Phase I Clinical Study of Ibrutinib Followed by BR (Bendamustine and Rituximab) as a Time-Limited Therapy for Waldenström Macroglobulinemia
Trial Snapshot
- Phase
- Phase 1
- Status
- Not yet recruiting
- Enrollment
- 21
- Primary Endpoint
- Phase 1: Dose Escalation (Part 1) Incidence of Dose-Limiting Toxicities (DLTs)
Study Overview
Brief Summary
This is a two-part, non-randomized, open-label Phase I clinical study. The research consists of:
- 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;
- 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:
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Ibrutinib: 420 mg/day
-
Rituximab: 375 mg/m²
Part I (3+3 Dose Escalation):
-
Start with 3 patients receiving bendamustine 70 mg/m².
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After 1 treatment cycle:
-
Assess Dose-Limiting Toxicity (DLT) (DLT criteria defined separately).
-
Patients without DLT proceed to 2 additional cycles of IBR.
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After 3 total cycles:
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Efficacy assessment is performed.
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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.
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Patients failing to achieve ≥MR are withdrawn.
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Primary Objective: Evaluate safety and identify MTD.
Part II (Dose Expansion):
-
Enroll 15 additional patients at MTD/RP2D.
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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.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Ibrutinib + BR Combination Therapy
- 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;
- A dose-expansion phase to evaluate the safety, tolerability, and efficacy of the time-limited regimen at the MTD/RP2D.
Intervention: Ibrutinib (Drug)
Ibrutinib + BR Combination Therapy
- 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;
- A dose-expansion phase to evaluate the safety, tolerability, and efficacy of the time-limited regimen at the MTD/RP2D.
Intervention: Bendamustine (Drug)
Ibrutinib + BR Combination Therapy
- 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;
- A dose-expansion phase to evaluate the safety, tolerability, and efficacy of the time-limited regimen at the MTD/RP2D.
Intervention: Rituximab (Drug)
Outcomes
Primary Outcomes
Phase 1: Dose Escalation (Part 1) Incidence of Dose-Limiting Toxicities (DLTs)
Time Frame: 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
Time Frame: 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)
Time Frame: 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
Time Frame: 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
Time Frame: 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 Outcomes
- 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))