A Study of Pirtobrutinib (LOXO-305) Versus Ibrutinib in Participants With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Prior treatment

• Previous treatment for CLL/SLL - Part 1: Treatment-naïve and previously treated, except prior exposure to BTK inhibitor (covalent or noncovalent).
  • Part 2: participants must be treatment naïve
• Concurrent use of investigational agent or anticancer therapy except hormonal therapy
• Use of \> 20 mg prednisone daily or equivalent dose of steroid at the time of first dose of study drug
• Vaccination with a live vaccine within 28 days prior to randomization
• Participants receiving chronic therapy with a strong cytochrome P450 (CYP)3A inhibitor (except posaconazole and voriconazole) which cannot be stopped within 3-5 half lives of the CYP3A inhibitor therapy prior to start of study drug treatment

Other illness

• A significant history of renal, neurologic, psychiatric, endocrine, metabolic or immunologic disease
• Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia \[AIHA\], idiopathic thrombocytopenic purpura \[ITP\])
• Active cytomegalovirus (CMV) infection
• Active uncontrolled systemic bacterial, viral, or fungal infection
• Clinically significant active malabsorption syndrome or other condition likely to affect GI absorption of the oral-administered study treatments
• Ongoing inflammatory bowel disease
• Participants with known hypersensitivity, including anaphylaxis, to any component or excipient of pirtobrutinib or ibrutinib

Lab values

• Significant cardiovascular disease including ejection fraction \< 40% and any grade ongoing atrial fibrillation or atrial flutter
• Hepatitis B or hepatitis C testing indicating active/ongoing infection, based on Screening laboratory tests
• Known human immunodeficiency virus (HIV) infection, regardless of cluster of differentiation 4 (CD4) count

Other

• Known or suspected Richter's transformation to diffuse large B-cell lymphoma (DLBCL), prolymphocytic leukemia, or Hodgkin's lymphoma at any time preceding enrollment
• Known or suspected central nervous system (CNS) involvement
• Participants requiring therapeutic anticoagulation with warfarin or another Vitamin K antagonist

• Confirmed diagnosis of CLL/SLL requiring therapy per iwCLL 2018 criteria
• Part 1 - Known 17p deletion status (wildtype or deleted). Part 2 - Must have deletion of 17p as determined by FISH testing
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
• Adequate organ function
  • Platelets greater than or equal to ≥ 50 x 10⁹/liter (L) or ≥30 x 10⁹/L in participants with documented bone marrow involvement considered to impair hematopoiesis,
  • Hemoglobin ≥8 grams/deciliter (g/dL) or ≥6 g/dL in participants with documented bone marrow involvement considered to impair hematopoiesis
  • Absolute neutrophil count ≥0.75 x 10⁹/L or ≥0.50 × 10⁹/L in participants with documented bone marrow involvement considered to impair hematopoiesis
  • Kidney function: Estimated creatinine clearance ≥30 milliliters per minute (mL/min)