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)
Summary
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.
Detailed description
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.
Arms & interventions
- ProcedureBiospecimen Collection
Undergo blood sample collection
- ProcedureBone Marrow Aspiration
Undergo bone marrow biopsy and aspiration
- ProcedureBone Marrow Biopsy
Undergo bone marrow biopsy and aspiration
- ProcedureComputed Tomography
Undergo CT or PET/CT
- DrugIbrutinib
Given PO
- ProcedurePositron Emission Tomography
Undergo PET/CT
- BiologicalRituximab
Given IV
- DrugVenetoclax
Given PO
- DrugZanubrutinib
Given PO
Outcome measures
Primary
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
Secondary
Progression-free survival
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
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
Time frame: From the date of registration to the date of complete response, assessed up to 5 years
Overall response rate
Time frame: Up to 5 years
Time to VGPR or better
Time frame: Up to 5 years
Incidence of adverse events
Time frame: Up to 5 years
Eligibility criteria
Study locations (133)
Banner University Medical Center - Tucson
Tucson, Arizona, 85719
University of Arizona Cancer Center-North Campus
Tucson, Arizona, 85719
UM Sylvester Comprehensive Cancer Center at Coral Gables
Coral Gables, Florida, 33146
UM Sylvester Comprehensive Cancer Center at Coral Springs
Coral Springs, Florida, 33065
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
Deerfield Beach, Florida, 33442
UM Sylvester Comprehensive Cancer Center at Doral
Doral, Florida, 33166
UM Sylvester Comprehensive Cancer Center at Hollywood
Hollywood, Florida, 33021
Mayo Clinic in Florida
Jacksonville, Florida, 32224-9980
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, 33136
UM Sylvester Comprehensive Cancer Center at Kendall
Miami, Florida, 33176
University of Miami Sylvester Comprehensive Cancer Center at Sole Mia
North Miami, Florida, 33181
UM Sylvester Comprehensive Cancer Center at Plantation
Plantation, Florida, 33324
Saint Alphonsus Cancer Care Center-Nampa
Nampa, Idaho, 83687
Centralia Oncology Clinic
Centralia, Illinois, 62801
Carle at The Riverfront
Danville, Illinois, 61832
Cancer Care Specialists of Illinois - Decatur
Decatur, Illinois, 62526
Carle Physician Group-Effingham
Effingham, Illinois, 62401
Crossroads Cancer Center
Effingham, Illinois, 62401
Carle Physician Group-Mattoon/Charleston
Mattoon, Illinois, 61938
Cancer Care Center of O'Fallon
O'Fallon, Illinois, 62269
Southern Illinois University School of Medicine
Springfield, Illinois, 62702
Springfield Clinic
Springfield, Illinois, 62702
Springfield Memorial Hospital
Springfield, Illinois, 62781
Carle Cancer Center
Urbana, Illinois, 61801
Mary Greeley Medical Center
Ames, Iowa, 50010
McFarland Clinic - Ames
Ames, Iowa, 50010
McFarland Clinic - Boone
Boone, Iowa, 50036
McFarland Clinic - Trinity Cancer Center
Fort Dodge, Iowa, 50501
McFarland Clinic - Jefferson
Jefferson, Iowa, 50129
McFarland Clinic - Marshalltown
Marshalltown, Iowa, 50158
Trinity Health Saint Joseph Mercy Hospital Ann Arbor
Ann Arbor, Michigan, 48106
Trinity Health IHA Medical Group Hematology Oncology - Brighton
Brighton, Michigan, 48114
Trinity Health Medical Center - Brighton
Brighton, Michigan, 48114
Trinity Health IHA Medical Group Hematology Oncology - Canton
Canton, Michigan, 48188
Trinity Health Medical Center - Canton
Canton, Michigan, 48188
Chelsea Hospital
Chelsea, Michigan, 48118
Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
Chelsea, Michigan, 48118
Hematology Oncology Consultants-Clarkston
Clarkston, Michigan, 48346
Newland Medical Associates-Clarkston
Clarkston, Michigan, 48346
Henry Ford Macomb Hospital-Clinton Township
Clinton Township, Michigan, 48038
Henry Ford Hospital
Detroit, Michigan, 48202
Cancer Hematology Centers - Flint
Flint, Michigan, 48503
Genesee Hematology Oncology PC
Flint, Michigan, 48503
Genesys Hurley Cancer Institute
Flint, Michigan, 48503
Hurley Medical Center
Flint, Michigan, 48503
University of Michigan Health - Sparrow Lansing
Lansing, Michigan, 48912
Trinity Health Saint Mary Mercy Livonia Hospital
Livonia, Michigan, 48154
Henry Ford Medical Center-Columbus
Novi, Michigan, 48377
Michigan Healthcare Professionals Pontiac
Pontiac, Michigan, 48341
Newland Medical Associates-Pontiac
Pontiac, Michigan, 48341
Trinity Health Saint Joseph Mercy Oakland Hospital
Pontiac, Michigan, 48341
MyMichigan Medical Center Saginaw
Saginaw, Michigan, 48601
Oncology Hematology Associates of Saginaw Valley PC
Saginaw, Michigan, 48604
MyMichigan Medical Center Tawas
Tawas City, Michigan, 48764
Henry Ford West Bloomfield Hospital
West Bloomfield, Michigan, 48322
Huron Gastroenterology PC
Ypsilanti, Michigan, 48106
Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus
Ypsilanti, Michigan, 48197
Abbott-Northwestern Hospital
Minneapolis, Minnesota, 55407
Hennepin County Medical Center
Minneapolis, Minnesota, 55415
Mayo Clinic in Rochester
Rochester, Minnesota, 55905
Park Nicollet Clinic - Saint Louis Park
Saint Louis Park, Minnesota, 55416
Regions Hospital
Saint Paul, Minnesota, 55101
United Hospital
Saint Paul, Minnesota, 55102
Saint Francis Medical Center
Cape Girardeau, Missouri, 63703
Siteman Cancer Center at Saint Peters Hospital
City of Saint Peters, Missouri, 63376
Siteman Cancer Center at West County Hospital
Creve Coeur, Missouri, 63141
Heartland Regional Medical Center
Saint Joseph, Missouri, 64506
Washington University School of Medicine
St Louis, Missouri, 63110
Mercy Hospital South
St Louis, Missouri, 63128
Siteman Cancer Center-South County
St Louis, Missouri, 63129
Siteman Cancer Center at Christian Hospital
St Louis, Missouri, 63136
Saint Vincent Frontier Cancer Center
Billings, Montana, 59102
Memorial Sloan Kettering Basking Ridge
Basking Ridge, New Jersey, 07920
Memorial Sloan Kettering Monmouth
Middletown, New Jersey, 07748
Memorial Sloan Kettering Bergen
Montvale, New Jersey, 07645
Memorial Sloan Kettering Commack
Commack, New York, 11725
Glens Falls Hospital
Glens Falls, New York, 12801
Memorial Sloan Kettering Westchester
Harrison, New York, 10604
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
New York, New York, 10032
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
University of Rochester
Rochester, New York, 14642
Memorial Sloan Kettering Nassau
Uniondale, New York, 11553
Carolinas Medical Center/Levine Cancer Institute
Charlotte, North Carolina, 28203
Southeastern Medical Oncology Center-Clinton
Clinton, North Carolina, 28328
Levine Cancer Institute-Gaston
Gastonia, North Carolina, 28054
Southeastern Medical Oncology Center-Goldsboro
Goldsboro, North Carolina, 27534
Southeastern Medical Oncology Center-Jacksonville
Jacksonville, North Carolina, 28546
Atrium Health Union/LCI-Union
Monroe, North Carolina, 28112
Strecker Cancer Center-Belpre
Belpre, Ohio, 45714
Adena Regional Medical Center
Chillicothe, Ohio, 45601
Mount Carmel East Hospital
Columbus, Ohio, 43213
Columbus Oncology and Hematology Associates Inc
Columbus, Ohio, 43214
Riverside Methodist Hospital
Columbus, Ohio, 43214
Grant Medical Center
Columbus, Ohio, 43215
The Mark H Zangmeister Center
Columbus, Ohio, 43219
Mount Carmel Health Center West
Columbus, Ohio, 43222
Doctors Hospital
Columbus, Ohio, 43228
Delaware Health Center-Grady Cancer Center
Delaware, Ohio, 43015
Grady Memorial Hospital
Delaware, Ohio, 43015
Dublin Methodist Hospital
Dublin, Ohio, 43016
Central Ohio Breast and Endocrine Surgery
Gahanna, Ohio, 43230
Mount Carmel Grove City Hospital
Grove City, Ohio, 43123
Fairfield Medical Center
Lancaster, Ohio, 43130
Saint Rita's Medical Center
Lima, Ohio, 45801
OhioHealth Mansfield Hospital
Mansfield, Ohio, 44903
Marietta Memorial Hospital
Marietta, Ohio, 45750
OhioHealth Marion General Hospital
Marion, Ohio, 43302
Knox Community Hospital
Mount Vernon, Ohio, 43050
Licking Memorial Hospital
Newark, Ohio, 43055
Newark Radiation Oncology
Newark, Ohio, 43055
Mercy Health - Perrysburg Hospital
Perrysburg, Ohio, 43551
Southern Ohio Medical Center
Portsmouth, Ohio, 45662
Mercy Health - Saint Vincent Hospital
Toledo, Ohio, 43608
Mercy Health - Saint Anne Hospital
Toledo, Ohio, 43623
Saint Ann's Hospital
Westerville, Ohio, 43081
Genesis Healthcare System Cancer Care Center
Zanesville, Ohio, 43701
Providence Cancer Institute Clackamas Clinic
Clackamas, Oregon, 97015
Providence Newberg Medical Center
Newberg, Oregon, 97132
Providence Willamette Falls Medical Center
Oregon City, Oregon, 97045
Providence Portland Medical Center
Portland, Oregon, 97213
Providence Saint Vincent Medical Center
Portland, Oregon, 97225
VCU Massey Comprehensive Cancer Center
Richmond, Virginia, 23298
Swedish Cancer Institute-Edmonds
Edmonds, Washington, 98026
Swedish Cancer Institute-Issaquah
Issaquah, Washington, 98029
Swedish Medical Center-First Hill
Seattle, Washington, 98122
ThedaCare Regional Cancer Center
Appleton, Wisconsin, 54911
Marshfield Medical Center-EC Cancer Center
Eau Claire, Wisconsin, 54701
Gundersen Lutheran Medical Center
La Crosse, Wisconsin, 54601
Marshfield Medical Center-Marshfield
Marshfield, Wisconsin, 54449
Marshfield Medical Center - Minocqua
Minocqua, Wisconsin, 54548
Marshfield Medical Center-Rice Lake
Rice Lake, Wisconsin, 54868
Marshfield Medical Center-River Region at Stevens Point
Stevens Point, Wisconsin, 54482
Marshfield Medical Center - Weston
Weston, Wisconsin, 54476