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

Phase 3

Active, not recruiting

• Conditions: Chronic Lymphocytic Leukemia
• Interventions: Drug: Chemoimmunotherapy; Drug: Acalabrutinib; Drug: Venetoclax; Drug: Obinutuzumab

• Registration Number: NCT03836261
• Lead Sponsor: Acerta Pharma BV

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2019-02-06
• Study First Submitted QC: 2019-02-08
• Study First Posted: 2019-02-11
• Study Start: 2019-02-25
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-24
• Last Update Posted: 2024-12-27
• Primary Completion: 2027-01-31
• Study Completion: 2027-01-31

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 984

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Chemoimmunotherapy	Chemoimmunotherapy	Chemoimmunotherapy FCR: Fludarabine, Cyclophosphamide and Rituximab BR: Bendamustine and Rituximab
Acalabrutinib, Venetoclax, Obinutuzumab	Acalabrutinib	Acalabrutinib in combination with Venetoclax with Obinutuzumab
Acalabrutinib, Venetoclax	Acalabrutinib	Acalabrutinib in combination with Venetoclax
Acalabrutinib, Venetoclax	Venetoclax	Acalabrutinib in combination with Venetoclax
Acalabrutinib, Venetoclax, Obinutuzumab	Obinutuzumab	Acalabrutinib in combination with Venetoclax with Obinutuzumab
Acalabrutinib, Venetoclax, Obinutuzumab	Venetoclax	Acalabrutinib in combination with Venetoclax with Obinutuzumab

Primary Outcome Measures

Name	Time	Method
To evaluate the efficacy of acalabrutinib with venetoclax (Arm A) compared to chemoimmunotherapy fludarabine/cyclophosphamide/rituximab [FCR] or bendamustine/rituximab [BR] (Arm C): PFS	6 years	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

Secondary Outcome Measures

Name	Time	Method
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.	6 years	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
To evaluate the efficacy of acalabrutinib with venetoclax in combination with obinutuzumab (Arm B) compared with FCR or BR (Arm C): PFS	6 years	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

Trial Locations

Locations (1)

Research Site; 🇬🇧 Wolverhampton, United Kingdom