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

NCT03765632 | Completed Phase 1 DMC

• 2 other identifiers: OTL-101-517IC04
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

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 \<18 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.

Conditions

Severe Combined Immunodeficiency Due to ADA Deficiency

Keywords

Gene therapy; Hematopoietic stem and progenitor cells; Lentiviral vector; ADA-SCID

Outcome Measures

Primary Outcomes (2)

• Overall survival at 12 months post OTL-101 infusion

  Overall survival is defined as the proportion of subjects alive

  12 Months

• Event free survival at 12 months post OTL-101 infusion

  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 stem cell transplant (SCT), or death

  12 Months

Secondary Outcomes (5)

• Overall survival at 24 months post OTL-101 infusion

  24 months

• Event free survival at 24 months post OTL-101 infusion

  24 Months

• Safety evaluation including infection rates

  12 and 24 months

• Safety evaluation including performance outcomes

  12 and 24 months

• Safety evaluation including immune reconstitution

  12 and 24 months

Study Arms (1)

Gene Therapy

EXPERIMENTAL

Infusion of autologous cryopreserved EFS-ADA LV CD34+ cells

Genetic: Infusion of autologous cryopreserved EFS-ADA LV CD34+ cells (OTL-101); Drug: Busulfan; Drug: Peg-Ada

Interventions

Infusion of autologous cryopreserved EFS-ADA LV CD34+ cells (OTL-101) GENETIC

Autologous cryopreserved EFS-ADA LV CD34+ cells (OTL-101) are infused intravenously

Also known as: OTL-101

Gene Therapy

Busulfan DRUG

Busulfan is used for non-myeloablative conditioning

Gene Therapy

Peg-Ada DRUG

Peg-Ada Enzyme Replacement Therapy (ERT) is discontinued at Day +30 (-3/+15 days) after successful engraftment

Gene Therapy

Eligibility Criteria

• Age: 30 Days - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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 foetal 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 \<400 cells/mL) OR absence or low number of T-cells (absolute CD3+ count \< 300 cells/mL), 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 or with no available matched family donor for 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.

You may not qualify if:

• Ineligible for autologous hematopoietic stem cell (HSC) procedure.
• 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.
• Haematologic abnormality, defined as:
• Anaemia (Hb \<8.0 g/dl). Evidence of bi/trilineage cytopaenia (haemoglobin \<8 g/dl, neutrophils \<0.5 x 109/L, platelets 50 x 109/L). Thrombocytopaenia (platelet count \<50,000/mm3). Prothrombin time or 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 of Peripheral Blood (PB), BM or amniotic fluid (if available). If cytogenetic testing has not been performed on cells from amniocentesis, assessment should be by karyotype, Comparative genomic hybridization (CGH), and or whole exome sequencing (WES).
• Prior allogeneic HSC transplant (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:

Sponsors & Collaborators

• Great Ormond Street Hospital for Children NHS Foundation Trust: lead
• Orchard Therapeutics: collaborator

Study Sites (1)

Great Ormond Street Hospital for Children NHS Foundation Trust

London, WC1N 3JH, United Kingdom

Location

MeSH Terms

Conditions

Severe combined immunodeficiency due to adenosine deaminase deficiency

Interventions

Busulfan; pegademase bovine

Intervention Hierarchy (Ancestors)

Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Study Officials

• Claire Booth, Dr

  Great Ormond Street Hospital NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 8, 2018
• First Posted: December 5, 2018
• Study Start: January 3, 2018
• Primary Completion: September 13, 2021
• Study Completion: September 28, 2022
• Last Updated: February 1, 2023

Record last verified: 2023-01

Locations

GB (1)