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

• ClinicalTrials.gov Identifier: NCT03836261
• Recruitment Status: Recruiting
• First Posted: February 11, 2019
• Last Update Posted: March 20, 2023
• Sponsor: Acerta Pharma BV
• Collaborator: AstraZeneca
• Information provided by (Responsible Party): Acerta Pharma BV

Tracking Information

• First Submitted Date: February 6, 2019
• First Posted Date: February 11, 2019
• Last Update Posted Date: March 20, 2023
• Actual Study Start Date: February 25, 2019
• Estimated Primary Completion Date: January 6, 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 8, 2019)

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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 23, 2019)

• To evaluate the efficacy of acalabrutinib with venetoclax in combination with obinutuzumab (Arm B) compared with FCR or BR (Arm C): PFS [ Time Frame: 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 (Arm A) compared with FCR or BR (Arm C): PFS defined the same as above per investigator assessment. [ Time Frame: 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

Original Secondary Outcome Measures (submitted: February 8, 2019)

To evaluate the efficacy of acalabrutinib with venetoclax in combination with obinutuzumab (Arm B) compared with FCR or BR (Arm C): PFS [ Time Frame: 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 according to the iwCLL 2018 criteria:

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Acalabrutinib (ACP-196) in Combination With Venetoclax (ABT-199), With and Without Obinutuzumab (GA101) Versus Chemoimmunotherapy for Previously Untreated CLL
• Official Title: 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
• 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 Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Chronic Lymphocytic Leukemia

Intervention

• Drug: Acalabrutinib
  Acalabrutinib,
  Other Name: Calquence (acalabrutinib)
• Drug: Venetoclax
  Venetoclax
  Other Name: Venclyxto, Venclexta
• Drug: Chemoimmunotherapy
  fludarabine/cyclophosphamide/rituximab (FCR), bendamustine/rituximab (BR)
• Drug: Obinutuzumab
  Obinutuzumab
  Other Name: Gazyva, Gazyvaro

Study Arms

• Experimental: Acalabrutinib, Venetoclax
  Acalabrutinib in combination with Venetoclax
  Interventions:

  • Drug: Acalabrutinib
  • Drug: Venetoclax
• Experimental: Acalabrutinib, Venetoclax, Obinutuzumab
  Acalabrutinib in combination with Venetoclax with or without Obinutuzumab
  Interventions:

  • Drug: Acalabrutinib
  • Drug: Venetoclax
  • Drug: Obinutuzumab
• Active Comparator: Chemoimmunotherapy

  Chemoimmunotherapy

  FCR: Fludarabine, Cyclophosphamide and Rituximab

  Intervention: Drug: Chemoimmunotherapy

Publications *

• Davids MS, Lampson BL, Tyekucheva S, Wang Z, Lowney JC, Pazienza S, Montegaard J, Patterson V, Weinstock M, Crombie JL, Ng SY, Kim AI, Jacobson CA, LaCasce AS, Armand P, Arnason JE, Fisher DC, Brown JR. Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. Lancet Oncol. 2021 Oct;22(10):1391-1402. doi: 10.1016/S1470-2045(21)00455-1. Epub 2021 Sep 14.
• Gordon MJ, Danilov AV. The evolving role of Bruton's tyrosine kinase inhibitors in chronic lymphocytic leukemia. Ther Adv Hematol. 2021 Jan 30;12:2040620721989588. doi: 10.1177/2040620721989588. eCollection 2021.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 8, 2019): 780
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: January 6, 2027
• Estimated Primary Completion Date: January 6, 2027 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 130 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: AstraZeneca Clinical Study Information Center; 1-877-240-9479; information.center@astrazeneca.com

• Listed Location Countries: Argentina, Australia, Austria, Brazil, Bulgaria, Canada, China, Czechia, Denmark, France, Germany, Hungary, Israel, Italy, Korea, Republic of, Mexico, Netherlands, Poland, Russian Federation, Saudi Arabia, Slovakia, South Africa, Spain, Sweden, Taiwan, Turkey, Ukraine, United Kingdom, United States
• Removed Location Countries: Belgium, Peru

Administrative Information

• NCT Number: NCT03836261
• Other Study ID Numbers: ACE-CL-311; D8221C00001 ( Other Identifier: AstraZeneca )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Acerta Pharma BV
• Original Responsible Party: Same as current
• Current Study Sponsor: Acerta Pharma BV
• Original Study Sponsor: Same as current
• Collaborators: AstraZeneca
• Investigators: Not Provided
• PRS Account: Acerta Pharma BV
• Verification Date: March 2023