to assess immunity and safety.

Condition or disease Intervention/treatment Phase
Severe Combined Immunodeficiency Due to ADA Deficiency Genetic: Infusion of autologous cryopreserved EFS-ADA LV CD34+ cells (OTL-101) Drug: busulfan Drug: PEG-ADA ERT Phase 1 Phase 2

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Efficacy and Safety of Cryopreserved Formulation of Autologous CD34+ Hematopoietic Stem Cells Transduced Ex Vivo With EFS Lentiviral Vector Encoding for Human ADA Gene in Subjects With Severe Combined Immunodeficiency Due to ADA Deficiency
Actual Study Start Date : December 16, 2016
Actual Primary Completion Date : October 11, 2018
Actual Study Completion Date : September 26, 2019

Arm Intervention/treatment
Experimental: Gene Therapy
Infusion of autologous cryopreserved EFS-ADA LV CD34+ cells
Genetic: Infusion of autologous cryopreserved EFS-ADA LV CD34+ cells (OTL-101)
autologous cryopreserved EFS-ADA LV CD34+ cells (OTL-101) are infused intravenously
Other Name: OTL-101

Drug: busulfan
Busulfan is used for non-myoablative conditioning

PEG-ADA ERT is discontinued at Day +30 (-3/+15 days) after successful engraftment

Primary Outcome Measures :
  1. The number of subjects with treatment success post OTL-101 infusion [ Time Frame: 6 Months ]

    Defined as meeting or exceeding the threshold for all three of the following parameters:

    1. Erythrocyte ADA enzyme activity above baseline/pre-treatment level (>0 Units),
    2. Evidence of immune reconstitution as measured by absolute number of CD3 cells ≥200/mm3),
    3. Detectable gene-marked granulocytes as measured by differential polymerase chain reaction (dPCR)/ quantitative PCR (qPCR) (≥1/10,000 cells).

  2. Overall survival [ Time Frame: 12 Months ]
    Overall survival is defined as the proportion of subjects alive.

  3. Event free survival [ Time Frame: 12 Months ]
    Event-free survival is defined as the proportion of subjects alive with no "event", an "event" being the resumption of PEG-ADA ERT or the need for a rescue allogenic Hematopoietic Stem Cell Transplant (HSCT), or death.

Secondary Outcome Measures :
  1. Overall survival [ Time Frame: 24 months ]
    Overall survival is defined as the proportion of subjects alive.

  2. Event free survival [ Time Frame: 24 months ]
    Event-free survival is defined as the proportion of subjects alive with no "event", an "event" being the resumption of PEG-ADA ERT or the need for a rescue allogenic HSCT, or death.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Layout table for eligibility information
Ages Eligible for Study:   up to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Provision of written informed consent prior to any study related procedures. In this study consent must be provided by the parents/legal guardians and, where applicable according to local laws, a signed assent from the child,
  2. Subjects ≥30 days and <18 years of age,
  3. With a diagnosis of ADA-SCID based on:

    Evidence of ADA deficiency, defined as:

    i. Decreased ADA enzymatic activity in erythrocytes, leukocytes, skin fibroblasts, or in cultured fetal cells to levels consistent with ADA-SCID as determined by the reference laboratory, or ii. Identified mutations in ADA alleles consistent with a severe reduction in ADA activity,

    Evidence of ADA-SCID based on either:

    i. Family history of a first order relative with ADA deficiency and clinical and laboratory evidence of severe immunologic deficiency, or ii. Evidence of severe immunologic deficiency in subjects prior to the institution of immune restorative therapy, based on

    • Lymphopenia (absolute lymphocyte count (ALC) <400 cells/µL) OR absence or low number of T cells (absolute CD3+ count < 300 cells/µL), or
    • Severely decreased T lymphocyte blastogenic responses to phytohemagglutinin (either <10% of lower limit of normal controls for the diagnostic laboratory, or <10% of the response of the normal control of the day, or stimulation index <10), or
    • Identification of SCID by neonatal screening revealing low T cell Receptor Excision Circle (TREC) levels.
  4. Ineligible for matched family allogeneic Bone Marrow (BM) transplantation, defined as the absence of a medically eligible HLA-identical sibling or family donor, with normal immune function, who could serve as an allogeneic bone marrow donor.
  5. Females of child-bearing age will be required to provide a negative pregnancy test 30 days prior to Visit 2.
  6. Subjects and their parents/legal guardians must be willing and able to comply with study restrictions and to remain at the clinic for the required duration during the study period and willing to return to the clinic for the follow up evaluation as specified in the protocol.

Exclusion Criteria:

  1. Ineligible for autologous HSCT as per clinical site criteria.
  2. Other conditions which in the opinion of the Principal Investigator and/or Co Investigators, contraindicate the harvest of bone marrow, the administration of Busulfan and the infusion of transduced cells, or which indicate an inability of the subject or subject's parent/legal guardian to comply with the protocol.
  3. Hematologic abnormality, defined as:

    • Anemia (Hb <8.0 g/dl).
    • Neutropenia (ANC <500/mm3). Note: ANC <500 with absence of myelodysplastic syndrome on bone marrow aspirate and biopsy and normal marrow cytogenetics are acceptable for eligibility.
    • Thrombocytopenia (platelet count <50,000/mm3, at any age).
    • Prothrombin time or international normalized ratio (INR) and partial thromboplastin time (PTT) >2 x upper limit of normal (ULN) (subjects with a correctable deficiency controlled on medication will not be excluded).
    • Cytogenetic abnormalities on peripheral blood or bone marrow or amniotic fluid (if available).
    • Prior allogeneic HSCT with cytoreductive conditioning.
  4. Pulmonary abnormality, defined as:

    • Resting O2 saturation by pulse oximetry <90% on room air.
    • Chest X-ray indicating active or progressive pulmonary disease. Note: Chest X ray indicating residual signs of treated pneumonitis is acceptable for eligibility.
  5. Cardiac abnormality, defined as:

    • Abnormal ECG indicating cardiac pathology.
    • Uncorrected congenital cardiac malformation with clinical symptoms.
    • Active cardiac disease, including clinical evidence of congestive heart failure, cyanosis, hypotension.
    • Poor cardiac function as evidenced by left ventricular ejection fraction <40% on echocardiogram.
  6. Neurologic abnormality, defined as:

    • Significant neurologic abnormality revealed by examination.
    • Uncontrolled seizure disorder.
  7. Renal abnormality, defined as:

    • Renal insufficiency: serum creatinine ≥1.2 mg/dl (106 µmol/L), or ≥3+ proteinuria.
    • Abnormal serum sodium, potassium, calcium, magnesium or phosphate levels at >2 x ULN.
  8. Hepatic/gastrointestinal abnormality, defined as:

    • Serum transaminases >5 x ULN.
    • Serum bilirubin >2 x ULN.
    • Serum glucose >1.5 x ULN.
  9. Oncologic disease, defined as:

    • Evidence of active malignant disease other than dermatofibrosarcoma protuberans (DFSP).
    • Evidence of DFSP expected to require anti-neoplastic therapy within the 5 years following the infusion of genetically corrected cells (if anti-neoplastic therapy has been completed, a subject with a history of DFSP can be included).
    • 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. Confirmation of an infectious disease by deoxyribonucleic acid (DNA) PCR positive at time of screening assessment for the following:

    • HIV-1,
    • Hepatitis B,
    • Parvovirus B19.
  12. The subject is pregnant or has a major congenital anomaly.
  13. Is likely to require treatment during the study with drugs that are not permitted by the study protocol.
  14. The subject has previously received another form of gene therapy.

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 identifier (NCT number): NCT02999984

Layout table for location information
United States, California
University of California, Los Angeles
Los Angeles, California, United States, 90095
Sponsors and Collaborators
Orchard Therapeutics
California Institute for Regenerative Medicine (CIRM)
University of California, Los Angeles
Layout table for investigator information
Study Director: Donald B. Kohn, MD University of California, Los Angeles
Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Orchard Therapeutics Identifier: NCT02999984    
Other Study ID Numbers: OTL-101-4
First Posted: December 21, 2016    Key Record Dates
Last Update Posted: April 13, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Keywords provided by Orchard Therapeutics:
gene therapy
hematopoietic and progenitor cells
lentiviral vector
Additional relevant MeSH terms:
Layout table for MeSH terms
Severe Combined Immunodeficiency
Immunologic Deficiency Syndromes
Immune System Diseases
Primary Immunodeficiency Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
DNA Repair-Deficiency Disorders
Metabolic Diseases
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Antineoplastic Agents
Myeloablative Agonists