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
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
A significant history of renal, neurologic, psychiatric, endocrine, metabolic or immunologic disease
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
Active cytomegalovirus (CMV) infection
Active uncontrolled systemic bacterial, viral, or fungal infection
Known human immunodeficiency virus (HIV) infection, regardless of cluster of differentiation 4 (CD4) count
Clinically significant active malabsorption syndrome or other condition likely to affect 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 hormonal therapy
Participants requiring therapeutic anticoagulation with warfarin or another Vitamin K antagonist
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
Participants with known hypersensitivity, including anaphylaxis, to any component or excipient of pirtobrutinib or ibrutinib
Clareo Health | A Study of Pirtobrutinib (LOXO-305) Versus Ibrutinib in Participants With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
