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 * Patients failing to achieve ≥MR are withdrawn.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
Single group
Ibrutinib
DrugOral Bruton's tyrosine kinase (BTK) inhibitor administered at a fixed dose of 420 mg once daily. Capsules must be swallowed whole with water; do not open, break, or chew. If a dose is missed by ≤6 hours, take immediately; if \>6 hours, skip the dose and resume normal schedule the next day. Avoid grapefruit and Seville oranges (moderate CYP3A inhibitors). Treatment duration: 3 cycles (28 days/cycle) or until disease progression/unacceptable toxicity. Dose reduction is mandated for specific toxicities: 420 mg → 280 mg → 140 mg → discontinuation (per protocol-specified criteria). Use with caution in hepatic impairment (Child-Pugh A: reduce to 80 mg/day; Child-Pugh B/C: contraindicated).
Bendamustine
DrugIntravenous alkylating agent dosed via a 3+3 dose de-escalation design (70 mg/m² → 60 mg/m² → 50 mg/m²). Infused over 60-120 minutes on Days 1-2 of each 28-day cycle for 3 cycles. Starting dose: 70 mg/m² (Dose Level 1); dose reduction triggered by Dose-Limiting Toxicity (DLT) events per protocol. In the dose-expansion phase, all subjects receive the MTD/RP2D established in Part 1. Concomitant live vaccines are prohibited. Dose delays (≤4 weeks) and reductions are required for Grade ≥3 hematologic/non-hematologic toxicities.
Rituximab
DrugIntravenous anti-CD20 monoclonal antibody administered at a fixed dose of 375 mg/m² on Day 0 of each 28-day cycle for 3 cycles. Initial infusion starts at 50 mg/hour; if tolerated, increase by 50 mg/hour every 30 minutes (maximum: 400 mg/hour). Subsequent infusions start at 100 mg/hour with the same escalation. Premedication with acetaminophen and an antihistamine is required prior to each infusion. Permanently discontinue for Grade 4 infusion-related reactions or severe/life-threatening toxicity.
Phase 1: Dose Escalation (Part 1) Incidence of Dose-Limiting Toxicities (DLTs)
Proportion of participants experiencing protocol-defined DLTs during Cycle 1 (28 days). DLTs include Grade ≥3 non-hematologic or specific hematologic toxicities (e.g., febrile neutropenia, Grade 4 thrombocytopenia \>7 days) attributed to IBR regimen per NCI CTCAE v4.0 criteria (Section 2.4).
Phase 1: Dose Escalation (Part 1) Maximum Tolerated Dose (MTD) of Bendamustine
Highest dose level (70/60/50 mg/m²) at which ≤1 of 6 participants experience DLTs during Cycle 1, determined via 3+3 dose-escalation design (Section 2.1).
Phase 1: Dose Escalation (Part 1) Recommended Phase 2 Dose (RP2D)
Optimal dose of Bendamustine for expansion phase, derived from MTD evaluation integrated with safety/tolerability data (Section 2.1).
Phase 2: Dose Expansion (Part 2) Treatment-Emergent Adverse Events (TEAEs) at RP2D
Frequency and severity of TEAEs (Grade ≥3 per NCI CTCAE v4.0) attributed to IBR regimen at the RP2D. Includes hematologic, non-hematologic, and serious adverse events.
IgM rebound rate
Proportion of participants experiencing an IgM rebound, defined as a ≥25% increase in serum IgM levels from the end-of-treatment measurement, within 2 months after discontinuation of the time-limited therapy.
Duration of Response (DOR)
Time from the date of initial documented response (partial response or better) to the date of documented disease progression or death from any cause, whichever occurs first.
Progression-Free Survival (PFS)
Time from the first dose of study drug to the date of documented disease progression or death from any cause, whichever occurs first.
Biomarker correlation with efficacy
Assessment of the association between specific biomarker levels (e.g., CXCR4 mutation status) and clinical efficacy outcomes (e.g., overall response rate).
Correlation of Baseline Biomarker Status with Treatment Efficacy
To assess the association between the presence of specific somatic mutations (e.g., MYD88, CXCR4) detected at baseline and the achievement of a clinical response (Partial Response or better as defined by IWWM-8 criteria) following combination therapy. The strength of the association will be measured using odds ratios from logistic regression analysis.
Biomarker Correlation with Adverse Reactions
To assess the impact of specific biomarkers (e.g., pharmacogenetic variants) on the incidence and severity of treatment-emergent adverse events (e.g., neutropenia, rash) after combination therapy. The association will be analyzed using appropriate statistical tests.
Temporal Changes in Biomarker Burden
Quantitative changes in mutation burden (e.g., MYD88 L265P variant allele frequency) from baseline to end of Cycle 3, measured by ddPCR in bone marrow/peripheral blood samples.
Impact of Germline Genetic Variants on Incidence of Specific Adverse Reactions
To evaluate the relationship between predefined germline pharmacogenetic variants (e.g., in genes encoding CYP metabolizing enzymes) and the occurrence of specific Grade ≥3 adverse events (e.g., neutropenia, rash) attributed to the study regimen. The analysis will report hazard ratios from a Cox proportional-hazards model.
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