Tafasitamab With Acalabrutinib and Venetoclax for the Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of tafasitamab in combination with acalabrutinib and venetoclax, as assessed by unacceptable toxicity, in patients with previously untreated CLL/SLL. (Safety lead-in) II. To evaluate efficacy of tafasitamab in combination with acalabrutinib and venetoclax, as assessed by complete response (CR) with undetectable minimal residual disease (MRD) by flow cytometry in peripheral blood, in patients with previously untreated CLL/SLL. (Phase 2) SECONDARY OBJECTIVES: I. To evaluate the safety and tolerability of tafasitamab in combination with acalabrutinib and venetoclax, as assessed by all toxicities. II. To evaluate efficacy of tafasitamab in combination with acalabrutinib and venetoclax, as assessed by overall response rate (ORR), progression-free survival (PFS), duration of response (DOR) and overall survival (OS). EXPLORATORY OBJECTIVES: I. To evaluate MRD status in the bone marrow by flow cytometry and by Clonoseq in patients with previously untreated CLL/SLL treated with tafasitamab in combination with acalabrutinib and venetoclax. II. To explore the association between the potential risk factors (including IGHV mutation, del17p/TP53 mutation, complex cytogenetics) and the clinical outcomes in patients with previously untreated CLL/SLL treated with tafasitamab in combination with acalabrutinib and venetoclax. OUTLINE: CYCLES 1 AND 2: Patients receive acalabrutinib orally (PO) twice daily (BID) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. CYCLES 3-5: Patients receive acalabrutinib PO BID, venetoclax PO once daily (QD) on days 1-28, and tafasitamab intravenously (IV) over 1.5-2.5 hours on days 1, 8, 15 and 22 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. CYCLES 6-8: Patients receive acalabrutinib PO BID, venetoclax PO QD on days 1-28, and tafasitamab IV over 1.5-2.5 hours on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. CYCLES 9-14: Patients receive acalabrutinib PO BID and venetoclax PO QD on days 1-28 and tafasitamab IV over 1.5-2.5 hours on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo urine sample collection and bone marrow biopsy at screening, as well as computed tomography (CT) scan or positron emission tomography (PET)-CT scan and blood sample collection throughout the study. After completion of study treatment, patients are followed up every 3 months until progressive disease, then every 6 months, up to 3 years.