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
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 25
- 试验地点
- 3
- 主要终点
- Number of Participants with Adverse Events(AEs) as Assessed by CTCAE v5.0
研究概览
简要总结
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.
详细描述
Phase I:
This stage is a single-arm, open-label, multicenter, dose-escalation clinical study. A total of 3 dose groups of 4 mg/kg, 6 mg/kg and 8 mg/kg, 3 patients per dose, 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 patients will be enrolled from the low-dose group to the high-dose group in turn. After the last patient 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 patients 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 patient, 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 patient experiences an important adverse event. If an important adverse event occurs, the investigator will perform related inspections based on the patient's condition, and for treatment.
After the patient completes four cycles of administration, if no significant safety events are found or the patient has not withdrawn from the trial due to significant safety events and has a significant treatment effect, and if the investigator determines that they may benefit from continuing the treatment, with the consent of both the investigator and the patient.
Phase I is planned to include 9 patients.
Phase II:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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; 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 patients 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.
排除标准
- •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.
研究组 & 干预措施
Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 4 mg/kg, q2w
Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 4 mg/kg as the low dose group in phase I.
干预措施: Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 4 mg/kg, q2w (Biological)
Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 6 mg/kg, q2w
Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 6 mg/kg, q2w as the middle dose group in phase I.
干预措施: Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 6 mg/kg, q2w (Biological)
Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 8 mg/kg, q2w
Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 8 mg/kg, q2w, as the high dose group in phase I.
干预措施: Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 8 mg/kg, q2w (Biological)
Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 6 mg/kg, q3w
Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 6 mg/kg, q3w, as the high dose group in phase II.
干预措施: Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 6 mg/kg, q3w (Biological)
Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 4mg/kg, q3w
Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 4mg/kg, q3w, as the low dose group in Phase II.
干预措施: Recombinant Humanized Anti-interleukin-6 Receptor Monoclonal Antibody Injection 4mg/kg,q3w (Biological)
结局指标
主要结局
Number of Participants with Adverse Events(AEs) as Assessed by CTCAE v5.0
时间窗: Through study completion, an average of 3 years in Phase I and 1 year in phase II
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.
Grades of all the Adverse Events(AEs) by CTCAE v5.0
时间窗: Through study completion, an average of 3 years in Phase I and 1 year in phase II
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.
次要结局
- Percentage of Participants Who Achieved Overall Response Rate（ORR）for Biochemical Response(Through study completion, an average of 3 years in Phase I and 1 year in phase II)
- Percentage of Participants Who Achieved Overall Response Rate（ORR）for Lymph Nodes(Through study completion, an average of 3 years in Phase I and 1 year in phase II)
- Percentage of Participants Who Achieved Overall Response Rate（ORR）for Symptomatic Response(Through study completion, an average of 3 years in Phase I and 1 year in phase II)
- Concentration of Anti-Drug Antibody (ADA)(Through study completion, an average of 2 years in Phase I and 1 year in phase II)
- Concentration of Neutralizing Antibody (NAb)(Through study completion, an average of 2 years in Phase I and 1 year in phase II)
- Concentration of Soluble Interleukin-6 Receptor (sIL-6R)(Through study completion, an average of 2 years in Phase I and 1 year in phase II)
- Concentration of Interleukin-6 (IL-6)(Through study completion, an average of 2 years in Phase I and 1 year in phase II)
- Cmax(Through study completion, an average of 2 years in Phase I and 1 year in phase II)
- AUC0-t(Through study completion, an average of 2 years in Phase I and 1 year in phase II)