Acalabrutinib in Combination With Venetoclax for the Treatment of Refractory or Recurrent Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma, The AVENUE-2 Trial

NCT04941716 | Recruiting Phase 2 DMC FDA Drug

• 3 other identifiers: RG1121341NCI-2021-0594710602
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II trial is to evaluate the effects of acalabrutinib in combination with venetoclax in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma that does not respond to treatment (refractory) or that has come back (recurrent). Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as venetoclax, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Given acalabrutinib and venetoclax may kill more cancer cells.

Conditions

Recurrent Chronic Lymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Small Lymphocytic Lymphoma

Outcome Measures

Primary Outcomes (1)

• Rate of undetectable measurable residual disease (uMRD)

  MRD will be assessed using multicolor flow cytometry (sensitivity 10\^-4) (uMRD4) from peripheral blood (PB).

  At the end of treatment (26 cycles, 1 cycle = 28 days)

Secondary Outcomes (6)

• Overall response rate (ORR)

  Up to 10 years

• Complete response (CR)

  Up to 10 years

• Partial response (PR)

  Up to 10 years

• Progression-free survival (PFS)

  Time from receiving the first treatment to the first observation of disease progression or death from any cause, whichever occurs first, assessed up to 10 years

• Overall survival (OS)

  Time from receiving the first treatment to death from any cause, assessed up to 10 years

Study Arms (1)

Treatment (acalabrutinib, venetoclax)

EXPERIMENTAL

Patients receive acalabrutinib PO BID and venetoclax PO QD on days 1-28. Patients receive acalabrutinib alone for the first three 28 day cycles. Venetoclax is added beginning with Cycle 4. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, bone marrow aspiration and biopsy, and CT or MRI throughout the trial.

Drug: Acalabrutinib; Drug: Venetoclax; Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging

Interventions

Acalabrutinib DRUG

Given PO

Also known as: ACP-196, Bruton Tyrosine Kinase Inhibitor ACP-196, Calquence

Treatment (acalabrutinib, venetoclax)

Venetoclax DRUG

Given PO

Also known as: ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto

Treatment (acalabrutinib, venetoclax)

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Treatment (acalabrutinib, venetoclax)

Bone Marrow Aspiration PROCEDURE

Undergo bone marrow aspiration and biopsy

Treatment (acalabrutinib, venetoclax)

Bone Marrow Biopsy PROCEDURE

Undergo bone marrow aspiration and biopsy

Treatment (acalabrutinib, venetoclax)

Computed Tomography PROCEDURE

Undergo CT

Also known as: CT Scan, CAT Scan, Computed Axial Tomography

Treatment (acalabrutinib, venetoclax)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: MRI

Treatment (acalabrutinib, venetoclax)

Eligibility Criteria

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

You may qualify if:

• Men and women \>= 18 years of age.
• Diagnosis of CLL or small lymphocytic lymphoma (SLL) that meets the published diagnostic criteria.
• Active disease per IWCLL 2018 criteria that require treatment. At least one of the following:
• Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia
• Massive (\> 6 cm below left costal margin), progressive, or symptomatic splenomegaly
• Massive nodes (\> 10 cm in longest diameter), or progressive or symptomatic lymphadenopathy
• Progressive lymphocytosis with an increase of \> 50% over a 2-month period or lymphocyte-doubling time of \< 6 months. Lymphocyte-doubling time may be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In patients with initial blood lymphocyte counts of \< 30 x 109/L lymphocyte-doubling time should not be used as a single parameter to define treatment indication. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL/SLL (e.g., infection) should be excluded.
• Constitutional symptoms, defined as any 1 or more of the following disease-related symptoms or signs
• Unintentional weight loss of \> 10% within the previous 6 months
• Significant fatigue
• Fevers \> 100.5 degrees Fahrenheit (F) or 38 degrees Celsius (C) for 2 weeks without other evidence of infection
• Night sweats for \> 1 month without evidence of infection
• Relapsed or refractory to at least 1 prior systemic therapy for CLL/SLL. A line of therapy is defined as completing at least 2 cycles of treatment of standard regimen according to current National Comprehensive Cancer Network (NCCN) guidelines, or of an investigational regimen on a clinical trial.
• Absolute neutrophil count (ANC) \>= 750 cells/microliter (0.75 x 10\^9/L); ANC \>= 500 cells/microliter (0.50 x 10\^9/L) in subjects with documented bone marrow involvement of CLL (independent of growth factor or transfusion support within 1 week of screening).
• Hemoglobin \>= 10 g/dL (independent of growth factor or transfusion support within 1 week of screening).

You may not qualify if:

• Known prolymphocytic leukemia or history of, or currently suspected, Richter's transformation (biopsy based on clinical suspicion may be needed to rule out transformation)
• Prior disease progression while on a BTK inhibitor
• Prior disease progression while on venetoclax
• Prior intolerance to acalabrutinib or venetoclax
• Prior malignancy (or any other malignancy requiring active treatment), except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, low-grade prostate carcinoma (Gleason grade =\< 6) or other cancer from which the subject has been disease free for \>= 2 years or which will not limit survival to \< 3 years
• Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 or 4 cardiac diseases as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) \> 480 msec at screening. Subjects with controlled, asymptomatic atrial fibrillation during screening can enroll on study.
• Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass. Patients with history of such operations are eligible if in treating physician's opinion they have no absorption issues.
• Known history of drug-specific hypersensitivity or anaphylaxis to acalabrutinib or venetoclax
• Active bleeding or history of bleeding diathesis (e.g. hemophilia or von Willebrand disease), or requires/is receiving anticoagulation with warfarin or equivalent vitamin K antagonists
• Prothrombin time (PT)/international normalized ratio (INR) or activated partial thromboplastic time (aPTT) (in the absence of lupus anticoagulant) \> 2 x ULN
• Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP)
• Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening
• Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor or inducers. The use of strong or moderate CYP3A inhibitors or inducers within 7 days of the first dose of study drug is prohibited.
• For patients receiving capsule formulation of acalabrutinib only: Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole) at the time of enrollment. Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study.
• History of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months before the first dose of study drug

Sponsors & Collaborators

• Fred Hutchinson Cancer Center: lead
• AstraZeneca: collaborator

Study Sites (1)

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

RECRUITING

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

acalabrutinib; venetoclax; Magnetic Resonance Spectroscopy

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

Intervention Hierarchy (Ancestors)

Spectrum Analysis; Chemistry Techniques, Analytical; Investigative Techniques

Study Officials

• Mazyar Shadman

  Fred Hutch/University of Washington Cancer Consortium

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Mazyar Shadman

CONTACT

206-667-5467; mshadman@fredhutch.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 21, 2021
• First Posted: June 28, 2021
• Study Start: May 31, 2023
• Primary Completion (Estimated): August 10, 2027
• Study Completion (Estimated): August 10, 2031
• Last Updated: November 19, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)