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

Official title

Phase I Clinical Study of Ibrutinib Followed by BR (Bendamustine and Rituximab) as a Time-Limited Therapy for Waldenström Macroglobulinemia

Overview

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 * Patients failing to achieve ≥MR are withdrawn.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.

Interventions

• Drug Ibrutinib
  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 toxici
• Drug Bendamustine
  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 hematologi
• Drug Rituximab
  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 toxicit

Primary outcome measures

• Phase 1: Dose Escalation (Part 1) Incidence of Dose-Limiting Toxicities (DLTs) [Time frame: Cycle 1 (Days 1-28)]
• Phase 1: Dose Escalation (Part 1) Maximum Tolerated Dose (MTD) of Bendamustine [Time frame: End of Dose Escalation Phase (approximately 6 months)]
• Phase 1: Dose Escalation (Part 1) Recommended Phase 2 Dose (RP2D) [Time frame: End of Dose Escalation Phase (approximately 6 months)]
• Phase 2: Dose Expansion (Part 2) Treatment-Emergent Adverse Events (TEAEs) at RP2D [Time frame: 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 [Time frame: At end of Cycle 3 (Day 84 ±3 days)]

Secondary outcome measures (4)

• IgM rebound rate [Time frame: At 2 months after the last dose of study treatment]
• Duration of Response (DOR) [Time frame: From the first documented response until disease progression/recurrence (assessed up to 24 months)]
• Progression-Free Survival (PFS) [Time frame: From first dose until disease progression or death (assessed up to 24 months)]
• Biomarker correlation with efficacy [Time frame: Biomarker samples collected at baseline; efficacy assessed through study completion (approximately 24 months)]

Eligibility criteria

Inclusion criteria

• 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).
• Patient has an estimated life expectancy ≥6 months.

Exclusion criteria

• 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.
• Known history of Human Immunodeficiency Virus (HIV) infection, or active Hepatitis B Virus (HBV) infection, or any uncontrolled active systemic infection requiring intravenous antibiotics.

Note: Active HBV infection is defined as meeting ALL THREE criteria: a. HBV DNA quantification ≥2000 IU/mL; b. ALT ≥2 × ULN; c. Hepatitis not attributable to other causes (e.g., disease itself, drugs). Patients initially diagnosed with active HBV infection who convert to inactive HBV status after anti-HBV therapy may be enrolled provided they receive adequate anti-HBV prophylaxis.

• Major surgery within 14 days prior to enrollment (excluding lymph node biopsy) or anticipated need for major surgery during the study.
• History or current diagnosis of another malignancy (except adequately controlled non-melanoma skin basal cell carcinoma, carcinoma in situ of the breast/cervix, and other malignancies effectively controlled without treatment for the past five years).
• Pregnant or lactating women, or women of childbearing potential not using contraception.
• Hypersensitivity to any of the study drugs or their components.
• Malabsorption syndrome, disease significantly affecting gastrointestinal function, gastrectomy, extensive small bowel resection potentially affecting absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restriction/bariatric surgery (e.g., gastric bypass).
• History of stroke or intracranial hemorrhage within 6 months prior to the first dose of study drug.
• History of bleeding diathesis (e.g., hemophilia, von Willebrand disease).
• Requirement for or ongoing anticoagulation therapy with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days prior to the first dose of study drug.
• Diagnosis of gastrointestinal ulcer by endoscopy within 3 months prior to the first dose of study drug.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07169565 · IIT2022026

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗