IIM- Idiopathic Inflammatory Myopathies, SLE - Systemic Lupus Erythematosus, SSc-Systemic Sclerosis
Conditions
Brief summary
This study is an open-label, multiple ascending dose investigator-initiated trial (IIT) designed to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of CC312 in adult patients with relapsed or refractory autoimmune diseases.
Interventions
BIOLOGICALCC312
The priming dose of CC312 will be administered intravenously on Day -3, followed by safety and tolerability evaluations on Day -1 (3 days post-first dose). The first therapeutic dose of CC312 will be administered on Day 1, with subsequent doses administered on Day 4, 8, and 11. Corresponding safety and tolerability assessments will be performed with each dose. Based on the evaluation of clinical efficacy, B-cell depletion, and safety/tolerability profile at the end of Day 14, the dose for the subsequent therapeutic dosing will be determined (maintained or escalated). Thereafter, therapeutic dosing will be administered on Days 15, 18, 22, and 25, accompanied by scheduled safety and tolerability assessments.
Sponsors
CytoCares Inc
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Fully understand the trial's purpose, nature, methodology, and potential adverse reactions, voluntarily participate as a subject, and sign the informed consent form. * Aged 18-65 years (inclusive, based on the date of signing the informed consent form), regardless of gender. * For Systemic Lupus Erythematosus (SLE): 1. Diagnosed with SLE according to the 2019 EULAR/ACR classification criteria； 2. Meet at least one of the following: positive antinuclear antibody (ANA) and/or anti-dsDNA antibody and/or anti-Sm antibody at screening； 3. Had an inadequate response or relapse after standard therapy, defined as any of the following (alone or combined): glucocorticoids, antimalarials (hydroxychloroquine), immunosuppressants (including mycophenolate mofetil, cyclophosphamide, leflunomide, methotrexate, tacrolimus, cyclosporine, azathioprine), or biologics (rituximab, belimumab, telitacicept). Each regimen must have been administered for ≥3 months, and the subject must have received ≥2 immunosuppressants and/or biologics； 4. At screening, meet SLEDAI-2000 ≥7 and have at least one BILAG A or two BILAG B organ domain scores； 5. Prior to the first dose, subjects must have received glucocorticoids and/or antimalarials and/or immunosuppressants for ≥12 weeks, with stable doses for ≥30 days； 6. If receiving oral glucocorticoids (e.g., prednisone), the dose must be ≤40 mg/day at screening and during the screening period； 7. If using glucocorticoids alone, the dose must be ≥7.5 mg/day prednisone (or equivalent). * For Idiopathic Inflammatory Myopathy (IIM): 1. Diagnosed with possible or definite IIM per the 2017 EULAR/ACR classification criteria (≥5.5 points without biopsy; ≥6.7 points with biopsy) ； 2. Have at least one positive myositis-specific autoantibody (MSA) , myositis-associated autoantibody (MAA), or ANA at or prior to screening； 3. Had an inadequate response or relapse after conventional therapy, defined as glucocorticoids (prednisone \>1 mg/kg/day or equivalent) and ≥1 immunomodulatory drug (immunosuppressants: azathioprine, mycophenolate mofetil, cyclophosphamide, methotrexate, leflunomide, tacrolimus, cyclosporine; biologics: rituximab, belimumab; small molecules: tofacitinib), each for ≥3 months； 4. Have active IIM at screening, defined as meeting ≥3 of MMT-8 total score ≤141/150 with ≥20% strength loss in affected muscles; Physician global activity ≥2; Patient global activity ≥2; myositis disease activity assessment tool (MDAAT) ≥2; ≥2 muscle enzymes elevated, with one ≥1.5× upper limit of normal (ULN); health assessment questionnaire (HAQ) ≥0.25； 5. Prior to the first dose, subjects must have received glucocorticoids and/or immunosuppressants for ≥12 weeks, with stable glucocorticoid doses for ≥30 days and immunosuppressant doses for ≥60 days. Glucocorticoid dose must be ≤60 mg/day prednisone during screening； 6. If a subject is receiving oral glucocorticoids alone, the dose should be at least 7.5 mg/day of prednisone (or an equivalent dose of other glucocorticoids). * For Systemic Sclerosis (SSc): 1. Diagnosed with diffuse cutaneous SSc per the 2013 EULAR/ACR criteria ； 2. Have positive ANA and/or SSc-related antibodies； 3. Disease duration ≤5 years (from initial diagnosis)； 4. Had an inadequate response or relapse after conventional therapy. Conventional therapy is defined as treatment with glucocorticoids plus any of the following immunomodulatory agents: cyclophosphamide, mycophenolate mofetil, methotrexate, leflunomide, azathioprine, tacrolimus, cyclosporine, and/or biologics (such as rituximab and belimumab), with a cumulative treatment duration of \>6 months； 5. Modified Rodnan Skin Score (mRSS) ≥15 and ≤30 at screening with progression within 6 months； 6. Prior to the first dose, subjects must have received glucocorticoids and/or immunosuppressants for ≥12 weeks, with stable glucocorticoid doses for ≥30 days and immunosuppressant doses for ≥60 days. The glucocorticoid dose during the screening period should not exceed 10 mg/day of prednisone (or an equivalent dose of other glucocorticoids). * Females of childbearing potential must use highly effective contraception from screening until 6 months after the last dose, refrain from oocyte donation, and ensure male partners use effective contraception. * Males of childbearing potential must use effective contraception from screening until 6 months after the last dose, with no plans for fertility or sperm donation, and ensure female partners use effective contraception.
Exclusion criteria
* Severe lupus nephritis within 8 weeks prior to screening (defined as urinary protein \>6 g/24 h, serum creatinine \>2.5 mg/dL or 221 μmol/L), requirement of prohibited medications for active nephritis per protocol, need for hemodialysis, or receipt of prednisone ≥100 mg/day (or equivalent glucocorticoids) for ≥14 days. * Central nervous system disorders (including but not limited to epilepsy, psychosis, interstitial encephalopathy syndrome, cerebrovascular accident, encephalitis, or CNS vasculitis) within 8 weeks prior to screening. * Other types of idiopathic inflammatory myopathies: inclusion body myositis, amyotrophic diabetes, or juvenile myositis; patients with severe muscle damage or permanent weakness/cardiac involvement due to non-IIM causes (e.g., stroke). * SSc-related pulmonary hypertension requiring treatment; rapidly progressive SSc-related lower gastrointestinal (small/large intestine) involvement requiring parenteral nutrition; active gastric antral vascular ectasia; history of SSc-related renal crisis. * History of major organ transplantation (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/bone marrow transplantation. * Other concurrent autoimmune diseases requiring systemic therapy. * IgA deficiency (serum IgA level \<10 mg/dL). * Abnormal laboratory findings at screening: Liver function: AST/ALT \>2× upper limit of normal (ULN) (except for IIM patients with elevated muscle enzymes); Hematology: hemoglobin \<85 g/L, white blood cell count \<2.5×10⁹/L, platelet count \<50×10⁹/L. * Participation in any other clinical trial (including cell or gene therapy) within 4 weeks prior to screening or within 5 half-lives of the investigational product (whichever is longer). * Received CAR-T therapy within 6 months prior to screening. * Treatment with B-cell-depleting agents (e.g., rituximab, or therapies targeting CD19/CD20/BAFF) within 1 month prior to screening, unless B-cell levels returned to pre-treatment or normal ranges. * Received non-standard anti-SLE therapies (e.g., Saphnelo) within 3 months or 5 half-lives of the drug (whichever is longer) prior to screening. * Received live/attenuated vaccination within 4 weeks prior to screening or plans to receive such during the trial. * Active severe infection requiring antibiotic treatment within 14 days prior to screening. * History of Grade 3-4 allergic reaction (per CTCAE v5.0) to another monoclonal antibody, or known hypersensitivity to any component of CC312 (e.g., recombinant proteins, polysorbate 80). Patients with transient (≤24 h) Grade ≤3 reactions may be included after discussion with the investigator. * Evidence of drug abuse, substance abuse, or alcohol addiction. * Major surgery within 4 weeks or minor surgery within 2 weeks prior to screening; wounds must be fully healed (procedures like catheter placement are excluded). * History of cardiovascular events within 6 months prior to screening: New York Heart Association (NYHA) Class III/IV heart failure, myocardial infarction, unstable angina, uncontrolled/symptomatic atrial arrhythmia, ventricular arrhythmia, or other clinically significant cardiac conditions. * Any other severe underlying disease (e.g., active gastric ulcer, uncontrolled seizures, cerebrovascular events, GI bleeding, severe coagulation disorders), psychiatric disorder, or social circumstances that may interfere with trial conduct, compliance, or pose high risk per investigator's judgment. * Concurrent malignancy diagnosed within \<5 years prior to screening. * Pregnant or lactating women. * Positive serology for Human Immunodeficiency Virus (HIV) antibody, Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus (HCV) antibody, or Treponema pallidum (TP) antibody at screening. * Active or latent tuberculosis at screening (positive TB-IGRA test). * Any other condition deemed ineligible by the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-limiting toxicity (DLT) | 2 years | A Dose-Limiting Toxicity (DLT) is defined as any adverse event occurring within the 29-day period following the initiation of CC312 intravenous infusion during the dose-escalation phase, assessed by the investigator as related to CC312 and meeting the following criteria: (1) Hematologic Toxicity: Grade 4 toxicity (excluding lymphopenia) persisting beyond 29 days and not attributable to underlying disease; (2) Non-Hematologic Toxicity: Any ≥Grade 4 toxicity potentially related to CC312 during the observation window, or any Grade 3 toxicity potentially related to CC312 that fails to resolve to ≤Grade 2 within 7 days. |
| Adverse events (AE)/serious adverse events (SAE) | 2 years | With the exception of CRS and ICANS, which will be graded according to the ASTCT criteria, the severity of all other adverse events (AEs) will be assessed and classified using the CTCAE (Common Terminology Criteria for Adverse Events) version 5.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serum Concentration of CC312 | 2 years | All subjects are required to undergo blood sampling for serum concentration analysis at the following time points: within 1 hour before the guide dose (0 h) and 1 hour after infusion; for the treatment dose, within 1 hour before administration (0 h) and 1 hour after infusion on the first and second dosing occasions of the first and third treatment weeks, within 1 hour before administration (0 h) and 1 hour after infusion on the first dosing occasion of the second and fourth treatment weeks; and at early withdrawal/end of study (EOS). |
| Counts of peripheral B cells | 2 years | All subjects are required to undergo blood sampling for peripheral B cells analysis at the following time points:within 1 hour before the priming dose (0 h), and 1 hour and 24 hours after infusion; for the treatment dose, within 1 hour before administration (0 h) and 1 hour and 24 hours after infusion on the first and second dosing occasions of Weeks 1 and 3, within 1 hour before administration (0 h) on the first dosing occasions of Week 2 and Week 4; if dosing is extended beyond Day 28, within 1 hour before the second weekly dose until the end of the extended dosing period; after the last dose, once monthly for 4 consecutive months; during the long-term follow-up period, once every 3 months; and at early withdrawal/end of study (EOS). |
| Cytokines | 2 years | All subjects are required to undergo blood sampling for cytokine analysis (IFN-γ、IFN-α、IL-2、IL-6、IL-10、TNF-α) at the following time points: within 1 hour before the priming dose (0 h), and 1 hour and 24 hours after infusion; for the treatment dose, within 1 hour before administration (0 h) and 1 hour and 24 hours after infusion on the first and second dosing occasions of Weeks 1 and 3; within 1 hour before administration (0 h) and 1 hour and 24 hours after infusion on the first dosing occasion of Weeks 2 and 4; and at early withdrawal/EOS. |
| Complement | 2 years | Blood samples for complement analysis will be collected from all subjects at the following time points: Screening/Baseline, within 1 hour before the priming dose (0 h); for the treatment dose, within 1 hour before the first weekly administration at Weeks 1, 2, 3, and 4, and at Weeks 8, 12, 24, and 48, as well as at early withdrawal. |
| Autoantibody | 2 years | For patients with systemic lupus erythematosus, anti-double-stranded DNA antibody (anti-dsDNA) shall be tested at the following time points: within 1 hour before the priming dose (0 h), within 1 hour before the first treatment dose at Week 3, and on Day 28. Other autoantibodies shall be tested at the following time points: within 1 hour before the priming dose (0 h), on Day 28, and at Weeks 8, 12, 24, 48, as well as at early withdrawal. |
| Immunogenicity | 2 years | Blood samples for immunogenicity analysis will be collected from all subjects at the following time points: within 1 hour before the priming dose (0 h), and within 1 hour before the first weekly treatment dose at Weeks 1, 2, 3, and 4; as well as at Weeks 8, 12, 16, and 24, and at early withdrawal or end of study (EOS). |
| SLE Responder Index-4 (SRI-4) response rate | 2 years | SLE Responder Index-4 (SRI-4) response rate will be assessed at the following time points: during the screening period, at baseline (prior to the first dose), at the end of Week 2 and Week 4, at safety follow-up visits, and at the end of study (EOS). Additionally, during the post-treatment follow-up period, assessments will be conducted every 12 weeks (i.e., at Weeks 12, 24, 36, and 48, respectively). |
| Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score | 2 years | SLEDAI-2K score will be assessed at the following time points: during the screening period, at baseline (prior to the first dose), at the end of Week 2 and Week 4, at safety follow-up visits, and at the end of study (EOS). Additionally, during the post-treatment follow-up period, assessments will be conducted every 12 weeks (i.e., at Weeks 12, 24, 36, and 48, respectively). |
| British Isles Lupus Assessment Group Index 2004 (BILAG-2004) | 2 years | BILAG-2004 (for SLE patients) will be assessed at the following time points: during the screening period, at baseline (prior to the first dose), at the end of Week 2 and Week 4, at safety follow-up visits, and at the end of study (EOS). Additionally, during the post-treatment follow-up period, assessments will be conducted every 12 weeks (i.e., at Weeks 12, 24, 36, and 48, respectively). |
| 24-hour urinary protein quantification | 2 years | 24-hour urinary protein quantification (for SLE patients) will be assessed at the following time points: during the screening period, at baseline (prior to the first dose), at the end of Week 2 and Week 4, at safety follow-up visits, and at the end of study (EOS). Additionally, during the post-treatment follow-up period, assessments will be conducted every 12 weeks (i.e., at Weeks 12, 24, 36, and 48, respectively). |
| Physician's and Patient's Global Assessment of disease activity (PGA and PtGA) | 2 years | PGA and PtGA (for SLE patients) will be assessed at the following time points: during the screening period, at baseline (prior to the first dose), at the end of Week 2 and Week 4, at safety follow-up visits, and at the end of study (EOS). Additionally, during the post-treatment follow-up period, assessments will be conducted every 12 weeks (i.e., at Weeks 12, 24, 36, and 48, respectively). |
| Total Improvement Score (TIS) | 2 years | TIS (for IIM patients) will be assessed at the following time points: during the screening period, at baseline (prior to the first dose), at the end of Week 2 and Week 4, at safety follow-up visits, and at the end of study (EOS). Additionally, during the post-treatment follow-up period, assessments will be conducted every 12 weeks (i.e., at Weeks 12, 24, 36, and 48, respectively). |
| EUSTAR Activity Index (EUSTAR-AI) | 2 years | EUSTAR-AI (for SSc patients) will be assessed at the following time points: during the screening period, at baseline (prior to the first dose), at the end of Week 2 and Week 4, at safety follow-up visits, and at the end of study (EOS). Additionally, during the post-treatment follow-up period, assessments will be conducted every 12 weeks (i.e., at Weeks 12, 24, 36, and 48, respectively). |
| modified Rodnan Skin Score (mRSS) | 2 years | mRSS (for SSc patients) will be assessed at the following time points: during the screening period, at baseline (prior to the first dose), at the end of Week 2 and Week 4, at safety follow-up visits, and at the end of study (EOS). Additionally, during the post-treatment follow-up period, assessments will be conducted every 12 weeks (i.e., at Weeks 12, 24, 36, and 48, respectively). |
Countries
China
Contacts
CONTACTCEO
Outcome results
None listed