A Study of Anti-IL-6R mAb Injection in Patients With iMCD

Study Overview
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Brief Summary
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This study is a single-arm, open-label, multicenter, dose-escalation clinical study.Its primary purpose is to evaluate the safety and tolerability of recombinant humanized anti-interleukin-6 receptor monoclonal antibody ( Anti-IL-6R mAb ) injection in patients with Idiopathic Multicentric Castleman's Disease ( iMCD ) and to determine the recommended dose for follow-up studies. Its secondary purpose is to evaluate the preliminary efficacy, immunogenicity and pharmacokinetic ( PK ) index, pharmacodynamic ( PD ) characteristics of Anti-IL-6R mAb injection in patients with iMCD.

Detailed Description
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A total of 3 dose groups of 4 mg/kg, 6 mg/kg and 8 mg/kg are designed in this study to explore the safety, tolerability and preliminary efficacy of the experimental drug administered for ≥4 cycles in patients with iMCD. Referring to the inclusion and exclusion criteria, the subjects will be enrolled from the low-dose group to the high-dose group in turn. After the last subject of each dose group completed the third administration and 2-week safety observation, the investigator and the sponsor will discuss the safety results of the subjects together in this dose group. If no any important adverse event occurs, they can enter the next dose group. If an important adverse event occurs in any subject, the investigator and the sponsor will discuss whether to continue the study in the next dose group. Dose escalation will be discontinued if more than one subject experiences an important adverse event. If an important adverse event occurs, the investigator will perform related inspections based on the subject's condition, and for treatment. After complete 4 cycles of dosing , no important adverse events are found in the subjects，or the subjects don't withdraw from the study although important adverse events and who's treatment effect is obvious. If the investigator judges that it may be beneficial to continue receiving the treatment for the subjects, the sponsor will continue to provide the subjects with the current dose of the experimental drug free of charge until the disease progresses, unacceptable toxicity occurs, or withdrawal of informed consent.

Official Title
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A Single-arm, Open-label, Multi-center Phase Ⅱa Clinical Study to Evaluate the Efficacy and Safety of Recombinant Humanized Anti-IL-6R mAb Injection in the Treatment of Patients With Idiopathic Multicentric Castleman's Disease

Conditions
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Idiopathic Multicentric Castleman's Disease

Intervention / Treatment
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* Biological: Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 4mg/kg
* Biological: Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 6mg/kg
* Biological: Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 8mg/kg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years old, gender is not limited; Biopsy or center pathology examination confirmed the measurable, symptomatic iMCD (iMCD diagnosis based on The consensus of the diagnosis and treatment of Castleman disease in China (2021)); Clinical laboratory test values within 4 weeks before treatment meet the following criteria: Absolute neutrophil count (ANC)≥1.0×10^9/L; Platelet count (Plt) ≥ 75×10^9/L; Alanine aminotransferase (ALT) < 2.5×upper limit of normal (ULN) ; Total bilirubin (TBIL) <2.5×ULN; Alkaline phosphatase (ALP) <2.5×ULN; Serum creatinine (Scr) ≤ 3.0 mg/dL (265 umol/L). ECOG PS physical status score of 0, 1 or 2 points; When using corticosteroids, the dose of prednisone should not exceed 1 mg/kg/day (or equivalent dose), and the dose should be maintained or reduced within 4 weeks before the first dose; Patients of childbearing age (males and females) must agree to take effective contraceptive measures during the trial and within 3 months after the last medication, males are not allowed to donate sperm, and females are not allowed to donate eggs; The subjects themselves (or their legally recognized representatives) must sign an informed consent form before performing any research-specific procedures, indicating that they understand the purpose of the research and the procedures that need to be performed, and voluntarily participate in this research. Exclusion Criteria: Human immunodeficiency virus (HIV) or human herpesvirus 8 (HHV-8) positive; Skin lesions are the only detectable lesions; Patients with concurrent malignant tumors (disease-free time < 5 years), except for the following cases: fully treated skin basal cell carcinoma or squamous cell carcinoma, cervical carcinoma in situ; Patients with diseases that may interfere with the research process or research results, such as autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, adult Still's disease, juvenile idiopathic arthritis, autoimmune lymphoproliferative syndrome) ), active systemic infection, poorly controlled diabetes, acute diffuse infiltrative lung disease; Those who use contraindicated treatments or plan to use the following treatments during the study period: Received IL-6 or IL-6R targeted drug therapy before the first dose; Received other concomitant anti-tumor therapy for Castleman's disease (such as anti-CD20 antibody, chemotherapy) within 8 weeks before the first dose; Received biologics such as anti-tumor necrosis factor-α (TNF-α) antibodies within 8 weeks before the first dose; Received immunosuppressive agents (other than stable doses of corticosteroids) within 8 weeks prior to the first dose; Received erythropoiesis-stimulating agents (ESAs) within 8 weeks prior to the first dose; Received any systemic therapy for Castleman's disease within 4 weeks prior to the first dose; Major surgery or radiotherapy within 4 weeks before the first dose; Are receiving or planning to receive treatment with a strong CYP3A inhibitor during the study period. Uncontrolled history of heart disease, such as unstable angina, congestive heart failure, myocardial infarction within the past 12 months, hemodynamic instability or known left ventricular ejection fraction (LVEF) <40% or clinically significant cardiac rhythm or conduction abnormalities; Persons with positive infectious disease test (positive hepatitis B surface antigen (HBsAg) and hepatitis B virus-DNA titer>1000IU/ml, hepatitis C virus , syphilis, active pulmonary tuberculosis); History of allogeneic transplantation (except corneal transplantation); Those who are known to have severe infusion reactions to monoclonal antibodies or murine, chimeric or human proteins; Pregnant or lactating women, or those who plan to become pregnant within 3 months after the last dose; Those who have been vaccinated with the new coronavirus vaccine or other live attenuated vaccines within 4 weeks before the first administration, or who plan to be vaccinated during the trial period; Those who have participated in other clinical trials within 1 month before the first administration; Patients with paraneoplastic pemphigus or bronchiolitis obliterans; Patients with a history of bleeding，including: Intracranial hemorrhage within 6 months before screening; Active bleeding within 2 months prior to screening. Patients with cerebral infarction within 6 months before screening (except lacunar infarction); Any other circumstances judged by the investigator to be inappropriate to participate in this study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 4mg/kg<br>Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 4mg/kg as the low dose group. | Biological: Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 4mg/kg<br>* Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 4mg/kg, intravenous injection for 60 to 90 minutes. Every 2 weeks is a cycle, the first day of each cycle is administered, a total of ≥ 4 cycles.<br>|
| Experimental: Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 6mg/kg<br>Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 6mg/kg as the middle dose group. | Biological: Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 6mg/kg<br>* Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 6mg/kg, intravenous injection for 60 to 90 minutes. Every 2 weeks is a cycle, the first day of each cycle is administered, a total of ≥ 4 cycles.<br>|
| Experimental: Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 8mg/kg<br>Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 8mg/kg as the high dose group. | Biological: Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 8mg/kg<br>* Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 8mg/kg, intravenous injection for 60 to 90 minutes. Every 2 weeks is a cycle, the first day of each cycle is administered, a total of ≥ 4 cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events(AEs) as Assessed by CTCAE v5.0 | An AE is any untoward medical occurrence in a clinical study participant administered a medicinal product. The AE can be any symptom, disease or abnormal laboratory finding, which does not necessarily have a causal relationship with this treatment. | Up to 8 weeks | 
| Grades of all the Adverse Events(AEs) by CTCAE v5.0 | Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline. | Up to 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved Overall Response Rate（ORR）for Lymph Nodes | ORR is Complete Response (CR) + Partial Response (PR) , assessed according to International Working Group ( IWG ) 1999 criteria. | Up to 8 weeks | 
| Percentage of Participants Who Achieved Overall Response Rate（ORR）for Symptomatic Response | ORR is CR + PR. The symptom response involves 4 symptoms, namely fatigue, anorexia, fever, and weight loss. CR is 4 symptoms returning to pre-onset. PR is improvement in all 4 symptoms, but not return to pre-onset. | Up to 8 weeks | 
| Percentage of Participants Who Achieved Overall Response Rate（ORR）for Biochemical Response | ORR is CR + PR. Biochemical indicators include 4 laboratory test indicators, namely C-reactive protein, hemoglobin, albumin and glomerular filtration rate. CR is the return of 4 biochemical indicators to normal. PR is a greater than 50% improvement in all four biochemical parameters. | Up to 8 weeks | 
| Concentration of Anti-Drug Antibody (ADA) | The concentrations of ADA in serum will be tested. | Up to 8 weeks | 
| Concentration of Neutralizing Antibody (NAb) | The concentration of NAb in serum will be tested when their ADA is positive. | Up to 8 weeks | 
| Concentration of Soluble Interleukin-6 Receptor (sIL-6R) | The concentrations of sIL-6R in the serum of each subject are measured. | Within 1 hour before the first dose. 24, 72, 168，336 hours first post-dose. | 
| Concentration of Interleukin-6 (IL-6) | The concentrations of IL-6 in the serum of each subject are measured. | Within 1 hour before the first dose. 8, 24, 72, 168，336 hours first post-dose. | 
| Cmax | Peak concentration. Obtain directly according to the measured data of blood concentration-time. | Up to 8 weeks | 
| AUC0-t | The area under the curve from time zero to the last time that the blood drug concentration can be quantitatively detected. | Up to 8 weeks |