A Study of Acalabrutinib Plus Venetoclax Versus Venetoclax Plus Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

NCT05057494 | Active Not Recruiting Phase 3 DMC FDA Drug

• 3 other identifiers: D8220C000272023-505866-27-002021-003936-10
• Study Type: interventional
• Target: 607
• Locations: 7 countries
• Sites: 38

Brief Summary

A study of acalabrutinib plus venetoclax (AV) versus venetoclax plus obinutuzumab (VO) in previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma.

Conditions

Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Keywords

Chronic lymphocytic leukemia; Small lymphocytic lymphoma; Acalabrutinib; Venetoclax; Obinutuzumab; B-cell lymphoma 2 inhibitors

Outcome Measures

Primary Outcomes (1)

• Progression-free Survival (PFS)

  To assess whether minimal residual disease (MRD)-driven finite AV treatment is NI to MRD-driven finite VO treatment with respect to PFS. PFS is defined as the time from the date of randomization until date of objective progressive disease per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria as assessed by the investigator or death from any cause in the absence of progression.

  Until progressive disease (PD) [assessed Up to 6.6 Years].

Secondary Outcomes (11)

• Rate of peripheral blood (PB) undetectable minimal residual disease (uMRD) based on a clonoSEQ^®

  Screening (Days -45 through -1); Arm A (AV): Day 28 of Cycles 8, 14 and 24 and post treatment follow up visits; Arm B (VO): Day 28 of Cycles 6, 12 and 24 and post treatment follow up visits

• Rate of peripheral blood (PB) and Bone marrow (BM) undetectable minimal residual disease (uMRD) by flow cytometry

  Cycle 14 (each Cycle length 28 days) Day 28 for Arm A (AV); Cycle 12 Day 28 for Arm B (VO) and Post treatment follow-up visits (assessed Up to 6.6 Years)

• Overall Survival (OS)

  Date of randomization until death from any cause (Assessed Up to 6.6 Years)

• Event-free Survival (EFS)

  Date of randomization until first occurrence of disease progression (Assessed Up to 6.6 Years)

• Overall Response Rate (ORR)

  Date of randomization until PD (Assessed Up to 6.6 Years)

Study Arms (2)

Arm A: Acalabrutinib plus Venetoclax (AV)

EXPERIMENTAL

Participants will receive acalabrutinib and venetoclax orally.

Drug: Acalabrutinib; Drug: Venetoclax

Arm B: Venetoclax plus Obinutuzumab (VO)

EXPERIMENTAL

Participants will receive Venetoclax orally and Obinutuzumab via IV infusion.

Drug: Venetoclax; Drug: Obinutuzumab

Interventions

Acalabrutinib DRUG

Dose formulation: Capsule or Tablet

Arm A: Acalabrutinib plus Venetoclax (AV)

Venetoclax DRUG

Dose formulation: Tablet

Arm A: Acalabrutinib plus Venetoclax (AV); Arm B: Venetoclax plus Obinutuzumab (VO)

Obinutuzumab DRUG

Dose formulation: Injection

Arm B: Venetoclax plus Obinutuzumab (VO)

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).
• Adequate BM function independent of growth factor or platelet transfusion support within 2 weeks of screening initiation as follows:
• Absolute neutrophil count ≥ 1.0 × 10 9 /L; absolute neutrophil count ≥ 500 cells/μL (≥ 0.50 × 109/L) with documented bone marrow (BM) involvement of chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL).
• 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 (Upper limit of normal (ULN) is based on institutional standards):
• 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).
• Total bilirubin ≤ 1.5 × ULN, unless directly attributable to Gilbert's syndrome.
• An ECOG (Eastern Cooperative Oncology Group) performance status performance status of 0 to 2 with no deterioration over the previous 2 weeks prior to baseline or day of first dosing.
• Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local patient privacy regulations).

You may not qualify if:

• 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.
• 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. Note: Participants with controlled, asymptomatic atrial fibrillation can enroll in the study.
• 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.
• Curatively treated basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) of the skin or carcinoma in situ of the cervix or carcinoma in situ of the prostate at any time prior to study.
• Other cancers that have been curatively treated from which the participant is disease-free for ≥ 3 years without further treatment.
• An individual organ system dysfunction limiting the ability to receive the study intervention or any other life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the participants' safety or interfere with the absorption, distribution, metabolism, or excretion of the study interventions (eg, refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow the formulated product, previous significant bowel resection, or impaired resorption in the gastrointestinal tract).
• Known history of infection with HIV or any active significant infection (eg, bacterial, viral, or fungal; including participants with positive cytomegalovirus (CMV) DNA PCR). CMV testing at screening must include serologic testing for CMV immunoglobulin G (CMV IgG), CMV immunoglobulin M (CMV IgM), and CMV DNA PCR testing. Participants must have a result for CMV DNA PCR that is negative at screening to be eligible for the study.
• History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML).
• Serologic status reflecting active hepatitis B or C infection:
• Hepatitis serology will include HBsAg, anti-HBs, anti-HBc and anti-HCV. Any participant who is both anti-HBc positive and HBsAg negative will need to have a negative HBV DNA PCR result before randomization and must be willing to undergo this PCR testing during the study. Any participant who is either HBsAg positive or hepatitis B DNA PCR positive will be excluded.
• Participants who are hepatitis C antibody positive or inconclusive will need to have a negative HCV RNA PCR result before randomization. Those who are hepatitis C PCR positive will be excluded.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (38)

Research Site

Tucson, Arizona, 85710, United States

Location

Research Site

La Jolla, California, 92093-0052, United States

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Longmont, Colorado, 80501, United States

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Jacksonville, Florida, 32256, United States

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Boston, Massachusetts, 02115, United States

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St Louis, Missouri, 63110, United States

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Buffalo, New York, 14263, United States

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New Hyde Park, New York, 11040, United States

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New York, New York, 10065, United States

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Rochester, New York, 14642, United States

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Charlotte, North Carolina, 28204, United States

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Cleveland, Ohio, 44195, United States

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Eugene, Oregon, 97401, United States

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Philadelphia, Pennsylvania, 19104, United States

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Nashville, Tennessee, 37203, United States

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Salt Lake City, Utah, 84112, United States

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Charlottesville, Virginia, 22908, United States

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Seattle, Washington, 98104, United States

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Seattle, Washington, 98109, United States

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Clayton, 3168, Australia

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Geelong, 3220, Australia

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Nedlands, 6009, Australia

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Waratah, 2298, Australia

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Hradec Králové, 500 05, Czechia

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Ostrava - Poruba, 708 52, Czechia

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Pilsen, 30460, CZ, Czechia

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Montpellier, 34295, France

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Tours, 37044, France

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Budapest, 1097, Hungary

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Debrecen, 4032, Hungary

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Bydgoszcz, 85-168, Poland

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Gdansk, 80-219, Poland

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Katowice, 40-519, Poland

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Krakow, 30-727, Poland

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Lódz, 93-513, Poland

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Lublin, 20-090, Poland

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Barcelona, 08025, Spain

Location

Research Site

Palma de Mallorca, 07010, Spain

Location

Related Publications (1)

• Ryan CE, Davids MS, Hermann R, Shahkarami M, Biondo J, Abhyankar S, Alhasani H, Sharman JP, Mato AR, Roeker LE. MAJIC: a phase III trial of acalabrutinib + venetoclax versus venetoclax + obinutuzumab in previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Future Oncol. 2022 Oct;18(33):3689-3699. doi: 10.2217/fon-2022-0456. Epub 2022 Sep 14.

  PMID: 36102212 DERIVED

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

acalabrutinib; venetoclax; obinutuzumab

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 16, 2021
• First Posted: September 27, 2021
• Study Start: September 12, 2022
• Primary Completion (Estimated): July 15, 2027
• Study Completion (Estimated): April 10, 2029
• Last Updated: February 18, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

AU (4); PL (6); ES (2); US (19); HU (2); CZ (3); FR (2)