A Phase III Open-Label Trial of Acalabrutinib Plus Venetoclax versus Venetoclax plus Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Phase 1

• Conditions: Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma; MedDRA version: 21.1Level: PTClassification code: 10008958Term: Chronic lymphocytic leukaemia Class: 100000004864; MedDRA version: 21.1Level: PTClassification code: 10003908Term: B-cell small lymphocytic lymphoma Class: 100000004864; Therapeutic area: Diseases [C] - Neoplasms [C04]

• Registration Number: CTIS2023-505866-27-00
• Lead Sponsor: Astrazeneca AB

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2024-02-15
• Last Update Posted: 22 July 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 758

Inclusion Criteria

Participant must be = 18 years at the time of signing the consent form, Documented TN CLL/SLL requiring treatment according to iwCLL guidelines 2018 (Hallek et al 2018) including a detectable clonal B-cell population at baseline for purposes of measuring for MRD, Adequate BM function independent of growth factor or platelet transfusion support within 2 weeks of screening initiation as follows: (a) Absolute neutrophil count = 1.0 × 10^9/L; absolute neutrophil count = 500 cells/µL (= 0.50 × 10^9/L) with documented BM involvement of CLL/SLL (b) Platelet counts = 30 × 10^9/L; platelet count = 10 × 10^9/L in participants with documented BM involvement of CLL/SLL, Estimated CrCL of = 30 mL/min, calculated by Cockcroft-Gault (using actual body weight), or serum creatinine < 2 × ULN: Males: CrCL (mL/min) = Weight (kg) × (140 - Age) / 72 × serum creatinine (mg/dL) Females: CrCL (mL/min) = Weight (kg) × (140 - Age) × 0.85 / 72 × serum creatinine (mg/dL), Meet the following laboratory parameters (ULN is based on institutional standards): (a) Serum AST and ALT = 3 × ULN (Higher thresholds may be allowed if hepatic dysfunction is attributable to CLL/SLL and after discussion with the Sponsor Hematology Safety Knowledge Group). (b) Total bilirubin = 1.5 × ULN, unless directly attributable to Gilbert's syndrome, An ECOG performance status of 0 to 2 with no deterioration over the previous 2 weeks prior to baseline or day of first dosing

Exclusion Criteria

As judged by the investigator, any evidence of past or current diseases that, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardize their safety or compliance with the protocol or would put the study at risk, Requires treatment with a strong cytochrome CYP3A4 inhibitor/inducer. The use of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeks of the first dose of study drug is prohibited, Concurrent participation in another therapeutic clinical trial. Use of investigational agents that interfere with the study intervention(s) within 30 days or 5 half-lives (whichever is longer) prior to registration for study screening, Prothrombin time/INR or activated partial thromboplastin time, in the absence of lupus anticoagulant or attributed to anticoagulant (eg, direct oral anticoagulant) > 2 × ULN, Currently pregnant (confirmed with positive pregnancy test) or breast feeding, Women of childbearing potential unless the following criteria are met: a negative pregnancy test at least 30 days before start of study intervention, followed by immediate highly effective contraception; further pregnancy testing will be performed monthly, Clinically significant cardiovascular disease, such as symptomatic arrhythmias, congestive heart failure, or myocardial infarction, within 6 months of screening or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, Active bleeding or history of bleeding diathesis (eg, hemophilia or von Willebrand disease), Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura, History of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months before the first dose of study intervention, Child-Pugh B/C liver cirrhosis, History of prior or current malignancy (including but not limited to known central nervous system involvement such as by CLL/SLL, leptomeningeal disease, or spinal cord compression, known prolymphocytic leukemia or history of, or currently suspected, Richter's syndrome) that could affect compliance with the protocol or interpretation of results. Possible examples where compliance or data interpretation may not be affected could include the following, per physician discretion. (a) Curatively treated BCC or SCC of the skin or carcinoma in situ of the cervix or carcinoma in situ of the prostate at any time prior to study. (b) Other cancers that have been curatively treated from which the participant is disease-free for = 3 years without further treatment, Any prior CLL/SLL-specific therapies, except prior rituximab if used for autoimmune cytopenias and not as anti-CLL/SLL treatment, Corticosteroid use > 20 mg within 1 week before the first dose of study intervention, except as indicated for other medical conditions, such as autoimmune cytopenias, inhaled steroid for asthma, topical steroid use, or as premedication for administration of study intervention or contrast

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To assess whether MRD-driven finite AV treatment is NI to MRD-driven finite VO treatment with respect to PFS;Secondary Objective: To assess the effect of AV treatment compared with VO treatment on uMRD at sequential timepoints, To assess the effect of AV treatment compared with VO treatment on OS, To assess the effect of AV treatment compared with VO treatment on EFS, To assess the effect of AV treatment compared with VO treatment on ORR, To assess symptoms, functional status, global health status/QoL, and patient perceived benefit-risk in participants treated with AV versus VO using the EORTC QLQ-C30, EORTC QLQCLL17, NCI PRO-CTCAE item for Bruising, and PGI-BR;Primary end point(s): PFS, defined as the time from the date of randomization until date of objective progressive disease per iwCLL 2018 criteria as assessed by the investigator or death from any cause in the absence of progression

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s):Rate of peripheral blood uMRD;Secondary end point(s):Overall survival;Secondary end point(s):Event-free survival;Secondary end point(s):Overall response rate;Secondary end point(s):CR rate after completion of 12 cycles of venetoclax;Secondary end point(s):Change from baseline in EORTC QLQ-C30, EORTC QLQ-CLL17 scales;Secondary end point(s):Proportion of participants experiencing bruising;Secondary end point(s):Proportion of participants reporting each response option of the PGI-BR