Ibrutinib Followed by BR (Bendamustine and Rituximab) as a Time-Limited Therapy for Waldenström Macroglobulinemia

NCT07169565 | Not Yet Recruiting Phase 1

• 1 other identifier: IIT2022026
• Study Type: interventional
• Target: 21
• Locations: 0 countries
• Sites: N/A

Brief Summary

This is a two-part, non-randomized, open-label Phase I clinical study. The research consists of:

• 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• Patients failing to achieve ≥MR are withdrawn.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.

Conditions

Waldenström Macroglobulinemia (WM)

Keywords

Waldenström Macroglobulinemia; ibrutinib; fixed dose

Outcome Measures

Primary Outcomes (5)

• 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).

  Cycle 1 (Days 1-28)

• 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).

  End of Dose Escalation Phase (approximately 6 months)

• 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).

  End of Dose Escalation Phase (approximately 6 months)

• 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.

  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

  Proportion of participants achieving ≥Partial Response (PR) per Consensus Panel Criteria from the 8th International Workshop on Waldenström Macroglobulinemia (IWWM-8) after 3 cycles of IBR therapy.

  At end of Cycle 3 (Day 84 ±3 days)

Secondary Outcomes (4)

• IgM rebound rate

  At 2 months after the last dose of study treatment

• Duration of Response (DOR)

  From the first documented response until disease progression/recurrence (assessed up to 24 months)

• Progression-Free Survival (PFS)

  From first dose until disease progression or death (assessed up to 24 months)

• Biomarker correlation with efficacy

  Biomarker samples collected at baseline; efficacy assessed through study completion (approximately 24 months)

Other Outcomes (4)

• Correlation of Baseline Biomarker Status with Treatment Efficacy

  Biomarker status: At screening (Day -28 to Day 1); Efficacy assessment: At the end of Cycle 3 (Day 84)

• Biomarker Correlation with Adverse Reactions

  Biomarker samples collected at baseline (Day 1 Cycle 1); safety assessed from first dose until 30 days after last dose (approximately 24 months)

• Temporal Changes in Biomarker Burden

  Baseline (screening) vs. End of Cycle 3 (Day 84 ±3 days)

Study Arms (1)

Ibrutinib + BR Combination Therapy

EXPERIMENTAL

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.

Drug: Ibrutinib; Drug: Bendamustine; Drug: Rituximab

Interventions

Ibrutinib DRUG

Oral 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).

Ibrutinib + BR Combination Therapy

Bendamustine DRUG

Intravenous 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.

Ibrutinib + BR Combination Therapy

Rituximab DRUG

Intravenous 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.

Ibrutinib + BR Combination Therapy

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• ECOG performance status score of 0-1.
• Patient has received ≥12 cycles of ibrutinib monotherapy, achieved a treatment response (but not Complete Response (CR) ), and is currently on a treatment plateau.
• Patient has maintained good treatment tolerance (experienced no Grade ≥3 adverse reactions during ibrutinib therapy) and is still receiving ibrutinib.
• Patient has no prior treatment with Bendamustine combined with Rituximab (BR) regimen.
• Laboratory values:
• Neutrophils ≥1.0 × 10⁹/L
• Platelets ≥50 × 10⁹/L
• Hemoglobin ≥70 g/L
• Total bilirubin ≤2 × Upper Limit of Normal (ULN)
• Alanine aminotransferase (ALT) / Aspartate aminotransferase (AST) ≤3 × ULN
• Creatinine clearance (CrCl) ≥30 mL/min (calculated by Cockcroft-Gault formula).

You may not qualify if:

• 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.
• Non-lymphoma related liver or kidney impairment:
• ALT \>3 × ULN
• AST \>3 × ULN
• Total bilirubin (TBIL) \>2 × ULN
• Serum creatinine clearance \<30 mL/min.
• Other severe medical conditions that could interfere with the study (e.g., uncontrolled diabetes, gastric ulcer, other severe cardiopulmonary diseases), as determined by the investigator.
• Cardiac function or disease meeting any of the following:
• Long QTc syndrome or QTc interval \>480 ms;
• Complete left bundle branch block, second- or third-degree atrioventricular block;
• Severe, uncontrolled arrhythmias requiring drug therapy;
• New York Heart Association (NYHA) classification ≥ Class III;
• Left ventricular ejection fraction (LVEF) \<50%;
• History within 6 months prior to enrollment: myocardial infarction, unstable angina, severe unstable ventricular arrhythmias, or any other arrhythmia requiring treatment; history of clinically significant pericardial disease; or ECG evidence of acute ischemia or active conduction system abnormalities.

Sponsors & Collaborators

• Institute of Hematology & Blood Diseases Hospital, China: lead

MeSH Terms

Conditions

Waldenstrom Macroglobulinemia

Interventions

ibrutinib; Bendamustine Hydrochloride; Rituximab

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Central Study Contacts

Shuhua Yi

CONTACT

86-15900265415; yishuhua@ihcams.ac.cn

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 31, 2025
• First Posted: September 11, 2025
• Study Start: September 1, 2025
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): September 1, 2028
• Last Updated: September 11, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share