Pirtobrutinib (LOXO-305) and Venetoclax for the Treatment of Patients with CLL or SLL Resistant to Covalent BTKi

Inclusion Criteria:

• Diagnosis of CLL or SLL according to the International Workshop on ChronicLymphocytic Leukemia (iwCLL) 2018 guidelines

• Detectable CLL on flow cytometry of the blood or marrow at time of enrollment

• Age ≥ 18 years old

• Eastern Cooperative Oncology Group (ECOG) performance 0-2

• Currently taking ibrutinib, acalabrutinib, or zanubrutinib at any daily dose andtolerating it for > 4 weeks

• Evidence of progressive disease by iwCLL 2018 criteria for progressive disease ordoubling of absolute lymphocyte count (ALC) in ≤ 6 months while on BTK inhibitorprovided ALC is > 5 k/uL

• Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≤ 3 x the upperlimit of normal (ULN) or ≤ 5 x ULN with documented liver involvement

• Bilirubin ≤ 1.5 x ULN or ≤ 3 x ULN with documented liver involvement and/orGilbert's disease

• Creatinine clearance (CrCl) ≥ 30 according to modified Cockcroft-Gault equation

• Absolute neutrophil count (ANC) ≥ 0.75 k/uL

• Without transfusion or growth factor administration in the 7 days prior toscreening

• Any values if cytopenias are due to bone marrow involvement with disease

• Hemoglobin ≥ 8 g/dL

• Without transfusion or growth factor administration in the 7 days prior toscreening

• Any values if cytopenias are due to bone marrow involvement with disease

• Platelets ≥ 50 k/uL

• Without transfusion or growth factor administration in the 7 days prior toscreening

• Any values if cytopenias are due to bone marrow involvement with disease

• Prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 1.5 x ULN

• No known inherited qualitative platelet defect (e.g. delta granule storage pooldeficiency)

• Willing and able to complete study activities and treatment

• Willing and capable of giving signed informed consent which includes compliance withthe requirements and restrictions listed in the informed consent form (ICF) and inthe protocol

• Willingness of men and women of reproductive potential and their partners to observeconventional and highly effective or acceptable birth control methods for theduration of treatment and for 6 months following the last dose of pirtobrutinib or 30 days from the last dose of venetoclax

• ELIGIBILITY FOR RE-TREATMENT WITH PIRTOBRUTINIB: Discontinued initial studytreatment ≤ 12 months ago

• ELIGIBILITY FOR RE-TREATMENT WITH PIRTOBRUTINIB: Meets iwCLL 2018 criteria forprogressive disease

Exclusion Criteria:

• Inability to tolerate 2 Liters of oral or intravenous (IV) hydration

• Prior venetoclax exposure > 13 months or known resistance to venetoclax

• Known hypersensitivity to any of the excipients of pirtobrutinib or venetoclax

• Need for treatment with warfarin or other vitamin K antagonist during studytreatment

• History of bleeding diathesis

• Patients who experienced a major bleeding event or grade ≥ 3 arrhythmia on priortreatment with a BTK inhibitor. Major bleeding is defined as bleeding having one ormore of the following features: potentially life-threatening bleeding with signs orsymptoms of hemodynamic compromise; bleeding associated with a decrease in thehemoglobin level of at least 2g per deciliter; or bleeding in a critical area ororgan (e.g., retroperitoneal, intraarticular, pericardial, epidural, or intracranialbleeding or intramuscular bleeding with compartment syndrome)

• History of stroke or intracranial hemorrhage within 6 months

• Inability to take pills or oral medications

• Clinically significant active malabsorption syndrome or other condition likely toaffect gastrointestinal (GI) absorption of either pirtobrutinib or venetoclax

• Current known central nervous system involvement with CLL or SLL. Patients withprevious treatment for central nervous system (CNS) involvement who areneurologically stable and without evidence of disease may be eligible if acompelling clinical rationale is provided by the investigator and with documentedapproval by the principal investigator

• Treatment with the following:

• Targeted agents, investigational agents, therapeutic monoclonal antibodies, orcytotoxic chemotherapy within 5 half-lives or 2 weeks, whichever is shorter

• Treatment with immunoconjugated antibody treatment within 10 weeks

• Receipt of broad field radiation ( ≥ 30% of the bone marrow or whole brainradiotherapy) within 14 days or palliative limited field radiation within 7days prior to study enrollment

• Note: Treatment with ibrutinib, acalabrutinib, or zanubrutinib is allowed.Treatment with topical chemotherapy agents for precancerous skin conditions orskin cancers is allowed

• Unresolved adverse events from prior treatment not resolved to grade ≤ 1 with theexception of alopecia or grade 2 peripheral neuropathy

• History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigenreceptor-modified T cell (CAR-T) therapy within 60 days. Patients with a history ofallogeneic stem cell transplant must be stable off all immunosuppression for atleast 2 months prior to study screening. Presence of any of the following,regardless of prior SCT and/or CAR-T therapy timing will be exclusionary:

• Active graft versus host disease (GVHD)

• Cytopenia from incomplete blood cell count recovery post-transplant

• Need for anti-cytokine therapy for toxicity from CAR-T therapy and/or residualsymptoms of neurotoxicity > grade 1 from CAR-T therapy

• Ongoing immunosuppressive therapy

• Active second malignancy unless in remission and with life expectancy > 2 years.Adjuvant endocrine therapy for breast or prostate cancer that is expected to becured is allowed. Non-melanoma skin cancers are permitted if adequately treated

• Psychiatric illness, or social situations that would limit compliance with studyrequirements

• Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA],idiopathic thrombocytopenic purpura [ITP]) for which new therapy was introduced orexisting therapy was escalated within the 4 weeks prior to study enrollment tomaintain adequate blood counts

• Evidence of other clinically significant uncontrolled condition(s) including but notlimited to, uncontrolled systemic bacterial, viral, fungal or parasitic infection (except for fungal nail infection), or other clinically significant active diseaseprocess which in the opinion of the investigator may pose a risk for patientparticipation. Screening for chronic conditions is not required

• Significant cardiovascular disease defined as:

• Unstable angina or acute coronary syndrome within the past 2 months

• History of myocardial infarction within 3 months

• Documented left ventricular ejection fraction (LVEF) by any method of ≤ 40% inthe 12 months

• ≥ grade 3 New York Heart Association (NYHA) functional classification system ofheart failure

• Uncontrolled or symptomatic arrhythmias

• Prolongation of the QT interval corrected for heart rate (Fridericia'sformula-corrected QT interval [QTcF]) > 470 msec. QTcF is calculated usingFridericia's formula

• Correction of suspected drug induced QTcF prolongation can be attempted at theinvestigator¡¦s discretion and only if clinically safe to do so with eitherdiscontinuation of the offending drug or switch to another drug not known to beassociated with QTcF prolongation

• Correction for underlying bundle branch block (BBB) allowed

• Note: Patients with pacemakers are eligible if they have no history of faintingor clinically relevant arrhythmias while using the pacemaker

• Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection based oncriteria below:

• Hepatitis B virus (HBV): Patients with positive hepatitis B surface antigen (HBsAg) are excluded. Patients with positive hepatitis B core antibody (anti-HBc) and negative HBsAg require hepatitis B polymerase chain reaction (PCR) evaluation before inclusion. Patients who are hepatitis B PCR positivewill be excluded

• Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis Cantibody result, patient will need to have a negative result for hepatitis Cribonucleic acid (RNA) before inclusion. Patients who are hepatitis C RNApositive will be excluded. Patients previously treated for hepatitis C > 6months previously with a negative RNA test are eligible

• Known HIV infection. For patients with unknown HIV status, HIV testing will beperformed at screening and result should be negative for enrollment

• Known active cytomegalovirus (CMV) infection. Unknown or negative status areeligible

• Treatment with a strong CYP3A inhibitor or inducer and/or strong P-gp inhibitorswithin 3 days of starting or during study treatment. Treatment with a moderate orstrong CYP3A inhibitor or inducer within 7 days prior to first dose of venetoclax orduring cycle 2 or 3 of study treatment. Patients may not plan to consume grapefruitor grapefruit products, Seville oranges or products from Seville oranges, or starfruit

• Pregnancy, lactation, or plan to breastfeed during the study or within 6 months ofthe last dose of either pirtobrutinib or venetoclax

• Major surgery within 4 weeks prior to screening

• Vaccination with live vaccine within 28 days of screening

• Currently incarcerated

• History of progressive multifocal leukoencephalopathy (PML) or human polyomavirus 2 (JC virus) infection

• History of seizure disorder unless controlled without a seizure in the year prior toscreening

• ELIGIBILITY FOR RE-TREATMENT WITH PIRTOBRUTINIB: Has not developed any new medicalconditions that would change the safety of treatment with pirtobrutinib