HOVON 180 CLL: Treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma with 24 cycles of pirtobrutinib in combination with 12 cycles of epcoritamab if the disease comes back after previous treatment.

Prior treatment

• 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, o Exception: Anti-CD20 monoclonal antibodies, covalent BTK inhibitors, and BCL2 inhibitors are permitted and may be continued up to the first dose of pirtobrutinib, o Immunoconjugated antibody treatment within 10 weeks or 5 half-lives, whichever is shorter, o Broad field radiation (≥ 30% of the bone marrow or whole brain radiotherapy) within 14 days, o Palliative limited field radiation within 7 days, o Prior treatment with a CD3 × CD20 bispecific antibody, o Prior treatment with pirtobrutinib within 24 months, o 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
• Use of any other experimental drug or therapy within 28 days of registration
• Major surgery within 28 days prior to registration
• Current participation in other clinical trial and using study medication
• Prior allogeneic stem cell transplantation and/or solid organ transplantation
• Patient receiving anti-coagulation therapy (e.g. warfarin, vitamin K antagonists, phenprocoumon)
• 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
• Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled: infection, auto-immune hemolysis, immune thrombocytopenia, diabetes, hypertension, hyperthyroidism or hypothyroidism etc.)
• Stroke or intracranial hemorrhage within 6 months prior to registration
• Vaccination with live vaccines within 28 days prior to registration

Other illness

• 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)
• Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule
• 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
• Known allergy to xanthine oxidase inhibitors and/or rasburicase
• Current seizure disorder requiring therapy
• Active tuberculose (TB) or history of completed treatment for active TB within the past 12 months
• 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 cytomegalovirus (CMV) infection
• Patient known to be Human Immunodeficiency Virus (HIV)-positive
• Severe neurological or psychiatric disease (CTCAE grade III-IV)
• Patient who has difficulty with or is unable to swallow oral medication, or has significant gastrointestinal disease that would limit absorption of oral medication

Lab values

• 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

Age

• 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

Other

• Pregnant women and nursing mothers
• Known central nervous system involvement
• 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
• Transformation of CLL (Richter’s transformation)
• Severe pulmonary dysfunction (CTCAE grade III-IV)
• Neuropathy > CTCAE grade II

• Documented relapsed or refractory CLL or SLL (SLL in Cohort Expansion only) following at least one systemic 1st-line treatment
• 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
• 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)
• 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. Please see the protocol for further explanation regarding this criterion