Venetoclax Treatment (26 Cycles) With 6 Cycles or 12 Cycles of Epcoritamab in Patients With Relapsed or Refractory CLL or SLL

Inclusion Criteria:

• Documented relapsed or refractory CLL or SLL (SLL in phase II part only) following atleast one systemic 1st-line treatment
• Requiring treatment according to IWCLL criteria (appendix A);
• Age at least 18 years;
• ECOG/WHO performance status 0-2;
• In case of prior venetoclax treatment, enrollment can only occur at least 24 monthsafter end of treatment and patients must not have progressed during venetoclaxtreatment;
• Adequate BM function defined as:
• Hemoglobin >5.6 mmol/l or Hb > 9 g/dL, unless low Hb is directly attributable toCLL infiltration of the BM, proven by BM biopsy;
• Absolute neutrophil count (ANC) >1.0 x 109/L (1,000/μL), unless low ANC isdirectly attributable to CLL infiltration of the BM, proven by BM biopsy;
• Platelet count >30 x 109/L (30,000/μL), unless low platelets is directlyattributable to CLL infiltration in the BM;
• Estimated Glomerular Filtration Rate (eGFR) (MDRD) or estimated creatinine clearance (CrCl) ≥ 50ml/min (Cockcroft-Gault appendix F);
• Adequate liver function as indicated:
• Serum aspartate transaminase (ASAT) and alanine transaminase (ALAT) ≤ 3.0 x upperlimit of normal (ULN);
• Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome orcontrolled autoimmune hemolytic anemia);
• Prothrombin time (PT)/International normal ratio (INR) <1.5x ULN and activated partialthromboplastin time (aPTT) <1.5 x ULN; unless receiving anticoagulation;
• Negative serological testing for hepatitis B virus (HBV) (Hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody (anti-HBc) negative) and hepatitis Cvirus (hepatitis C antibody). Patients who are positive for anti-HBc or hepatitis Cantibody may be included if they have a negative PCR within 6 weeks before enrollment.Those who are PCR positive will be excluded; Please note: For patients positive foranti-HBc, HBV-DNA PCR has to be repeated every month until 12 months after last doseof study treatment.
• Patient is able and willing to adhere to the study visit schedule and other protocolrequirements;
• Patient is capable of giving informed consent;
• Written informed consent.

Exclusion Criteria:

• Active CLL/SLL directed therapy within the last 14 days;
• Prior treatment with a CD3 × CD20 bispecific antibody or CAR T-cell therapy
• Transformation of CLL (Richter's transformation);
• Prior allogeneic stem cell transplantation and/or solid organ transplantation;
• Patient with a history of confirmed progressive multifocal leukoencephalopathy (PML);
• Malignancies other than CLL currently requiring systemic therapy or not treated incurative intention or showing signs of progression after curative treatment;
• Known allergy to xanthine oxidase inhibitors and/or rasburicase;
• History of drug-specific hypersensitivity or anaphylaxis to any study drug (includingactive product or excipient components);
• Active bleeding or uncontrolled severe bleeding diathesis (e.g., hemophilia or severevon Willebrand disease);
• Active fungal, bacterial, and/or viral infection CTCAEgrade > 1; Please note: activecontrolled as well as chronic/recurrent infections are at risk ofreactivation/infection during treatment;
• 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 HIV-positive;
• Patient requiring treatment with a strong cytochrome P450 (CYP) 3A inhibitor/inducer (see appendix J) or anticoagulant therapy with warfarin or phenoprocoumon or othervitamin K antagonists;
• CTCAE grade III-IV cardiovascular disease including but not limited to:
• Unstable or uncontrolled disease/condition related to or affecting cardiacfunction, eg, unstable angina, congestive heart failure grade III or IV asclassified by the New York Heart Association (see appendix E), uncontrolledclinically significant cardiac arrhythmia (CTCAE grade II or higher), orclinically significant electrocardiogram (ECG) abnormalities.
• Myocardial infarction, intracranial bleed, or stroke within the past 6 months.
• Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia'sformula (QTcF) >480 msec. NOTE: this criterion does not apply to subjects with aleft bundle branch block.
• Stroke or intracranial hemorrhage within 6 months prior to registration.
• Severe pulmonary dysfunction (CTCAE grade III-IV, see appendix D);
• Severe neurological or psychiatric disease (CTCAE grade III-IV, see appendix D);
• Neuropathy > CTCAE grade II
• Patient who has difficulty with or are unable to swallow oral medication, or havesignificant 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 unless: (1) surgically sterile or ≥ 2years after the onset of menopause; (2) willing to use a highly effectivecontraceptive method such as oral contraceptives, intrauterine device, sexualabstinence or combination of male condom with either cap, diaphragm, or sponge withspermicide (double barrier methods) during study treatment and for 12 months afterlast dose of epcoritamab and 30 days after last dose of venetoclax;
• Previous participation in the HOVON 139 CLL or HOVON 140 CLL trial and eligible forand willing to participate in the HOVON 159 CLL trial;
• Current participation in other clinical trial with medicinal products;
• Any psychological, familial, sociological and geographical condition potentiallyhampering compliance with the study protocol and follow-up schedule.