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

Inclusion Criteria:

1. Confirmed diagnosis of CLL/SLL requiring therapy per iwCLL 2018 criteria
2. Part 1 - Known 17p deletion status (wildtype or deleted). Part 2 - Must have deletion of 17p as determined by FISH testing
3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
4. Adequate organ function

1. 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,
2. Hemoglobin ≥8 grams/deciliter (g/dL) or ≥6 g/dL in participants with documented bone marrow involvement considered to impair hematopoiesis
3. Absolute neutrophil count ≥0.75 x 10⁹/L or ≥0.50 × 10⁹/L in participants with documented bone marrow involvement considered to impair hematopoiesis
4. Kidney function: Estimated creatinine clearance ≥30 milliliters per minute (mL/min)

Exclusion Criteria:

1. Known or suspected Richter's transformation to diffuse large B-cell lymphoma (DLBCL), prolymphocytic leukemia, or Hodgkin's lymphoma at any time preceding enrollment
2. Known or suspected central nervous system (CNS) involvement
3. A significant history of renal, neurologic, psychiatric, endocrine, metabolic or immunologic disease
4. Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA], idiopathic thrombocytopenic purpura [ITP])
5. Significant cardiovascular disease including ejection fraction < 40% and any grade ongoing atrial fibrillation or atrial flutter
6. Hepatitis B or hepatitis C testing indicating active/ongoing infection, based on Screening laboratory tests
7. Active cytomegalovirus (CMV) infection
8. Active uncontrolled systemic bacterial, viral, or fungal infection
9. Known human immunodeficiency virus (HIV) infection, regardless of cluster of differentiation 4 (CD4) count
10. Clinically significant active malabsorption syndrome or other condition likely to affect GI absorption of the oral-administered study treatments
11. Ongoing inflammatory bowel disease
12. 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

1. Concurrent use of investigational agent or anticancer therapy except hormonal therapy
2. Participants requiring therapeutic anticoagulation with warfarin or another Vitamin K antagonist
3. Use of > 20 mg prednisone daily or equivalent dose of steroid at the time of first dose of study drug
4. Vaccination with a live vaccine within 28 days prior to randomization
5. 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
6. Participants with known hypersensitivity, including anaphylaxis, to any component or excipient of pirtobrutinib or ibrutinib