A Phase 3 Open Label, Randomized Study of LOXO 305 versus Investigator's Choice of Idelalisib plus Rituximab or Bendamustine plus Rituximab in BTK Inhibitor Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (BRUIN CLL 321)

Prior treatment

• Prior exposure to non covalent (reversible) BTK inhibitor
• Current treatment with strong cytochrome P450 (CYP) 3A4 (CYP3A4) inhibitors or inducers
• Vaccination with a live vaccine within 28 days prior to randomization
• Patients with the following hypersensitivity: 1. Known hypersensitivity, including anaphylaxis, to any component or excipient of pirtobrutinib. For patients planned to receive idelalisib, known hypersensitivity, including anaphylaxis, to any component or excipient of idelalisib. For patients planned to receive bendamustine, known hypersensitivity, including anaphylaxis, to any component or excipient of bendamustine. Prior significant hypersensitivity to rituximab
• Ongoing drug induced liver injury

Other illness

• Clinically significant active malabsorption syndrome or inflammatory bowel disease
• Known or suspected history of central nervous system (CNS) involvement by CLL/SLL
• Significant cardiovascular disease
• History of allogeneic or stem cell transplantation (SCT) or chimeric antigen receptor modified T cells (CAR T) therapy within the past 60 days
• Active hepatitis B or hepatitis C
• Known active cytomegalovirus (CMV) infection
• Active uncontrolled systemic bacterial, viral, fungal or parasitic infection

Lab values

• Known Human Immunodeficiency Virus (HIV) infection, regardless of CD4 count

Other

• Known or suspected Richter's transformation at any time preceding enrollment
• Patients requiring therapeutic anticoagulation with warfarin or another Vitamin K antagonist
• Active uncontrolled auto immune cytopenia

• Age 18 or older per local regulations at time of enrollment.
• Estimated creatinine clearance of ≥ 30 mL/min
• Willing and capable of giving signed informed consent as described in Section 10.1.2 Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
• Confirmed diagnosis of CLL/SLL requiring therapy as defined by iwCLL 2018 criteria
• Previously treated with a covalent BTK inhibitor
• Eastern Cooperative Oncology Group (ECOG) 0 2
• Absolute neutrophil count ≥ 0.75 × 10^9/L without granulocyte colony stimulating factor support, or ≥ 0.50 × 10^9/L in patients with documented bone marrow involvement considered to impair hematopoiesis. Granulocyte colony stimulating factor support is permitted in patients with documented bone marrow involvement
• Hemoglobin ≥ 8 g/dL or ≥ 6 g/dL in patients with documented bone marrow involvement considered to impair hematopoiesis. Transfusion support is permitted in patients with bone marrow involvement
• Platelets ≥ 50 × 10^9/L. If an investigator has chosen bendamustine/rituximab as the Arm B treatment, platelets must be ≥ 75 × 10^9/L. Patients may enroll below these thresholds if the Investigator determines the cytopenia is related to bone marrow involvement considered to impair hematopoiesis. Patients with a platelet count < 30 x 10^9/L are excluded
• AST and ALT ≤ 3.0 x upper limit of normal (ULN)
• Total bilirubin ≤ 1.5 x ULN