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RECRUITING Phase 2 ClinicalTrials.gov

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

Sponsor: National Cancer Institute (NCI) • ClinicalTrials.gov ID: NCT04840602

Registry updated: 2026-10-14
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Description

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

  • Biospecimen Collection (Procedure)
    Undergo blood sample collection
  • Bone Marrow Aspiration (Procedure)
    Undergo bone marrow biopsy and aspiration
  • Bone Marrow Biopsy (Procedure)
    Undergo bone marrow biopsy and aspiration
  • Computed Tomography (Procedure)
    Undergo CT or PET/CT
  • Ibrutinib (Drug)
    Given PO
  • Positron Emission Tomography (Procedure)
    Undergo PET/CT
  • Rituximab (Biological)
    Given IV
  • Venetoclax (Drug)
    Given PO
  • Zanubrutinib (Drug)
    Given PO

Eligibility criteria

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

Conditions

Lymphoplasmacytic Lymphoma Waldenstrom Macroglobulinemia

Locations

  • Banner University Medical Center - Tucson — Tucson, Arizona, United States
  • University of Arizona Cancer Center-North Campus — Tucson, Arizona, United States
  • City of Hope at Irvine Lennar — Irvine, California, United States
  • UM Sylvester Comprehensive Cancer Center at Coral Gables — Coral Gables, Florida, United States
  • UM Sylvester Comprehensive Cancer Center at Coral Springs — Coral Springs, Florida, United States
  • UM Sylvester Comprehensive Cancer Center at Deerfield Beach — Deerfield Beach, Florida, United States
  • UM Sylvester Comprehensive Cancer Center at Doral — Doral, Florida, United States
  • UM Sylvester Comprehensive Cancer Center at Hollywood — Hollywood, Florida, United States
  • Mayo Clinic in Florida — Jacksonville, Florida, United States
  • University of Miami Miller School of Medicine-Sylvester Cancer Center — Miami, Florida, United States
  • UM Sylvester Comprehensive Cancer Center at Kendall — Miami, Florida, United States
  • University of Miami Sylvester Comprehensive Cancer Center at Sole Mia — North Miami, Florida, United States
  • UM Sylvester Comprehensive Cancer Center at Plantation — Plantation, Florida, United States
  • Saint Alphonsus Cancer Care Center-Boise — Boise, Idaho, United States
  • Saint Alphonsus Cancer Care Center-Caldwell — Caldwell, Idaho, United States
  • Idaho Urologic Institute-Meridian — Meridian, Idaho, United States
  • Saint Alphonsus Cancer Care Center-Nampa — Nampa, Idaho, United States
  • Centralia Oncology Clinic — Centralia, Illinois, United States
  • Carle at The Riverfront — Danville, Illinois, United States
  • Cancer Care Specialists of Illinois - Decatur — Decatur, Illinois, United States
  • Carle Physician Group-Effingham — Effingham, Illinois, United States
  • Crossroads Cancer Center — Effingham, Illinois, United States
  • Carle Physician Group-Mattoon/Charleston — Mattoon, Illinois, United States
  • Loyola University Medical Center — Maywood, Illinois, United States
  • Cancer Care Center of O'Fallon — O'Fallon, Illinois, United States
  • Southern Illinois University School of Medicine — Springfield, Illinois, United States
  • Springfield Clinic — Springfield, Illinois, United States
  • Springfield Memorial Hospital — Springfield, Illinois, United States
  • Carle Cancer Center — Urbana, Illinois, United States
  • Mary Greeley Medical Center — Ames, Iowa, United States
  • McFarland Clinic - Ames — Ames, Iowa, United States
  • McFarland Clinic - Boone — Boone, Iowa, United States
  • McFarland Clinic - Trinity Cancer Center — Fort Dodge, Iowa, United States
  • McFarland Clinic - Jefferson — Jefferson, Iowa, United States
  • McFarland Clinic - Marshalltown — Marshalltown, Iowa, United States
  • Lahey Clinic — Burlington, Massachusetts, United States
  • Trinity Health Saint Joseph Mercy Hospital Ann Arbor — Ann Arbor, Michigan, United States
  • Trinity Health IHA Medical Group Hematology Oncology - Brighton — Brighton, Michigan, United States
  • Trinity Health Medical Center - Brighton — Brighton, Michigan, United States
  • Trinity Health IHA Medical Group Hematology Oncology - Canton — Canton, Michigan, United States
  • Trinity Health Medical Center - Canton — Canton, Michigan, United States
  • Chelsea Hospital — Chelsea, Michigan, United States
  • Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital — Chelsea, Michigan, United States
  • Hematology Oncology Consultants-Clarkston — Clarkston, Michigan, United States
  • Newland Medical Associates-Clarkston — Clarkston, Michigan, United States
  • Henry Ford Macomb Hospital-Clinton Township — Clinton Township, Michigan, United States
  • Wayne State University/Karmanos Cancer Institute — Detroit, Michigan, United States
  • Henry Ford Hospital — Detroit, Michigan, United States
  • Weisberg Cancer Treatment Center — Farmington Hills, Michigan, United States
  • Cancer Hematology Centers - Flint — Flint, Michigan, United States
  • Genesee Hematology Oncology PC — Flint, Michigan, United States
  • Genesys Hurley Cancer Institute — Flint, Michigan, United States
  • Hurley Medical Center — Flint, Michigan, United States
  • University of Michigan Health - Sparrow Lansing — Lansing, Michigan, United States
  • Trinity Health Saint Mary Mercy Livonia Hospital — Livonia, Michigan, United States
  • Henry Ford Medical Center-Columbus — Novi, Michigan, United States
  • Michigan Healthcare Professionals Pontiac — Pontiac, Michigan, United States
  • Newland Medical Associates-Pontiac — Pontiac, Michigan, United States
  • Trinity Health Saint Joseph Mercy Oakland Hospital — Pontiac, Michigan, United States
  • MyMichigan Medical Center Saginaw — Saginaw, Michigan, United States
  • Oncology Hematology Associates of Saginaw Valley PC — Saginaw, Michigan, United States
  • MyMichigan Medical Center Tawas — Tawas City, Michigan, United States
  • Henry Ford West Bloomfield Hospital — West Bloomfield, Michigan, United States
  • Huron Gastroenterology PC — Ypsilanti, Michigan, United States
  • Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus — Ypsilanti, Michigan, United States
  • Mercy Hospital — Coon Rapids, Minnesota, United States
  • Abbott-Northwestern Hospital — Minneapolis, Minnesota, United States
  • Hennepin County Medical Center — Minneapolis, Minnesota, United States
  • Mayo Clinic in Rochester — Rochester, Minnesota, United States
  • Park Nicollet Clinic - Saint Louis Park — Saint Louis Park, Minnesota, United States
  • Regions Hospital — Saint Paul, Minnesota, United States
  • United Hospital — Saint Paul, Minnesota, United States
  • Saint Francis Medical Center — Cape Girardeau, Missouri, United States
  • Siteman Cancer Center at Saint Peters Hospital — City of Saint Peters, Missouri, United States
  • Siteman Cancer Center at West County Hospital — Creve Coeur, Missouri, United States
  • Heartland Regional Medical Center — Saint Joseph, Missouri, United States
  • Washington University School of Medicine — St Louis, Missouri, United States
  • Mercy Hospital South — St Louis, Missouri, United States
  • Siteman Cancer Center-South County — St Louis, Missouri, United States
  • Siteman Cancer Center at Christian Hospital — St Louis, Missouri, United States
  • Saint Vincent Frontier Cancer Center — Billings, Montana, United States
  • Memorial Sloan Kettering Basking Ridge — Basking Ridge, New Jersey, United States
  • Memorial Sloan Kettering Monmouth — Middletown, New Jersey, United States
  • Memorial Sloan Kettering Bergen — Montvale, New Jersey, United States
  • Memorial Sloan Kettering Commack — Commack, New York, United States
  • Glens Falls Hospital — Glens Falls, New York, United States
  • Memorial Sloan Kettering Westchester — Harrison, New York, United States
  • NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center — New York, New York, United States
  • Memorial Sloan Kettering Cancer Center — New York, New York, United States
  • University of Rochester — Rochester, New York, United States
  • Memorial Sloan Kettering Nassau — Uniondale, New York, United States
  • Wilmot Cancer Institute at Webster — Webster, New York, United States
  • Carolinas Medical Center/Levine Cancer Institute — Charlotte, North Carolina, United States
  • Southeastern Medical Oncology Center-Clinton — Clinton, North Carolina, United States
  • Levine Cancer Institute-Gaston — Gastonia, North Carolina, United States
  • Southeastern Medical Oncology Center-Goldsboro — Goldsboro, North Carolina, United States
  • Southeastern Medical Oncology Center-Jacksonville — Jacksonville, North Carolina, United States
  • Atrium Health Union/LCI-Union — Monroe, North Carolina, United States
  • Strecker Cancer Center-Belpre — Belpre, Ohio, United States
  • Adena Regional Medical Center — Chillicothe, Ohio, United States
  • Mount Carmel East Hospital — Columbus, Ohio, United States
  • Columbus Oncology and Hematology Associates Inc — Columbus, Ohio, United States
  • Riverside Methodist Hospital — Columbus, Ohio, United States
  • Grant Medical Center — Columbus, Ohio, United States
  • The Mark H Zangmeister Center — Columbus, Ohio, United States
  • Mount Carmel Health Center West — Columbus, Ohio, United States
  • Doctors Hospital — Columbus, Ohio, United States
  • Delaware Health Center-Grady Cancer Center — Delaware, Ohio, United States
  • Grady Memorial Hospital — Delaware, Ohio, United States
  • Dublin Methodist Hospital — Dublin, Ohio, United States
  • Central Ohio Breast and Endocrine Surgery — Gahanna, Ohio, United States
  • Mount Carmel Grove City Hospital — Grove City, Ohio, United States
  • Fairfield Medical Center — Lancaster, Ohio, United States
  • Saint Rita's Medical Center — Lima, Ohio, United States
  • OhioHealth Mansfield Hospital — Mansfield, Ohio, United States
  • Marietta Memorial Hospital — Marietta, Ohio, United States
  • OhioHealth Marion General Hospital — Marion, Ohio, United States
  • Knox Community Hospital — Mount Vernon, Ohio, United States
  • Licking Memorial Hospital — Newark, Ohio, United States
  • Newark Radiation Oncology — Newark, Ohio, United States
  • Mercy Health - Perrysburg Hospital — Perrysburg, Ohio, United States
  • Southern Ohio Medical Center — Portsmouth, Ohio, United States
  • Mercy Health - Saint Vincent Hospital — Toledo, Ohio, United States
  • Mercy Health - Saint Anne Hospital — Toledo, Ohio, United States
  • Saint Ann's Hospital — Westerville, Ohio, United States
  • Genesis Healthcare System Cancer Care Center — Zanesville, Ohio, United States
  • Saint Alphonsus Cancer Care Center-Baker City — Baker City, Oregon, United States
  • Providence Cancer Institute Clackamas Clinic — Clackamas, Oregon, United States
  • Providence Newberg Medical Center — Newberg, Oregon, United States
  • Saint Alphonsus Cancer Care Center-Ontario — Ontario, Oregon, United States
  • Providence Willamette Falls Medical Center — Oregon City, Oregon, United States
  • Providence Portland Medical Center — Portland, Oregon, United States
  • Providence Saint Vincent Medical Center — Portland, Oregon, United States
  • VCU Massey Comprehensive Cancer Center — Richmond, Virginia, United States
  • Swedish Cancer Institute-Edmonds — Edmonds, Washington, United States
  • Swedish Cancer Institute-Issaquah — Issaquah, Washington, United States
  • Swedish Medical Center-First Hill — Seattle, Washington, United States
  • ThedaCare Regional Cancer Center — Appleton, Wisconsin, United States
  • Marshfield Medical Center-EC Cancer Center — Eau Claire, Wisconsin, United States
  • Gundersen Lutheran Medical Center — La Crosse, Wisconsin, United States
  • Marshfield Medical Center-Marshfield — Marshfield, Wisconsin, United States
  • Marshfield Medical Center - Minocqua — Minocqua, Wisconsin, United States
  • Marshfield Medical Center-Rice Lake — Rice Lake, Wisconsin, United States
  • Marshfield Medical Center-River Region at Stevens Point — Stevens Point, Wisconsin, United States
  • Marshfield Medical Center - Weston — Weston, Wisconsin, United States
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Official Source

Data sourced from ClinicalTrials.gov, a service of the U.S. National Institutes of Health.

View Official Record