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

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

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  • Patients failing to achieve ≥MR are withdrawn.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.

Inclusion Criteria

1. Patient fully understands the study, voluntarily participates, and signs the Informed Consent Form (ICF).

2. Patient of any gender, aged ≥18 years and ≤75 years.

3. Patient must meet diagnostic criteria for Waldenström Macroglobulinemia (WM) and be MYD88 L265P mutation positive.

4. 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.

5. ECOG performance status score of 0-1.

6. Patient has received ≥12 cycles of ibrutinib monotherapy, achieved a treatment response (but not Complete Response (CR) ), and is currently on a treatment plateau.

7. Patient has maintained good treatment tolerance (experienced no Grade ≥3 adverse reactions during ibrutinib therapy) and is still receiving ibrutinib.

8. Patient has no prior treatment with Bendamustine combined with Rituximab (BR) regimen.

9. 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).

10. Patient has an estimated life expectancy ≥6 months.

Exclusion Criteria

1. 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.

2. Clinical evidence of transformation to large cell lymphoma.

3. Non-lymphoma related liver or kidney impairment:

   • ALT >3 × ULN
   • AST >3 × ULN
   • Total bilirubin (TBIL) >2 × ULN
   • Serum creatinine clearance <30 mL/min.

4. 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.

5. Cardiac function or disease meeting any of the following:

   1. Long QTc syndrome or QTc interval >480 ms;
   2. Complete left bundle branch block, second- or third-degree atrioventricular block;
   3. Severe, uncontrolled arrhythmias requiring drug therapy;
   4. New York Heart Association (NYHA) classification ≥ Class III;
   5. Left ventricular ejection fraction (LVEF) <50%;
   6. 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.

6. 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.

7. Major surgery within 14 days prior to enrollment (excluding lymph node biopsy) or anticipated need for major surgery during the study.

8. 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).

9. Pregnant or lactating women, or women of childbearing potential not using contraception.

10. Hypersensitivity to any of the study drugs or their components.

11. 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).

12. History of stroke or intracranial hemorrhage within 6 months prior to the first dose of study drug.

13. History of bleeding diathesis (e.g., hemophilia, von Willebrand disease).

14. 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.

15. Diagnosis of gastrointestinal ulcer by endoscopy within 3 months prior to the first dose of study drug.