Zanuburutinib in Relapsed and Refractory iMCD: a Prospective, Single-center, Single-arm Trial

Study Overview
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Brief Summary
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To explore the effectiveness and safety of Zanuburutinib in relapsed and refractory idiopathic Multicentric Castleman's disease (iMCD) patients.

Detailed Description
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This is a single center, open-labeled , single arm, prospective study which includes a safety run-in phase. The primary endpoint is the overall response rate which includes complete response (CR) and partial response (PR) at Week 12 and Week 24. The secondary endpoints include progression-free survival (PFS), overall survival (OS), and adverse events. There are two phases of the study. The first phase is the 'safety run-in phase'which plans to enroll 6 patients who would be observed for safety issues for 12 weeks after study drug administration. If no Grade ≥ 4 (CTCAE) adverse events (AE) occurs during this phase, the study would enter the second phase; if Grade ≥ 4 (CTCAE) AE happens during this phase, the study would be terminated. In the second phase of the study, another 24 patients would be enrolled. All enrolled patients would receive the study drug until progression of disease, intolerability of the drugs or Week 96 and would be followed every 4 weeks in the first 12 weeks, every 12 weeks until Week 48 and every 24 weeks until Week 96. The follow-up phase to assess PFS and OS will last from initiation of study drug to 36 months after enrollment (evaluation would be carried out every 24 weeks after Week 96). The total study duration will be 4 years after the last patient starts study medication.

Official Title
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The Efficacy and Safety of Zanuburutinib in Relapsed and Refractory Idiopathic Multicentric Castleman Disease (iMCD): a Prospective, Single-center, Single-arm Trial

Conditions
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Idiopathic Multicentric Castleman's Disease

Intervention / Treatment
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* Drug: Zanubrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: fulfilled the CDCN (Castleman Disease Collaborative Network) diagnostic criteria of iMCD relapsed or refractory disease. Relapsed = patients who ever achieved overall partial response (PR) or complete response (CR) with prior lines of therapy suffered from progressive disease (PD); refractory = iMCD patients who never achieved PR or CR with the first-line treatment but suffered from PD during treatment. Eastern Cooperative Oncology Group performance status (ECOG-PS ≤ 2) Neutrophil count ≥ 0.75×10^9/L, hemoglobin ≥ 70 g/L and platelet count > 30×10^9/L Total bilirubin ≤ 2 x ULN (upper limit of normal), AST（aspartate aminotransferase） or ALT（Alanine aminotransferase）≤ 2.5 x ULN INR （international normalized ratio) and APTT(activated partial thromboplastin time) ≤ 1.5 x ULN；eGFR>25ml/min/1.73m2 estimated survival ≥ 3 months agree to take birth control methods during study period for women of reproductive age agree to provide informed consent Exclusion Criteria: concurrent malignancies prior history of receiving any kind of BTK (Bruton's tyrosine kinase) inhibitors patients with SLE (systemic lupus erythematosus), HHV-8 (human herpesvirus-8) infection or POEMS syndrome History of major surgery or radiation therapy within 4 weeks before initiation of study drug history of myocardial infarction within 1 years patient with history of heart failure (NYHA 3 or 4) would be excluded unless his LVEF(left ventricular ejection fraction) ≥ 50% within 1 months primary cardiomyopathy; Qtc > 450ms for men and > 470ms for women breast feeding or pregnant women intolerance for oral regimen due to gastro-intestinal disorders uncontrolled infection positive HBV(hepatitis B virus)-DNA titers or positive HbsAg; positive HCV(hepatitis C virus)antibody; patients with HIV infection patients with history of bleeding disorders cerebral infarction or intracranial bleeding within 6 months active bleeding disorders within 2 months taking anti-platelet or anticoagulation drugs taking drugs which strongly inhibit P450 CYP3A patients or their relatives fail to understand the purpose of the study any other conditions that the investigators consider to be not appropriate for inclusion

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
Intervention Model: Single Group Assignment
Interventional Model Description: This will be a single center, single arm, phase 2 study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zanuburutinib<br>Oral Zanuburutinib 160mg twice a day | Drug: Zanubrutinib<br>* Oral Zanuburutinib, 160mg twice a day<br>* Other names: brukinsa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) at Week 12 | Overall response (including partial response and complete response) rate at week 12 after zanuburutinib therapy | From date of treatment initiation to 12 weeks after treatment | 
| Overall response rate (ORR) at Week 24 | Overall response (including partial response and complete response) rate at week 24 after zanuburutinib therapy | From date of treatment initiation to 24 weeks after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Time to disease progression or death | From date of treatment initiation until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months | 
| Overall survival | Time to death | From date of treatment initiation until the date of death from any cause, whichever came first, assessed up to 36 months | 
| Number of Participants With Treatment-related Adverse Events | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 ( ≥1 Grade) | From initiation study regimen to 3 months after the end of treatment or to time point of the initiation of second line therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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iMCD, Zanuburutinib, efficacy, safety