Testing the Addition of Anti-Cancer Drug Sonrotoclax, to the Standard Treatment Zanubrutinib, for Previously Untreated CLL/SLL
Start Date
4/30/2026
Completion Date
9/30/2038
Summary
This phase III trial compares the effect of adding sonrotoclax to zanubrutinib versus zanubrutinib alone for the treatment of patients with untreated chronic lymphoblastic leukemia (CLL)/small lymphocytic lymphoma (SLL). Sonrotoclax 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 is in a class of medications called kinase inhibitors. It blocks a protein called BTK, which is present on B-cell (a type of white blood cells) cancers such as mantel cell lymphoma at abnormal levels. This may help keep cancer cells from growing and spreading. Giving sonrotoclax and zanubrutinib may be more effective than zanubrutinib alone for the treatment of untreated CLL/SLL.
Detailed Description
PRIMARY OBJECTIVES: I. To compare the progression free survival (PFS) between minimal residual disease (MRD)-guided zanubrutinib sonrotoclax therapy to continuous zanubrutinib as control. II. To determine the PFS comparing fixed duration zanubrutinib sonrotoclax therapy to continuous zanubrutinib as control. SECONDARY OBJECTIVES: I. To compare the PFS between the patients with MRD-detectable disease treated with fixed duration zanubrutinib sonrotoclax to the PFS of the patients with MRD detectable disease who receive one additional year of combination therapy. II. To determine the overall survival of all arms of the study. III. To determine the frequency of patients with MRD-detectable disease who convert to undetectable MRD, and at what depth and for how long, after receiving an extra year of combination therapy on the MRD-guided zanubrutinib sonrotoclax therapy arm. IV. To determine and compare the overall response rate (ORR defined as PR, CR, CCR, CRi) and complete remission rate (CR) after 14 cycles of therapy among the three arms. V. To compare time to the next CLL/SLL therapy among treatment arms. VI. To determine the rates and severity of toxicity in each arm, with a particular focus on adverse events of special interest that include infections, cardiovascular events (arrhythmias, heart failure, hypertension), tumor lysis syndrome, bleeding events, cytopenias, and second malignancies. VII. To compare patient-reported symptomatic adverse events as assessed by the Patient Reported Outcome-Common Terminology Criteria for Adverse Events (PRO-CTCAE) between arms 1 and 2. EXPLORATORY OBJECTIVES: I. To compare the best achieved rate of undetectable MRD (uMRD) between the fixed duration zanubrutinib sonrotoclax arm and the MRD guided zanubrutinib sonrotoclax arm. II. To compare rates of undetectable MRD measured by the immunoglobulin heavy chain (IGH) sequencing assay ClonoSeq (sensitivity 1 in 10\^-6) to undetectable MRD measured by standard six-color flow cytometry (uMRD4), and to compare results from bone marrow to peripheral blood. OUTLINE: Patients are randomized to 1 of 2 arms. ARM 1: Patients receive zanubrutinib orally (PO) twice daily (BID) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo restaging starting at cycle 15 day 1. Patients with at least partial remission continue therapy as described above. Patients with progressive disease proceed to follow up. Patients undergo computed tomography (CT) scan, bone marrow aspiration and blood sample collection throughout the study. ARM 2: Patients receive zanubrutinib PO BID on days 1-28 of each cycle. Starting cycle 4 day 1 patients also receive sonrotoclax PO daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo restaging starting at cycle 15 day 1. Patients with undetectable MRD and a response of PR, partial response with persistent lymphocytosis (PR-L), CR, CCR or CRi stop therapy at cycle 15 day 28 and proceed to follow up. Patients with detectable MRD and an objective response to therapy are re-randomized to arm 2B or arm 2C. ARM 2B: Patients continue zanubrutinib PO BID sonrotoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for an additonal 12 cycles in the absence of disease progression or unacceptable toxicity. ARM 2C: Patients discontinue therapy starting at cycle 15 day 28 and proceed to follow up. Patients undergo CT scan, bone marrow aspiration and blood sample collection throughout the study. After completion of study treatment, patients are followed up every 3 months for 3 years then every 6 months until 10 years for study registration. Patients with progression or the start of non protocol CLL directed therapy are followed every 6 months for 10 years from registration.
Eligibility Criteria
Age Range: 65 years to No maximum
Interventions
Zanubrutinib
Sonrotoclax
Computed Tomography
Bone Marrow Aspiration
Biospecimen Collection
Survey Administration
Conditions
Locations
Cedars-Sinai Medical Center
Los Angeles, California 90048
United States
Jupiter Medical Center
Jupiter, Florida 33458
United States
Saint Alphonsus Cancer Care Center-Boise
Boise, Idaho 83706
United States
Saint Alphonsus Cancer Care Center-Caldwell
Caldwell, Idaho 83605
United States
Kootenai Health - Coeur d'Alene
Coeur d'Alene, Idaho 83814
United States
Idaho Urologic Institute-Meridian
Meridian, Idaho 83642
United States
Saint Alphonsus Cancer Care Center-Nampa
Nampa, Idaho 83687
United States
Kootenai Clinic Cancer Services - Post Falls
Post Falls, Idaho 83854
United States
Kootenai Clinic Cancer Services - Sandpoint
Sandpoint, Idaho 83864
United States
Illinois CancerCare-Bloomington
Bloomington, Illinois 61704
United States
Illinois CancerCare-Canton
Canton, Illinois 61520
United States
Illinois CancerCare-Carthage
Carthage, Illinois 62321
United States
Northwestern University
Chicago, Illinois 60611
United States
Carle at The Riverfront
Danville, Illinois 61832
United States
Cancer Care Specialists of Illinois - Decatur
Decatur, Illinois 62526
United States
Decatur Memorial Hospital
Decatur, Illinois 62526
United States
Illinois CancerCare-Dixon
Dixon, Illinois 61021
United States
Carle Physician Group-Effingham
Effingham, Illinois 62401
United States
Illinois CancerCare-Eureka
Eureka, Illinois 61530
United States
Illinois CancerCare-Galesburg
Galesburg, Illinois 61401
United States
Illinois CancerCare-Kewanee Clinic
Kewanee, Illinois 61443
United States
Illinois CancerCare-Macomb
Macomb, Illinois 61455
United States
Carle Physician Group-Mattoon/Charleston
Mattoon, Illinois 61938
United States
Carle BroMenn Medical Center
Normal, Illinois 61761
United States
Carle Cancer Institute Normal
Normal, Illinois 61761
United States
Cancer Care Center of O'Fallon
O'Fallon, Illinois 62269
United States
HSHS Saint Elizabeth's Hospital
O'Fallon, Illinois 62269
United States
Illinois CancerCare-Ottawa Clinic
Ottawa, Illinois 61350
United States
Illinois CancerCare-Pekin
Pekin, Illinois 61554
United States
Illinois CancerCare-Peoria
Peoria, Illinois 61615
United States
Illinois CancerCare-Peru
Peru, Illinois 61354
United States
Illinois CancerCare-Princeton
Princeton, Illinois 61356
United States
Memorial Hospital East
Shiloh, 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
Illinois CancerCare - Washington
Washington, Illinois 61571
United States
UI Health Care Mission Cancer and Blood - Ankeny Clinic
Ankeny, Iowa 50023
United States
Saint Anthony Regional Hospital
Carroll, Iowa 51401
United States
Mercy Hospital
Cedar Rapids, Iowa 52403
United States
Oncology Associates at Mercy Medical Center
Cedar Rapids, Iowa 52403
United States
UI Health Care Mission Cancer and Blood - West Des Moines Clinic
Clive, Iowa 50325
United States
Iowa Methodist Medical Center
Des Moines, Iowa 50309
United States
UI Health Care Mission Cancer and Blood - Des Moines Clinic
Des Moines, Iowa 50309
United States
Broadlawns Medical Center
Des Moines, Iowa 50314
United States
Mercy Medical Center - Des Moines
Des Moines, Iowa 50314
United States
UI Health Care Mission Cancer and Blood - Laurel Clinic
Des Moines, Iowa 50314
United States
UI Healthcare Mission Cancer and Blood - Fort Dodge
Fort Dodge, Iowa 50501
United States
UI Healthcare Mission Cancer and Blood - Pella
Pella, Iowa 50219
United States
UI Health Care Mission Cancer and Blood - Waukee Clinic
Waukee, Iowa 50263
United States
Cancer Center of Kansas - Chanute
Chanute, Kansas 66720
United States
Cancer Center of Kansas - Dodge City
Dodge City, Kansas 67801
United States
Cancer Center of Kansas - El Dorado
El Dorado, Kansas 67042
United States
Cancer Center of Kansas-Independence
Independence, Kansas 67301
United States
University of Kansas Cancer Center
Kansas City, Kansas 66160
United States
Cancer Center of Kansas-Kingman
Kingman, Kansas 67068
United States
Cancer Center of Kansas-Liberal
Liberal, Kansas 67905
United States
Cancer Center of Kansas - McPherson
McPherson, Kansas 67460
United States
Cancer Center of Kansas - Newton
Newton, Kansas 67114
United States
The University of Kansas Cancer Center - Olathe
Olathe, Kansas 66061
United States
University of Kansas Cancer Center-Overland Park
Overland Park, Kansas 66210
United States
Cancer Center of Kansas - Parsons
Parsons, Kansas 67357
United States
Cancer Center of Kansas - Pratt
Pratt, Kansas 67124
United States
Cancer Center of Kansas - Salina
Salina, Kansas 67401
United States
University of Kansas Health System Saint Francis Campus
Topeka, Kansas 66606
United States
Cancer Center of Kansas - Wellington
Wellington, Kansas 67152
United States
University of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas 66205
United States
Cancer Center of Kansas-Wichita Medical Arts Tower
Wichita, Kansas 67208
United States
Ascension Via Christi Hospitals Wichita
Wichita, Kansas 67214
United States
Cancer Center of Kansas - Wichita
Wichita, Kansas 67214
United States
Cancer Center of Kansas - Winfield
Winfield, Kansas 67156
United States
The James Graham Brown Cancer Center at University of Louisville
Louisville, Kentucky 40202
United States
UofL Health Medical Center Northeast
Louisville, Kentucky 40245
United States
Trinity Health IHA Medical Group Hematology Oncology - Brighton
Brighton, Michigan 48114
United States
Trinity Health IHA Medical Group Hematology Oncology - Canton
Canton, Michigan 48188
United States
Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
Chelsea, Michigan 48118
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
Trinity Health Saint Joseph Mercy Oakland Hospital
Pontiac, Michigan 48341
United States
Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus
Ypsilanti, Michigan 48197
United States
Sanford Joe Lueken Cancer Center
Bemidji, Minnesota 56601
United States
Essentia Health Saint Joseph's Medical Center
Brainerd, Minnesota 56401
United States
Mercy Hospital
Coon Rapids, Minnesota 55433
United States
Essentia Health - Deer River Clinic
Deer River, Minnesota 56636
United States
Essentia Health Cancer Center
Duluth, Minnesota 55805
United States
Essentia Health Hibbing Clinic
Hibbing, Minnesota 55746
United States
Abbott-Northwestern Hospital
Minneapolis, Minnesota 55407
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
Essentia Health Sandstone
Sandstone, Minnesota 55072
United States
Essentia Health Virginia Clinic
Virginia, Minnesota 55792
United States
Baptist Memorial Hospital and Cancer Center-Desoto
Southhaven, Mississippi 38671
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
Parkland Health Center - Farmington
Farmington, Missouri 63640
United States
University of Kansas Cancer Center - Briarcliff
Kansas City, Missouri 64116
United States
University of Kansas Cancer Center - North
Kansas City, Missouri 64154
United States
University of Kansas Cancer Center - Lee's Summit
Lee's Summit, Missouri 64064
United States
Sainte Genevieve County Memorial Hospital
Sainte Genevieve, Missouri 63670
United States
Washington University School of Medicine
St Louis, Missouri 63110
United States
Siteman Cancer Center-South County
St Louis, Missouri 63129
United States
Missouri Baptist Medical Center
St Louis, Missouri 63131
United States
Siteman Cancer Center at Christian Hospital
St Louis, Missouri 63136
United States
Missouri Baptist Sullivan Hospital
Sullivan, Missouri 63080
United States
Community Hospital of Anaconda
Anaconda, Montana 59711
United States
Billings Clinic Cancer Center
Billings, Montana 59101
United States
Bozeman Health Deaconess Hospital
Bozeman, Montana 59715
United States
Benefis Sletten Cancer Institute
Great Falls, Montana 59405
United States
Logan Health Medical Center
Kalispell, Montana 59901
United States
Community Medical Center
Missoula, Montana 59804
United States
Jefferson Cherry Hill Hospital
Cherry Hill, New Jersey 08002
United States
Sidney Kimmel Cancer Center Washington Township
Sewell, New Jersey 08080
United States
University of Rochester
Rochester, New York 14642
United States
Wilmot Cancer Institute at Webster
Webster, New York 14580
United States
UNC Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina 27599
United States
Duke University Medical Center
Durham, North Carolina 27710
United States
Margaret R Pardee Memorial Hospital
Hendersonville, North Carolina 28791
United States
Sanford Bismarck Medical Center
Bismarck, North Dakota 58501
United States
Essentia Health Cancer Center-South University Clinic
Fargo, North Dakota 58103
United States
Sanford Broadway Medical Center
Fargo, North Dakota 58122
United States
Sanford Roger Maris Cancer Center
Fargo, North Dakota 58122
United States
Ohio State University Comprehensive Cancer Center
Columbus, Ohio 43210
United States
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma 73104
United States
Saint Alphonsus Cancer Care Center-Baker City
Baker City, Oregon 97814
United States
Providence Newberg Medical Center
Newberg, Oregon 97132
United States
Saint Alphonsus Cancer Care Center-Ontario
Ontario, Oregon 97914
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
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania 19107
United States
Jefferson Torresdale Hospital
Philadelphia, Pennsylvania 19114
United States
Sanford Cancer Center Oncology Clinic
Sioux Falls, South Dakota 57104
United States
Sanford USD Medical Center - Sioux Falls
Sioux Falls, South Dakota 57117-5134
United States
Avera Cancer Institute at Yankton
Yankton, South Dakota 57078
United States
Baptist Memorial Hospital and Cancer Center-Collierville
Collierville, Tennessee 38017
United States
Baptist Memorial Hospital and Cancer Center-Memphis
Memphis, Tennessee 38120
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
Duluth Clinic Ashland
Ashland, Wisconsin 54806
United States
Saint Vincent Hospital Cancer Center Green Bay
Green Bay, Wisconsin 54301
United States
Saint Vincent Hospital Cancer Center at Saint Mary's
Green Bay, Wisconsin 54303
United States
Gundersen Lutheran Medical Center
La Crosse, Wisconsin 54601
United States
William S Middleton VA Medical Center
Madison, Wisconsin 53705
United States
ProHealth D N Greenwald Center
Mukwonago, Wisconsin 53149
United States
ProHealth Oconomowoc Memorial Hospital
Oconomowoc, Wisconsin 53066
United States
Saint Vincent Hospital Cancer Center at Oconto Falls
Oconto Falls, Wisconsin 54154
United States
Saint Vincent Hospital Cancer Center at Sturgeon Bay
Sturgeon Bay, Wisconsin 54235-1495
United States
UW Cancer Center at ProHealth Care
Waukesha, Wisconsin 53188
United States