Study of Acalabrutinib (ACP-196) in Combination With Venetoclax (ABT-199), With and Without Obinutuzumab (GA101) Versus Chemoimmunotherapy for Previously Untreated CLL

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of acalabrutinib in combination with venetoclax and acalabrutinib in combination with venetoclax with and without obinutuzumab compared to chemoimmunotherapy in subjects with previously untreated CLL

Detailed Description
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This randomized, global, multicenter, open-label, Phase 3 study will evaluate the efficacy and safety of AV and AVG versus chemoimmunotherapy (FCR or BR) in subjects with previously untreated CLL without del(17p) or TP53. Subjects will be randomized in a 1:1:1 ratio into 3 arms through a block stratified randomization procedure. The study includes screening (35 days), treatment (from randomization until study drug discontinuation) and follow-up phase.

Official Title
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A Randomized, Multicenter, Open-Label, Phase 3 Study to Compare the Efficacy and Safety of Acalabrutinib (ACP-196) in Combination With Venetoclax With and Without Obinutuzumab Compared to Investigator's Choice of Chemoimmunotherapy in Subjects With Previously Untreated Chronic Lymphocytic Leukemia Without Del(17p) or TP53 Mutation

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: Acalabrutinib
* Drug: Venetoclax
* Drug: Chemoimmunotherapy
* Drug: Obinutuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women ≥18 years of age. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Diagnosis of CLL that meets published diagnostic criteria (Hallek et al. 2018) Active disease per IWCLL 2018 criteria that requires treatment. Participants must use highly effective birth control throughout the study. Exclusion Criteria: Any prior CLL-specific therapies. Detected del(17p) or TP53 mutation. Transformation of CLL to aggressive non-Hodgkin lymphoma (NHL) (e.g., Richter's transformation, prolymphocytic leukemia [PLL], or diffuse large B cell lymphoma [DLBCL]), or central nervous system (CNS) involvement by leukemia. History of confirmed progressive multifocal leukoencephalopathy (PML). Received any investigational drug within 30 days before first dose of study drug. Major surgical procedure within 30 days before the first dose of study drug. 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. Note: Subjects with controlled, asymptomatic atrial fibrillation are allowed to enroll on study. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach, or extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass. Received a live virus vaccination within 28 days of first dose of study drug. Known history of infection with human immunodeficiency virus (HIV). Serologic status reflecting active hepatitis B or C infection. History of known hypersensitivity or anaphylactic reactions to study drugs or excipients. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug. Known bleeding disorders. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists. Female participants must not be breastfeeding or pregnant. Concurrent participation in another therapeutic clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acalabrutinib, Venetoclax<br>Acalabrutinib in combination with Venetoclax | Drug: Acalabrutinib<br>* Acalabrutinib,<br>* Other names: Calquence (acalabrutinib);Drug: Venetoclax<br>* Venetoclax<br>* Other names: Venclyxto, Venclexta;|
| Experimental: Acalabrutinib, Venetoclax, Obinutuzumab<br>Acalabrutinib in combination with Venetoclax with or without Obinutuzumab | Drug: Acalabrutinib<br>* Acalabrutinib,<br>* Other names: Calquence (acalabrutinib);Drug: Venetoclax<br>* Venetoclax<br>* Other names: Venclyxto, Venclexta;Drug: Obinutuzumab<br>* Obinutuzumab<br>* Other names: Gazyva, Gazyvaro;|
| Active Comparator: Chemoimmunotherapy<br>Chemoimmunotherapy FCR: Fludarabine, Cyclophosphamide and Rituximab | Drug: Chemoimmunotherapy<br>* fludarabine/cyclophosphamide/rituximab (FCR), bendamustine/rituximab (BR)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the efficacy of acalabrutinib with venetoclax (Arm A) compared to chemoimmunotherapy fludarabine/cyclophosphamide/rituximab [FCR] or bendamustine/rituximab [BR] (Arm C): PFS | Progression-free survival (PFS) after randomization, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the Independent Review Committee (IRC) according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 criteria | 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the efficacy of acalabrutinib with venetoclax in combination with obinutuzumab (Arm B) compared with FCR or BR (Arm C): PFS | PFS after randomization, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the IRC assessment and investigator assessment | 6 years | 
| To evaluate the efficacy of acalabrutinib with venetoclax (Arm A) compared with FCR or BR (Arm C): PFS defined the same as above per investigator assessment. | PFS after randomization, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the IRC assessment and investigator assessment | 6 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CLL, Chronic Leukemia Lymphocytic, Leukemia