RESET-Myositis: An Open-Label Study to Evaluate the Safety and Efficacy of CABA-201 in Subjects With Active Idiopathic Inflammatory Myopathy or Juvenile Idiopathic Inflammatory Myopathy

Official title

A Phase 1/2, Open-Label Study to Evaluate the Safety and Efficacy of Autologous CD19-specific Chimeric Antigen Receptor T Cells (CABA-201) in Subjects With Active Idiopathic Inflammatory Myopathy or Juvenile Idiopathic Inflammatory Myopathy

Overview

RESET-Myositis: Open-Label Study to Evaluate the Safety and Efficacy of CABA-201 in Subjects with Active Idiopathic Inflammatory Myopathy or Juvenile Idiopathic Inflammatory Myopathy

Detailed description

Idiopathic inflammatory myopathies (IIMs, or myositis) are a group of rare autoimmune diseases characterized by inflammation and muscle weakness. Though the cause of IIM is not well understood, some subtypes of IIM, including dermatomyositis (DM), anti-synthetase syndrome (ASyS), immune-mediated necrotizing myopathy (IMNM), and juvenile idiopathic inflammatory myopathy (JIIM), are thought to involve B cells that cause the body to attack different tissues in the body. This study is being conducted to evaluate the safety and efficacy of an investigational cell therapy, CABA-201, that can be given to patients with DM, ASyS, IMNM, or JIIM who have active disease. A single dose of CABA-201 in combination with cyclophosphamide (CY) and fludarabine (FLU) will be evaluated.

Interventions

• Biological CABA-201 following preconditioning with fludarabine and cyclophosphamide
  Single intravenous infusion of CABA-201 at a single dose level following preconditioning with fludarabine and cyclophosphamide

Primary outcome measures

• Phase 1/2: Incidence and severity of adverse events (AEs) [Time frame: Up to 28 days after CABA-201 infusion]
• Phase 2b Sub-study 1: Proportion of DM & ASyS subjects achieving at least a moderate Total Improvement Score (TIS) without any immunomodulatory medications and no or low dose of steroids [Time frame: Within 16 weeks]
• Phase 2b Sub-study 2: Proportion of subjects with IMNM achieving at least a minimal TIS without any immunomodulatory medications and no or low dose of steroids [Time frame: Within 24 weeks]

Secondary outcome measures (12)

• Incidence of adverse events and laboratory abnormalities [Time frame: Up to 156 weeks (Phase 1/2) and through 52 weeks (Sub-study 1 and 2)]
• Pharmacodynamics (PD) [Time frame: Up to 156 weeks (Phase 1/2) and through 52 weeks (Sub-study 1 and 2)]
• Pharmacokinetics (PK) [Time frame: Up to 156 weeks (Phase 1/2) and through 52 weeks (Sub-study 1 and 2)]
• Change in disease-related biomarkers of muscle inflammation [Time frame: Up to 156 weeks (Phase 1/2)]
• Change in autoantibody-related biomarkers [Time frame: Up to 156 weeks (Phase 1/2)]
• Proportion of DM subjects achieving at least a moderate TIS without any immunomodulatory medications and no or low dose of steroids [Time frame: Week 16 (Sub-study 1)]
• Mean change from baseline on the MMT-8 in subjects with DM and ASyS without any immunomodulatory medications and no or low dose of steroids [Time frame: Week 16 (Sub-study 1)]
• Proportion of DM and ASyS subjects achieving a major TIS response without any immunomodulatory medications and no or low dose of steroids [Time frame: Week 16 (Sub-study 1)]
• Proportion of subjects with DM & ASyS achieving moderate TIS without any immunomodulatory medications on no or low dose of steroids [Time frame: Week 52 (Sub-study 1)]
• Proportion of subjects with DM achieving moderate TIS without any immunomodulatory medications on no or low dose of steroids [Time frame: Week 52 (Sub-study 1)]
• Mean change from baseline on the MMT-8 in subjects with IMNM without any immunomodulatory medications and no or low dose of steroids [Time frame: Week 24 (Sub-study 2)]
• Proportion of subjects with IMNM achieving at least minimal TIS response without immunomodulatory medications and no or low dose of steroids [Time frame: Week 52 (Sub-study 2)]

Eligibility criteria

Adult Cohorts

Inclusion criteria

• Age ≥18 and ≤75
• A clinical diagnosis of IIM, based on the 2017 The European League Against Rheumatism/American College of Rheumatology classification criteria
• Diagnosis of DM, ASyS, or IMNM
• Evidence of active disease, despite prior or current treatment with standard of care treatments, as defined by the presence of elevated creatine kinase (CK), DM rash, or active disease on muscle biopsy, magnetic resonance imaging (MRI), or electromyography
• Presence of muscle weakness

Other protocol-defined criteria apply.

Exclusion criteria

• Contraindication to leukapheresis
• History of anaphylactic or severe systemic reaction to fludarabine, cyclophosphamide or any of their metabolites
• Active infection requiring medical intervention at screening
• Current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary, psychiatric, cardiac, neurological, or cerebral disease, including severe and uncontrolled infections, such as sepsis and opportunistic infections
• Concomitant medical conditions that, in the opinion of the investigator, might place the subject at unacceptable risk for participation in this study, interfere with the assessment of the effects or safety of the investigational product or with the study procedures
• Significant lung or cardiac impairment
• Previous CAR T cell therapy
• Prior solid organ (heart, liver, kidney, lung) transplant or hematopoietic cell transplant

Other protocol-defined criteria apply.

Juvenile Cohort

Inclusion criteria

• Age ≥6 and ≤17 years at enrollment
• A clinical diagnosis of IIM, based on the 2017 The European League Against Rheumatism/American College of Rheumatology classification criteria
• Evidence of active disease, despite prior or current treatment with standard of care treatments, as defined by the presence of elevated muscle enzymes, DM rash, or active disease on muscle biopsy, magnetic resonance imaging (MRI), or electromyography

Other protocol-defined criteria apply.

Exclusion criteria

• Contraindication to leukapheresis
• History of anaphylactic or severe systemic reaction to fludarabine, cyclophosphamide or any of their metabolites
• Active infection requiring medical intervention at screening
• Current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary, psychiatric, cardiac, neurological, or cerebral disease, including severe and uncontrolled infections, such as sepsis and opportunistic infections.
• Concomitant medical conditions that, in the opinion of the investigator, might place the subject at unacceptable risk for participation in this study, interfere with the assessment of the effects or safety of the investigational product or with the study procedures
• Significant lung or cardiac impairment
• Previous CAR T cell therapy
• Prior solid organ (heart, liver, kidney, lung) transplant or hematopoietic cell transplant

Other protocol-defined criteria apply.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 31 centers

• University of California Irvine - Accepting Adult Patients — Orange
• University of California, San Francisco Benioff Children's Hospital - Accepting Young Adul — San Francisco
• Children's Hospital Colorado - Accepting Juvenile Patients — Aurora
• Mayo Clinic Florida - Accepting Adult Patients — Jacksonville
• Johns Hopkins All Children's Hospital - Accepting Juvenile Patients — St. Petersburg
• Children's Healthcare of Atlanta - Accepting Juvenile Patients — Atlanta
• Emory University - Accepting Adult Patients — Atlanta
• Ann & Robert H. Lurie Children's Hospital of Chicago - Accepting Young Adult and Juvenile — Chicago
• … and 23 more centers

United Kingdom · 4 centers

• Kings College Hospital NHS Foundation Trust - Accepting Adult Patients — London
• University College London Hospitals NHS Foundation Trust - Accepting Adult Patients — London
• Manchester Royal Infirmary - Accepting Adult Patients — Manchester
• Salford Royal Hospital - Accepting Adult Patients — Salford

Publications

• Volkov J, Nunez D, Mozaffar T, Stadanlick J, Werner M, Vorndran Z, Ellis A, Williams J, Cicarelli J, Lam Q, Furmanak T, Schmitt C, Hadi-Nezhad F, Thompson D, Miller C, Little C, Chang D, Basu S. Case study of CD19 CAR T therapy in a subject with immune-mediate necrotizing myopathy treated in the RESET-Myositis phase I/II trial. Mol Ther. 2024 Nov 6;32(11):3821-3828. doi: 10.1016/j.ymthe.2024.09.00 PMID 39245937

Identifiers

NCT: NCT06154252 · CAB-201-002

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗