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
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)
- Lymphoplasmacytic Lymphoma
- Waldenstrom Macroglobulinemia
At a glance
- Phase
- Phase 2
- Study type
- Interventional
- Sponsor
- National Cancer Institute (NCI)
- Enrolment target
- 92
- Started
- 5 January 2022
- Main results due
- 31 March 2028
- Study sites
- 145
- Registry updated
- 24 September 2026
Can you take part?
- Aged 18 years and over.
- Open to any sex.
- You need the condition being studied — healthy volunteers are not accepted.
These are the headline rules only. Every study has a longer list, and whether you are eligible is decided by the research team at the site — never by this page.
Read the full 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 registrationWhat this study is about
In the sponsor’s own words, from the registry.
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.
Study sites(145)
Banner University Medical Center - Tucson
Tucson, Arizona, United States
Recruiting
University of Arizona Cancer Center-North Campus
Tucson, Arizona, United States
Recruiting
City of Hope at Irvine Lennar
Irvine, California, United States
Recruiting
UM Sylvester Comprehensive Cancer Center at Coral Gables
Coral Gables, Florida, United States
Recruiting
UM Sylvester Comprehensive Cancer Center at Coral Springs
Coral Springs, Florida, United States
Recruiting
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
Deerfield Beach, Florida, United States
Recruiting
UM Sylvester Comprehensive Cancer Center at Doral
Doral, Florida, United States
Recruiting
UM Sylvester Comprehensive Cancer Center at Hollywood
Hollywood, Florida, United States
Recruiting
Mayo Clinic in Florida
Jacksonville, Florida, United States
Recruiting
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, United States
Recruiting
UM Sylvester Comprehensive Cancer Center at Kendall
Miami, Florida, United States
Recruiting
University of Miami Sylvester Comprehensive Cancer Center at Sole Mia
North Miami, Florida, United States
Recruiting
UM Sylvester Comprehensive Cancer Center at Plantation
Plantation, Florida, United States
Recruiting
Saint Alphonsus Cancer Care Center-Boise
Boise, Idaho, United States
Recruiting
Saint Alphonsus Cancer Care Center-Caldwell
Caldwell, Idaho, United States
Recruiting
Idaho Urologic Institute-Meridian
Meridian, Idaho, United States
Recruiting
Saint Alphonsus Cancer Care Center-Nampa
Nampa, Idaho, United States
Recruiting
Centralia Oncology Clinic
Centralia, Illinois, United States
Recruiting
Carle at The Riverfront
Danville, Illinois, United States
Recruiting
Cancer Care Specialists of Illinois - Decatur
Decatur, Illinois, United States
Recruiting
Carle Physician Group-Effingham
Effingham, Illinois, United States
Recruiting
Crossroads Cancer Center
Effingham, Illinois, United States
Recruiting
Carle Physician Group-Mattoon/Charleston
Mattoon, Illinois, United States
Recruiting
Loyola University Medical Center
Maywood, Illinois, United States
Recruiting
Cancer Care Center of O'Fallon
O'Fallon, Illinois, United States
Recruiting
Southern Illinois University School of Medicine
Springfield, Illinois, United States
Recruiting
Springfield Clinic
Springfield, Illinois, United States
Recruiting
Springfield Memorial Hospital
Springfield, Illinois, United States
Recruiting
Carle Cancer Center
Urbana, Illinois, United States
Recruiting
Mary Greeley Medical Center
Ames, Iowa, United States
Recruiting
McFarland Clinic - Ames
Ames, Iowa, United States
Recruiting
McFarland Clinic - Boone
Boone, Iowa, United States
Suspended
McFarland Clinic - Trinity Cancer Center
Fort Dodge, Iowa, United States
Recruiting
McFarland Clinic - Jefferson
Jefferson, Iowa, United States
Suspended
McFarland Clinic - Marshalltown
Marshalltown, Iowa, United States
Recruiting
Lahey Clinic
Burlington, Massachusetts, United States
Recruiting
Trinity Health Saint Joseph Mercy Hospital Ann Arbor
Ann Arbor, Michigan, United States
Recruiting
Trinity Health IHA Medical Group Hematology Oncology - Brighton
Brighton, Michigan, United States
Recruiting
Trinity Health Medical Center - Brighton
Brighton, Michigan, United States
Recruiting
Trinity Health IHA Medical Group Hematology Oncology - Canton
Canton, Michigan, United States
Recruiting
Trinity Health Medical Center - Canton
Canton, Michigan, United States
Recruiting
Chelsea Hospital
Chelsea, Michigan, United States
Recruiting
Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
Chelsea, Michigan, United States
Recruiting
Hematology Oncology Consultants-Clarkston
Clarkston, Michigan, United States
Recruiting
Newland Medical Associates-Clarkston
Clarkston, Michigan, United States
Suspended
Henry Ford Macomb Hospital-Clinton Township
Clinton Township, Michigan, United States
Recruiting
Wayne State University/Karmanos Cancer Institute
Detroit, Michigan, United States
Recruiting
Henry Ford Hospital
Detroit, Michigan, United States
Recruiting
Weisberg Cancer Treatment Center
Farmington Hills, Michigan, United States
Recruiting
Cancer Hematology Centers - Flint
Flint, Michigan, United States
Recruiting
Genesee Hematology Oncology PC
Flint, Michigan, United States
Suspended
Genesys Hurley Cancer Institute
Flint, Michigan, United States
Recruiting
Hurley Medical Center
Flint, Michigan, United States
Recruiting
University of Michigan Health - Sparrow Lansing
Lansing, Michigan, United States
Recruiting
Trinity Health Saint Mary Mercy Livonia Hospital
Livonia, Michigan, United States
Recruiting
Henry Ford Medical Center-Columbus
Novi, Michigan, United States
Recruiting
Michigan Healthcare Professionals Pontiac
Pontiac, Michigan, United States
Recruiting
Newland Medical Associates-Pontiac
Pontiac, Michigan, United States
Recruiting
Trinity Health Saint Joseph Mercy Oakland Hospital
Pontiac, Michigan, United States
Recruiting
MyMichigan Medical Center Saginaw
Saginaw, Michigan, United States
Recruiting
Showing 60 of 145 sites — filter to narrow it down. 99 of the 145 sites on this study are recruiting right now — a site can stop enrolling while the study as a whole is still open.
Source: ClinicalTrials.gov record NCT04840602. Trialion does not run this study, is not paid to refer anyone to it, and cannot enrol you. Eligibility is always decided by the research team at the site.
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