Efficacy of Venetoclax in Combination With Rituximab in Waldenström's Macroglobulinemia

Summary

In Waldenström's macroglobulinemia (WM) chemotherapy induces only low CR/VGPR rates and response duration is limited. In addition, WM patients are often elderly, partly not tolerating chemotherapy related toxicities. 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 and favorable toxicity profile in indolent B-NHL such as CLL, Venetoclax was approved for the treatment of this diseases by the FDA and the European Medicines Agency (EMA). First data in relapsed/refractory WM have documented high activity and low toxicity of Venetoclax also in WM, including patients with prior Ibrutinib treatment or patients carrying CXCR4 mutations. Ibrutinib itself has high activity and a relatively low toxicity profile in WM, but has also major disadvantages: the main disadvantage is the need to apply this drug continuously. Furthermore, Ibrutinib efficacy depends largely on the genotype with a substantial drop in major responses and PFS in the presence of CXCR4 mutations and non-mutated MYD88. In particular the need of continuous treatment for Ibrutinib has prevented that Ibrutinib has become the standard of care outcompeting conventional Rituximab/chemotherapy. This is reflected in current guidelines such as the NCCN and the ESMO guidelines, which still see immunochemotherapy as a backbone of treatment, largely because of the advantage of a timely fixed application. Data in CLL in the relapsed as well as in the first line setting have convincingly shown that in contrast to Ibrutinib Venetoclax is highly efficient also when used in a timely defined application scheme over 12 months in combination with the anti-CD20 antibody Rituximab. Data documented deep responses including molecular responses and a highly significant advantage over immunochemotherapy in large international Phase III trials, changing the standard of care in this disease.

Based on this the hypothesis is that timely fixed application of the combination of Venetoclax and Rituximab induces significantly superior treatment outcomes compared to chemotherapy and Rituximab (DRC) in patients with treatment naïve WM, regardless of the genotype. A first indication for this assumption in the proposed trial will allow the performance of confirmatory phase 3 trials that might change the standard of care in WM.

Conditions

• Waldenstrom Macroglobulinemia
• Treatment Naive

Interventions

DRUG

Venetoclax; Rituximab

Combination of venetoclax and rituximab

DRUG

DRC

Combination of Dexamethasone / Rituximab / Cyclophosphamide

Sponsors & Collaborators

• Ludwig-Maximilians - University of Munich

  collaborator OTHER

• Zentrum für Klinische Studien Ulm

  collaborator OTHER

• AbbVie

  collaborator INDUSTRY

• Pfizer

  collaborator INDUSTRY

• University of Ulm

  collaborator OTHER

• University Hospital Schleswig-Holstein

  collaborator OTHER

• Christian Buske

  lead OTHER

Principal Investigators

• Christian Buske, Prof. Dr. · University Hospital Ulm Department of Internal Medicine III

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2025-03-21

Primary Completion

2028-03-31

Completion

2033-03-31

Countries

• Germany
• Greece

Study Locations