Phase III Evaluation of Fixed Duration Zanubrutinib Plus Sonrotoclax-Based Therapy Compared to Continuous Zanubrutinib in Previously Untreated Older Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)
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.
Arms & interventions
- DrugZanubrutinib
Given PO
- DrugSonrotoclax
Given PO
- ProcedureComputed Tomography
Undergo CT scan
- ProcedureBone Marrow Aspiration
Undergo bone marrow aspiration
- ProcedureBiospecimen Collection
Undergo blood sample collection
- OtherSurvey Administration
Ancillary studies
Outcome measures
Primary
Progression free survival (PFS)
From initial randomization date until the earlier of disease progression or death from any cause. PFS estimates for zanubrutinib plus sonrotoclax therapy to continuous Zanubrutinib.
Time frame: From initial randomization date until the earlier of disease progression or death from any cause, up to 10 years
Eligibility criteria
Study locations (141)
Cedars-Sinai Medical Center
Los Angeles, California, 90048
Jupiter Medical Center
Jupiter, Florida, 33458
Saint Alphonsus Cancer Care Center-Boise
Boise, Idaho, 83706
Saint Alphonsus Cancer Care Center-Caldwell
Caldwell, Idaho, 83605
Kootenai Health - Coeur d'Alene
Coeur d'Alene, Idaho, 83814
Idaho Urologic Institute-Meridian
Meridian, Idaho, 83642
Saint Alphonsus Cancer Care Center-Nampa
Nampa, Idaho, 83687
Kootenai Clinic Cancer Services - Post Falls
Post Falls, Idaho, 83854
Kootenai Clinic Cancer Services - Sandpoint
Sandpoint, Idaho, 83864
Illinois CancerCare-Bloomington
Bloomington, Illinois, 61704
Illinois CancerCare-Canton
Canton, Illinois, 61520
Illinois CancerCare-Carthage
Carthage, Illinois, 62321
Northwestern University
Chicago, Illinois, 60611
Carle at The Riverfront
Danville, Illinois, 61832
Cancer Care Specialists of Illinois - Decatur
Decatur, Illinois, 62526
Decatur Memorial Hospital
Decatur, Illinois, 62526
Illinois CancerCare-Dixon
Dixon, Illinois, 61021
Carle Physician Group-Effingham
Effingham, Illinois, 62401
Illinois CancerCare-Eureka
Eureka, Illinois, 61530
Illinois CancerCare-Galesburg
Galesburg, Illinois, 61401
Illinois CancerCare-Kewanee Clinic
Kewanee, Illinois, 61443
Illinois CancerCare-Macomb
Macomb, Illinois, 61455
Carle Physician Group-Mattoon/Charleston
Mattoon, Illinois, 61938
Carle BroMenn Medical Center
Normal, Illinois, 61761
Carle Cancer Institute Normal
Normal, Illinois, 61761
Cancer Care Center of O'Fallon
O'Fallon, Illinois, 62269
HSHS Saint Elizabeth's Hospital
O'Fallon, Illinois, 62269
Illinois CancerCare-Ottawa Clinic
Ottawa, Illinois, 61350
Illinois CancerCare-Pekin
Pekin, Illinois, 61554
Illinois CancerCare-Peoria
Peoria, Illinois, 61615
Illinois CancerCare-Peru
Peru, Illinois, 61354
Illinois CancerCare-Princeton
Princeton, Illinois, 61356
Memorial Hospital East
Shiloh, 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
Illinois CancerCare - Washington
Washington, Illinois, 61571
UI Health Care Mission Cancer and Blood - Ankeny Clinic
Ankeny, Iowa, 50023
Saint Anthony Regional Hospital
Carroll, Iowa, 51401
Mercy Hospital
Cedar Rapids, Iowa, 52403
Oncology Associates at Mercy Medical Center
Cedar Rapids, Iowa, 52403
UI Health Care Mission Cancer and Blood - West Des Moines Clinic
Clive, Iowa, 50325
Iowa Methodist Medical Center
Des Moines, Iowa, 50309
UI Health Care Mission Cancer and Blood - Des Moines Clinic
Des Moines, Iowa, 50309
Broadlawns Medical Center
Des Moines, Iowa, 50314
Mercy Medical Center - Des Moines
Des Moines, Iowa, 50314
UI Health Care Mission Cancer and Blood - Laurel Clinic
Des Moines, Iowa, 50314
UI Healthcare Mission Cancer and Blood - Fort Dodge
Fort Dodge, Iowa, 50501
UI Healthcare Mission Cancer and Blood - Pella
Pella, Iowa, 50219
UI Health Care Mission Cancer and Blood - Waukee Clinic
Waukee, Iowa, 50263
Cancer Center of Kansas - Chanute
Chanute, Kansas, 66720
Cancer Center of Kansas - Dodge City
Dodge City, Kansas, 67801
Cancer Center of Kansas - El Dorado
El Dorado, Kansas, 67042
Cancer Center of Kansas-Independence
Independence, Kansas, 67301
University of Kansas Cancer Center
Kansas City, Kansas, 66160
Cancer Center of Kansas-Kingman
Kingman, Kansas, 67068
Cancer Center of Kansas-Liberal
Liberal, Kansas, 67905
Cancer Center of Kansas - McPherson
McPherson, Kansas, 67460
Cancer Center of Kansas - Newton
Newton, Kansas, 67114
The University of Kansas Cancer Center - Olathe
Olathe, Kansas, 66061
University of Kansas Cancer Center-Overland Park
Overland Park, Kansas, 66210
Cancer Center of Kansas - Parsons
Parsons, Kansas, 67357
Cancer Center of Kansas - Pratt
Pratt, Kansas, 67124
Cancer Center of Kansas - Salina
Salina, Kansas, 67401
Cancer Center of Kansas - Wellington
Wellington, Kansas, 67152
University of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas, 66205
Cancer Center of Kansas-Wichita Medical Arts Tower
Wichita, Kansas, 67208
Ascension Via Christi Hospitals Wichita
Wichita, Kansas, 67214
Cancer Center of Kansas - Wichita
Wichita, Kansas, 67214
Cancer Center of Kansas - Winfield
Winfield, Kansas, 67156
The James Graham Brown Cancer Center at University of Louisville
Louisville, Kentucky, 40202
Trinity Health IHA Medical Group Hematology Oncology - Brighton
Brighton, Michigan, 48114
Trinity Health IHA Medical Group Hematology Oncology - Canton
Canton, Michigan, 48188
Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
Chelsea, Michigan, 48118
University of Michigan Health - Sparrow Lansing
Lansing, Michigan, 48912
Trinity Health Saint Mary Mercy Livonia Hospital
Livonia, Michigan, 48154
Trinity Health Saint Joseph Mercy Oakland Hospital
Pontiac, Michigan, 48341
Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus
Ypsilanti, Michigan, 48197
Sanford Joe Lueken Cancer Center
Bemidji, Minnesota, 56601
Essentia Health Saint Joseph's Medical Center
Brainerd, Minnesota, 56401
Essentia Health - Deer River Clinic
Deer River, Minnesota, 56636
Essentia Health Cancer Center
Duluth, Minnesota, 55805
Essentia Health Hibbing Clinic
Hibbing, Minnesota, 55746
Abbott-Northwestern Hospital
Minneapolis, Minnesota, 55407
Regions Hospital
Saint Paul, Minnesota, 55101
United Hospital
Saint Paul, Minnesota, 55102
Essentia Health Sandstone
Sandstone, Minnesota, 55072
Essentia Health Virginia Clinic
Virginia, Minnesota, 55792
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
Parkland Health Center - Farmington
Farmington, Missouri, 63640
University of Kansas Cancer Center - Briarcliff
Kansas City, Missouri, 64116
University of Kansas Cancer Center - North
Kansas City, Missouri, 64154
University of Kansas Cancer Center - Lee's Summit
Lee's Summit, Missouri, 64064
Sainte Genevieve County Memorial Hospital
Sainte Genevieve, Missouri, 63670
Washington University School of Medicine
St Louis, Missouri, 63110
Siteman Cancer Center-South County
St Louis, Missouri, 63129
Missouri Baptist Medical Center
St Louis, Missouri, 63131
Siteman Cancer Center at Christian Hospital
St Louis, Missouri, 63136
Missouri Baptist Sullivan Hospital
Sullivan, Missouri, 63080
Community Hospital of Anaconda
Anaconda, Montana, 59711
Billings Clinic Cancer Center
Billings, Montana, 59101
Benefis Sletten Cancer Institute
Great Falls, Montana, 59405
Logan Health Medical Center
Kalispell, Montana, 59901
Community Medical Center
Missoula, Montana, 59804
Jefferson Cherry Hill Hospital
Cherry Hill, New Jersey, 08002
Sidney Kimmel Cancer Center Washington Township
Sewell, New Jersey, 08080
University of Rochester
Rochester, New York, 14642
Wilmot Cancer Institute at Webster
Webster, New York, 14580
UNC Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, 27599
Duke University Medical Center
Durham, North Carolina, 27710
Margaret R Pardee Memorial Hospital
Hendersonville, North Carolina, 28791
Sanford Bismarck Medical Center
Bismarck, North Dakota, 58501
Essentia Health Cancer Center-South University Clinic
Fargo, North Dakota, 58103
Sanford Broadway Medical Center
Fargo, North Dakota, 58122
Sanford Roger Maris Cancer Center
Fargo, North Dakota, 58122
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210
Saint Alphonsus Cancer Care Center-Baker City
Baker City, Oregon, 97814
Providence Newberg Medical Center
Newberg, Oregon, 97132
Saint Alphonsus Cancer Care Center-Ontario
Ontario, Oregon, 97914
Providence Willamette Falls Medical Center
Oregon City, Oregon, 97045
Providence Portland Medical Center
Portland, Oregon, 97213
Providence Saint Vincent Medical Center
Portland, Oregon, 97225
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania, 19107
Jefferson Torresdale Hospital
Philadelphia, Pennsylvania, 19114
Sanford Cancer Center Oncology Clinic
Sioux Falls, South Dakota, 57104
Sanford USD Medical Center - Sioux Falls
Sioux Falls, South Dakota, 57117-5134
Swedish Cancer Institute-Edmonds
Edmonds, Washington, 98026
Swedish Cancer Institute-Issaquah
Issaquah, Washington, 98029
Swedish Medical Center-First Hill
Seattle, Washington, 98122
Duluth Clinic Ashland
Ashland, Wisconsin, 54806
Saint Vincent Hospital Cancer Center Green Bay
Green Bay, Wisconsin, 54301
Saint Vincent Hospital Cancer Center at Saint Mary's
Green Bay, Wisconsin, 54303
Gundersen Lutheran Medical Center
La Crosse, Wisconsin, 54601
ProHealth D N Greenwald Center
Mukwonago, Wisconsin, 53149
ProHealth Oconomowoc Memorial Hospital
Oconomowoc, Wisconsin, 53066
Saint Vincent Hospital Cancer Center at Oconto Falls
Oconto Falls, Wisconsin, 54154
Saint Vincent Hospital Cancer Center at Sturgeon Bay
Sturgeon Bay, Wisconsin, 54235-1495
UW Cancer Center at ProHealth Care
Waukesha, Wisconsin, 53188