Ibrutinib Followed by BR (Bendamustine and Rituximab) as a Time-Limited Therapy for Waldenström Macroglobulinemia
- Conditions
- Waldenström Macroglobulinemia (WM)
- Interventions
- Registration Number
- NCT07169565
- Brief Summary
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* Patients failing to achieve ≥MR are withdrawn.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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 21
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Ibrutinib + BR Combination Therapy Ibrutinib 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. Ibrutinib + BR Combination Therapy Bendamustine 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. Ibrutinib + BR Combination Therapy Rituximab 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.
- Primary Outcome Measures
Name Time Method Phase 1: Dose Escalation (Part 1) Incidence of Dose-Limiting Toxicities (DLTs) Cycle 1 (Days 1-28) 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 End of Dose Escalation Phase (approximately 6 months) 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) End of Dose Escalation Phase (approximately 6 months) 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 From first dose until 30 days after last dose (up to 5 months) 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.
Phase 2: Dose Expansion (Part 2) Overall Response Rate (ORR) at RP2D At end of Cycle 3 (Day 84 ±3 days) 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.
- Secondary Outcome Measures
Name Time Method IgM rebound rate At 2 months after the last dose of study treatment 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) From the first documented response until disease progression/recurrence (assessed up to 24 months) 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) From first dose until disease progression or death (assessed up to 24 months) 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 Biomarker samples collected at baseline; efficacy assessed through study completion (approximately 24 months) Assessment of the association between specific biomarker levels (e.g., CXCR4 mutation status) and clinical efficacy outcomes (e.g., overall response rate).