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

NCT05099471 | Recruiting Phase 2 DMC

• 1 other identifier: VIWA-1
• Study Type: interventional
• Target: 80
• Locations: 2 countries
• Sites: 14

Brief 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

Keywords

Hematology; Oncology; Venetoclax; Rituximab; DRC; Lymphoma; NHL; indolent; monoclonal IgM

Outcome Measures

Primary Outcomes (1)

• Rate of CR / VGPR

  CR / VGPR 12 months after randomization

  12 months

Secondary Outcomes (13)

• Interim reponse

  12 months

• Response rate

  12 months

• Best response

  24 months

• Time to first overall response

  24 months

• Time to first major response

  24 months

Study Arms (2)

Venetoclax / Rituximab

EXPERIMENTAL

Cycle 1 (28-days cycle) Stepwise dose escalation of Venetoclax in all patients with a target dose of xy mg/d QD PO. Day 1-7: Venetoclax xy mg/d QD PO Day 8-14: Venetoclax xy mg/d QD PO Day 15-28: Venetoclax xy mg/d QD PO Cycle 2-12: Day 1: Rituximab 375 mg/m2 IV Day 1-28: Venetoclax xy mg/d QD PO

Drug: Venetoclax; Rituximab

Dexamethasone / Rituximab / Cyclophosphamide

ACTIVE COMPARATOR

Cycle 1-6: Day 1: Dexamethasone 20 mg PO Day 1: Rituximab 375 mg/m2 IV Day 1-5: Cyclophosphamide 100 mg/m2 BID PO

Drug: DRC

Interventions

Venetoclax; Rituximab DRUG

Combination of venetoclax and rituximab

Also known as: Venetoclax / Rituximab

Venetoclax / Rituximab

DRC DRUG

Combination of Dexamethasone / Rituximab / Cyclophosphamide

Also known as: Dexamethasone / Rituximab / Cyclophosphamide

Dexamethasone / Rituximab / Cyclophosphamide

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Proven clinicopathological diagnosis of WM as defined by consensus panel one of the Second International Workshop on WM (IWWM). Histopathology has to be perfomed before randomization but within the last 4 months before start of treatment. In addition, pathological specimens have to be sent to the national pathological reference center prior to randomization for the determination of the mutational status of MYD88 and CXCR4 prior to randomization if the mutational status hasn't been determined before. Pathological reference center must confirm the diagnosis of WM.
• De novo WM independent of the genotype.
• Patients must have at least one of the following criteria to start study treatment as partly defined by consensus panel criteria from the Seventh IWWM and ESMO Guideline:
• Recurrent fever, night sweats, weight loss, fatigue (at least one of them).
• Hyperviscosity.
• Lymphadenopathy which is either symptomatic or bulky (≥ 5 cm in maximum diameter).
• Symptomatic hepatomegaly and / or splenomegaly.
• Symptomatic organomegaly and / or organ or tissue infiltration.
• Peripheral neuropathy due to WM.
• Symptomatic cryoglobulinemia.
• Symptomatic Cold agglutinin anemia.
• Autoimmune hemolytic anemia and/or thrombocytopenia.
• Nephropathy related to WM.
• Amyloidosis related to WM.
• Hemoglobin ≤ 10 g/dL (patients should not have received red blood cells transfusions for at least 7 days prior to obtaining the screening hemoglobin).

You may not qualify if:

• Serious medical or psychiatric illness (especially undergoing treatment) likely to interfere with participation in this clinical study.
• Subject is known to be positive for HIV.
• Active severe infection
• Congenital or acquired severe immunodeficiency not attributed to lymphoma (clinical appearance: recurrent infections, necessity of immunoglobulin substitution therapy, patients after transplantation)
• Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
• Uncontrolled systemic infection (viral, bacterial or fungal).
• Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate
• inadequate pulmonary function as demonstrated by DLCO ≤ 65% or FEV1 ≤ 65%.
• Creatinine clearance ≥ 30 mL/min to \< 45 ml/min
• Uncontrolled diabetes mellitus (as indicated by metabolic derangements and / or severe diabetes mellitus related uncontrolled organ complications).
• Uncontrolled hypertension.
• Cardiac history of CHF requiring treatment or Ejection Fraction ≤ 50% or chronic stable angina.
• Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months prior to start therapy.
• Clinically significant cardiac arrhythmia that is symptomatic or requires treatment, or asymptomatic sustained ventricular tachycardia.
• Subject has a cardiovascular disability status of New York Heart Association Class \> 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain.

Sponsors & Collaborators

• Christian Buske: lead
• Ludwig-Maximilians - University of Munich: collaborator
• Zentrum für Klinische Studien Ulm: collaborator
• AbbVie: collaborator
• Pfizer: collaborator
• University of Ulm: collaborator
• University Hospital Schleswig-Holstein: collaborator

Study Sites (14)

Onkologische Schwerpunktpraxis Bielefeld

Bielefeld, 33604, Germany

RECRUITING

Klinikum Chemnitz gGmbH

Chemnitz, 09116, Germany

RECRUITING

Klinikverbund Allgaeu gGmbH

Kempten, 87439, Germany

RECRUITING

Universitaetsklinikum Schleswig-Holstein AöR

Kiel, 24105, Germany

RECRUITING

Gemeinschaftsklinikum Mittelrhein gGmbH

Koblenz, 56073, Germany

RECRUITING

Dr. Vehling-Kaiser MVZ GmbH

Landshut, 84036, Germany

RECRUITING

Kliniken Maria Hilf GmbH Moenchengladbach

Mönchengladbach, 41063, Germany

RECRUITING

Kliniken Ostalb, Standort Stauferklinikum Schwäbisch Gmünd

Mutlangen, 73557, Germany

NOT YET RECRUITING

Haematologie und Onkologie Muenchen-Pasing MVZ GmbH

München, 81241, Germany

RECRUITING

Universitaet Muenster

Münster, 48149, Germany

RECRUITING

Christliches Klinikum Paderborn, Brüderkrankenhaus St. Josef Paderborn

Paderborn, 33098, Germany

RECRUITING

Universitätsmedizin Rostock

Rostock, 18057, Germany

NOT YET RECRUITING

University Hospital Ulm

Ulm, 89081, Germany

RECRUITING

Alexandra Hospital

Athens, 115 28, Greece

RECRUITING

Related Publications (1)

• Buske C, Dimopoulos MA, Morel P. Reply to S. Sarosiek et al. J Clin Oncol. 2023 Aug 20;41(24):4060-4061. doi: 10.1200/JCO.23.00877. Epub 2023 Jun 22. No abstract available.

  PMID: 37348018 DERIVED

MeSH Terms

Conditions

Waldenstrom Macroglobulinemia; Neoplasms; Lymphoma

Interventions

venetoclax; Rituximab; Dexamethasone; Cyclophosphamide

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Christian Buske, Prof. Dr.

  University Hospital Ulm Department of Internal Medicine III

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Dajana Kaszynski, MSc

CONTACT

+49 731 500; studien.gla@uniklinik-ulm.de

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. Dr.

Study Record Dates

• First Submitted: October 4, 2021
• First Posted: October 29, 2021
• Study Start: March 21, 2025
• Primary Completion (Estimated): March 1, 2028
• Study Completion (Estimated): March 1, 2033
• Last Updated: May 5, 2026

Record last verified: 2026-04

Locations

GR (1); DE (13)