This is a two-part, non-randomized, open-label Phase I clinical study. The research consists of:
1. A 3+3 dose-escalation phase to determine the Maximum Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D) of the I+BR regimen in Waldenström Macroglobulinemia (WM) patients; 2. A dose-expansion phase to evaluate the safety, tolerability, and efficacy of the time-limited regimen at the MTD/RP2D.
Key Study Design Details:
Pre-enrollment \& Eligibility:
* Patients undergo efficacy and tolerability assessment before enrollment. * Eligible patients receive I+BR therapy.
Treatment Regimen:
* Bendamustine: Tested at three dose levels (70 mg/m², 60 mg/m², and 50 mg/m²) based on prior IBR data in B-cell lymphomas. A 3+3 dose de-escalation design is employed. * Fixed Doses:
* Ibrutinib: 420 mg/day * Rituximab: 375 mg/m²
Part I (3+3 Dose Escalation):
* Start with 3 patients receiving bendamustine 70 mg/m². * After 1 treatment cycle:
* Assess Dose-Limiting Toxicity (DLT) (DLT criteria defined separately). * Patients without DLT proceed to 2 additional cycles of IBR. * After 3 total cycles:
* Efficacy assessment is performed. * Patients achieving minimal response (MR) or better (i.e., MR, PR, VGPR, CR) receive 1 cycle of BR, then cease treatment and enter follow-up. * Patients failing to achieve ≥MR are withdrawn. * Primary Objective: Evaluate safety and identify MTD.
Part II (Dose Expansion):
* Enroll 15 additional patients at MTD/RP2D. * Objectives:
* Further assess safety and efficacy; * Monitor IgM rebound within 2 months after completing therapy (3 cycles I+BR → 1 cycle BR); * Explore correlations between biomarkers and clinical outcomes.
Terminology Notes:
* I+BR: Ibrutinib + Bendamustine/Rituximab * DLT: Dose-Limiting Toxicity * MTD: Maximum Tolerated Dose * RP2D: Recommended Phase II Dose * Efficacy thresholds: MR (Minimal Response), PR (Partial Response), VGPR (Very Good Partial Response), CR (Complete Response) * Time-limited therapy: Fixed-duration treatment designed to avoid indefinite dosing.
Patient fully understands the study, voluntarily participates, and signs the Informed Consent Form (ICF).
Patient of any gender, aged ≥18 years and ≤75 years.
Patient must meet diagnostic criteria for Waldenström Macroglobulinemia (WM) and be MYD88 L265P mutation positive.
Patient has documented baseline IgM levels and disease assessment parameters (including liver, spleen, lymph nodes; if extramedullary lesions exist, include assessment of other extramedullary sites) prior to ibrutinib use, to facilitate subsequent efficacy evaluation.
Diagnosis or treatment for a malignancy other than B-cell Non-Hodgkin Lymphoma (B-NHL) within the past year (including active Central Nervous System lymphoma). Received other anti-tumor therapies (including chemotherapy, targeted therapy, hormonal therapy, anti-tumor Chinese herbs with activity) within 4 weeks prior to study drug administration (excluding ibrutinib) or participated in other clinical trials receiving investigational drugs.
Clinical evidence of transformation to large cell lymphoma.
ALT >3 × ULN
AST >3 × ULN