Gene therapy study using a frozen formulation of OTL-103 in patients with Wiskott-Aldrich Syndrome (WAS)

• Register: EUCTR
• Last refreshed on: 3 December 2024
• Main ID: EUCTR2018-003842-18-IT
• Date of registration: 19/11/2018
• Prospective Registration: Yes
• Primary sponsor: Orchard Therapeutics Ltd.
• Public title: Gene therapy study using a frozen formulation of OTL-103 in patients with Wiskott-Aldrich Syndrome (WAS)
• Scientific title: A Single Arm, Open Label Clinical Study of Haematopoietic Stem Cell Gene Therapy with Cryopreserved Autologous CD34+ Cells Transduced with Lentiviral Vector encoding WAS cDNA in Subjects with Wiskott-Aldrich Syndrome (WAS). - Clinical study using cryopreserved OTL-103 for treatment of WAS.
• Date of first enrolment: 08/01/2019
• Target sample size: 6
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-003842-18
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Italy

Contacts

• Name: Clinical
• Affiliation: Orchard Therapeutics Ltd.

• Name: Clinical
• Affiliation: Orchard Therapeutics Ltd.

Key inclusion & exclusion criteria

Inclusion criteria:
•Age: up to 65 years.
• Diagnosis of WAS defined by genetic mutation and at least one of the following criteria:
Severe WASP mutation;
Absent WASP expression;
Severe clinical score (Zhu clinical score = 3);
Family member affected by WAS with life-threatening or fatal clinical events.
• No human leukocyte antigen (HLA)-identical related donor available.
• Parental/guardian/subject-signed informed consent, and subject assent (if appropriate).
•For all subjects in the reproductive age range, agreement to use highly
effective and adequate method of contraception (as detailed in Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information) while receiving treatment and for at least 12 months following drug administration.
Are the trial subjects under 18? yes
Number of subjects for this age range: 6
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 1
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. End-organ dysfunction, severe active infection not responsive to treatment or other severe disease or clinical condition which, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
In addition to the potential infections tested per protocol, the PI should Tissue Directive as clinically appropriate and discuss the results with the medical monitor prior to cell harvest.
Patients with ALT >2x upper limit of normal (ULN) or total bilirubin >1.5 x ULN may be included only after discussed and agreed with the medical monitor and considered in the context of the criterion for excluding patients with other severe disease.
Isolated elevation of total bilirubin >1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35% of total.
2. Malignant neoplasia (except local skin cancer) or a documented history of hereditary cancer syndrome . Patients with a prior successfully treated malignancy and a sufficient follow-up to exclude recurrence (based on oncologist opinion) can be included after discussion and approval by the medical monitor.
3. Myelodysplasia, cytogenetic alterations characteristic of myelodysplastic syndrome and acute myeloid leukaemia , or other serious haematological disorders.
4. Prior allogeneic hematopoietic stem cell transplantation, with evidence of residual cells of donor origin.
5. Documented HIV infection (positive HIV RNA and/or anti-p24 antibodies).
6. Current participation in other interventional clinical trials.
7. Previous gene therapy.
8. Symptomatic herpes zoster, not responsive to specific treatment.
Patients with a recent history of herpes zoster may be included in the study. In such cases, inclusion, additional monitoring and treatment of the condition must be discussed and approved by the medical monitor.
9. Evidence of active tuberculosis (TB) based upon medical examination, chest imaging and TB testing i.e. QuantiFERON®-TB Gold test and microbiological evidence.
Patients with latent TB, as documented by medical history and/or TB testing may be included in the study if receiving antibiotic prophylaxis (e.g. isoniazid). Inclusion, monitoring and treatment of TB in such patients must be discussed and approved by the medical monitor.
10. Acute or chronic stable Hepatitis B as evidenced by positive Hepatitis B surface antigen (HBsAg) test result at screening or within 3 months prior to start of conditioning and/or positive HBV DNA.
Patients with positive Hepatitis B core antibody due to prior resolved disease may be eligible to be included, only if a confirmatory negative HBsAg and negative Hepatitis B DNA test are obtained. Inclusion, monitoring and treatment of hepatitis in such patients must be discussed and approved by the medical monitor.
11. Presence of positive Hepatitis C RNA test result at screening. Patients who have previously tested positive for HCV can be treated, provided they demonstrate absence of ongoing infection using a nucleic acid test with a limit of quantification of =15 international units/mL.
Negative test results are required on at least 3 sequential occasions over a period of at least 4 weeks, after completion of treatment for hepatitis C, with the final test conducted no more than 3 days prior to cell harvest.
Inclusion, monitoring and treatment of hepatitis in such subjects must be discussed and approved by the medical monitor.
12. Patients that are not eligible for mobilisation protocols in order to obtain CD34+ cells f

Age minimum:
Age maximum:
Gender:
Female: no
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Wiskott-Aldrich Syndrome
MedDRA version: 20.0 Level: PT Classification code 10061598 Term: Immunodeficiency System Organ Class: 10021428 - Immune system disorders

Intervention(s)

Product Name: OTL-103 Dispersion for Infusion
Product Code: OTL-103
Pharmaceutical Form: Dispersion for infusion
INN or Proposed INN: Other hematological Agents
CAS Number: NA
Current Sponsor code: NA
Other descriptive name: Autologous CD34+ enriched cell fraction that contains CD34+ cells transduced with lentiviral vector that encodes for the human Wiskott Aldrich Syndrome (WAS) cDNA sequence
Concentration unit: Other
Concentration type: up to
Concentration number: 10000000-

Trade Name: Busilvex
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: BUSULFAN
CAS Number: 55-98-1
Current Sponsor code: NA
Other descriptive name: NA
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 6-

Trade Name: Fludarabina Accord
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: FLUDARABINE
CAS Number: 21679-14-1
Current Sponsor code: NA
Other descriptive name: NA
Concentration unit: mg/l milligram(s)/litre
Concentration type: equal
Concentration number: 25-

Trade Name: MabThera
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: RITUXIMAB
CAS Number: 174722-31-7
Current Sponsor code: NA
Other descriptive name: NA
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Trade Name: Mozobil,
Pharmaceutical Form: Solution for injection
INN or Proposed INN: plerixafor
CAS Number: 110078-46-1
Current Sponsor code: NA
Other descriptive name: PLERIXAFOR
Concentration unit: mg/l milligram(s)/litre
Concentration type: equal
Concentration number: 20-

Trade Name: MYELOSTIM
Product Name: granulocyte colony stimulating factor (G-CSF)
Pharmaceutical Form: Powder and solvent for solution for injection
INN or Proposed INN:

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: 6 months and 60 days post treatment.

Main Objective: To evaluate the engraftment and biological efficacy of the cryopreserved formulation of OTL-103 at 6 months

Primary end point(s): • Evaluation of engraftment and biological efficacy at 6 months:
1) haematological reconstitution at 60 days post treatment (absolute neutrophil count >500 cells/µL);
2) vector copy number (VCN)/cell of >0.1 in peripheral blood (PB)-derived CD3+ cells at 6 months;
3) WAS protein (WASP) expression increased from pretreatment levels in lymphocytes and platelets at 6 months.

Secondary Objective: • to evaluate the safety of treatment with OTL-103
• to evaluate the biological efficacy of the cryopreserved formulation of OTL-103 at 12 months and 2 years
• to evaluate the clinical efficacy of the cryopreserved formulation of OTL-103 at 2 years
• to evaluate sustained engraftment of the cryopreserved formulation of OTL-103 at 2 years
• to evaluate the immunological function after treatment with OTL-103 at 2 years
• to evaluate the effect of OTL-103 on health-related quality of life at 2 years

Secondary Outcome(s)

Secondary end point(s): Evaluation of the safety of treatment
1) safety and tolerability as measured by adverse event (AE) reporting;
2) absence of malignancy or abnormal clonal proliferation (ACP) development due to insertional oncogenesis;
3) absence of replication-competent lentivirus (RCL).

• Evaluation of biological correlates of efficacy at 12 months and 2 years:
1) VCN/cell of >0.1 in PB-derived CD3+ cells;
2) WASP expression increased from pretreatment levels in lymphocytes and platelets.
• Evaluation of clinical efficacy at 2 years:
1) reduction in the annualised rate of severe infections from 6 months to 2 years after gene therapy (GT) compared with 1 year prior to GT;
2) reduction in the annualised rate of severe bleeding episodes from 6 months to 2 years after GT compared with 1 year prior to GT;
3) improved platelet count compared with baseline;
4) normalised mean platelet volume (MPV);
5) reduction of eczema severity compared with baseline;
6) reduction of autoimmunity phenomena compared with baseline;
7) reduction in the annualised rate of hospitalisation due to infections or bleeding episodes from 6 months to 2 years after GT compared with 1 year prior to GT.
• Evaluation of sustained engraftment at 2 years
1) >10% lentiviral vector (LV)-positive clonogenic progenitors in bone marrow;
2) VCN/cell of >0.04 in BM-derived CD34+ cells;
3) VCN/cell of >0.1 in PB-derived CD3+ cells.
• Evaluation of immunological function at 2 years
1) T cell function (proliferation to stimuli);
2) response to vaccination, only if performed
• Evaluation of the effect of treatment on health-related quality of life at 2 years
1) Improvement from baseline in Paediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scale scores

Timepoint(s) of evaluation of this end point: 6 months, 12 months and 2 years

Secondary ID(s)

OTL-103-4

Source(s) of Monetary Support

Orchard Therapeutics Ltd

Ethics review

Status: Approved
Approval date: 08/01/2019
Contact: