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 * Patients failing to achieve ≥MR are withdrawn.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.
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Phase 1: Dose Escalation (Part 1) Incidence of Dose-Limiting Toxicities (DLTs)
Timeframe: Cycle 1 (Days 1-28)
Phase 1: Dose Escalation (Part 1) Maximum Tolerated Dose (MTD) of Bendamustine
Timeframe: End of Dose Escalation Phase (approximately 6 months)
Phase 1: Dose Escalation (Part 1) Recommended Phase 2 Dose (RP2D)
Timeframe: End of Dose Escalation Phase (approximately 6 months)
Phase 2: Dose Expansion (Part 2) Treatment-Emergent Adverse Events (TEAEs) at RP2D
Timeframe: From first dose until 30 days after last dose (up to 5 months)
Phase 2: Dose Expansion (Part 2) Overall Response Rate (ORR) at RP2D
Timeframe: At end of Cycle 3 (Day 84 ±3 days)