MT2018-18: Sleeping Beauty Transposon-Engineered Plasmablasts for Hurler Syndrome Post Allo HSCT

Sleeping Beauty Transposon-Engineered Plasmablasts for Expression and Delivery of Alpha-L-iduronidase in Patients With Hurler Syndrome That Have Previously Undergone Allogeneic Transplantation

This is a single center, Phase 1/2 study in which patients with Hurler syndrome who have previously undergone allogeneic hematopoietic stem cell transplantation are treated with autologous plasmablasts engineered to express α-L-iduronidase (IDUA) using the Sleeping Beauty transposon system.

Study Overview

• Status: Withdrawn
• Conditions: Mucopolysaccharidosis Type IH; Mucopolysaccharidosis Type IH (MPS IH, Hurler Syndrome); MPS IH, Hurler Syndrome
• Intervention / Treatment: Drug: Autologous Plasmablasts

• Study Type: Interventional
• Phase: Phase 2; Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 8 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of Mucopolysaccharidosis type IH (MPS IH, Hurler syndrome)
• Underwent a previous hematopoietic stem cell transplant >1 year prior to study enrollment
• Age ≥3 years and ≤8 years at time of study registration
• ≥ 10 kilograms body weight
• Creatinine <1.5 normal for gender and age.
• Ejection fraction ≥ 40% by echocardiogram
• Must commit to traveling to the University of Minnesota for the necessary followup evaluations
• Must agree to stay in the Twin Cities area (<45-minute drive from the Masonic Children's Hospital) for a minimum of 5 days after each cell infusion
• Voluntary written parental consent prior to the performance of any study related procedures

Exclusion Criteria:

• Prior enzyme replacement therapy within 4 months prior to enrolling on study
• History of B cell related cancer, EBV lymphoproliferative disease or autoimmune disorders
• Evidence of active graft vs. host disease
• Requirement for systemic immune suppression
• Requirement for continuous supplemental oxygen
• Any medical condition likely to interfere with assessment of safety or efficacy of the study treatment.
• In the investigator's judgement, the subject is unlikely to complete all protocol required study visits or procedures, including follow up visits, or comply with the study requirements for participation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1: Dose Escalation	Drug: Autologous Plasmablasts; Autologous Plasmablasts engineered to express α-L-iduronidase (IDUA) using the Sleeping Beauty transposon system. Phase 1: Dose Level 1: 5 x 10e7 cells/kg on Day 0; Dose Level 2: 1 x 10e8 cells/kg on Day 0; Dose Level 3: 1 x 10e8 cells/kg x 2 doses on Day 0 and Day 30 +/-3 days. Phase 2: - Maximum Tolerated Dose (MTD) established in Phase I; Other Names: Sleeping Beauty
Experimental: Phase 2 - Expansion at MTD	Drug: Autologous Plasmablasts; Autologous Plasmablasts engineered to express α-L-iduronidase (IDUA) using the Sleeping Beauty transposon system. Phase 1: Dose Level 1: 5 x 10e7 cells/kg on Day 0; Dose Level 2: 1 x 10e8 cells/kg on Day 0; Dose Level 3: 1 x 10e8 cells/kg x 2 doses on Day 0 and Day 30 +/-3 days. Phase 2: - Maximum Tolerated Dose (MTD) established in Phase I; Other Names: Sleeping Beauty

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD)	Maximum tolerated dose (MTD) of autologous plasmablasts engineered to express large amounts of α-L-iduronidase (IDUA) using a Sleeping Beauty transposon approach	1 Year
Growth Velocity (cm/year)	Growth velocity in centimeters/year over a one-year period through determinations of sitting and standing height at baseline and post infusion	1 Year
Safety and Tolerability after Infusion: Incidence of Adverse Events	Incidence of Adverse Events	1 Year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Z-score Growth Rate	Estimate the 1-year Z-score growth rate standardized for age and gender	1 Year
Donor Engraftment	Estimate percent myeloid donor chimerism (CD33/66b) at baseline and at 6 and 12 months.	Baseline, 6 months and 1 Year
Levels of circulating antibodies (IgG, IgM, IgA and IgE)	Determine levels of circulating antibodies (IgG, IgM, IgA and IgE) at baseline and at scheduled time points post infusion.	1 Year

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota
• Investigators: Principal Investigator: Paul Orchard, MD, University of Minnesota, Department of Pediatrics

Study record dates

Study Major Dates

• Study Start (Anticipated): December 1, 2022
• Primary Completion (Anticipated): June 1, 2023
• Study Completion (Anticipated): June 1, 2023

Study Registration Dates

• First Submitted: November 11, 2019
• First Submitted That Met QC Criteria: February 24, 2020
• First Posted (Actual): February 25, 2020

Study Record Updates

• Last Update Posted (Actual): October 7, 2022
• Last Update Submitted That Met QC Criteria: October 5, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Hurler syndrome; MPS IH
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Disease; Genetic Diseases, Inborn; Connective Tissue Diseases; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Syndrome; Mucopolysaccharidoses; Mucopolysaccharidosis I
• Other Study ID Numbers: 2018LS094; MT2018-18 (Other Identifier: University of Minnesota Masonic Cancer Center)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No