Pirtobrutinib (LOXO-305) and Venetoclax for the Treatment of Patients With CLL or SLL Resistant to Covalent BTKi

NCT06466122 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: OSU-22172NCI-2024-04627
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II trial tests how well pirtobrutinib (LOXO-305) and venetoclax works in treating patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that remains despite treatment (resistant) with covalent bruton tyrosine kinase inhibitors (BTKi). Pirtobrutinib is in a class of medications called kinase inhibitors. It works by blocking the action of the a protein that signals cancer cells to multiply. 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. Giving pirtobrutinib and venetoclax may kill more cancer cells in patients with CLL or SLL that is resistant to covalent BTKi.

Conditions

Small Lymphocytic Lymphoma; Chronic Lymphocytic Leukemia

Outcome Measures

Primary Outcomes (1)

• Rate of undetectable minimal residual disease (uMRD)

  The rate of uMRD will be defined as the percentage of patients who have uMRD in both the peripheral blood and bone marrow at C21D1.

  At cycle 21 day 1 (C21D1) [each cycle lasts 28 days]

Secondary Outcomes (7)

• Best overall response rate (ORR)

  At cycle 21 day 1 (C21D1) [each cycle lasts 28 days]

• Overall Response Rate (ORR)

  At cycle 21 day 1 (C21D1) [each cycle lasts 28 days]

• Progression-free survival (PFS) for all patients

  At start of treatment to progression or death up to 18 months after completion of study treatment

• PFS in patients who achieve uMRD and those who do not achieve uMRD with pirtobrutinib and venetoclax

  At end of treatment to progression or death up to 18 months after completion of study treatment

• Overall survival (OS) for all patients

  At start of treatment to death up to 18 months after completion of study treatment

Study Arms (1)

Treatment (pirtobrutinib, venetoclax)

EXPERIMENTAL

Patients receive pirtobrutinib PO QD on days 1-28 of each cycle and receive venetoclax PO QD on days 1-28 of cycles 2-20. Cycles repeat every 28 days for up to 20 cycles in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression within 12 months of stopping combination treatment may receive pirtobrutinib PO QD in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, bone marrow aspiration and biopsy and CT throughout the study.

Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Procedure: Computed Tomography; Drug: Pirtobrutinib; Drug: Venetoclax

Interventions

Biospecimen Collection PROCEDURE

Undergo blood sample collection

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

Treatment (pirtobrutinib, venetoclax)

Bone Marrow Aspiration PROCEDURE

Undergo bone marrow aspiration and biopsy

Treatment (pirtobrutinib, venetoclax)

Bone Marrow Biopsy PROCEDURE

Undergo bone marrow aspiration and biopsy

Also known as: Biopsy of Bone Marrow, Biopsy, Bone Marrow

Treatment (pirtobrutinib, venetoclax)

Computed Tomography PROCEDURE

Undergo CT

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

Treatment (pirtobrutinib, venetoclax)

Pirtobrutinib DRUG

Given PO

Also known as: 5-Amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-((2S)-1,1,1-trifluoropropan-2-yl)-1h-pyrazole-4-carboxamide, BTK Inhibitor LOXO-305, Jaypirca, LOXO 305, LOXO-305, LOXO305, LY3527727

Treatment (pirtobrutinib, venetoclax)

Venetoclax DRUG

Given PO

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

Treatment (pirtobrutinib, venetoclax)

Eligibility Criteria

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

You may qualify if:

• Diagnosis of CLL or SLL according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 guidelines
• Detectable CLL on flow cytometry of the blood or marrow at time of enrollment
• Age ≥ 18 years old
• Eastern Cooperative Oncology Group (ECOG) performance 0-2
• Currently taking ibrutinib, acalabrutinib, or zanubrutinib at any daily dose and tolerating it for \> 4 weeks
• Evidence of progressive disease by iwCLL 2018 criteria for progressive disease or doubling of absolute lymphocyte count (ALC) in ≤ 6 months while on BTK inhibitor provided ALC is \> 5 k/uL
• Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≤ 3 x the upper limit of normal (ULN) or ≤ 5 x ULN with documented liver involvement
• Bilirubin ≤ 1.5 x ULN or ≤ 3 x ULN with documented liver involvement and/or Gilbert's disease
• Creatinine clearance (CrCl) ≥ 30 according to modified Cockcroft-Gault equation
• Absolute neutrophil count (ANC) ≥ 0.75 k/uL
• Without transfusion or growth factor administration in the 7 days prior to screening
• Any values if cytopenias are due to bone marrow involvement with disease
• Hemoglobin ≥ 8 g/dL
• Without transfusion or growth factor administration in the 7 days prior to screening
• Any values if cytopenias are due to bone marrow involvement with disease

You may not qualify if:

• Inability to tolerate 2 Liters of oral or intravenous (IV) hydration
• Prior venetoclax exposure \> 13 months or known resistance to venetoclax
• Known hypersensitivity to any of the excipients of pirtobrutinib or venetoclax
• Need for treatment with warfarin or other vitamin K antagonist during study treatment
• History of bleeding diathesis
• Patients who experienced a major bleeding event or grade ≥ 3 arrhythmia on prior treatment with a BTK inhibitor. Major bleeding is defined as bleeding having one or more of the following features: potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in the hemoglobin level of at least 2g per deciliter; or bleeding in a critical area or organ (e.g., retroperitoneal, intraarticular, pericardial, epidural, or intracranial bleeding or intramuscular bleeding with compartment syndrome)
• History of stroke or intracranial hemorrhage within 6 months
• Inability to take pills or oral medications
• Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of either pirtobrutinib or venetoclax
• Current known central nervous system involvement with CLL or SLL. Patients with previous treatment for central nervous system (CNS) involvement who are neurologically stable and without evidence of disease may be eligible if a compelling clinical rationale is provided by the investigator and with documented approval by the principal investigator
• Treatment with the following:
• Targeted agents, investigational agents, therapeutic monoclonal antibodies, or cytotoxic chemotherapy within 5 half-lives or 2 weeks, whichever is shorter
• Treatment with immunoconjugated antibody treatment within 10 weeks
• Receipt of broad field radiation ( ≥ 30% of the bone marrow or whole brain radiotherapy) within 14 days or palliative limited field radiation within 7 days prior to study enrollment
• Note: Treatment with ibrutinib, acalabrutinib, or zanubrutinib is allowed. Treatment with topical chemotherapy agents for precancerous skin conditions or skin cancers is allowed

Sponsors & Collaborators

• Kerry Rogers: lead

Study Sites (1)

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

RECRUITING

Related Links

• The Jamesline

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

Specimen Handling; Biopsy; pirtobrutinib; venetoclax

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)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Cytodiagnosis; Cytological Techniques; Diagnostic Techniques, Surgical; Surgical Procedures, Operative

Study Officials

• Kerry A Rogers, MD

  Ohio State University Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

The Ohio State University Comprehensive Cancer Center

CONTACT

800-293-5066; OSUCCCClinicaltrials@osumc.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 INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 7, 2024
• First Posted: June 20, 2024
• Study Start: November 7, 2024
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: February 19, 2026

Record last verified: 2026-02

Locations

US (1)