Waldenstrom MacroglobulinemiaPhase 2VIWA-1NCT05099471
Efficacy of Venetoclax in Combination With Rituximab in Waldenström's Macroglobulinemia
A Phase 2 study testing Venetoclax; Rituximab and DRC in people with Waldenstrom Macroglobulinemia and Treatment Naive, run by Christian Buske at 14 sites in 2 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Waldenstrom Macroglobulinemia, Treatment Naive
- What is being tested?
- Venetoclax; Rituximab and DRC
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 80 participants
- Where
- 14 sitesin 2 countries
- Study dates
- 21 Mar 2025to Mar 2033
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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).
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- 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).
- Platelet count < 100 x 109/L (caused by bone marrow [BM] infiltration of the lymphoma).
- Serum monoclonal protein > 5 g/dL, even with no overt clinical symptoms.
- IgM serum concentration ≥ 6 g/dL.
- and other WM associated relevant symptoms
- Subject must be ≥ 18 years of age.
- Life expectancy > 3 months.
- World Health Organization (WHO) / ECOG performance status ≤ 2.
- Left ventricular ejection fraction ≥ 40% as assessed by transthoracic echocardiogram (TTE).
- Baseline platelet count ≥ 50x109/L, absolute neutrophil count ≥ 0.75x109/L (if not due to BM infiltration by the lymphoma).
- . Adequate hepatic function per local laboratory reference range as follows:
- Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0 x ULN.
- Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin).
- Subject must have adequate renal function as demonstrated by a creatinine clearance ≥ 30 mL/min; calculated by the Cockcroft Gault formula or measured by 24 hours urine collection.
- Women of childbearing potential (WCBP), i.e. fertile, following menarche and until becoming postmenopausal must have negative results for pregnancy test and must agree to use a highly effective method of birth control for the duration of the therapy up to 12 months after end of therapy
- Men must agree not to father a child for the duration of therapy and 12 months after and must agree to advice their female partner to use a highly effective method of birth control. Males must refrain from sperm donation for the duration of treatment and at least 12 months after the last dose of study medication.
- Each patient must voluntarily date and sign an informed consent form in the native language of the patient indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Patients must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
- Affiliation to a social security scheme (relevant for France only).
Who cannot join
- 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).
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- 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.
- History of stroke or intracranial haemorrhage within 6 months prior start of treatment
- Known pericardial disease.
- Known interstitial lung disease.
- Infiltrative pulmonary disease, known pulmonary hypertension.
- Prior history of malignancies unless the subject has been free of the disease for ≥ 3 years. Exceptions include the following:
- Basal cell carcinoma of the skin,
- Squamous cell carcinoma of the skin,
- Carcinoma in situ of the cervix,
- Carcinoma in situ of the breast,
- Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b).
- Known cirrhosis (meeting child-pugh stage C).
- Chemotherapy with approved or investigational anticancer therapeutic within 21 days prior to start of therapy
- Glucocorticoid therapy within 14 days prior to therapy that exceeds a cumulative dose of 160 mg of dexamethasone or equivalent dose of other corticosteroids given for anti-neoplastic intent.
- Treatment with any of the following within 7 days prior to the first dose of study drug:
- moderate or strong cytochrome P450 3A (CYP3A) inhibitors (such as fluconazole, ketoconazole, and clarithromycin).
- moderate or strong CYP3A inducers (such as rifampin, carbamazepine, phenytoin, St. John's wort).
- Contraindication to the active substances or any of the other excipients of the Investigational Medicinal Products as well as to any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs.
- Vaccination with live attenuated vaccines within 4 weeks prior to start of therapy.
- History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or sponsor, if consulted, would pose a risk to subject safely or interfere with the study evaluation, procedures or completion.
- Women who are pregnant as well as women who are breast-feeding and do not consent to discontinue breast-feeding.
- Participation in another clinical trial within four weeks before start of therapy in this study.
- No consent for registration, storage and processing of the individual disease-characteristics.
- Administration or consumption of any of the following within 3 days prior to the first dose of study drug:
- grapefruit or grapefruit products.
- Seville oranges (including marmalade containing Seville oranges).
- star fruit.
- Person of legal age who is incapable of comprehending the nature, significance and implications of the clinical trial and of determining his/her will in the light of these facts
Trial locations and contacts
14 sites in 2 countries. Contact the study team or a site near you to ask about taking part.
14 sites in 2 countries
Germany13 sites, 13 recruiting
- Recruiting
Onkologische Schwerpunktpraxis Bielefeld
Bielefeld, 33604
Paul Düwel, Dr., +49521-9887770, studien@onkologie-bielefeld.de
- Recruiting
Klinikum Chemnitz gGmbH
Chemnitz, 09116
Annette Haenel, Dr., +49371-333 ext. 44519, a.haenel@skc.de
- Recruiting
Klinikverbund Allgaeu gGmbH
Kempten, 87439
Christian Langer, Prof. Dr., +49831-530 ext. 2228, christian.langer@klinikverbund-allgaeu.de
- Recruiting
Universitaetsklinikum Schleswig-Holstein AöR
Kiel, 24105
Christiane Pott, Prof. Dr., +49431500-25 ext. 55, c.pott@med2.uni-kiel.de
- Recruiting
Gemeinschaftsklinikum Mittelrhein gGmbH
Koblenz, 56073
Jens-Marcus Chemnitz, Prof. Dr., +49261-137 ext. 7226, jensMarcus.Chemnitz@gk.de
- Recruiting
Dr. Vehling-Kaiser MVZ GmbH
Landshut, 84036
Florian Kaiser, Dr., +4987197403445, studien@vehling-kaiser.de
- Recruiting
Kliniken Maria Hilf GmbH Moenchengladbach
Mönchengladbach, 41063
Ullrich Graeven, Prof. Dr., +492161-892 ext. 2201, ullrich.graeven@mariahilf.de
- Recruiting
Haematologie und Onkologie Muenchen-Pasing MVZ GmbH
München, 81241
Matthias Zingerle, Dr., +49898299660, zingerle@onkologie-pasing.de
- Recruiting
Universitaet Muenster
Münster, 48149
Andrea Kerkhoff, Dr., +49251-83 ext. 46020, Andrea.Kerkhoff@ukmuenster.de
- Not yet recruiting
Kliniken Ostalb, Standort Stauferklinikum Schwäbisch Gmünd
Mutlangen, 73557
Holger Hebart, Prof. Dr. med., 07171-7011 ext. 302, Holger.Hebart@kliniken-ostalb.de
- Recruiting
Christliches Klinikum Paderborn, Brüderkrankenhaus St. Josef Paderborn
Paderborn, 33098
Tobias Gaska, Dr. med., +49 5251 702 ext. 1425, t.gaska@bbtgruppe.de
- Not yet recruiting
Universitätsmedizin Rostock
Rostock, 18057
Sebastian Böttcher, Prof. Dr. med., +49 381 494 ext. 7405, Sebastian.Boettcher@med.uni-rostock.de
- Recruiting
University Hospital Ulm
Ulm, 89081
Christian Buske, Prof. Dr. med., +49731500 ext. 65801, christian.buske@uni-ulm.de
Greece1 site, 1 recruiting
- Recruiting
Alexandra Hospital
Athens, 115 28
Meletios A. Dimopoulos, Prof., +3021321625401, mdimop@med.uoa.gr
About this study
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.
Read the detailed description
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.
This study is an International phase II explorative, multicenter, open label, and randomized trial.
The study will consist of an open labeled, stratified 1:1 randomization between Arm A and Arm B for de novo WM patients in need of treatment (phase II). Stratification factors are MYD88 and CXCR4 status (positive vs. negative). A stratified central block randomization will be used. The central randomization service will be used to avoid predictability of the treatment arm.
The primary goal of this study is to explore the efficacy of Venetoclax plus Rituximab versus Dexamethasone/Cyclophosphamide/Rituximab in the treatment of de novo WM patients (Arm A vs. Arm B).
80 patients are planned to be recruited for this study at approcimately 30 sites in Germany, Greece and France.
- Conditions
- Waldenstrom Macroglobulinemia, Treatment Naive
- Being tested
- Venetoclax; Rituximab, DRC
- Keywords
- Hematology, Oncology, Venetoclax, Rituximab, DRC, Lymphoma, NHL, indolent, monoclonal IgM
- Medical subject headings
- Waldenstrom Macroglobulinemia, Neoplasms, Lymphoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Venetoclax; RituximabDrug
Also called Venetoclax / Rituximab
Combination of venetoclax and rituximab
DRCDrug
Also called Dexamethasone / Rituximab / Cyclophosphamide
Combination of Dexamethasone / Rituximab / Cyclophosphamide
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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 Receives: Drug: DRC |
What is being measured
The primary outcome is the main question the study is designed to answer.
Rate of CR / VGPR
CR / VGPR 12 months after randomization
Measured: 12 months
Secondary outcomes (13)
Interim reponse
response at C4D1; C7D1 (arm A) / 28 days after C6D1 (arm B); C10D1 (arm A) / post treatment staging 1 (arm B) (categories: CR, VGPR, PR, MR, SD, PD, death)
Measured: 12 months
Response rate
response rates (CR, VGPR, PR, MR, SD, PD, death)
Measured: 12 months
Best response
Best response is determined in the time interval from start of treatment up to 24 months (categories: CR, VGPR, PR, MR, SD, PD, death).
Measured: 24 months
Time to first overall response
Time to first overall response is defined as the time from randomization to first overall response (MR, PR, VGPR or CR) within 24 months from start of treatment.
Measured: 24 months
Time to first major response
Time to first major response is defined as the time from randomization to first major response the patient achieves (CR, VGPR, PR) within 24 months from start of treatment.
Measured: 24 months
Event free survival (EFS)
EFS is defined as the date of randomization to the first event of death from any cause or progression or stop of treatment due to toxicity or add-on of new anti-cancer therapy.
Measured: 12 months
Response duration (RD)
Remission duration will be calculated in patients with overall response (CR, VGPR, PR, MR) from the first date of response to the date of progression, relapse or death from any cause.
Measured: 12 months
Progression Free Survival (PFS)
PFS will be calculated from the date of randomization to the following events: the date of progression and the date of death if it occurred earlier.
Measured: 6 years
Lymphoma specific survival (LSS)
Lymphoma specific survival is defined as the period from randomization to death from lymphoma or lymphoma related cause (e.g. infections, bleeding, amyloid caused organ failure).
Measured: 6 years
Overall survival (OS)
Overall survival is defined as the period from randomization to death from any cause. Patients who have not died until the time of the analysis will be censored at their last contact date.
Measured: 6 years
Safety of participants including number of adverse events according to NCI-CTCAE v5.0, SAEs, laboratory parameters, ECG and vital signs.
Adverse events according to NCI-CTCAE version 5.0, SAEs, laboratory parameters (hematology, serum chemistry, b2-microglobulin, coagulation, urine analysis, quantitative immunoglobulins, serum free light chain, cold agglutinin test, serum protein electrophoresis, serum immunofixation, Anti-HIV, HBV, HCV), 12-lead ECG (including PR-, QT- and QTc interval), vital signs (heart rate, blood pressure and temperature)
Measured: 12 months
Quality of life assessed by FACT-Lym questionnaire
Quality of Life will be assessed by the FACT-Lym questionnaire which is a scoring instrument to measure the management of chronic illness in lymphoma patients. A higher score indicates a better quality of life
Measured: 12 months
Comparison of response rates between CXCR4 mutated and CXCR4 wildtype patients
Response rates of CXCR4 mutated and CXCR4 wildtype patients will be compared.
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Oct 2021
- Study start21 Mar 2025
- Primary completionMar 2028 (estimated)
- Study completionMar 2033 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Waldenstrom MacroglobulinemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 80 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Christian Buske
- Sponsor type
- University, hospital or other
- Collaborators
- Ludwig-Maximilians - University of Munich, Zentrum für Klinische Studien Ulm, AbbVie, Pfizer, University of Ulm, University Hospital Schleswig-Holstein
- Responsible party
- Sponsor-investigator, Christian Buske, University of Ulm
- Investigators
- Christian Buske, Prof. Dr., Principal investigator, University Hospital Ulm Department of Internal Medicine III
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05099471
- Sponsor's protocol ID
- VIWA-1
- Acronym
- VIWA-1
- Status last verified
- Apr 2026
- First submitted
- 4 Oct 2021
- Last updated
- 5 May 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
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.
PubMed 37348018
Study at a glance
From the registry record, last updated by the sponsor on 5 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Efficacy of Venetoclax in Combination With Rituximab in Waldenström's Macroglobulinemia
- ClinicalTrials.gov ID
- NCT05099471
- Acronym / sponsor ID
- VIWA-1 / VIWA-1
- Conditions
- Waldenstrom Macroglobulinemia, Treatment Naive
- Keywords
- Hematology, Oncology, Venetoclax, Rituximab, DRC, Lymphoma, NHL, indolent
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 80 participants (estimated)
- Lead sponsor
- Christian BuskeUniversity, hospital or other
- Collaborators
- Ludwig-Maximilians - University of Munich, Zentrum für Klinische Studien Ulm, AbbVie, Pfizer, University of Ulm, University Hospital Schleswig-Holstein
- Study start
- 21 Mar 2025 (actual)
- Primary completion
- Mar 2028 (estimated)
- Study completion
- Mar 2033 (estimated)
- First posted
- 29 Oct 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
This study is an International phase II explorative, multicenter, open label, and randomized trial.
The study will consist of an open labeled, stratified 1:1 randomization between Arm A and Arm B for de novo WM patients in need of treatment (phase II). Stratification factors are MYD88 and CXCR4 status (positive vs. negative). A stratified central block randomization will be used. The central randomization service will be used to avoid predictability of the treatment arm.
The primary goal of this study is to explore the efficacy of Venetoclax plus Rituximab versus Dexamethasone/Cyclophosphamide/Rituximab in the treatment of de novo WM patients (Arm A vs. Arm B).
80 patients are planned to be recruited for this study at approcimately 30 sites in Germany, Greece and France.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Venetoclax / Rituximab | Experimental | Drug: Venetoclax; RituximabCycle 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 |
| Dexamethasone / Rituximab / Cyclophosphamide | Active comparator | Drug: DRCCycle 1-6: Day 1: Dexamethasone 20 mg PO Day 1: Rituximab 375 mg/m2 IV Day 1-5: Cyclophosphamide 100 mg/m2 BID PO |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (32 listed)
- 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:
- Subject must be ≥ 18 years of age.
- Life expectancy > 3 months.
Key exclusion criteria (42 listed)
- 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:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Venetoclax; RituximabAlso: Venetoclax / RituximabCombination of venetoclax and rituximab | Drug | Venetoclax / Rituximab |
| DRCAlso: Dexamethasone / Rituximab / CyclophosphamideCombination of Dexamethasone / Rituximab / Cyclophosphamide | Drug | Dexamethasone / Rituximab / Cyclophosphamide |
Primary outcome
Rate of CR / VGPR
Time frame: 12 months
CR / VGPR 12 months after randomization
13 secondary outcomes
Interim reponse
Time frame: 12 months
Response rate
Time frame: 12 months
Best response
Time frame: 24 months
Time to first overall response
Time frame: 24 months
Time to first major response
Time frame: 24 months
Event free survival (EFS)
Time frame: 12 months
Response duration (RD)
Time frame: 12 months
Progression Free Survival (PFS)
Time frame: 6 years
Lymphoma specific survival (LSS)
Time frame: 6 years
Overall survival (OS)
Time frame: 6 years
Safety of participants including number of adverse events according to NCI-CTCAE v5.0, SAEs, laboratory parameters, ECG and vital signs.
Time frame: 12 months
Quality of life assessed by FACT-Lym questionnaire
Time frame: 12 months
Comparison of response rates between CXCR4 mutated and CXCR4 wildtype patients
Time frame: 12 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 May 2026.
- Derived from this study: PubMed 37348018Buske 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.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Christian Buske, Prof. Dr. principal investigator
University Hospital Ulm Department of Internal Medicine III
14 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Venetoclax; Rituximab and DRC in people with Waldenstrom Macroglobulinemia and Treatment Naive, run by Christian Buske at 14 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 32 inclusion and 42 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 5 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 14 sites in Germany, Greece. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Dajana Kaszynski, MSc (+49 731 500 ext. 65833, studien.gla@uniklinik-ulm.de), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Rate of CR / VGPR (time frame: 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05099471, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 May 2026.