Efficacy and Safety of Carfilzomib in Combination With Ibrutinib vs Ibrutinib in Waldenström's Macroglobulinemia

Sponsor
Christian Buske
Study ID
NCT04263480
Phase
PHASE2
Status
Active Not Recruiting

Conditions

  • Waldenstrom Macroglobulinemia

Eligibility Criteria

Sex
ALL
Age
18 Years - N/A
Healthy Volunteers
Not accepted

Interventions

  • Carfilzomib + Ibrutinib — DRUG
    Carfilzomib: Cycle 1, day 1: 20 mg/m² i.v. Cycle 1, day 8, day 15: 70 mg/m² i.v. Cycle 2 - 12, day 1, day 8, day 15: 70 mg/m² i.v. Cycle 13 - 24, day 1, day 15: 70 mg/m² i.v. Ibrutinib: 420 mg p.o daily until disease progression or non-tolerable toxicities
  • Ibrutinib — DRUG
    Ibrutinib: 420 mg p.o daily until disease progression or non-tolerable toxicities

Study Details

In Waldenström macroglobulinemia (WM) chemotherapy induces only low CR/VGPR (Complete Remission/ Very Good Partial Response) rates and responses of short duration compared to other indolent lymphomas. Thus, innovative approaches are needed which combine excellent activity and tolerability in WM. Chemotherapy-free approaches are highly attractive for this patient group. Based on its high activity in WM and its low toxicity, Ibrutinib was approved for the treatment of WM by the European Medicines Agency (EMA). However, also Ibrutinib fails to induce CRs and the VGPR rate is 16% in relapsed patients. In addition, activity of Ibrutinib depends on the genotype: compared to MYD88mut/CXCR4WT patients Ibrutinib single agent therapy induces substantially lower response rates in patients with the MYD88mut/CXCR4mut or the MYD88WT/CXCR4WT genotype (major response (at least PR) in 91.7 % compared to 61.9 and 0 %, respectively). Phase II data have indicated that the proteasome inhibitor Carfilzomib is able to overcome the inferior prognosis of Ibrutinib in MYD88mut/CXCR4mut and MYD88WT/CXCR4WT patients, as response rates were high for all genotypes in a phase II study combining Carfilzomib with Rituximab and Dexamethasone. Based on this the investigators hypothesize that addition of Carfilzomib to Ibrutinib will increase the VGPR/CR rate compared to Ibrutinib alone in patients with WM, in particular in patients carrying the CXCR4 mutation. In addition, the investigators hypothesize, that the combination Carfilzomib and Ibrutinib will be also highly active in MYD88 wildtype patients and that this combination will be at least as efficient in treatment naïve patients as in relapsed/refractory patients.

Key Dates

Start date
Aug 18, 2021
Status verified
May 2026
Primary completion
May 31, 2028
Completion
May 31, 2028

Study Design

Enrollment
99 participants (estimated)
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT

Arms

  • Experimental: Arm A: Carfilzomib + Ibrutinib
    Patients will be treated with Ibrutinib until evidence of progressive disease or no longer tolerated. Patients will receive in addition Carfilzomib for two years.
  • Active Comparator: Arm B: Ibrutinib
    Patients will be treated with Ibrutinib until evidence of progressive disease or no longer tolerated.

Primary Outcome Measure

CR/VGPR [ Time Frame: 12 months ]

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