PIPOZA: A study evaluating a targeted therapy called pirtobrutinib in the treatment of people with relapsed or refractory chronic lymphocytic leukaemia (CLL)Clonal Dynamics of Chronic Lymphocytic Leukaemia Treated With Pirtobrutinib After Previous Treatment With Zanubrutinib

Exclusion

1. Known or suspected Richter's Transformation to diffuse large B-cell lymphoma, prolymphocytic leukaemia, or Hodgkin lymphoma at any time prior to registration
2. Known or suspected history of central nervous system involvement

3. History of allogeneic or autologous stem cell transplant or chimeric antigen receptor T-cell (CAR-T) therapy within the past 60 days and/or with any of the following:

   • Active graft versus host disease
   • Cytopenias from incomplete blood cell count recovery post-transplant or CAR-T therapy
   • Need for anti-cytokine therapy for toxicity from CAR-T therapy; residual symptoms of neurotoxicity Grade > 1 from CAR-T therapy
   • Ongoing immunosuppressive therapy
4. Positive serology for human immunodeficiency virus (HIV) test in Screening 5. Concurrent anticancer therapy

6. Use of ≥ 20 mg prednisone QD or equivalent dose of steroid per day within 7 days prior to the planned pirtobrutinib start date on Day 1 Cycle 1. Patients may not be on prednisone of any dose intended for antineoplastic use 7. Vaccination with a live vaccine within 28 days prior to registration 8. Prolongation of the corrected QT interval using the Fredericia formula (QTcF) > 470 msec (QTcF is calculated using Fridericia's Formula: QTcF = QT / [RR0.33])

• Correction of suspected drug induced QTcF prolongation can be attempted at the investigator's discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation
• Manual correction for underlying bundle branch block is allowed Note: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker 9. Female patient who is pregnant or plans to become pregnant within 1 month after the last dose of study treatment 10. Female patient who is lactating or plans to breastfeed during the study or within 1 week after the last dose of study drug 11. Active second malignancy 12. Clinically significant active malabsorption syndrome including surgical resection of small intestine or other condition likely to affect gastrointestinal (GI) absorption of the oral administered study drugs 13. Active hepatitis B or C infection defined as:
• Hepatitis B virus (HBV): positive hepatitis B surface antigen (HbsAg) or hepatitis B core antibody (anti-HBc). If anti-HBc positive with surface antigen negative, patient will need to have a negative result for hepatitis B DNA before start of study therapy. Patients who are anti-HBc positive and hepatitis B polymerase chain reaction positive will be excluded
• Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis C antibody result, patient will need to have a negative result for hepatitis C ribonucleic acid (RNA) before start of study therapy. Patients who are hepatitis C RNA positive will be excluded 14. Known active cytomegalovirus infection Note: Patients with an unknown or negative status are eligible 15. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, uncontrolled systemic infection (viral, bacterial, parasitic, or fungal) or other clinically significant active disease process which, in the opinion of the investigator, may pose a risk for patient participation. Screening for chronic conditions is not required 16. Active uncontrolled auto-immune cytopenia (e.g., autoimmune haemolytic anaemia, idiopathic thrombocytopenic purpura) where new therapy is introduced, or concomitant medication escalated within the 4 weeks prior to registration is required to maintain adequate blood counts. Stable controlled auto-immune cytopenias are allowed as long as required blood count criteria are met 17. Prior treatment with pirtobrutinib 18. Patients requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist 19. Known hypersensitivity to any component or excipient of pirtobrutinib 20. Significant cardiovascular disease defined as:
• Unstable angina or acute coronary syndrome within the past 2 months prior to registration
• History of myocardial infarction within 3 months prior to registration
• Documented left ventricular ejection fraction by any method of ≤ 40% in the 12 months prior to registration
• ≥ Grade 3 New York Heart Association functional classification system of heart failure
• Uncontrolled or symptomatic arrhythmias 21. History of uncontrolled or symptomatic arrhythmias including Grade ≥ 3 arrhythmia on a prior BTKi 22. History of major bleeding on a prior BTKi NOTE: Major bleeding is defined as bleeding having 1 or more of the following features: potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in the Hb level of at least 20 g/L; or bleeding in a critical area or organ (e.g., retroperitoneal, intra-articular, pericardial, epidural, or intracranial bleeding or intramuscular bleeding with compartment syndrome) 23. History of stroke or intracranial haemorrhage within 6 months prior to registration 24. Major surgery within 4 weeks prior to registration 25. History of bleeding diathesis 26. Current treatment with strong P-glycoprotein (P-gp) inhibitors