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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
NCT04840602 · National Cancer Institute (NCI)
In plain English
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Official title
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)
About this study
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.
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
Study design
Enrollment target: 92 participants
Allocation: randomized
Masking: none
Age groups: adult, older_adult
Timeline
Starts: 2022-01-05
Estimated completion: 2028-03-31
Last updated: 2026-09-16
Interventions
Procedure: Biospecimen CollectionProcedure: Bone Marrow AspirationProcedure: Bone Marrow BiopsyProcedure: Computed TomographyDrug: IbrutinibProcedure: Positron Emission TomographyBiological: RituximabDrug: VenetoclaxDrug: Zanubrutinib
Primary outcomes
- • Very good partial response or better (VGPR or better) rate (Up to 5 years)
Sponsor
National Cancer Institute (NCI) · nih
Contacts & investigators
InvestigatorSikander Ailawadhi · principal_investigator, SWOG Cancer Research Network
All locations (144)
Banner University Medical Center - TucsonRecruiting
Tucson, Arizona, United States
University of Arizona Cancer Center-North CampusRecruiting
Tucson, Arizona, United States
City of Hope at Irvine LennarRecruiting
Irvine, California, United States
UM Sylvester Comprehensive Cancer Center at Coral GablesRecruiting
Coral Gables, Florida, United States
UM Sylvester Comprehensive Cancer Center at Coral SpringsRecruiting
Coral Springs, Florida, United States
UM Sylvester Comprehensive Cancer Center at Deerfield BeachRecruiting
Deerfield Beach, Florida, United States
UM Sylvester Comprehensive Cancer Center at DoralRecruiting
Doral, Florida, United States
UM Sylvester Comprehensive Cancer Center at HollywoodRecruiting
Hollywood, Florida, United States
Mayo Clinic in FloridaRecruiting
Jacksonville, Florida, United States
University of Miami Miller School of Medicine-Sylvester Cancer CenterRecruiting
Miami, Florida, United States
UM Sylvester Comprehensive Cancer Center at KendallRecruiting
Miami, Florida, United States
University of Miami Sylvester Comprehensive Cancer Center at Sole MiaRecruiting
North Miami, Florida, United States
UM Sylvester Comprehensive Cancer Center at PlantationRecruiting
Plantation, Florida, United States
Saint Alphonsus Cancer Care Center-BoiseRecruiting
Boise, Idaho, United States
Saint Alphonsus Cancer Care Center-CaldwellRecruiting
Caldwell, Idaho, United States
Idaho Urologic Institute-MeridianRecruiting
Meridian, Idaho, United States
Saint Alphonsus Cancer Care Center-NampaRecruiting
Nampa, Idaho, United States
Centralia Oncology ClinicRecruiting
Centralia, Illinois, United States
Carle at The RiverfrontRecruiting
Danville, Illinois, United States
Cancer Care Specialists of Illinois - DecaturRecruiting
Decatur, Illinois, United States
Carle Physician Group-EffinghamRecruiting
Effingham, Illinois, United States
Crossroads Cancer CenterRecruiting
Effingham, Illinois, United States
Carle Physician Group-Mattoon/CharlestonRecruiting
Mattoon, Illinois, United States
Loyola University Medical CenterRecruiting
Maywood, Illinois, United States
Cancer Care Center of O'FallonRecruiting
O'Fallon, Illinois, United States
Southern Illinois University School of MedicineRecruiting
Springfield, Illinois, United States
Springfield ClinicRecruiting
Springfield, Illinois, United States
Springfield Memorial HospitalRecruiting
Springfield, Illinois, United States
Carle Cancer CenterRecruiting
Urbana, Illinois, United States
Mary Greeley Medical CenterRecruiting
Ames, Iowa, United States
McFarland Clinic - AmesRecruiting
Ames, Iowa, United States
McFarland Clinic - BooneSuspended
Boone, Iowa, United States
McFarland Clinic - Trinity Cancer CenterRecruiting
Fort Dodge, Iowa, United States
McFarland Clinic - JeffersonSuspended
Jefferson, Iowa, United States
McFarland Clinic - MarshalltownRecruiting
Marshalltown, Iowa, United States
Lahey ClinicRecruiting
Burlington, Massachusetts, United States
Trinity Health Saint Joseph Mercy Hospital Ann ArborRecruiting
Ann Arbor, Michigan, United States
Trinity Health IHA Medical Group Hematology Oncology - BrightonRecruiting
Brighton, Michigan, United States
Trinity Health Medical Center - BrightonRecruiting
Brighton, Michigan, United States
Trinity Health IHA Medical Group Hematology Oncology - CantonRecruiting
Canton, Michigan, United States
Trinity Health Medical Center - CantonRecruiting
Canton, Michigan, United States
Chelsea HospitalRecruiting
Chelsea, Michigan, United States
Trinity Health IHA Medical Group Hematology Oncology - Chelsea HospitalRecruiting
Chelsea, Michigan, United States
Hematology Oncology Consultants-ClarkstonRecruiting
Clarkston, Michigan, United States
Newland Medical Associates-ClarkstonSuspended
Clarkston, Michigan, United States
Henry Ford Macomb Hospital-Clinton TownshipRecruiting
Clinton Township, Michigan, United States
Wayne State University/Karmanos Cancer InstituteRecruiting
Detroit, Michigan, United States
Henry Ford HospitalRecruiting
Detroit, Michigan, United States
Weisberg Cancer Treatment CenterRecruiting
Farmington Hills, Michigan, United States
Cancer Hematology Centers - FlintRecruiting
Flint, Michigan, United States
Genesee Hematology Oncology PCSuspended
Flint, Michigan, United States
Genesys Hurley Cancer InstituteRecruiting
Flint, Michigan, United States
Hurley Medical CenterRecruiting
Flint, Michigan, United States
University of Michigan Health - Sparrow LansingRecruiting
Lansing, Michigan, United States
Trinity Health Saint Mary Mercy Livonia HospitalRecruiting
Livonia, Michigan, United States
Henry Ford Medical Center-ColumbusRecruiting
Novi, Michigan, United States
Michigan Healthcare Professionals PontiacRecruiting
Pontiac, Michigan, United States
Newland Medical Associates-PontiacRecruiting
Pontiac, Michigan, United States
Trinity Health Saint Joseph Mercy Oakland HospitalRecruiting
Pontiac, Michigan, United States
MyMichigan Medical Center SaginawRecruiting
Saginaw, Michigan, United States
Oncology Hematology Associates of Saginaw Valley PCSuspended
Saginaw, Michigan, United States
MyMichigan Medical Center TawasRecruiting
Tawas City, Michigan, United States
Henry Ford West Bloomfield HospitalRecruiting
West Bloomfield, Michigan, United States
Huron Gastroenterology PCRecruiting
Ypsilanti, Michigan, United States
Trinity Health IHA Medical Group Hematology Oncology Ann Arbor CampusRecruiting
Ypsilanti, Michigan, United States
Mercy HospitalRecruiting
Coon Rapids, Minnesota, United States
Abbott-Northwestern HospitalRecruiting
Minneapolis, Minnesota, United States
Hennepin County Medical CenterRecruiting
Minneapolis, Minnesota, United States
Mayo Clinic in RochesterRecruiting
Rochester, Minnesota, United States
Park Nicollet Clinic - Saint Louis ParkRecruiting
Saint Louis Park, Minnesota, United States
Regions HospitalRecruiting
Saint Paul, Minnesota, United States
United HospitalRecruiting
Saint Paul, Minnesota, United States
Saint Francis Medical CenterRecruiting
Cape Girardeau, Missouri, United States
Siteman Cancer Center at Saint Peters HospitalActive Not Recruiting
City of Saint Peters, Missouri, United States
Siteman Cancer Center at West County HospitalActive Not Recruiting
Creve Coeur, Missouri, United States
Heartland Regional Medical CenterRecruiting
Saint Joseph, Missouri, United States
Washington University School of MedicineActive Not Recruiting
St Louis, Missouri, United States
Mercy Hospital SouthRecruiting
St Louis, Missouri, United States
Siteman Cancer Center-South CountyActive Not Recruiting
St Louis, Missouri, United States
Siteman Cancer Center at Christian HospitalActive Not Recruiting
St Louis, Missouri, United States
Saint Vincent Frontier Cancer CenterRecruiting
Billings, Montana, United States
Memorial Sloan Kettering Basking RidgeRecruiting
Basking Ridge, New Jersey, United States
Memorial Sloan Kettering MonmouthRecruiting
Middletown, New Jersey, United States
Memorial Sloan Kettering BergenRecruiting
Montvale, New Jersey, United States
Memorial Sloan Kettering CommackRecruiting
Commack, New York, United States
Glens Falls HospitalActive Not Recruiting
Glens Falls, New York, United States
Memorial Sloan Kettering WestchesterRecruiting
Harrison, New York, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer CenterActive Not Recruiting
New York, New York, United States
Memorial Sloan Kettering Cancer CenterRecruiting
New York, New York, United States
University of RochesterRecruiting
Rochester, New York, United States
Memorial Sloan Kettering NassauRecruiting
Uniondale, New York, United States
Carolinas Medical Center/Levine Cancer InstituteRecruiting
Charlotte, North Carolina, United States
Southeastern Medical Oncology Center-ClintonRecruiting
Clinton, North Carolina, United States
Levine Cancer Institute-GastonRecruiting
Gastonia, North Carolina, United States
Southeastern Medical Oncology Center-GoldsboroRecruiting
Goldsboro, North Carolina, United States
Southeastern Medical Oncology Center-JacksonvilleRecruiting
Jacksonville, North Carolina, United States
Atrium Health Union/LCI-UnionRecruiting
Monroe, North Carolina, United States
Strecker Cancer Center-BelpreSuspended
Belpre, Ohio, United States
Adena Regional Medical CenterSuspended
Chillicothe, Ohio, United States
Mount Carmel East HospitalSuspended
Columbus, Ohio, United States
Columbus Oncology and Hematology Associates IncSuspended
Columbus, Ohio, United States
Riverside Methodist HospitalSuspended
Columbus, Ohio, United States
Grant Medical CenterSuspended
Columbus, Ohio, United States
The Mark H Zangmeister CenterSuspended
Columbus, Ohio, United States
Mount Carmel Health Center WestSuspended
Columbus, Ohio, United States
Doctors HospitalSuspended
Columbus, Ohio, United States
Delaware Health Center-Grady Cancer CenterSuspended
Delaware, Ohio, United States
Grady Memorial HospitalSuspended
Delaware, Ohio, United States
Dublin Methodist HospitalSuspended
Dublin, Ohio, United States
Central Ohio Breast and Endocrine SurgerySuspended
Gahanna, Ohio, United States
Mount Carmel Grove City HospitalSuspended
Grove City, Ohio, United States
Fairfield Medical CenterSuspended
Lancaster, Ohio, United States
Saint Rita's Medical CenterSuspended
Lima, Ohio, United States
OhioHealth Mansfield HospitalSuspended
Mansfield, Ohio, United States
Marietta Memorial HospitalSuspended
Marietta, Ohio, United States
OhioHealth Marion General HospitalSuspended
Marion, Ohio, United States
Knox Community HospitalSuspended
Mount Vernon, Ohio, United States
Licking Memorial HospitalRecruiting
Newark, Ohio, United States
Newark Radiation OncologySuspended
Newark, Ohio, United States
Mercy Health - Perrysburg HospitalSuspended
Perrysburg, Ohio, United States
Southern Ohio Medical CenterSuspended
Portsmouth, Ohio, United States
Mercy Health - Saint Vincent HospitalSuspended
Toledo, Ohio, United States
Mercy Health - Saint Anne HospitalSuspended
Toledo, Ohio, United States
Saint Ann's HospitalSuspended
Westerville, Ohio, United States
Genesis Healthcare System Cancer Care CenterSuspended
Zanesville, Ohio, United States
Saint Alphonsus Cancer Care Center-Baker CityRecruiting
Baker City, Oregon, United States
Providence Cancer Institute Clackamas ClinicSuspended
Clackamas, Oregon, United States
Providence Newberg Medical CenterSuspended
Newberg, Oregon, United States
Saint Alphonsus Cancer Care Center-OntarioRecruiting
Ontario, Oregon, United States
Providence Willamette Falls Medical CenterSuspended
Oregon City, Oregon, United States
Providence Portland Medical CenterRecruiting
Portland, Oregon, United States
Providence Saint Vincent Medical CenterRecruiting
Portland, Oregon, United States
VCU Massey Comprehensive Cancer CenterRecruiting
Richmond, Virginia, United States
Swedish Cancer Institute-EdmondsRecruiting
Edmonds, Washington, United States
Swedish Cancer Institute-IssaquahRecruiting
Issaquah, Washington, United States
Swedish Medical Center-First HillRecruiting
Seattle, Washington, United States
ThedaCare Regional Cancer CenterRecruiting
Appleton, Wisconsin, United States
Marshfield Medical Center-EC Cancer CenterActive Not Recruiting
Eau Claire, Wisconsin, United States
Gundersen Lutheran Medical CenterRecruiting
La Crosse, Wisconsin, United States
Marshfield Medical Center-MarshfieldActive Not Recruiting
Marshfield, Wisconsin, United States
Marshfield Medical Center - MinocquaActive Not Recruiting
Minocqua, Wisconsin, United States
Marshfield Medical Center-Rice LakeActive Not Recruiting
Rice Lake, Wisconsin, United States
Marshfield Medical Center-River Region at Stevens PointRecruiting
Stevens Point, Wisconsin, United States
Marshfield Medical Center - WestonRecruiting
Weston, Wisconsin, United States