Muscular Diseases, Neuromuscular Manifestations, Autoimmune, Autoimmune Diseases, Autoimmune Diseases of the Nervous System, Myasthenia Gravis, Muscle Weakness
Conditions
Keywords
ARC-311, CART, CAR-T, BCMA, Anito-cel, Generalized Myasthenia Gravis, gMG, MG, Myasthenia Gravis, non-oncology plasma cell, autoimmune, auto-antibody, chimeric antigen receptor, D-Domain chimeric antigen receptor, B-cell maturation antigen (BCMA), anitocabtagene autoleucel
Brief summary
A Phase 1 dose-escalation study designed to evaluate the safety, tolerability, and preliminary efficacy of anito-cel in subjects with generalized myasthenia gravis (GMG). Anitocabtagene autoleucel (anito-cel) is a BCMA-directed CAR-T cell therapy.
Detailed description
This is a Phase 1 open-label, multi-center safety and dose-escalation study of anito-cel\* in adult subjects with GMG (MGFA Grade 2 to 4a), in whom immunosuppressive therapy is clinically indicated in the judgement of the treating neurologist. The primary objective of this study is to assess the safety profile, including any DLT and identification of a MTD (if applicable), to support selection of the RP2D of anito-cel when administered to subjects with GMG. The study will have the following sequential phases: screening, enrollment (leukapheresis), pretreatment with lymphodepletion (LD) chemotherapy, treatment with anito-cel and follow-up. Optional bridging therapy is allowed at investigator discretion while anito-cel is being manufactured. Following a single infusion of anito-cel both safety and efficacy data will be assessed. The DLTs will be assessed in the first 28 days following anito-cel administration, and safety data will be collected throughout the study. \*Anitocabtagene autoleucel (anito-cel) drug product consists of autologous T cells that have been genetically modified ex vivo to express a D-domain Chimeric Antigen Receptor (CAR), followed by a cluster of differentiation 8 (CD8) hinge and transmembrane region that is fused to the intracellular signaling domains for 4-1BB and CD3ξ, that specifically recognizes B-cell maturation antigen (BCMA). The active substance of anitocabtagene autoleucel is CAR+ CD3+ T cells that have undergone ex vivo T-cell activation, gene transfer by replication-deficient lentiviral vector, and expansion.
Interventions
BIOLOGICALanito-cel
Anitocabtagene autoleucel BCMA directed CAR T-cell therapy using a novel, synthetic binding domain, called a D-Domain
Standard lymphodepletion regimen subject receive 5 days prior to CAR T infusion
Sponsors
Arcellx, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject must be 18 years of age or older * Must have MGFA clinical classification Grades 2-4A at time of screening * Subject must have clinically active disease and requiring ongoing therapy for GMG * MG-ADL score 6 and QMG score \>10 at screening * GMG specific autoantibodies must be above the reference laboratory ULN
Exclusion criteria
* Subject is pregnant or breastfeeding * Treatment with Anti-CD20 agents, calcineurin inhibitors, FcRN inhibitors, azathioprine, mycophenolate mofetil, methotrexate, or cyclophosphamide within the specified time frame prior to leukapheresis or prior to anito-cel infusion * Previous treatment with any gene therapy, chimeric antigen receptor therapy or T cell engager * Previous thymectomy within 6 months of screening * Major chronic illness that is not well managed at the time of study entry and in the opinion of the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Assess safety profile, including any DLT and MTD (if applicable) | 24 months | Type, incidence, and severity of treatment-emergent adverse events (TEAEs), including DLT(s) and laboratory abnormalities |
| Selection of RP2D | 24 months | Evaluate the MTD and establish the RP2D |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Quantify Clinical Effect of Anito-cel in the Myasthenia Gravis Activities of Daily Living (MG ADL) score | 24 months | The proportion of subjects achieving a ≥2-point change in the MG ADL score from Baseline at any timepoint after treatment. The MG-ADL is an 8-item patient-reported outcome measure assessing GMG symptoms and functional activities related to activities of daily living and producing a total score ranging from 0 to 24, where higher scores indicate greater severity of disease symptoms. |
| Quantify Clinical Effect of Anito-cel in the Quantitative Myasthenia Gravis (QMG) score | 24 months | The proportion of subjects achieving a ≥3-point change in the QMG from Baseline at any timepoint after treatment. The QMG score is a 13-item direct physician assessment scoring system that quantifies disease severity, based on impairments of body functions and structures. The total QMG score ranges from 0 to 39, where higher scores indicate greater disease severity. |
| Quantify Clinical Effect of Anito-cel in the Myasthenia Gravis Composite (MGC) scale. | 24 months | The proportion of subjects achieving a ≥3-point change in the MGC score from Baseline at any timepoint after treatment. The MGC is a 10-item assessment that measures signs and symptoms of GMG based on physical examination findings and patient history. The total score ranges from 0 to 50, where higher scores indicate more severe impairment. |
| Mean change in QMG score | 24 months | The mean change in the QMG score from Baseline at any timepoint after treatment. The QMG score is a 13-item direct physician assessment scoring system that quantifies disease severity, based on impairments of body functions and structures. The total QMG score ranges from 0 to 39, where higher scores indicate greater disease severity. |
| Mean change in MG-ADL score | 24 months | The mean change in the MG-ADLscore from Baseline at any timepoint after treatment. The MG-ADL is an 8-item patient-reported outcome measure assessing GMG symptoms and functional activities related to activities of daily living and producing a total score ranging from 0 to 24, where higher scores indicate greater severity of disease symptoms. |
| Mean change in MCG score | 24 months | The mean change in the MGC score from Baseline at any timepoint after treatment. The MGC is a 10-item assessment that measures signs and symptoms of GMG based on physical examination findings and patient history. The total score ranges from 0 to 50, where higher scores indicate more severe impairment. |
| Mean change in MG-QoL15R score | 24 months | The mean change in the MG QoL15R score from Baseline at any timepoint after treatment. The MG-QoL15 is a 15-item questionnaire that allows clinicians to estimate a patient's quality of life relevant to GMG. The cumulative scores range from 0 to 60, with higher scores representing decreased quality of life. |
| Change in titer of myasthenia specific autoantibodies | 24 months | The proportion of subjects achieving ≥50% reduction in myasthenia-specific autoantibody titers from Baseline at any timepoint after treatment |
| PK Parameter for anito-cel: Cmax | Day 1 up to 24 months | Cmax is defined as the maximum observed concentration of anitocel measured/quantified using vector copy number (VCN) on peripheral blood mononuclear cells |
| PK Parameter for anito-cel: Tmax | Day 1 up to 24 months | Tmax is defined as the time (observed time point) of Cmax of anitocel measured/quantified using vector copy number (VCN) on peripheral blood mononuclear cells |
| PK Parameter for anito-cel: Area under the curve (AUC) | Day 1 up to 24 months | AUC is a measure of the anitocel concentration in the blood measured/quantified using VCN on peripheral blood mononuclear cells over time. |
Countries
United States
Contacts
CONTACTClinical Information
Outcome results
None listed