Primary Objective:~I. To estimate the therapeutic efficacy of pirtobrutinib consolidation in patients who have detectable CLL in peripheral blood after receiving venetoclax for at least 12 cycles. The primary endpoint will be the rate of undetectable MRD (U-MRD4) in the peripheral blood, assessed by NGS at a threshold of 0.01% sensitivity, after 24 cycles of combination therapy.~SECONDARY OBJECTIVES:~I. Determine the complete remission (CR)/complete remission with incomplete marrow recovery (CRi) rate after 6, 12 18 and 24 cycles of combination therapy, in patients who were not in CR/CRi at study initiation and estimate the time to best response with this combination.~II. Determine the cumulative rate of blood and bone marrow minimal residual disease undetectable minimal residual disease (MRD) by next generation sequencing (NGS) at thresholds of 0.01% sensitivity (MRD4), 0.001% sensitivity (MRD5) and 0.0001% sensitivity (MRD6).~III. Achievement of undetectable MRD at a sensitivity of 0.0001% (MRD6) in the bone marrow in patients who achieve undetectable (U)-MRD6 in peripheral blood.~IV. Determine the safety of combined pirtobrutinib and venetoclax. V. Determine the progression-free and overall survival.~OUTLINE:~Patients receive pirtobrutinib orally (PO) once daily (QD) and venetoclax PO QD on days 1-28. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. After 24 cycles of combination therapy, patients who achieve U-MRD4 discontinue therapy. Patients who do not achieve U-MRD4 receive pirtobrutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 36 cycles in the absence of disease progression or unacceptable toxicity.~After completion of study treatment, patients are followed up at 4 weeks, and then every 24 weeks (6 months) for up to 5 years.
To learn if the combination of LOXO-305 (pirtobrutinib) and venetoclax can help to control previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).