Acalabrutinib, Venetoclax and Durvalumab for the Treatment of Richter Transformation From Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

NCT05388006 | Recruiting Phase 2 DMC FDA Drug

• 3 other identifiers: MC198BNCI-2022-0206820-006487
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 3

Brief Summary

This phase II trial tests whether acalabrutinib, venetoclax, and durvalumab work in treating patients with Richter transformation from chronic lymphocytic leukemia or small lymphocytic lymphoma. Richter transformation is a rare condition in which chronic lymphocytic leukemia or small lymphocytic lymphoma changes into a fast-growing type of lymphoma. Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving acalabrutinib, venetoclax, and durvalumab may help improve survival in patients with Richter transformation.

Conditions

Richter Syndrome; Small Lymphocytic Lymphoma; Chronic Lymphocytic Leukemia

Outcome Measures

Primary Outcomes (1)

• Progression free survival

  Progression will be defined by Lugano positron emission tomography (PET)-computed tomography (CT) based criteria or chronic lymphocytic leukemia (CLL) criteria. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Ninety-five percent confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner. If patients are censored prior to 6 months, a Kaplan Meier estimate for progression-free survival at 6 months along with the 95% confidence intervals will be reported.

  At 6 months (end of cycle 6). Each cycle is 28 days.

Secondary Outcomes (5)

• Overall response rate

  Up to 1 year

• Overall survival

  From registration to death due to any cause, assessed up to 5 years

• Progression-free survival (PFS)

  From registration to progression or death due to any cause, assessed up to 2 years

• Treatment-free survival

  From registration to subsequent treatment or death due to any cause, assessed up to 5 years

• Incidence of adverse events

  Up to 30 days after last dose of study drug

Study Arms (1)

Treatment (acalabrutinib, durvalumab, venetoclax)

EXPERIMENTAL

Patients receive acalabrutinib PO BID on days 1-28, durvalumab IV over 1 hour on day 1, and venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive acalabrutinib PO BID and venetoclax PO QD on days 1-90 of each cycle. Cycles repeat every 90 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, bone marrow aspiration and biopsy, and PET/CT or CT throughout the study.

Drug: Acalabrutinib; Biological: Durvalumab; Drug: Venetoclax; Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Procedure: Positron Emission Tomography (PET); Procedure: Computed Tomography

Interventions

Durvalumab BIOLOGICAL

Given IV

Also known as: Imfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736

Treatment (acalabrutinib, durvalumab, venetoclax)

Venetoclax DRUG

Given PO

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

Treatment (acalabrutinib, durvalumab, venetoclax)

Bone Marrow Aspiration PROCEDURE

Undergo bone marrow aspiration

Treatment (acalabrutinib, durvalumab, venetoclax)

Bone Marrow Biopsy PROCEDURE

Undergo bone marrow biopsy

Also known as: Biopsy of Bone Marrow

Treatment (acalabrutinib, durvalumab, venetoclax)

Positron Emission Tomography (PET) PROCEDURE

Undergo PET/CT

Also known as: Medical Imaging, Positron Emission Tomography, PET, Pet Scan, positron emission tomography scan, PT

Treatment (acalabrutinib, durvalumab, venetoclax)

Computed Tomography PROCEDURE

Undergo PET/CT or CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized Tomography (CT) scan, CT

Treatment (acalabrutinib, durvalumab, venetoclax)

Acalabrutinib DRUG

Given PO

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

Treatment (acalabrutinib, durvalumab, venetoclax)

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Treatment (acalabrutinib, durvalumab, venetoclax)

Eligibility Criteria

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

You may qualify if:

• Age \>= 18 years willing to provide consent and follow-up
• Diagnosis of CLL according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 criteria (Hallek et al., 2018) or small lymphocytic lymphoma (SLL) according to the World Health Organization (WHO) 2008 criteria (Harris, 1999). This includes previous documentation of:
• Biopsy-proven SLL according to WHO 2008 criteria, or
• Diagnosis of CLL according to IWCLL 2018 criteria as evidenced by all of the following:
• Peripheral blood B cell count of \>= 5 x 10\^9/L consisting of small to moderate size lymphocytes (If there are enough evidence to document the prior diagnosis of CLL, it is not required to meet the criteria of peripheral blood B cell count more than 5 x 10\^9/L )
• Immunophenotyping consistent with CLL defined as:
• The predominant population of lymphocytes share both B-cell antigens (CD19, CD20 \[typically dim expression\], or CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc.)
• Clonality as evidenced by kappa or lambda light chain expression (typically dim immunoglobulin expression) or other genetic method (e.g. immunoglobulin heavy chain variable \[IGHV\] analysis)
• NOTE: Splenomegaly, hepatomegaly, or lymphadenopathy are not required for the diagnosis of CLL
• Before diagnosing CLL or SLL, mantle cell lymphoma must be excluded by demonstrating a negative fluorescence in situ hybridization (FISH) analysis for t(11;14)(IgH/CCND1) on peripheral blood or tissue biopsy or negative immunohistochemical stains for cyclin D1 on involved tissue biopsy
• If prior CLL diagnosis was confirmed, or CLL diagnosis was confirmed on bone marrow examination or tissue biopsy, peripheral blood B cell count less than 5 x 10\^9/L is allowed
• Biopsy proven Richter's transformation of the CLL
• NOTE: Previously treated patients including CLL therapy can be enrolled. If Richter's transformation (RT) developed from prior untreated CLL and has not received any RT directed therapy, then patient is not eligible
• Richter patients with prior or concurrent CLL diagnosis and do not have other option for standard therapy per treating physician's discretion
• Measurable disease can be detected in positron emission tomography (PET) or computed tomography (CT) (\>= 1 cm in diameter)

You may not qualify if:

• Any of the following uncontrolled intercurrent illness:
• Clinically significant cardiovascular disease such as:
• Symptomatic arrhythmias
• Congestive heart failure
• Myocardial infarction =\< 3 months prior to registration
• Any class 3 or 4 cardiac disease as defined by the New York Heart Association functional classification
• Uncontrolled hypertension
• Unstable angina pectoris
• Note: Subjects with controlled, asymptomatic atrial fibrillation can enroll on study
• Serious chronic gastrointestinal conditions associated with diarrhea
• History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML)
• History of stroke or intracranial hemorrhage within 6 months before first dose of study drug
• History of bleeding diathesis (e.g., hemophilia, von Willebrand disease)
• Active uncontrolled infection (e.g., bacterial, viral or fungal, including subjects with positive cytomegalovirus \[CMV\] deoxyribonucleic acid \[DNA\] polymerase chain reaction \[PCR\]) requiring systemic therapy. NOTE: When the infection is controlled with systemic therapy, patients are permitted for this study
• Active tuberculosis infection (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis \[TB\] testing in line with local practice)

Sponsors & Collaborators

• Mayo Clinic: lead

Study Sites (3)

Stanford Cancer Institute Palo Alto

Palo Alto, California, 94304, United States

NOT YET RECRUITING

Mayo Clinic in Rochester

Rochester, Minnesota, 55905, United States

RECRUITING

Washington University School of Medicine

St Louis, Missouri, 63110, United States

WITHDRAWN

Related Links

• Mayo Clinic Clinical Trials

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

acalabrutinib; durvalumab; Immunoglobulin G; Disulfides; venetoclax; Specimen Handling; 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)

Immunoglobulin Isotypes; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Sulfides; Anions; Ions; Electrolytes; Inorganic Chemicals; Hydrogen Sulfide; Sulfur Compounds; Organic Chemicals; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Spectrum Analysis; Chemistry Techniques, Analytical

Study Officials

• Paul J. Hampel, MD

  Mayo Clinic in Rochester

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Clinical Trials Referral Office

CONTACT

855-776-0015; mayocliniccancerstudies@mayo.edu

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: May 19, 2022
• First Posted: May 24, 2022
• Study Start: January 5, 2023
• Primary Completion (Estimated): February 22, 2027
• Study Completion (Estimated): February 22, 2027
• Last Updated: March 25, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)