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

NCT07321652 · Alliance for Clinical Trials in Oncology
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Official title
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)
About this study
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
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
Study design
Enrollment target: 466 participants
Allocation: randomized
Masking: none
Age groups: older_adult
Timeline
Starts: 2026-04-30
Estimated completion: 2038-09-30
Last updated: 2026-07-02
Interventions
Drug: ZanubrutinibDrug: SonrotoclaxProcedure: Computed TomographyProcedure: Bone Marrow AspirationProcedure: Biospecimen CollectionOther: Survey Administration
Primary outcomes
  • Progression free survival (PFS) (From initial randomization date until the earlier of disease progression or death from any cause, up to 10 years)
Sponsor
Alliance for Clinical Trials in Oncology · other
With: National Cancer Institute (NCI)
Contacts & investigators
ContactJayke Giese · contact · leukemiaprotocols@alliancenctn.org · 773-702-9171
InvestigatorJennifer R Brown, MD · study_chair, Alliance for Clinical Trials in Oncology
All locations (152)
Cedars-Sinai Medical CenterRecruiting
Los Angeles, California, United States
Jupiter Medical CenterRecruiting
Jupiter, Florida, United States
Saint Alphonsus Cancer Care Center-BoiseRecruiting
Boise, Idaho, United States
Saint Alphonsus Cancer Care Center-CaldwellRecruiting
Caldwell, Idaho, United States
Kootenai Health - Coeur d'AleneRecruiting
Coeur d'Alene, Idaho, United States
Idaho Urologic Institute-MeridianRecruiting
Meridian, Idaho, United States
Saint Alphonsus Cancer Care Center-NampaRecruiting
Nampa, Idaho, United States
Kootenai Clinic Cancer Services - Post FallsRecruiting
Post Falls, Idaho, United States
Kootenai Clinic Cancer Services - SandpointRecruiting
Sandpoint, Idaho, United States
Illinois CancerCare-BloomingtonRecruiting
Bloomington, Illinois, United States
Illinois CancerCare-CantonRecruiting
Canton, Illinois, United States
Illinois CancerCare-CarthageRecruiting
Carthage, Illinois, United States
Northwestern UniversityRecruiting
Chicago, Illinois, United States
Carle at The RiverfrontRecruiting
Danville, Illinois, United States
Cancer Care Specialists of Illinois - DecaturRecruiting
Decatur, Illinois, United States
Decatur Memorial HospitalRecruiting
Decatur, Illinois, United States
Illinois CancerCare-DixonRecruiting
Dixon, Illinois, United States
Carle Physician Group-EffinghamRecruiting
Effingham, Illinois, United States
Illinois CancerCare-EurekaRecruiting
Eureka, Illinois, United States
Illinois CancerCare-GalesburgRecruiting
Galesburg, Illinois, United States
Illinois CancerCare-Kewanee ClinicRecruiting
Kewanee, Illinois, United States
Illinois CancerCare-MacombRecruiting
Macomb, Illinois, United States
Carle Physician Group-Mattoon/CharlestonRecruiting
Mattoon, Illinois, United States
Carle BroMenn Medical CenterRecruiting
Normal, Illinois, United States
Carle Cancer Institute NormalRecruiting
Normal, Illinois, United States
Cancer Care Center of O'FallonRecruiting
O'Fallon, Illinois, United States
HSHS Saint Elizabeth's HospitalRecruiting
O'Fallon, Illinois, United States
Illinois CancerCare-Ottawa ClinicRecruiting
Ottawa, Illinois, United States
Illinois CancerCare-PekinRecruiting
Pekin, Illinois, United States
Illinois CancerCare-PeoriaRecruiting
Peoria, Illinois, United States
Illinois CancerCare-PeruRecruiting
Peru, Illinois, United States
Illinois CancerCare-PrincetonRecruiting
Princeton, Illinois, United States
Memorial Hospital EastRecruiting
Shiloh, Illinois, United States
Southern Illinois University School of MedicineRecruiting
Springfield, Illinois, United States
Springfield ClinicRecruiting
Springfield, Illinois, United States
Springfield Memorial HospitalRecruiting
Springfield, Illinois, United States
Carle Cancer CenterRecruiting
Urbana, Illinois, United States
Illinois CancerCare - WashingtonRecruiting
Washington, Illinois, United States
UI Health Care Mission Cancer and Blood - Ankeny ClinicRecruiting
Ankeny, Iowa, United States
Saint Anthony Regional HospitalRecruiting
Carroll, Iowa, United States
Mercy HospitalRecruiting
Cedar Rapids, Iowa, United States
Oncology Associates at Mercy Medical CenterRecruiting
Cedar Rapids, Iowa, United States
UI Health Care Mission Cancer and Blood - West Des Moines ClinicRecruiting
Clive, Iowa, United States
Iowa Methodist Medical CenterRecruiting
Des Moines, Iowa, United States
UI Health Care Mission Cancer and Blood - Des Moines ClinicRecruiting
Des Moines, Iowa, United States
Broadlawns Medical CenterRecruiting
Des Moines, Iowa, United States
Mercy Medical Center - Des MoinesRecruiting
Des Moines, Iowa, United States
UI Health Care Mission Cancer and Blood - Laurel ClinicRecruiting
Des Moines, Iowa, United States
UI Healthcare Mission Cancer and Blood - Fort DodgeRecruiting
Fort Dodge, Iowa, United States
UI Healthcare Mission Cancer and Blood - PellaRecruiting
Pella, Iowa, United States
UI Health Care Mission Cancer and Blood - Waukee ClinicRecruiting
Waukee, Iowa, United States
Cancer Center of Kansas - ChanuteRecruiting
Chanute, Kansas, United States
Cancer Center of Kansas - Dodge CityRecruiting
Dodge City, Kansas, United States
Cancer Center of Kansas - El DoradoRecruiting
El Dorado, Kansas, United States
Cancer Center of Kansas-IndependenceRecruiting
Independence, Kansas, United States
University of Kansas Cancer CenterRecruiting
Kansas City, Kansas, United States
Cancer Center of Kansas-KingmanRecruiting
Kingman, Kansas, United States
Cancer Center of Kansas-LiberalRecruiting
Liberal, Kansas, United States
Cancer Center of Kansas - McPhersonRecruiting
McPherson, Kansas, United States
Cancer Center of Kansas - NewtonRecruiting
Newton, Kansas, United States
The University of Kansas Cancer Center - OlatheRecruiting
Olathe, Kansas, United States
University of Kansas Cancer Center-Overland ParkRecruiting
Overland Park, Kansas, United States
Cancer Center of Kansas - ParsonsRecruiting
Parsons, Kansas, United States
Cancer Center of Kansas - PrattRecruiting
Pratt, Kansas, United States
Cancer Center of Kansas - SalinaRecruiting
Salina, Kansas, United States
University of Kansas Health System Saint Francis CampusRecruiting
Topeka, Kansas, United States
Cancer Center of Kansas - WellingtonRecruiting
Wellington, Kansas, United States
University of Kansas Hospital-Westwood Cancer CenterRecruiting
Westwood, Kansas, United States
Cancer Center of Kansas-Wichita Medical Arts TowerRecruiting
Wichita, Kansas, United States
Ascension Via Christi Hospitals WichitaRecruiting
Wichita, Kansas, United States
Cancer Center of Kansas - WichitaRecruiting
Wichita, Kansas, United States
Cancer Center of Kansas - WinfieldRecruiting
Winfield, Kansas, United States
The James Graham Brown Cancer Center at University of LouisvilleRecruiting
Louisville, Kentucky, United States
UofL Health Medical Center NortheastRecruiting
Louisville, Kentucky, United States
Trinity Health IHA Medical Group Hematology Oncology - BrightonRecruiting
Brighton, Michigan, United States
Trinity Health IHA Medical Group Hematology Oncology - CantonRecruiting
Canton, Michigan, United States
Trinity Health IHA Medical Group Hematology Oncology - Chelsea HospitalRecruiting
Chelsea, Michigan, United States
University of Michigan Health - Sparrow LansingRecruiting
Lansing, Michigan, United States
Trinity Health Saint Mary Mercy Livonia HospitalRecruiting
Livonia, Michigan, United States
Trinity Health Saint Joseph Mercy Oakland HospitalRecruiting
Pontiac, Michigan, United States
Trinity Health IHA Medical Group Hematology Oncology Ann Arbor CampusRecruiting
Ypsilanti, Michigan, United States
Sanford Joe Lueken Cancer CenterRecruiting
Bemidji, Minnesota, United States
Essentia Health Saint Joseph's Medical CenterRecruiting
Brainerd, Minnesota, United States
Mercy HospitalRecruiting
Coon Rapids, Minnesota, United States
Essentia Health - Deer River ClinicRecruiting
Deer River, Minnesota, United States
Essentia Health Cancer CenterRecruiting
Duluth, Minnesota, United States
Essentia Health Hibbing ClinicRecruiting
Hibbing, Minnesota, United States
Abbott-Northwestern HospitalRecruiting
Minneapolis, Minnesota, United States
Park Nicollet Clinic - Saint Louis ParkRecruiting
Saint Louis Park, Minnesota, United States
Regions HospitalRecruiting
Saint Paul, Minnesota, United States
United HospitalRecruiting
Saint Paul, Minnesota, United States
Essentia Health SandstoneRecruiting
Sandstone, Minnesota, United States
Essentia Health Virginia ClinicRecruiting
Virginia, Minnesota, United States
Baptist Memorial Hospital and Cancer Center-DesotoRecruiting
Southhaven, Mississippi, United States
Saint Francis Medical CenterRecruiting
Cape Girardeau, Missouri, United States
Siteman Cancer Center at Saint Peters HospitalRecruiting
City of Saint Peters, Missouri, United States
Siteman Cancer Center at West County HospitalRecruiting
Creve Coeur, Missouri, United States
Parkland Health Center - FarmingtonRecruiting
Farmington, Missouri, United States
University of Kansas Cancer Center - BriarcliffRecruiting
Kansas City, Missouri, United States
University of Kansas Cancer Center - NorthRecruiting
Kansas City, Missouri, United States
University of Kansas Cancer Center - Lee's SummitRecruiting
Lee's Summit, Missouri, United States
Sainte Genevieve County Memorial HospitalRecruiting
Sainte Genevieve, Missouri, United States
Washington University School of MedicineRecruiting
St Louis, Missouri, United States
Siteman Cancer Center-South CountyRecruiting
St Louis, Missouri, United States
Missouri Baptist Medical CenterRecruiting
St Louis, Missouri, United States
Siteman Cancer Center at Christian HospitalRecruiting
St Louis, Missouri, United States
Missouri Baptist Sullivan HospitalRecruiting
Sullivan, Missouri, United States
Community Hospital of AnacondaRecruiting
Anaconda, Montana, United States
Billings Clinic Cancer CenterRecruiting
Billings, Montana, United States
Bozeman Health Deaconess HospitalRecruiting
Bozeman, Montana, United States
Benefis Sletten Cancer InstituteRecruiting
Great Falls, Montana, United States
Logan Health Medical CenterRecruiting
Kalispell, Montana, United States
Community Medical CenterRecruiting
Missoula, Montana, United States
Jefferson Cherry Hill HospitalRecruiting
Cherry Hill, New Jersey, United States
Sidney Kimmel Cancer Center Washington TownshipRecruiting
Sewell, New Jersey, United States
University of RochesterRecruiting
Rochester, New York, United States
Wilmot Cancer Institute at WebsterRecruiting
Webster, New York, United States
UNC Lineberger Comprehensive Cancer CenterRecruiting
Chapel Hill, North Carolina, United States
Duke University Medical CenterRecruiting
Durham, North Carolina, United States
Margaret R Pardee Memorial HospitalRecruiting
Hendersonville, North Carolina, United States
Sanford Bismarck Medical CenterRecruiting
Bismarck, North Dakota, United States
Essentia Health Cancer Center-South University ClinicRecruiting
Fargo, North Dakota, United States
Sanford Broadway Medical CenterRecruiting
Fargo, North Dakota, United States
Sanford Roger Maris Cancer CenterRecruiting
Fargo, North Dakota, United States
Ohio State University Comprehensive Cancer CenterRecruiting
Columbus, Ohio, United States
University of Oklahoma Health Sciences CenterRecruiting
Oklahoma City, Oklahoma, United States
Saint Alphonsus Cancer Care Center-Baker CityRecruiting
Baker City, Oregon, United States
Providence Newberg Medical CenterRecruiting
Newberg, Oregon, United States
Saint Alphonsus Cancer Care Center-OntarioRecruiting
Ontario, Oregon, United States
Providence Willamette Falls Medical CenterRecruiting
Oregon City, Oregon, United States
Providence Portland Medical CenterRecruiting
Portland, Oregon, United States
Providence Saint Vincent Medical CenterRecruiting
Portland, Oregon, United States
Thomas Jefferson University HospitalRecruiting
Philadelphia, Pennsylvania, United States
Jefferson Torresdale HospitalRecruiting
Philadelphia, Pennsylvania, United States
Sanford Cancer Center Oncology ClinicRecruiting
Sioux Falls, South Dakota, United States
Sanford USD Medical Center - Sioux FallsRecruiting
Sioux Falls, South Dakota, United States
Avera Cancer Institute at YanktonRecruiting
Yankton, South Dakota, United States
Baptist Memorial Hospital and Cancer Center-ColliervilleRecruiting
Collierville, Tennessee, United States
Baptist Memorial Hospital and Cancer Center-MemphisRecruiting
Memphis, Tennessee, United States
Swedish Cancer Institute-EdmondsRecruiting
Edmonds, Washington, United States
Swedish Cancer Institute-IssaquahRecruiting
Issaquah, Washington, United States
Swedish Medical Center-First HillRecruiting
Seattle, Washington, United States
Duluth Clinic AshlandRecruiting
Ashland, Wisconsin, United States
Saint Vincent Hospital Cancer Center Green BayRecruiting
Green Bay, Wisconsin, United States
Saint Vincent Hospital Cancer Center at Saint Mary'sRecruiting
Green Bay, Wisconsin, United States
Gundersen Lutheran Medical CenterRecruiting
La Crosse, Wisconsin, United States
William S Middleton VA Medical CenterRecruiting
Madison, Wisconsin, United States
ProHealth D N Greenwald CenterRecruiting
Mukwonago, Wisconsin, United States
ProHealth Oconomowoc Memorial HospitalRecruiting
Oconomowoc, Wisconsin, United States
Saint Vincent Hospital Cancer Center at Oconto FallsRecruiting
Oconto Falls, Wisconsin, United States
Saint Vincent Hospital Cancer Center at Sturgeon BayRecruiting
Sturgeon Bay, Wisconsin, United States
UW Cancer Center at ProHealth CareRecruiting
Waukesha, Wisconsin, United States
Testing the Addition of Anti-Cancer Drug Sonrotoclax, to the Standard Treatment Zanubrutinib, for Previously Untreated CLL/SLL · TrialPath