Back to Trials
NCT07321652PHASE3Recruiting

Testing the Addition of Anti-Cancer Drug Sonrotoclax, to the Standard Treatment Zanubrutinib, for Previously Untreated CLL/SLL

Alliance for Clinical Trials in Oncology

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

Inclusion Criteria: * STEP 0: This bone marrow or peripheral blood submission to Adaptive is mandatory prior to registration/randomization for real-time identification of the clone needed for MRD testing. The bone marrow sample should be from the first aspiration (i.e., first pull). Aspirate needle should be redirected if needed to get first pull bone marrow aspirate. It should be obtained as soon after pre-registration as possible to confirm registration eligibility * STEP 0: Patients must be diagnosed with CLL/SLL according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 criteria that includes all of the following: * ≥ 5 x10\^9 /L B lymphocytes (5000/μL) in the peripheral blood (CLL) or a lymph node biopsy demonstrating SLL with the below immunophenotype (SLL) * On morphologic review, the leukemic cells must be small mature lymphocytes * Immunophenotype of CLL cells (performed locally) must reveal a clonal B-cell population, which coexpress the B cell surface markers of CD19 and CD20, as well as the T-cell antigen CD5. Patients with bright surface immunoglobulin expression or lack of CD23 expression in \> 10% of cells must lack t(11;14) translocation by interphase cytogenetics * STEP 0: Patients must meet criteria for treatment as defined by IWCLL 2018 guidelines which includes at least one of the following criteria: * Evidence of marrow failure as manifested by the development or worsening of anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or thrombocytopenia), typically hemoglobin (Hb) \< 10 g/dL, platelet count \< 100,000/mm\^3 * Massive (\> 6 cm below the costal margin), progressive or symptomatic splenomegaly * Massive nodes (ie, \> 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy * Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy * Constitutional symptoms, which include any of the following: * Unintentional weight loss of ≥ 10% within the previous 6 months * Significant fatigue (ie. Eastern Cooperative Oncology Group \[ECOG\] performance status \[PS\] ≥ 2) * Fevers \>100.5 °F or 38.0°C for 2 weeks or more without evidence of infection * Night sweats \> 1 month without evidence of infection * STEP 0: Patients must not have had prior therapy for CLL (except palliative steroids or treatment of autoimmune complications of CLL with rituximab or steroids) * STEP 0: Treatment with rituximab and/or high-dose corticosteroids for autoimmune complications of CLL must be completed prior to enrollment. Palliative steroids must be at a dose not higher than 20 mg/day of prednisone or equivalent corticosteroid at the time of registration * STEP 0: Age ≥ 65 years * STEP 0: ECOG performance status ≤ 2 * STEP 0: Patients with known HIV infection on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible for this trial * STEP 0: For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated * STEP 0: Patients with a history of hepatitis C virus (HCV), infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load * STEP 0: Patients must not be receiving active systemic anticoagulation with warfarin. Patients must be off warfarin therapy for at least 5 half-lives washout and with normal INR prior to enrollment * STEP 0: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients must be class 2B or better. Patients with acute cardiac events within 6 months prior to registration should be carefully evaluated for their suitability for enrollment * STEP 0: No patients with a history of a severe bleeding disorder or a history of hemorrhagic stroke or intracranial hemorrhage * STEP 0: No patients with known active progressive central nervous system (CNS) disease * STEP 0: No known medical condition causing an inability to swallow oral formulations of agents * STEP 1: The adaptive report confirming a measurable and trackable B cell clone * STEP 1: Patients may not have had major surgery within 7 days of enrollment, or minor surgery within 5 days of enrollment. Examples of minor surgery include dental surgery, insertion of a venous access device, skin biopsy, or aspiration of a joint. The decision about whether a surgery is major or minor can be made at the discretion of the treating physician * STEP 1: No patients with ongoing active fungal, bacterial or viral infection requiring systemic therapy except those described in the protocol document * STEP 1: Patients must not require more than 20 mg prednisone or equivalent corticosteroid daily * STEP 1: Patients must not have uncontrolled active systemic infection requiring intravenous antibiotics * STEP 1: Patients must not have continued requirement for therapy with a strong CYP3A4/5 inhibitor or inducer. Any such inhibitor or inducer must have been discontinued at least 14 days or 5 half-lives (whichever is shorter) before the first dose of study drug * STEP 1: Absolute neutrophil count (ANC) ≥ 1,000/mm3 unless due to marrow involvement * STEP 1: Platelet count ≥ 30,000/mm3 * STEP 1: Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (unless due to liver involvement, hemolysis or Gilbert's disease) * STEP 1: Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/ alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3.0 x upper limit of normal (ULN) unless due to disease infiltration of the liver * STEP 1: Calculated (calc.) creatinine clearance by Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) ≥ 30 mL/min * STEP 1: Urine protein to creatinine ratio \< 1 or urine protein ≤ 1+ * STEP 2: Detectable MRD ≥ 10 residual clonal cells per million nucleated cells in peripheral blood at the C15 restaging evaluation from ClonoSEQ * STEP 2: Response of PR, PR-L, CR, CCR or CRi to zanubrutinib sonrotoclax therapy

Interventions

DRUG

Zanubrutinib

DRUG

Sonrotoclax

PROCEDURE

Computed Tomography

PROCEDURE

Bone Marrow Aspiration

PROCEDURE

Biospecimen Collection

OTHER

Survey Administration

Interested in This Trial?

Contact the trial locations directly using the information below to learn more about enrollment.

Expressing interest lets you review the study and consent before we connect you with the research site.

Conditions

Chronic Lymphocytic LeukemiaSmall Lymphocytic Leukemia

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