Refractory Immune-mediated Necrotizing Myopathy
Conditions
Keywords
Immune-mediated necrotizing myopathy, Refractory, Eque-cel, anti-SRP antibody, anti-HMGCR antibody, MMT-8
Brief summary
This is an open-label, single-arm Phase I/II clinical study to evaluate the efficacy and safety of Eque-cel Injection in patients with refractory immune-mediated necrotizing myopathy.
Detailed description
This study is an open-label, single-arm Phase I/II clinical trial evaluating the safety and efficacy of Eque-cel in subjects with immune-mediated necrotizing myopathy (IMNM). The study consists of two phases: Phase I and Phase II. The Phase I component will evaluate the safety, tolerability and preliminary efficacy of Eque-cel to identify the recommended Phase 2 dose (RP2D). Following RP2D determination from Phase I, the Phase II stage will enroll additional subjects at this dose level to confirm the efficacy of Eque-cel injection in patients with IMNM. All subjects will undergo a primary follow-up period of 2 years after infusion of Eque-cel injection, followed by long-term follow-up extending up to 15 years.
Interventions
DRUGEquecabtagene Autoleucel Injection (Eque-cel)
Eque-cel is a personalized, BCMA-targeted gene-modified autologous T-cell immunotherapy product capable of recognizing and eliminating both malignant and normal cells expressing BCMA. The CAR specifically identifies BCMA via a fully human single-chain variable fragment (scFv) with low immunogenicity, activates, proliferates, secretes cytokines, and kills target cells through the CD3ζ domain, while enhancing CAR-T expansion and persistence via 4-1BB costimulation signaling. Eque-cel demonstrates high affinity for the BCMA antigen both in vitro and in vivo, as well as efficient killing of antigen-loaded cells.
Sponsors
Nanjing IASO Biotechnology Co., Ltd.
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
* 1\. At the time of signing the informed consent form, the age is ≥ 18 years old. * 2.Based on the 2016 ENMC classification criteria, the clinical diagnosis is IMNM. * 3.At the time of screening, the anti-SRP antibody or anti-HMGCR antibody is positive. * 4\. Refractory IMNM that failed or relapsed after standard treatment, and the disease is still active at the time of screening. * 5.The subjects must have appropriate organ functions. * 6.The subjects and their spouses agree to take effective contraceptive measures (excluding safe period contraception) from the time of the subject signing the informed consent form until one year after the CAR-T cell infusion. * 7\. The subjects must agree to sign or personally write and present the informed consent form approved by the ethics committee before starting any screening procedures.
Exclusion criteria
* 1\. Having end-stage myositis with involvement of terminal organs may pose additional risks or interfere with the study assessment. * 2.Presence of irreversible muscle involvement and/or severe atrophy may bring additional risks or interfere with the study assessment. * 3.Uncontrolled interstitial lung disease or any other uncontrolled manifestations of IIM, as judged by the investigator, may require the use of prohibited drugs during the study period. * 4\. Diagnosed with other inflammatory or non-inflammatory myopathies. * 5.Any other known autoimmune disease that the investigator considers to interfere with the accurate assessment of clinical symptoms of IMNM or place the patient at excessive risk. * 6\. Those with a history of solid organ transplantation. * 7\. History of autologous or allogeneic stem cell transplantation. * 8\. Previous history of BCMA-targeted drug treatment. * 9.Having occurred or planned to undergo major surgery or surgical treatment within 4 weeks before enrollment or within 12 weeks after infusion. * 10\. Known primary immunodeficiency (congenital or acquired). * 11\. Having a clear history of mental disorder or a history of substance abuse for mental disorders that cannot be quit. * 12.The subject has uncontrollable active fungal， viral， bacterial or other infections (having persistent infection-related signs/symptoms， without improvement after appropriate anti-infection treatment) or infections requiring intravenous anti-infection drug treatment. * 13.Positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) and abnormal peripheral blood hepatitis B virus (HBV) DNA test (defined as HBV DNA quantification ≥ 100IU/ml or ≥ 1000 copies /ml or above the normal reference range of the testing center or positive for qualitative HBV DNA detection) ; hepatitis C virus (HCV) antibody positive and peripheral blood HCV RNA positive (defined as ≥ 1000 IU/mL); human immunodeficiency virus (HIV) antibody positive; cytomegalovirus (CMV) DNA positive (defined as ≥ 1000 IU/mL); Treponema pallidum specific antibody positive and positive for the rapid plasma reagin test for syphilis. * 14.Severe heart disease: including but not limited to unstable angina pectoris and/or myocardial infarction within 12 months of the screening period, any congestive heart failure (NYHA classification ≥ III), and a history of severe arrhythmia. * 15.Severe asthma or chronic obstructive pulmonary disease (COPD). Note: Mild or moderate asthma or COPD patients with stable conditions, after assessment and approval by the investigator and the sponsor, can be enrolled. * 16.Acute cerebrovascular disease events occurred within 6 months before enrollment, including transient ischemic attack or stroke history. * 17.Any serious and/or uncontrolled comorbid diseases as determined by the investigator to potentially interfere with the study assessment. * 18.Malignant tumors within 5 years before screening, excluding cured cervical carcinoma in situ, basal cell or squamous epithelial cell skin cancer, locally advanced prostate cancer after radical surgery, breast duct carcinoma in situ after radical surgery, or thyroid papillary carcinoma after radical surgery. * 19\. Known history of allergy to cyclophosphamide, fludarabine, components of Eque-cel injection or supportive drugs required for toxicity management of CAR-T cell therapy (such as tocilizumab). * 21.Pregnant or lactating women. * 21\. Other situations as determined by the investigator to be unsuitable for enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Safety endpoint - Adverse Events (AEs) | up to 2 years from Eque-cel Injection infusion | Incidence and severity of adverse events as assessed by NCI-CTCAE v5.0 (except CRS and ICANS assessed according to the criteria of 2019 ASTCT criteria). |
| Phase I: Safety endpoint-incidence of Dose-limiting toxicity (DLT) | Time Frame: up to 28 days from Eque-cel Injection infusion | Percentage of participants who experienced DLT within 28 days after Eque-cel administration. |
| Phase II: Efficacy endpoint- TIS response | up to the 2 years after Eque-cel Injection infusion | Proportion of participants achieving TIS response |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Efficacy endpoint -TIS response | up to the 2 years after Eque-cel Injection Infusion | Proportion of participants achieving TIS response |
| Phase II:Efficacy endpoint -Proportion of participants achieving minimal improvement response (TIS ≥ 20 points) | From baseline to 12 months after Eque-cel Injection Infusion | Defined as achieving The Total Improvement Score (TIS)≥ 20 points (minimum improvement) |
| Phase I/II:Efficacy endpoint -Change in mean Total Improvement Score (TIS) value | up to 2 years from Eque-cel Injection infusion | Defined as achieving the Total Improvement Score (TIS) |
| Phase I/II:Efficacy endpoint -The changes in PtGA scores | up to 2 years from Eque-cel Injection infusion | The PhGA scale will be completed by patients at each study visit. |
| Phase I/II:Efficacy endpoint -The changes in PhGA scores | up to 2 years from Eque-cel Injection infusion | The PhGA scale will be completed by investigators at each study visit. |
| Phase I/II:Efficacy endpoint-MMT-8 | up to 2 years from Eque-cel Injection infusion | The changes in Manual Muscle Testing-8 (MMT-8) As measured by testing proximal muscles. |
| Phase I/II:Efficacy endpoint -HAO Scale | up to 2 years from Eque-cel Injection infusion | HAQ will be completed by subjects at each study visit. |
| Phase I/II:Efficacy endpoint -CK | up to 2 years from Eque-cel Injection infusion | Changes in the levels of Creatine Kinase (CK) |
| The changes in MDAAT scores | up to 2 years from Eque-cel Injection infusion | MDAAT will be completed by investigators at each study visit. |
| Phase I/II:Efficacy endpoint -hormone dosage reduction | From baseline to 6 and 12 months after Eque-cel Injection Infusion | The proportion of subjects whose hormone dosage reduction. |
| Phase II:Safety endpoint - Adverse Events (AEs) | up to 2 years from Eque-cel Injection infusion | Incidence and severity of adverse events as assessed by NCI-CTCAE v5.0 (except CRS and ICANS assessed according to the criteria of 2019 ASTCT criteria) |
| Phase I/II Pharmacokinetic Endpoint - Cmax (CAR-T cells) | up to 2 years from Eque-cel Injection infusion | The maximum concentration (Cmax) of BCMA CAR-T in peripheral blood after CAR-T infusion. |
| Phase I/II Pharmacokinetic Endpoint - Tmax (CAR-T cells) | up to 2 years from Eque-cel Injection infusion | The time for BCMA CAR-T to reach the maximum concentration (Tmax) after CAR-T infusion. |
| Phase I/II Pharmacokinetic Endpoint - AUC (CAR-T cells) | up to 2 years from Eque-cel Injection infusion | Area under the curve of 28 days, 90 days and the last time point. (AUC0-28d, AUC0-90,AUC0-last) for BCMA CAR-T. |
| Phase I/II Pharmacokinetic Endpoint - Cmax (VCN) | up to 2 years from Eque-cel Injection infusion | The maximum concentration (Cmax) of lentiviral vector copy number (VCN) in peripheral blood after infusion. |
| Phase I/II Pharmacokinetic Endpoint - Tmax (VCN) | up to 2 years from Eque-cel Injection infusion | The time for VCN to reach the maximum concentration (Tmax) after infusion. |
| Phase I/II Pharmacokinetic Endpoint - AUC (VCN) | up to 2 years from Eque-cel Injection infusion | Area under the curve of 28 days, 90 days and the last time point (AUC0-28d, AUC0-90d, AUC0-last) for VCN. |
| hase I/II Pharmacodynamic Endpoint - inflammatory markers | up to 2 years from Eque-cel Injection infusion | Changes in levels of inflammatory markers, including CRP, Ferritin, and IL-6. |
| Phase I/II Pharmacodynamic Endpoint - Serum immunoglobulin | up to 2 years from Eque-cel Injection infusion | Changes in serum immunoglobulin (IgG, IgA, IgM) levels from baseline. |
| Phase I/II Pharmacodynamic Endpoint-sBCMA | up to 2 years from Eque-cel Injection infusion | The concentration of soluble BCMA in peripheral blood of experimental group at each time point. |
Countries
China
Outcome results
None listed