ClinicalTrials.gov record NCT04840602

Testing the Combination of Venetoclax and Rituximab, in Comparison to the Usual Treatment (Ibrutinib Plus Rituximab or Zanubrutinib Alone) for Waldenstrom's Macroglobulinemia/Lymphoplasmacytic Lymphoma

Record copied from ClinicalTrials.gov: Oct 10, 2026AI summaries generated: Sep 17, 2026

A Phase II Randomized Study Comparing BTK Inhibitors (Ibrutinib Plus Rituximab or Zanubrutinib Alone) vs. BCL-2 Inhibitor (Venetoclax) and Rituximab in Previously Untreated Waldenström's Macroglobulinemia (WM) / Lymphoplasmacytic Lymphoma (LPL)

StatusRecruitingThe study is currently enrolling participants. Only the study team can say whether a particular person can join.
Study typeInterventionalA study in which researchers assign participants to one or more interventions, such as a drug, procedure, device, behavioural programme or other approach, to measure their effects.
PhasePhase 2A study that tests whether a treatment has the intended effect and continues to check safety, usually in a larger group than phase 1.
Age18 years old and older
SexAll
LocationUnited States
AI summaryWhat this study is about, in plain languageShow ▾Hide ▴

AI-written from the registry record, not the study's own wording. May contain errors or omissions. Check the registry text on this page and the original record ↗ before acting on it.

This Phase II randomized trial compares two upfront treatment approaches for people with previously untreated Waldenstrom macroglobulinemia/lymphoplasmacytic lymphoma. One arm receives ibrutinib (with rituximab in specified cycles) or zanubrutinib; the other receives venetoclax plus rituximab. Treatment is given in 28-day cycles for up to 24 cycles, with scans, bone marrow biopsies, and blood samples collected during the study. Participants whose disease progresses during treatment may cross over to the other arm.

What it is studying. Whether initial treatment with venetoclax plus rituximab produces different response rates and outcomes than starting treatment with ibrutinib plus rituximab or zanubrutinib alone in previously untreated WM/LPL. The primary focus is the rate of very good partial response (VGPR) or better; the study also compares overall and complete response rates, progression-free and overall survival, time to response, and safety, and includes specimen banking for future studies.

What the researchers hope to learn. To compare the rate of very good partial response or better (VGPR or better) between the two treatment approaches; to compare overall response rate, complete response rate, progression-free survival, overall survival, time to VGPR, duration of response, and time to next treatment; to evaluate safety; and to bank specimens for future correlative research.

What this study is about

The study's own summary, as published on ClinicalTrials.gov. Underlined terms have a short explanation.

This phase II trial studies the effects of venetoclax and rituximab in comparison to ibrutinib and rituximab or zanubrutinib in treating patients with previously untreated Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Zanubrutinib, a type of tyrosine kinase inhibitor, blocks a protein called BTK, which may help keep cancer cells from growing. Giving venetoclax and rituximab may work better in treating patients with previously untreated Waldenstrom's macroglobulinemia than ibrutinib with rituximab or zanubrutinib alone.

Interventions being studied

Being studied in this trial does not mean the treatment or procedure is approved or available for this condition.

Drug
  • Ibrutinib
  • Venetoclax
  • Zanubrutinib
Biological
  • Rituximab
Procedure
  • Biospecimen Collection
  • Bone Marrow Aspiration
  • Bone Marrow Biopsy
  • Computed Tomography
  • Positron Emission Tomography

Eligibility

The criteria exactly as listed on ClinicalTrials.gov. Only the study team can say whether they apply to you.

Inclusion criteria

  • Participants must have had a confirmed diagnosis of Waldenstrom's macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL). Participants must have measurable disease as determined by IgM protein quantification.
  • IgM Spike: ≥ 500 mg/dL (≥ 5 g/L)
  • Extramedullary disease: The manifestation of a lymphoid mass outside of the bone marrow, resulting in enlargement in extramedullary organs such as the lymph nodes or spleen. Note: all participants must have measurable IgM spike, but are not required to have extramedullary disease
  • Testing to establish baseline disease status must be performed within 28 days prior to registration
  • Participants must have at least one of the criteria to require therapy for WM including:
  • Anemia
  • Thrombocytopenia
  • Neuropathy related to WM
  • Symptomatic hyperviscosity or serum viscosity levels ≥ 4.0 centipoises
  • WM associated glomerulonephritis or renal disease, bulky disease, or constitutional symptoms
  • Constitutional symptoms can be described as:
  • Unintentional weight loss >= 10% within the previous 6 months prior to screening
  • Fevers higher than 100.5 degrees Fahrenheit (F) or 38.0 degrees Celsius (C) for 2 or more weeks prior to screening without evidence of infection
  • Night sweats for more than 1 month prior to screening without evidence of infection
  • Clinically relevant fatigue which is not relieved by rest due to WM
  • Participants who require ongoing use or received a moderate or strong CYP3A inducer, moderate or strong CYP3A inhibitor, P-gp inhibitor within 7 days prior to the first dose of study drug will be excluded from the study. If such participants can be safely switched to an alternative agent, then the participants will be eligible to enroll
  • Participants must not have had prior systemic therapy. Prior therapy with rituximab will be allowed as long as the last rituximab dose was at least 6 months prior to registration
  • Participants must be >= 18 years of age
  • Participants must have history and physical exam within 28 days prior to registration
  • Participants must have Zubrod performance status =< 2
  • Participants must have evidence of adequate renal function, as defined by creatinine clearance (CrCl) >= 30 mL/min. Values must be obtained within 14 days prior to registration
  • Total bilirubin =< 1.5 x IULN (institutional upper limit of the norm) (within 14 days prior to registration)
  • Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< 3 x IULN (within 14 days prior to registration)
  • Alkaline phosphatase =< 3 x IULN (within 14 days prior to registration)
  • Platelet count >= 50,000 cells/mm\^3 (within 14 days prior to registration)
  • NOTE: Transfusion and/or growth factor support is allowed up to 7 days prior to registration
  • Hemoglobin >= 7.0 g/dL (within 14 days prior to registration)
  • NOTE: Transfusion and/or growth factor support is allowed up to 7 days prior to registration
  • Absolute neutrophil count (ANC) >= 1,000 cells/mm\^3 (within 14 days prior to registration)
  • NOTE: Transfusion and/or growth factor support is allowed up to 7 days prior to registration
  • Participants with known human immunodeficiency virus (HIV)-infection are eligible providing they are on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test and within 6 months prior to registration
  • Participants must be able to take and swallow oral medication (capsules) whole. Participants may not have any known impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of the study drug (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
  • Participants must not be intolerant to rituximab
  • Participants must not have known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding localized skin and nail bed fungal infections) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) 4 weeks prior to registration
  • Participants must not be seropositive for hepatitis C (except in the setting of sustained virologic response, defined as undetectable viral load at least 12 weeks after completion of antiviral therapy). Hepatitis C virus (HCV) testing is only required if clinically indicated or if the participant has a history of HCV
  • Participants must not consume grapefruit, Seville oranges or starfruit within 3 days prior to the first dose of venetoclax
  • Participants must not be pregnant or nursing because venetoclax has not been studied in pregnant or nursing women and the mechanism of action is expected to cause fetal harm. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" e.g., implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence, or sterilized partner) and a barrier method (e.g., condom, cervical ring, sponge, etc.). This also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate participant chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures throughout the study and for at least 30 days after competition of therapy
  • No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the participant is currently in complete remission, or any other cancer from which the participant has been disease free for two years or watchful waiting is appropriate in the opinion of the treating physician. Also, malignancy that in the opinion of the investigator, is considered cured with minimal risk of recurrence within 5 years, is permissible consideration of eligibility for this trial
  • Participants must be offered the opportunity to participate in specimen banking
  • Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines. For participants with impaired decision-making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and Central Institutional Review Board (CIRB) regulations
  • As a part of the Oncology Participant Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
  • CROSSOVER CRITERIA: Participants must have been registered and received treatment in the IR/Z or VR arm and must show progression of disease at any time during cycles 3-24
  • CROSSOVER CRITERIA: In case of transformation to intermediate or high-grade lymphoma or development of Bing-Neel syndrome the participants will not undergo registration step 2 crossover and will be taken off the study
  • CROSSOVER CRITERIA: Participants must have Zubrod performance status =< 2
  • CROSSOVER CRITERIA: Participants must have evidence of adequate renal function, as defined by creatinine clearance (CrCl) >= 30 mL/min. Values must be obtained within 14 days prior to registration
  • CROSSOVER CRITERIA: Participants must have no evidence of marked hepatic dysfunction on any recent liver function tests within 14 days prior to registration
  • CROSSOVER CRITERIA: Platelet count >= 50,000 cells/mm\^3 (without within 14 days prior to registration)
  • NOTE: Transfusion and/or growth factor support is allowed up to 7 days prior to registration
  • CROSSOVER CRITERIA: Hemoglobin >= 7.0 g/dL (without within 14 days prior to registration)
  • NOTE: Transfusion and/or growth factor support is allowed up to 7 days prior to registration
  • CROSSOVER CRITERIA: Absolute neutrophil count (ANC) >= 1,000 cells/mm\^3 (without within 14 days prior to registration)
  • NOTE: Transfusion and/or growth factor support is allowed up to 7 days prior to registration

Study description and what participation involves

The study's detailed description, as published on ClinicalTrials.gov.

Show the detailed description from the registry

PRIMARY OBJECTIVE: I. To compare the rate of very good partial response or better (VGPR or better) in previously untreated participants with Waldenström's macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) who are treated upfront with ibrutinib + rituximab (IR) or zanubrutinib alone (Z) versus (vs.) venetoclax +/- rituximab (VR) regimen. SECONDARY OBJECTIVES: I. To compare overall response rates (ORR) in WM participants treated upfront with ibrutinib + rituximab or zanubrutinib alone vs. venetoclax + rituximab. II. To compare progression-free survival (PFS), time to next treatment, duration of response in WM participants treated upfront with ibrutinib + rituximab or zanubrutinib alone vs. venetoclax + rituximab. III. To compare the rate of complete response (CR) in WM participants treated upfront with ibrutinib + rituximab or zanubrutinib alone vs. venetoclax + rituximab. IV. To evaluate the safety of ibrutinib + rituximab or zanubrutinib alone vs. venetoclax + rituximab in participants with WM. V. To evaluate the time to VGPR in WM participants treated upfront with ibrutinib + rituximab or zanubrutinib alone vs. venetoclax + rituximab. VI. To evaluate the ORR in participants who progress on treatment with ibrutinib + rituximab or zanubrutinib alone and venetoclax + rituximab are crossed over to the other respective arm. VII. To compare overall survival (OS) in WM participants treated upfront with ibrutinib + rituximab or zanubrutinib alone vs. venetoclax + rituximab. VIII. To evaluate the rate of VGPR or better and the ORR in WM participants treated upfront with ibrutinib plus rituximab vs. those treated with zanubrutinib alone. BANKING OBJECTIVE: I. To bank specimens for future correlative studies. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28 of cycles 1-24 and rituximab intravenously (IV) on days 1, 8, 15, and 22 of cycles 2 and 5, or zanubrutinib PO QD or twice daily (BID) on days 1-28 of cycles 1-24. Cycles repeat every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients with progressive disease during Arm I may receive rituximab and venetoclax as in Arm II for up to an additional 24 cycles. Patients undergo computed tomography (CT) or positron emission tomography (PET)/CT and bone marrow biopsy and aspiration as well as blood sample collection throughout the trial. ARM II: Patients receive venetoclax PO QD on days 1-28 of each cycle and rituximab IV on days 1, 8, 15, and 22 of cycles 2 and 5. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients with progressive disease during Arm II may receive ibrutinib and rituximab as in Arm I for up to an additional 24 cycles. Patients undergo CT or PET/CT and bone marrow biopsy and aspiration as well as blood sample collection throughout the trial. After completion of study treatment, patients removed from protocol prior to progression are followed every 3 months until progression, death or 5 years after initial registration, whichever occurs first. Patients followed after progression of disease are followed every 6 months until death or 5 years after initial registration.

AI summaryWhat participation may involve, in plain languageShow ▾Hide ▴

AI-written from the registry record, not the study's own wording. May contain errors or omissions. Check the registry text on this page and the original record ↗ before acting on it.

You would be randomly assigned to one of two treatment groups: Arm I receives either daily oral ibrutinib with rituximab given by IV on days 1, 8, 15, and 22 of cycles 2 and 5, or oral zanubrutinib alone; Arm II receives daily oral venetoclax with rituximab on the same IV schedule. Treatment is given in 28-day cycles and may continue for up to 24 cycles unless the disease progresses or side effects prevent continuing. During the study you will have blood samples taken and undergo imaging (CT or PET/CT) and bone marrow biopsy and aspiration (invasive procedures) at planned times. If your disease progresses you may be allowed to switch (crossover) to the other treatment for up to an additional 24 cycles; after stopping study treatment you will be followed every 3 months until progression, death, or five years from registration, and after progression you will be followed every 6 months until death or five years.

How the study is structured. Randomized, open-label (not masked) Phase II treatment trial with two arms. Participants are randomly assigned to receive either ibrutinib (with rituximab in specified cycles) or zanubrutinib, or venetoclax plus rituximab, given in 28-day cycles for up to 24 cycles if tolerated. The study includes planned CT or PET/CT scans, bone marrow biopsy/aspiration, and blood sample collection during treatment. If disease progresses during cycles 3–24, participants may be crossed over to the other treatment arm.

Questions you could ask

These questions are suggestions for a conversation with the study team or your own clinician, not advice.

  • The listed sites are in United States. Is any of them reachable for me, and does the study help with travel?
  • Which of the eligibility criteria would need to be checked with tests before I could join?

More on Waldenström macroglobulinemia

Important dates

Study start
Jan 5, 2022
Primary completion
Mar 31, 2028 (estimated)
Study completion
Mar 31, 2028 (estimated)
Target enrollment
92 participants (estimated)
Last updated on registry
Oct 6, 2026
Data verified
Oct 10, 2026

Sponsor and research team

The lead sponsor funds and oversees the trial. A pharmaceutical or biotech company sponsor typically means the study is testing that company's drug or device; a hospital, university, or government agency usually indicates investigator-initiated or publicly funded research.

Lead sponsor
National Cancer Institute (NCI)

Participating sites (145)

  • Banner University Medical Center - TucsonRecruiting

    Tucson, Arizona, 85719 · United States

  • University of Arizona Cancer Center-North CampusRecruiting

    Tucson, Arizona, 85719 · United States

  • City of Hope at Irvine LennarRecruiting

    Irvine, California, 92618 · United States

  • UM Sylvester Comprehensive Cancer Center at Coral GablesRecruiting

    Coral Gables, Florida, 33146 · United States

  • UM Sylvester Comprehensive Cancer Center at Coral SpringsRecruiting

    Coral Springs, Florida, 33065 · United States

  • UM Sylvester Comprehensive Cancer Center at Deerfield BeachRecruiting

    Deerfield Beach, Florida, 33442 · United States

  • UM Sylvester Comprehensive Cancer Center at DoralRecruiting

    Doral, Florida, 33166 · United States

  • UM Sylvester Comprehensive Cancer Center at HollywoodRecruiting

    Hollywood, Florida, 33021 · United States

  • Mayo Clinic in FloridaRecruiting

    Jacksonville, Florida, 32224-9980 · United States

  • University of Miami Miller School of Medicine-Sylvester Cancer CenterRecruiting

    Miami, Florida, 33136 · United States

Terms used on this page · explanations by MedicalUpdates.ai

previously untreated
Has not previously received the treatment, or the type of treatment, that the study is about.
baseline
Measurements taken at the start of the study, before any study treatment, so that later results can be compared with them.
prior to screening
The checks done before enrolment to see whether a person qualifies, such as tests, scans or a review of medical history.
study drug
A treatment that is being tested and has not been approved for this use. It may be approved for a different condition. Being studied does not mean it works or is available outside the study.
Prior therapy
Treatment a person has already had for the condition. A 'line of therapy' is one course of treatment; studies often require, or limit, the number of prior lines.
performance status
A scale from 0 to 5 that describes how a person's condition affects daily activity. 0 means fully active; 1 means restricted in strenuous activity; 2 means able to self-care but unable to work; higher numbers mean more limitation.
creatinine clearance
A measure of kidney function, calculated from a blood creatinine level together with age, weight and sex.
Absolute neutrophil count
The number of neutrophils, a type of white blood cell that fights infection, in a blood sample. Studies often require it to be above a set level.
enrollment
The number of participants a study plans to include, or has included. 'Estimated' means the planned number; 'actual' means the number who joined.
complete remission
No sign of the condition can be found with the tests used in the study. It does not always mean the condition is gone permanently, and the definition depends on the condition and the study.
informed consent
The process of explaining a study, including its risks and what participation involves, so that a person can decide freely whether to take part. Consent is usually documented in writing, and a participant can choose to leave the study later.
CROSSOVER
Each participant receives more than one intervention, one after the other, usually with a gap (a washout) in between. Participants act as their own comparison.
Inclusion Criteria
The conditions a person must meet to be considered for the study, for example a confirmed diagnosis, an age range or a test result.
PRIMARY OBJECTIVE
The main result the study is designed to measure and report on. Other results, called secondary outcomes, are also collected.
very good partial response
A response category used in some blood conditions meaning the disease marker has fallen a great deal but not disappeared. The exact definition depends on the condition and the study.
progression-free survival
The length of time during and after treatment that a person lives without the condition getting worse, as defined by the study.
overall survival
The length of time from the start of the study or treatment that participants are alive, whatever the cause of death.
randomized
Participants are assigned to the study groups by chance, like a coin toss, rather than chosen by the doctor or the participant. This is done so the groups are comparable.
computed tomography
An X-ray scan that builds detailed cross-section images of the body. 'High-resolution' CT (HRCT) is used to look closely at the lungs.
positron emission tomography
A scan in which a small amount of a radioactive tracer is injected so that activity in tissues can be seen. Often combined with a CT or MRI scan.
biopsy
Removal of a small piece of tissue so it can be examined under a microscope. 'Biopsy-proven' or 'histologically confirmed' means the diagnosis was confirmed by examining tissue under a microscope.

The study record on this page is reproduced from ClinicalTrials.gov, a database of the U.S. National Library of Medicine, where it was submitted by the study sponsor. MedicalUpdates.ai does not own this content, is not affiliated with or endorsed by ClinicalTrials.gov, NIH, or the U.S. Government, and does not verify the record. Plain-language notes, the glossary and the questions above are added by this site; text in the boxes marked "AI summary" was written by an AI model and may contain errors. Registry records change over time. Check the original record for the current version and discuss eligibility or participation with a qualified healthcare professional.

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