- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04140539
A Clinical Study to Enable Process Validation of Commercial Grade OTL-101
A Single Arm, Open Label Clinical Study to Enable Process Validation of Commercial Grade Ex Vivo Hematopoietic Stem Cell Gene Therapy (OTL-101) in Subjects With Severe Combined Immunodeficiency Due to Adenosine Deaminase Deficiency (ADA-SCID)
Study Overview
Status
Intervention / Treatment
Detailed Description
The safety and efficacy of OTL-101 for the treatment of patients with ADA- SCID have been established in previous clinical trials. The purpose of the current study is to treat at least 3 ADA-SCID patients with OTL-101 prepared by the commercial manufacturing process in order to facilitate collection of data necessary for final manufacturing.
Assessments will focus on monitoring safety and engraftment, through the evaluation of parameters describing immunological recovery, ADA enzyme activity and persistence of gene marking (VCN) at 6 months and 12 months. After completion of 12 months of follow-up on the current study protocol, subjects will be enrolled in an observational long-term follow-up study, in order to monitor the long-term safety of treatment with OTL-101.
Study Type
Phase
- Phase 2
- Phase 3
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 by the subject or parent(s)/legal guardian(s), prior to any study related procedures taking place. Where consent is provided by the parent(s)/legal guardian(s), assent by the subject should also be sought, if appropriate
- Age ≥30 days and <18 years
Diagnosis of ADA-SCID based on either:
- 1) Evidence of ADA deficiency, defined as 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 Identified mutations in ADA alleles consistent with a severe reduction in ADA activity
2) Evidence of ADA-SCID, defined as Family history of a first order relative with ADA deficiency and clinical and laboratory evidence of severe immunologic deficiency OR Evidence of severe immunologic deficiency in subjects prior to the institution of immune restorative therapy, based on at least one of the following:
- Lymphopenia (absolute lymphocyte count <400 cells/μL) OR absence or low number of T cells (absolute CD3+ count < 300 cells/μL)
- 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)
- Identification of SCID by neonatal screening revealing low T cell receptor excision circles (TREC) levels
- Ineligible for allogeneic bone marrow transplantation from an Human leukocyte antigen (HLA)-identical sibling donor, with normal immune function
- For females of child-bearing potential, negative pregnancy test up to 30 days prior to the Screening visit. For all subjects in the reproductive age range, agreement to use highly effective and adequate method of contraception while receiving treatment and for at least 12 months following drug administration
- Willingness and ability of the subjects and parent(s)/legal guardian(s) to comply with study procedures and requirements, including remaining at the clinic for the required duration of conditioning and treatment and compliance with follow-up evaluations
Exclusion Criteria:
- Ineligible for autologous HSCT as per clinical site criteria.
Hematologic abnormality, defined as:
- Anemia (Hb <8.0 g/dL)
- Neutropenia (absolute neutrophil count (ANC) <500 cells/mm3). Note: ANC <500 cells/mm3 with absence of myelodysplastic syndrome on bone marrow aspirate and biopsy and normal marrow cytogenetics are acceptable for eligibility
- Thrombocytopenia (platelet count <50,000 platelets/mm3)
- Prothrombin Time (PT) or International Normalized Ratio (INR) and Partial thromboplastin time (PTT) >2 times the 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 oxygen (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 electrocardiogram 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 times the ULN
Hepatic/gastrointestinal abnormality, defined as:
- Serum transaminases >5 times the ULN
- Serum bilirubin >2 times the ULN
- Serum glucose >1.5 times the 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 infectious disease at time of Screening assessment for:
- Human Immunodeficiency Virus (HIV)-1 and HIV-2
- Hepatitis B and Hepatitis C
- Parvovirus B19
- Human T-cell lymphotropic virus (HTLV)-1 and HTLV-2
- Pregnant at the time of Screening
- Affected by a major congenital anomaly
- Likely to require treatment during the study with drugs that are not permitted by the study protocol
- Previously treated with another form of gene therapy
- Affected by any other condition(s) which, in the opinion of the Principal Investigator, contraindicate bone marrow harvest, the administration of busulfan and the infusion of OTL-101, or which indicate an inability of the subject or subject's parent(s)/legal guardian(s) to comply with the protocol
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 |
---|---|
Experimental: Gene Therapy
Infusion OTL-101
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Autologous CD34+ cell enriched population that contains hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo using a lentiviral vector (LV) encoding the human adenosine deaminase (ADA) gene.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Adenosine Deaminase (ADA) enzyme activity
Time Frame: 6 months post treatment
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ADA enzyme activity in red blood cells
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6 months post treatment
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T cell (CD3+) count
Time Frame: 6 months post treatment
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Absolute count of CD3+ cells
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6 months post treatment
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Vector Copy Number (VCN)
Time Frame: 6 months post treatment
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VCN in granulocytes
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6 months post treatment
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Overall Survival (OS)
Time Frame: 12 months post treatment
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OS will be defined as the proportion of subjects alive at 12 months post-treatment with OTL-101
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12 months post treatment
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Event-free Survival (EvFS)
Time Frame: 12 months post treatment
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EvFS will be defined as the proportion of subjects alive with no "event", an event being the resumption of Pegylated adenosine deaminase (PEG-ADA) Enzyme Replacement Therapy (ERT) or the need for a rescue allogeneic hematopoietic stem cell transplant (HSCT) at 12 months post-treatment with OTL-101
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12 months post treatment
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Collaborators and Investigators
Investigators
- Study Director: Orchard Therapeutics Clinical Trials, Orchard Therapeutics (Europe) Limited
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 (Actual)
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
Other Study ID Numbers
- OTL-101-7
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
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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.
Clinical Trials on Severe Combined Immunodeficiency Due to ADA Deficiency
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University of California, Los AngelesOrchard Therapeutics; California Institute for Regenerative Medicine (CIRM)CompletedSevere Combined Immunodeficiency Due to ADA DeficiencyUnited States
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Fondazione TelethonCompletedSevere Combined Immunodeficiency Due to ADA DeficiencyItaly
-
Great Ormond Street Hospital for Children NHS Foundation...Orchard TherapeuticsCompletedSevere Combined Immunodeficiency Due to ADA DeficiencyUnited Kingdom
-
Fondazione TelethonActive, not recruitingSevere Combined Immunodeficiency Due to ADA DeficiencyItaly
-
Shenzhen Geno-Immune Medical InstituteUnknownAdenosine DeAminase Severe Combined ImmunoDeficiency (ADA-SCID)China
-
Leiden University Medical CenterZonMw: The Netherlands Organisation for Health Research and Development; Horizon...RecruitingSevere Combined Immunodeficiency Due to RAG1 DeficiencySpain, Netherlands, Italy, Poland, Australia, Turkey, United Kingdom
-
National Institute of Allergy and Infectious Diseases...National Center for Advancing Translational Sciences (NCATS); Office of Rare... and other collaboratorsEnrolling by invitationOmenn Syndrome | Reticular Dysgenesis | Severe Combined Immunodeficiency (SCID) | XSCID | Leaky SCID | ADA SCIDUnited States, Canada
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National Institute of Allergy and Infectious Diseases...TerminatedGrowth Failure | X-linked Severe Combined Immunodeficiency (XSCID) | Growth Hormone ResistenceUnited States
-
Leadiant Biosciences, Inc.CompletedSevere Combined Immunodeficiency | ADA-SCID | Adenosine Deaminase DeficiencyUnited States
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Great Ormond Street Hospital for Children NHS Foundation...UnknownX-linked Severe Combined ImmunodeficiencyUnited Kingdom
Clinical Trials on OTL-101
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University of California, Los AngelesOrchard Therapeutics; California Institute for Regenerative Medicine (CIRM)CompletedSevere Combined Immunodeficiency Due to ADA DeficiencyUnited States
-
Fondazione TelethonOspedale San RaffaeleActive, not recruitingWiskott-Aldrich SyndromeItaly, United States
-
Orchard TherapeuticsOspedale San RaffaeleActive, not recruitingLysosomal Storage Diseases | Metachromatic LeukodystrophyItaly
-
University of California, Los AngelesNational Institute of Allergy and Infectious Diseases (NIAID); National Heart... and other collaboratorsCompleted
-
Great Ormond Street Hospital for Children NHS Foundation...Orchard TherapeuticsCompletedSevere Combined Immunodeficiency Due to ADA DeficiencyUnited Kingdom
-
Fondazione TelethonOspedale San RaffaeleCompleted
-
Orchard TherapeuticsOspedale San RaffaeleActive, not recruitingLysosomal Storage Disease | Metachromatic LeukodystrophyItaly
-
Orchard TherapeuticsOspedale San RaffaeleActive, not recruitingLysosomal Storage Disease | Metachromatic LeukodystrophyItaly
-
Orchard TherapeuticsRecruitingMPS-IH (Hurler Syndrome)Netherlands, United States, Italy, United Kingdom
-
TR TherapeuticsCompleted