This study is an open-label, multiple-dose escalation, Investigator-Initiated Trial (IIT) clinical trial designed to evaluate the safety and tolerability of CC312 in adult patients with relapsed and refractory autoimmune diseases. The trial also assesses pharmacokinetics (PK) and preliminary efficacy.
CC312 is a trispecific T cell engager (TriTE) that targets the B cell surface antigen CD19, the T cell antigen CD3, and the T cell co-stimulatory molecule CD28. Given its mechanism of action, which is similar to the "biopharmaceutical version" of CAR-T, there is a higher risk of cytokine release syndrome (CRS) at the onset of infusion administration. Therefore, a lower priming dose will be administered before the therapeutic dosing phase to mitigate this risk and ensure safety, followed by a therapeutic dose to achieve and maintain efficacy.
The study is divided into three dose groups, with 3-6 subjects enrolled in each group, resulting in a total of 9-18 subjects in the study. A "3+3" dose escalation design is employed to systematically evaluate the safety and determine the optimal dose of CC312.
Subjects who fully understand the objectives, nature, methods of the study, and possible adverse reactions, voluntarily participate as subjects, and sign the informed consent form (ICF).
Age ≥18 years (inclusive, based on the time of signing ICF), male or female.
Subjects who are diagnosed with SLE according to the 2019 European League Against Rheumatism (EULAR)/1997 American College of Rheumatology (ACR) diagnostic classification criteria;
SLEDAI-2000 score of ≥ 8 points and at least one BILAG grade A or two BILAG grade B under standard treatment conditions;
Subjects who have severe lupus nephritis (defined as urinary protein >6 g/24 h or serum creatinine >2.5 mg/dL or 221 μmol/L), or required treatment of active nephritis with protocol-prohibited drugs, or required hemodialysis or received prednisone ≥100 mg/d or equivalent glucocorticoid therapy for ≥14 days within 8 weeks before screening.
Subjects who have central nervous system diseases caused by SLE or not caused by SLE within 8 weeks before screening (including but not limited to epilepsy, psychosis, posterior reversible encephalopathy syndrome, cerebrovascular accident, encephalitis, central nervous system vasculitis, etc.).
Other types of IIM: inclusion body myositis, diabetic amyotrophy, juvenile myositis; severe muscle injury or myositis causing permanent weakness or cardiac involvement due to non-IIM causes (e.g., stroke).
Pulmonary arterial hypertension associated with SSc requiring treatment; or rapidly progressive SSc-related lower gastrointestinal tract (small and large intestine) involvement (requiring parenteral nutrition), active antral vascular ectasia; previous renal crisis caused by SSc.
Single group
CC312
Biological/VaccineAfter a 28-day screening period, subjects who meet the inclusion and exclusion criteria will be enrolled for baseline assessments and biological sample collection prior to the guided administration period. The guided dose of CC312 will be administered via IV infusion on Day -3, followed by safety and tolerability assessments on the third day after the initial administration (i.e., Day -1). The therapeutic dose of CC312 will be administered via IV infusion on Day 1, with subsequent infusions scheduled on Day 4, Day 8, Day 11, Day 15, Day 18, Day 22, and Day 25. Comprehensive safety and tolerability assessments will be conducted at each of these time points.
Dose-limiting toxicity (DLT)
Hematological DLT is defined as a Grade 4 toxic reaction (excluding lymphopenia) that is not attributable to the underlying disease and persists for more than 29 days. Non-hematological DLT refers to any Grade ≥4 toxicities that may be associated with CC312 treatment, or Grade 3 toxicities that may be associated with CC312 treatment and persist for ≥7 days during the DLT observation period following CC312 infusion.
Adverse events (AE)/serious adverse events (SAE)
All adverse events will be evaluated and graded according to the severity criteria of CTCAE (Common Terminology Criteria for Adverse Events) version 5.0, with the exception of Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), which will be assessed using the ASTCT (American Society for Transplantation and Cellular Therapy) standard.
Maximum Serum Concentration (Cmax) of CC312
Blood samples will be collected for serum concentration analysis at the following time points: within 1 hour before (0 hour) and 1 hour after the infusion of the initial dose; within 1 hour before (0 hour) and 1 hour after the infusion of the first and second doses in the first and third weeks of the therapeutic dose; within 1 hour before (0 hour) and 1 hour after the infusion of the first dose in the second and fourth weeks of the therapeutic dose; and at the time of early withdrawal/end of study (EOS).
Area Under the Concentration-time Curve (AUC) of CC312
The area under the concentration-time curve (AUC) over the dosing interval of 72 hours was calculated using the linear trapezoidal rule.
Minimum Concentration (Cmin) of CC312
The timing of blood sample collection is consistent with the sampling time for Cmax determination.
Counts of peripheral B cells
Blood samples will be collected for CD19+ and CD20+ B cell subsets analysis: For the priming dose: within 1 hour before (0 hour) and at 1 hour and 24 hours after infusion. For the therapeutic dose in the first week: within 1 hour before (0 hour) and at 1 hour and 24 hours after the first and second doses. At early withdrawal/End of Study (EOS).
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