Phase 2 Study of Combination Pirtobrutinib (LOXO-305) and Venetoclax in CLL Patients With Resistance to Covalent BTKi
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.
• 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
• Platelets ≥ 50 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
• Prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 1.5 x ULN
• No known inherited qualitative platelet defect (e.g. delta granule storage pool deficiency)
• Willing and able to complete study activities and treatment
• Willing and capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol
• Willingness of men and women of reproductive potential and their partners to observe conventional and highly effective or acceptable birth control methods for the duration of treatment and for 6 months following the last dose of pirtobrutinib or 30 days from the last dose of venetoclax
• ELIGIBILITY FOR RE-TREATMENT WITH PIRTOBRUTINIB: Discontinued initial study treatment ≤ 12 months ago
• ELIGIBILITY FOR RE-TREATMENT WITH PIRTOBRUTINIB: Meets iwCLL 2018 criteria for progressive disease