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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
92
Undergo blood sample collection
Undergo bone marrow biopsy and aspiration
Undergo bone marrow biopsy and aspiration
Undergo CT or PET/CT
Given PO
Undergo PET/CT
Given IV
Given PO
Given PO
Banner University Medical Center - Tucson
Tucson, Arizona, United States
RECRUITINGUniversity of Arizona Cancer Center-North Campus
Tucson, Arizona, United States
RECRUITINGUM Sylvester Comprehensive Cancer Center at Coral Gables
Coral Gables, Florida, United States
RECRUITINGUM Sylvester Comprehensive Cancer Center at Coral Springs
Coral Springs, Florida, United States
Very good partial response or better (VGPR or better) rate
A Cochran-Mantel-Haenszel test will be performed to compare the VGPR in the ibrutinib plus rituximab or zanubrutinib alone arm and the venetoclax plus rituximab arm accounting for the stratification factor of prior rituximab, and VGPR or better rate will be reported in each study arm with a binomial confidence interval.
Time frame: Up to 5 years
Progression-free survival
Will be analyzed using the Kaplan-Meier method, and a stratified log-rank test will be performed to compare survival outcomes in the ibrutinib plus rituximab or zanubrutinib alone and venetoclax plus rituximab arms while controlling for the effects from the stratification factor of prior rituximab treatment.
Time frame: From the date of registration to the date of first documentation of progressive disease or symptomatic deterioration, or death due to any cause, assessed up to 5 years
Overall survival
Will be analyzed using the Kaplan-Meier method, and a stratified log-rank test will be performed to compare survival outcomes in the ibrutinib plus rituximab or zanubrutinib alone and venetoclax plus rituximab arms while controlling for the effects from the stratification factor of prior rituximab treatment.
Time frame: From the date of registration to the date of death due to any cause, assessed up to 5 years
Rate of complete response
Will be analyzed using the cumulative incidence competing risks method.
Time frame: From the date of registration to the date of complete response, assessed up to 5 years
Overall response rate
Defined as the percentage of participants achieving a best response of complete response, very good partial response, or partial response while on study. Will be reported with a binomial confidence interval.
Time frame: Up to 5 years
Time to VGPR or better
Defined as the percentage of participants achieving a best response of very good partial response or better while on study. Will be reported with a binomial confidence interval.
Time frame: Up to 5 years
Incidence of adverse events
As assessed by Common Terminology Criteria for Adverse Events Version 5.0.
Time frame: Up to 5 years
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UM Sylvester Comprehensive Cancer Center at Deerfield Beach
Deerfield Beach, Florida, United States
RECRUITINGUM Sylvester Comprehensive Cancer Center at Doral
Doral, Florida, United States
RECRUITINGUM Sylvester Comprehensive Cancer Center at Hollywood
Hollywood, Florida, United States
RECRUITINGMayo Clinic in Florida
Jacksonville, Florida, United States
RECRUITINGUniversity of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, United States
RECRUITINGUM Sylvester Comprehensive Cancer Center at Kendall
Miami, Florida, United States
RECRUITING...and 115 more locations