A prospective, multicenter, phase-II trial of ibrutinib plus venetoclax in physically fit patients with creatinine clearance ≥ 30 ml/min who have relapsed or refractory chronic lymphocytic leukemia (RR-CLL) with or without TP53 aberrations, HOVON 141 CLL / VIsion Trial of the HOVON and Nordic CLL study groups

Prior treatment

• Any prior therapy with ibrutinib and/or venetoclax
• Major surgery within 28 days prior to registration
• Use of investigational agents which might interfere with the study drug within 28 days prior to registration
• Vaccination with live vaccines within 28 days prior to registration
• Steroid therapy within 7 days prior to registration, with the exception of inhaled steroids for asthma, topical steroids, steroids up to 25 mg of prednisolone daily to control autoimmune phenomenon’s, or replacement/stress corticosteroids
• Patients requiring treatment with a strong cytochrome P450 (CYP) 3A inhibitor or anticoagulant therapy with warfarin or phenoprocoumon or other vitamin K antagonists. Please note: Patients being treated with NOACs can be included, but must be properly informed about the potential risk of bleeding under treatment with ibrutinib
• History of stroke or intracranial hemorrhage within 6 months prior to registration

Other illness

• Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule
• Patients with a history of confirmed progressive multifocal leukoencephalopathy (PML)
• Malignancies other than CLL currently requiring systemic therapies or not being treated in curative intention before or showing signs of progression after curative treatment
• Known allergy to xanthine oxidase inhibitors and/or rasburicase if no other appropriate prevention of tumorlysis is considered feasible by the treating physician
• Known bleeding disorders (e.g., von Willebrand’s disease or hemophilia)
• Uncontrolled or active infection

Other

• Pregnant women and nursing mothers
• Transformation of CLL (Richter’s transformation)

• Documented relapsed/refractory CLL or SLL requiring treatment according to IWCLL criteria (no limits on previous treatment lines; CD20 and steroids are not considered prior therapy lines)
• Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements
• Written informed consent
• Age at least 18 years
• Adequate bone marrow function, unless directly attributable to CLL infiltration of the bone marrow, proven by bone marrow biopsy
• Creatinine clearance (CrCL) ≥ 30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24hr urine collection.
• Adequate liver function as indicated
• Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 12 months after last dose), negative testing for hepatitis C RNA within 42 days prior to registration
• Male and female subjects of reproductive potential must agree to use both a highly effective method of birth control and a barrier method during the period of therapy and for 90 days after the last dose of study drug.
• Negative pregnancy test at study entry (for women of childbearing potential)
• WHO/ECOG performance status 0-3 stage 3 only if attributable to CLL