- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02999984
Efficacy and Safety of the Cryopreserved Formulation of OTL-101 in Subjects With ADA-SCID
Efficacy and Safety of Cryopreserved Formulation of Autologous CD34+ Hematopoietic Stem Cells Transduced Ex Vivo With Elongation Factor 1 Alpha Shortened (EFS) Lentiviral Vector Encoding for Human ADA Gene in Subjects With Severe Combined Immunodeficiency Due to ADA Deficiency
Study Overview
Status
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
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California
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Los Angeles, California, United States, 90095
- University of California, Los Angeles
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- 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,
- Subjects ≥30 days and <18 years of age,
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.
- 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.
- Females of child-bearing age will be required to provide a negative pregnancy test 30 days prior to Visit 2.
- 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:
- Ineligible for autologous Hematopoietic Stem Cell Transplantation (HSCT) as per clinical site criteria.
- 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.
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.
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.
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.
Neurologic abnormality, defined as:
- Significant neurologic abnormality revealed by examination.
- Uncontrolled seizure disorder.
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.
Hepatic/gastrointestinal abnormality, defined as:
- Serum transaminases >5 x ULN.
- Serum bilirubin >2 x ULN.
- Serum glucose >1.5 x ULN.
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.
- Known sensitivity to Busulfan.
Confirmation of an infectious disease by deoxyribonucleic acid (DNA) Polymerase chain reaction (PCR) positive at time of screening assessment for the following:
- HIV-1,
- Hepatitis B,
- Parvovirus B19.
- The subject is pregnant or has a major congenital anomaly.
- Is likely to require treatment during the study with drugs that are not permitted by the study protocol.
- The subject has previously received another form of gene therapy.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Gene Therapy
Infusion of autologous cryopreserved EFS-ADA LV CD34+ cells
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Busulfan is used for non-myeloablative conditioning
PEG-ADA ERT is discontinued at Day +30 (-3/+15 days) after successful engraftment
autologous cryopreserved EFS-ADA LV CD34+ cells (OTL-101) are infused intravenously
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Percentage of Participants With Treatment Efficacy After Treatment With OTL 101 (6 Months)
Time Frame: 6 months
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Efficacy of OTL-101 treatment at 6 months post OTL-101 infusion based on the following parameters and thresholds:
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6 months
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Overall Survival (OS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year)
Time Frame: 12 Months
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Overall survival is defined as the percentage of subjects alive at 12 months post- treatment with cryopreserved OTL-101.
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12 Months
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Event-free Survival (EvFS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year)
Time Frame: 12 Months
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Event-free survival is defined as the percentage of subjects alive with no "event", an "event" being the resumption of PEG-ADA ERT or the need for a rescue allogeneic Hematopoietic Stem Cell Transplant (HSCT), or death.
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12 Months
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
EvFS of Subjects Treated With Investigational Medicinal Product (IMP) (2 Years)
Time Frame: 24 months
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Event-free survival is defined as the percentage 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.
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24 months
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OS of Subjects Treated With Investigational Medicinal Product (IMP) (2 Years)
Time Frame: 24 months
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OS is defined as the percentage of subjects alive at 24 months post- treatment with cryopreserved OTL-101.
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24 months
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Change From Baseline in CD3+ T Cell Counts (2 Years)
Time Frame: 24 months
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Immune reconstitution was assessed by change in CD3+ T Cell counts over time.
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24 months
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Severe Infections Excluding First 3 Months After Treatment
Time Frame: 24 months
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The infections of interest in this study were severe infections or opportunistic infectious episodes, defined as infections requiring hospitalization or prolonging hospitalization and/or documented infections by opportunistic pathogens.
Infections that took place in the first 3 months of follow-up post treatment were excluded from calculations to avoid possible bias introduced in the data by the effects of conditioning.
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24 months
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Change From Baseline in Quality of Life Measures (2 Years)
Time Frame: 24 months
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Assessment of quality of life was measured by the Lansky Performance Status Scale.
The maximum score on the Lansky Performance Scale is 100 - the child is fully active and able to carry on normal activity with no special care needed.
The minimum score is 10 - the child is completely disabled, not even passive play.
The scores at baseline (pre-treatment with OTL-101) and scores at Month 24 post-treatment with OTL-101 were compared to establish if there were any changes in the child's score in this timeframe.
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24 months
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Percentage of Patients Who Stopped Immunoglobulin Replacement Therapy (IgRT) (2 Years)
Time Frame: 24 months
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Use of immunoglobulin replacement therapies prior to and after gene therapy were monitored.
Indications for considering the discontinuation of immunoglobulin replacement therapy included: absolute CD4+ >200, absolute B cell >100/μl, IgA or IgM > lower limit of normal for age or gene marking >1% detectable in B cells.
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24 months
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Time to Cessation of IgRT for Those Who Stopped (2 Years)
Time Frame: 24 months
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Use of immunoglobulin replacement therapies prior to and after gene therapy were monitored.
For subjects who stopped IgRT during the study, the time of cessation was recorded.
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24 months
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Collaborators and Investigators
Investigators
- Study Director: Donald B. Kohn, MD, University of California, Los Angeles
Publications and helpful links
General Publications
- Carbonaro DA, Zhang L, Jin X, Montiel-Equihua C, Geiger S, Carmo M, Cooper A, Fairbanks L, Kaufman ML, Sebire NJ, Hollis RP, Blundell MP, Senadheera S, Fu PY, Sahaghian A, Chan RY, Wang X, Cornetta K, Thrasher AJ, Kohn DB, Gaspar HB. Preclinical demonstration of lentiviral vector-mediated correction of immunological and metabolic abnormalities in models of adenosine deaminase deficiency. Mol Ther. 2014 Mar;22(3):607-622. doi: 10.1038/mt.2013.265. Epub 2013 Nov 20.
- Kohn DB, Booth C, Shaw KL, Xu-Bayford J, Garabedian E, Trevisan V, Carbonaro-Sarracino DA, Soni K, Terrazas D, Snell K, Ikeda A, Leon-Rico D, Moore TB, Buckland KF, Shah AJ, Gilmour KC, De Oliveira S, Rivat C, Crooks GM, Izotova N, Tse J, Adams S, Shupien S, Ricketts H, Davila A, Uzowuru C, Icreverzi A, Barman P, Campo Fernandez B, Hollis RP, Coronel M, Yu A, Chun KM, Casas CE, Zhang R, Arduini S, Lynn F, Kudari M, Spezzi A, Zahn M, Heimke R, Labik I, Parrott R, Buckley RH, Reeves L, Cornetta K, Sokolic R, Hershfield M, Schmidt M, Candotti F, Malech HL, Thrasher AJ, Gaspar HB. Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency. N Engl J Med. 2021 May 27;384(21):2002-2013. doi: 10.1056/NEJMoa2027675. Epub 2021 May 11.
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Metabolic Diseases
- Immune System Diseases
- Infant, Newborn, Diseases
- Genetic Diseases, Inborn
- DNA Repair-Deficiency Disorders
- Primary Immunodeficiency Diseases
- Immunologic Deficiency Syndromes
- Severe Combined Immunodeficiency
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Myeloablative Agonists
- Busulfan
Other Study ID Numbers
- OTL-101-4
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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