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

Inclusion Criteria:

• Confirmed diagnosis of CLL/SLL requiring therapy per iwCLL 2018 criteria

• Part 1 - Known 17p deletion status (wildtype or deleted). Part 2 - Must havedeletion 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 inparticipants with documented bone marrow involvement considered to impairhematopoiesis,

• Hemoglobin ≥8 grams/deciliter (g/dL) or ≥6 g/dL in participants with documentedbone marrow involvement considered to impair hematopoiesis

• Absolute neutrophil count ≥0.75 x 10⁹/L or ≥0.50 × 10⁹/L in participants withdocumented bone marrow involvement considered to impair hematopoiesis

• Kidney function: Estimated creatinine clearance ≥30 milliliters per minute (mL/min)

Exclusion Criteria:

• Known or suspected Richter's transformation to diffuse large B-cell lymphoma (DLBCL), prolymphocytic leukemia, or Hodgkin's lymphoma at any time precedingenrollment

• Known or suspected central nervous system (CNS) involvement

• A significant history of renal, neurologic, psychiatric, endocrine, metabolic orimmunologic disease

• Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA],idiopathic thrombocytopenic purpura [ITP])

• Significant cardiovascular disease including ejection fraction < 40% and any gradeongoing atrial fibrillation or atrial flutter

• Hepatitis B or hepatitis C testing indicating active/ongoing infection, based onScreening laboratory tests

• Active cytomegalovirus (CMV) infection

• Active uncontrolled systemic bacterial, viral, or fungal infection

• Known human immunodeficiency virus (HIV) infection, regardless of cluster ofdifferentiation 4 (CD4) count

• Clinically significant active malabsorption syndrome or other condition likely toaffect GI absorption of the oral-administered study treatments

• Ongoing inflammatory bowel disease

• 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 hormonaltherapy

• Participants requiring therapeutic anticoagulation with warfarin or another VitaminK antagonist

• Use of > 20 mg prednisone daily or equivalent dose of steroid at the time of firstdose of study drug

• Vaccination with a live vaccine within 28 days prior to randomization

• Participants receiving chronic therapy with a strong cytochrome P450 (CYP)3Ainhibitor (except posaconazole and voriconazole) which cannot be stopped within 3-5half lives of the CYP3A inhibitor therapy prior to start of study drug treatment

• Participants with known hypersensitivity, including anaphylaxis, to any component orexcipient of pirtobrutinib or ibrutinib