Treatment of Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma With Pirtobrutinib in Combination With Epcoritamab if the Disease Comes Back After Previous Treatment.

In order to be eligible to participate in this study, a patient must meet all of the following criteria: * Documented relapsed or refractory CLL or SLL (SLL in Cohort Expansion only) following at least one systemic 1st-line treatment * Requiring treatment according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria; * Age at least 18 years; * Eastern Cooperative Oncology Group (ECOG)/World Health Organization (WHO) performance status 0-2; * Adequate BM function defined as: * Hemoglobin (Hb) \>5 mmol/l or \>8 g/dL. * Absolute neutrophil count (ANC) \>1.0 x 109/L (1,000/μL) * Platelet count \>30 x 109/L (30,000/μL); Please note: If the patient is cytopenic there should be no evidence of myelodysplasia or hypoplastic bone marrow. * Estimated Glomerular Filtration Rate (eGFR) Modification of Diet in Renal Disease (MDRD) or estimated creatinine clearance (CrCl) ≥ 45 ml/min (Cockcroft-Gault); * Adequate liver function as indicated: * Serum aspartate transaminase (AS(A)T) and alanine transaminase (AL(A)T) ≤ 3.0 x upper limit of normal (ULN); * Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or controlled autoimmune hemolytic anemia); * Prothrombin time (PT)/International normal ratio (INR) \<1.5x ULN and activated partial thromboplastin time (aPTT) \<1.5 x ULN; * Patients must have negative serological testing for hepatitis B and C, defined as negative hepatitis B surface antigen (HBsAg) and negative hepatitis B core antibody (anti-HBc), as well as negative hepatitis C antibody. * Participants who are hepatitis B core antibody (anti-HBc) positive and HBsAg negative, or who are hepatitis C antibody positive, may be eligible if hepatitis B deoxyribonucleic acid (HBV-DNA) or hepatitis C ribonucleic acid (HCV-RNA) polymerase chain reaction (PCR), respectively, is negative within 6 weeks prior to enrolment. Participants with a positive HBV-DNA or HCV-RNA PCR will be excluded. Please note: Patients who are anti-HBc positive, HBsAg negative, and HBV-DNA negative and will be treated with pirtobrutinib in combination with a B-cell-depleting agent (e.g., rituximab, obinutuzumab or epcoritamab) must receive prophylactic antiviral therapy with a nucleos(t)ide analogue (e.g., entecavir or tenofovir), starting prior to treatment initiation and continuing for 6-12 months after completion of study treatment. * For patients who are anti-HBc positive or hepatitis C antibody positive, HBV-DNA or HCV-RNA PCR, respectively, must be monitored every 1 to 3 months during study treatment and for at least 6 months after the last dose. * If HBV-DNA becomes detectable during study treatment, it is recommended to initiate antiviral therapy (e.g., entecavir or tenofovir) and to discontinue pirtobrutinib. * Patient is able and willing to adhere to the study visit schedule and other protocol requirements; * Patient is capable of giving informed consent; * Written informed consent. A patient who meets any of the following criteria cannot be included in this study: ♦ The patient has received any of the following anticancer therapies: o Targeted therapies, investigational agents, therapeutic monoclonal antibodies, or cytotoxic chemotherapy within either: 5 drug half-lives, or 2 weeks prior to the first dose of study treatment, whichever is shorter. Exception: Anti-CD20 monoclonal antibodies, covalent BTK inhibitors, and BCL2 inhibitors are permitted and may be continued up to the first dose of pirtobrutinib. * Immunoconjugated antibody treatment within 10 weeks or 5 half-lives, whichever is shorter * Broad field radiation (≥ 30% of the bone marrow or whole brain radiotherapy) within 14 days * Palliative limited field radiation within 7 days * Prior treatment with a CD3 × CD20 bispecific antibody * Prior treatment with pirtobrutinib within 24 months * CAR-T-cell therapy within 100 days prior to first dose of study drug or need of anti-cytokine therapy for toxicity from CAR-T therapy and/or residual symptoms of neurotoxicity \> Grade 1 from CAR-T therapy * Transformation of CLL (Richter's transformation); * Known central nervous system involvement * Prior allogeneic stem cell transplantation and/or solid organ transplantation; * Patient with a history of confirmed progressive multifocal leukoencephalopathy (PML); * Current autoimmune disease-requiring immunosuppressive therapy except for up to 20 mg daily prednisone or equivalent. * Current seizure disorder requiring therapy * Active tuberculose (TB) or history of completed treatment for active TB within the past 12 months. * Patient receiving anti-coagulation therapy (e.g. warfarin, vitamin K antagonists, phenprocoumon). Please note: Patients being treated with direct oral anticoagulants (DOACs) can be included, but must be properly informed about the potential risk of bleeding under treatment; * Malignancies other than CLL/SLL unless in remission defined as treated non-melanoma skin cancer or other neoplasias treated curatively ≥ 1 year ago, without signs of progression and not requiring systemic therapies (with the exception of ongoing anti-hormonal therapy); * Known allergy to xanthine oxidase inhibitors and/or rasburicase; * History of severe allergic or anaphylactic reactions to anti-CD20 monoclonal or bi-specific antibody therapy, or known significant allergy or intolerance to any component or excipient constituents of the study treatment (and their excipients) and/or other products in the same class; * History of bleeding diathesis; * Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) within 2 weeks prior to first dose of study treatment; * Known active cytomegalovirus (CMV) infection; * Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled: infection, auto- immune hemolysis, immune thrombocytopenia, diabetes, hypertension, hyperthyroidism or hypothyroidism etc.); * Patient known to be Human Immunodeficiency Virus (HIV)-positive; * CTCAE grade III-IV cardiovascular disease including but not limited to: Significant cardiovascular disease defined as: * unstable angina or acute coronary syndrome within the past 3 months prior to treatment initiation or a history of myocardial infarction within 3 months prior to treatment initiation or * documented Left Ventricular Ejection Fraction (LVEF) by any method of ≤ 40% in the 12 months prior to treatment initiation * ≥ Grade 3 New York Heart Association (NYHA) functional classification system of heart failure * Uncontrolled or symptomatic arrhythmias ♦ Screening 12-lead Electrocardiogram (ECG) showing a baseline QT (Q and T wave) interval as corrected by Fridericia's formula (QTcF) \>480 msec. Please note: this criterion does not apply to patients with a left bundle branch block. * Stroke or intracranial hemorrhage within 6 months prior to registration. * Severe pulmonary dysfunction (CTCAE grade III-IV); * Severe neurological or psychiatric disease (CTCAE grade III-IV); * Neuropathy \> CTCAE grade II; * Patient who has difficulty with or is unable to swallow oral medication, or has significant gastrointestinal disease that would limit absorption of oral medication; * Vaccination with live vaccines within 28 days prior to registration; * Use of any other experimental drug or therapy within 28 days of registration; * Major surgery within 28 days prior to registration; * Pregnant women and nursing mothers; * Fertile men or women of childbearing potential (WOCBP) unless: (1) surgically sterile or ≥ 2 years after the onset of menopause; (2) willing to use a highly effective contraceptive method such as oral contraceptives, intrauterine device, sexual abstinence or combination of male condom with either cap, diaphragm, or sponge with spermicide (double barrier methods) during study treatment and for 4 months after last dose of epcoritamab and 5 weeks (women) or 3 months (men) after last dose of pirtobrutinib; * Patients who are planning egg donation (ova, oocytes) for the purposes of assisted reproduction or sperm donation during study treatment, until 4 months after last dose of epcoritamab and 5 weeks after last dose of pirtobrutinib for egg donation and 3 months after last dose of pirtobrutinib for sperm donation; * Current participation in other clinical trial and using study medication; * Any psychological, familial, sociological and geographical condition potentially hampering ompliance with the study protocol and follow-up schedule