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NCT04840602PHASE2Recruiting

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

National Cancer Institute (NCI)

Start Date

1/5/2022

Completion Date

3/31/2028

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.

Eligibility Criteria

Age Range: 18 years to No maximum

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

Interventions

PROCEDURE

Biospecimen Collection

PROCEDURE

Bone Marrow Aspiration

PROCEDURE

Bone Marrow Biopsy

PROCEDURE

Computed Tomography

DRUG

Ibrutinib

PROCEDURE

Positron Emission Tomography

BIOLOGICAL

Rituximab

DRUG

Venetoclax

DRUG

Zanubrutinib

Interested in This Trial?

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Conditions

Lymphoplasmacytic LymphomaWaldenstrom Macroglobulinemia

Locations

Banner University Medical Center - Tucson

Tucson, Arizona 85719

United States

University of Arizona Cancer Center-North Campus

Tucson, Arizona 85719

United States

City of Hope at Irvine Lennar

Irvine, California 92618

United States

UM Sylvester Comprehensive Cancer Center at Coral Gables

Coral Gables, Florida 33146

United States

UM Sylvester Comprehensive Cancer Center at Coral Springs

Coral Springs, Florida 33065

United States

UM Sylvester Comprehensive Cancer Center at Deerfield Beach

Deerfield Beach, Florida 33442

United States

UM Sylvester Comprehensive Cancer Center at Doral

Doral, Florida 33166

United States

UM Sylvester Comprehensive Cancer Center at Hollywood

Hollywood, Florida 33021

United States

Mayo Clinic in Florida

Jacksonville, Florida 32224-9980

United States

University of Miami Miller School of Medicine-Sylvester Cancer Center

Miami, Florida 33136

United States

UM Sylvester Comprehensive Cancer Center at Kendall

Miami, Florida 33176

United States

University of Miami Sylvester Comprehensive Cancer Center at Sole Mia

North Miami, Florida 33181

United States

UM Sylvester Comprehensive Cancer Center at Plantation

Plantation, Florida 33324

United States

Saint Alphonsus Cancer Care Center-Nampa

Nampa, Idaho 83687

United States

Centralia Oncology Clinic

Centralia, Illinois 62801

United States

Carle at The Riverfront

Danville, Illinois 61832

United States

Cancer Care Specialists of Illinois - Decatur

Decatur, Illinois 62526

United States

Carle Physician Group-Effingham

Effingham, Illinois 62401

United States

Crossroads Cancer Center

Effingham, Illinois 62401

United States

Carle Physician Group-Mattoon/Charleston

Mattoon, Illinois 61938

United States

Loyola University Medical Center

Maywood, Illinois 60153

United States

Cancer Care Center of O'Fallon

O'Fallon, Illinois 62269

United States

Southern Illinois University School of Medicine

Springfield, Illinois 62702

United States

Springfield Clinic

Springfield, Illinois 62702

United States

Springfield Memorial Hospital

Springfield, Illinois 62781

United States

Carle Cancer Center

Urbana, Illinois 61801

United States

Mary Greeley Medical Center

Ames, Iowa 50010

United States

McFarland Clinic - Ames

Ames, Iowa 50010

United States

McFarland Clinic - Boone

Boone, Iowa 50036

United States

McFarland Clinic - Trinity Cancer Center

Fort Dodge, Iowa 50501

United States

McFarland Clinic - Jefferson

Jefferson, Iowa 50129

United States

McFarland Clinic - Marshalltown

Marshalltown, Iowa 50158

United States

Trinity Health Saint Joseph Mercy Hospital Ann Arbor

Ann Arbor, Michigan 48106

United States

Trinity Health IHA Medical Group Hematology Oncology - Brighton

Brighton, Michigan 48114

United States

Trinity Health Medical Center - Brighton

Brighton, Michigan 48114

United States

Trinity Health IHA Medical Group Hematology Oncology - Canton

Canton, Michigan 48188

United States

Trinity Health Medical Center - Canton

Canton, Michigan 48188

United States

Chelsea Hospital

Chelsea, Michigan 48118

United States

Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital

Chelsea, Michigan 48118

United States

Hematology Oncology Consultants-Clarkston

Clarkston, Michigan 48346

United States

Newland Medical Associates-Clarkston

Clarkston, Michigan 48346

United States

Henry Ford Macomb Hospital-Clinton Township

Clinton Township, Michigan 48038

United States

Wayne State University/Karmanos Cancer Institute

Detroit, Michigan 48201

United States

Henry Ford Hospital

Detroit, Michigan 48202

United States

Weisberg Cancer Treatment Center

Farmington Hills, Michigan 48334

United States

Cancer Hematology Centers - Flint

Flint, Michigan 48503

United States

Genesee Hematology Oncology PC

Flint, Michigan 48503

United States

Genesys Hurley Cancer Institute

Flint, Michigan 48503

United States

Hurley Medical Center

Flint, Michigan 48503

United States

University of Michigan Health - Sparrow Lansing

Lansing, Michigan 48912

United States

Trinity Health Saint Mary Mercy Livonia Hospital

Livonia, Michigan 48154

United States

Henry Ford Medical Center-Columbus

Novi, Michigan 48377

United States

Michigan Healthcare Professionals Pontiac

Pontiac, Michigan 48341

United States

Newland Medical Associates-Pontiac

Pontiac, Michigan 48341

United States

Trinity Health Saint Joseph Mercy Oakland Hospital

Pontiac, Michigan 48341

United States

MyMichigan Medical Center Saginaw

Saginaw, Michigan 48601

United States

Oncology Hematology Associates of Saginaw Valley PC

Saginaw, Michigan 48604

United States

MyMichigan Medical Center Tawas

Tawas City, Michigan 48764

United States

Henry Ford West Bloomfield Hospital

West Bloomfield, Michigan 48322

United States

Huron Gastroenterology PC

Ypsilanti, Michigan 48106

United States

Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus

Ypsilanti, Michigan 48197

United States

Mercy Hospital

Coon Rapids, Minnesota 55433

United States

Abbott-Northwestern Hospital

Minneapolis, Minnesota 55407

United States

Hennepin County Medical Center

Minneapolis, Minnesota 55415

United States

Mayo Clinic in Rochester

Rochester, Minnesota 55905

United States

Park Nicollet Clinic - Saint Louis Park

Saint Louis Park, Minnesota 55416

United States

Regions Hospital

Saint Paul, Minnesota 55101

United States

United Hospital

Saint Paul, Minnesota 55102

United States

Saint Francis Medical Center

Cape Girardeau, Missouri 63703

United States

Siteman Cancer Center at Saint Peters Hospital

City of Saint Peters, Missouri 63376

United States

Siteman Cancer Center at West County Hospital

Creve Coeur, Missouri 63141

United States

Heartland Regional Medical Center

Saint Joseph, Missouri 64506

United States

Washington University School of Medicine

St Louis, Missouri 63110

United States

Mercy Hospital South

St Louis, Missouri 63128

United States

Siteman Cancer Center-South County

St Louis, Missouri 63129

United States

Siteman Cancer Center at Christian Hospital

St Louis, Missouri 63136

United States

Saint Vincent Frontier Cancer Center

Billings, Montana 59102

United States

Memorial Sloan Kettering Basking Ridge

Basking Ridge, New Jersey 07920

United States

Memorial Sloan Kettering Monmouth

Middletown, New Jersey 07748

United States

Memorial Sloan Kettering Bergen

Montvale, New Jersey 07645

United States

Memorial Sloan Kettering Commack

Commack, New York 11725

United States

Glens Falls Hospital

Glens Falls, New York 12801

United States

Memorial Sloan Kettering Westchester

Harrison, New York 10604

United States

NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center

New York, New York 10032

United States

Memorial Sloan Kettering Cancer Center

New York, New York 10065

United States

University of Rochester

Rochester, New York 14642

United States

Memorial Sloan Kettering Nassau

Uniondale, New York 11553

United States

Carolinas Medical Center/Levine Cancer Institute

Charlotte, North Carolina 28203

United States

Southeastern Medical Oncology Center-Clinton

Clinton, North Carolina 28328

United States

Levine Cancer Institute-Gaston

Gastonia, North Carolina 28054

United States

Southeastern Medical Oncology Center-Goldsboro

Goldsboro, North Carolina 27534

United States

Southeastern Medical Oncology Center-Jacksonville

Jacksonville, North Carolina 28546

United States

Atrium Health Union/LCI-Union

Monroe, North Carolina 28112

United States

Strecker Cancer Center-Belpre

Belpre, Ohio 45714

United States

Adena Regional Medical Center

Chillicothe, Ohio 45601

United States

Mount Carmel East Hospital

Columbus, Ohio 43213

United States

Columbus Oncology and Hematology Associates Inc

Columbus, Ohio 43214

United States

Riverside Methodist Hospital

Columbus, Ohio 43214

United States

Grant Medical Center

Columbus, Ohio 43215

United States

The Mark H Zangmeister Center

Columbus, Ohio 43219

United States

Mount Carmel Health Center West

Columbus, Ohio 43222

United States

Doctors Hospital

Columbus, Ohio 43228

United States

Delaware Health Center-Grady Cancer Center

Delaware, Ohio 43015

United States

Grady Memorial Hospital

Delaware, Ohio 43015

United States

Dublin Methodist Hospital

Dublin, Ohio 43016

United States

Central Ohio Breast and Endocrine Surgery

Gahanna, Ohio 43230

United States

Mount Carmel Grove City Hospital

Grove City, Ohio 43123

United States

Fairfield Medical Center

Lancaster, Ohio 43130

United States

Saint Rita's Medical Center

Lima, Ohio 45801

United States

OhioHealth Mansfield Hospital

Mansfield, Ohio 44903

United States

Marietta Memorial Hospital

Marietta, Ohio 45750

United States

OhioHealth Marion General Hospital

Marion, Ohio 43302

United States

Knox Community Hospital

Mount Vernon, Ohio 43050

United States

Licking Memorial Hospital

Newark, Ohio 43055

United States

Newark Radiation Oncology

Newark, Ohio 43055

United States

Mercy Health - Perrysburg Hospital

Perrysburg, Ohio 43551

United States

Southern Ohio Medical Center

Portsmouth, Ohio 45662

United States

Mercy Health - Saint Vincent Hospital

Toledo, Ohio 43608

United States

Mercy Health - Saint Anne Hospital

Toledo, Ohio 43623

United States

Saint Ann's Hospital

Westerville, Ohio 43081

United States

Genesis Healthcare System Cancer Care Center

Zanesville, Ohio 43701

United States

Providence Cancer Institute Clackamas Clinic

Clackamas, Oregon 97015

United States

Providence Newberg Medical Center

Newberg, Oregon 97132

United States

Providence Willamette Falls Medical Center

Oregon City, Oregon 97045

United States

Providence Portland Medical Center

Portland, Oregon 97213

United States

Providence Saint Vincent Medical Center

Portland, Oregon 97225

United States

VCU Massey Comprehensive Cancer Center

Richmond, Virginia 23298

United States

Swedish Cancer Institute-Edmonds

Edmonds, Washington 98026

United States

Swedish Cancer Institute-Issaquah

Issaquah, Washington 98029

United States

Swedish Medical Center-First Hill

Seattle, Washington 98122

United States

ThedaCare Regional Cancer Center

Appleton, Wisconsin 54911

United States

Marshfield Medical Center-EC Cancer Center

Eau Claire, Wisconsin 54701

United States

Gundersen Lutheran Medical Center

La Crosse, Wisconsin 54601

United States

Marshfield Medical Center-Marshfield

Marshfield, Wisconsin 54449

United States

Marshfield Medical Center - Minocqua

Minocqua, Wisconsin 54548

United States

Marshfield Medical Center-Rice Lake

Rice Lake, Wisconsin 54868

United States

Marshfield Medical Center-River Region at Stevens Point

Stevens Point, Wisconsin 54482

United States

Marshfield Medical Center - Weston

Weston, Wisconsin 54476

United States