A prospective, multicenter, phase-II trial of ibrutinib plus venetoclax in patients with creatinine clearance >= 30 ml/min who have relapsed or refractory chronic lymphocytic leukemia (RR-CLL) with or without TP53 aberrations

♦ Documented CLL or SLL requiring treatment according to IWCLL criteria after either being refractory to first line therapy or relapse after initial therapy.

♦ Age at least 18 years.

♦ Adequate bone marrow function defined as:

- Absolute neutrophil count (ANC) >0.75 x 109/L

- Platelet count >30,000 /¦ÌL 30 x 109/L.

- Hemoglobin >8.0 g/dL (5 mmol/L)

Unless directly attributable to CLL infiltration of the bone marrow, proven by bone marrow biopsy

♦ Creatinine clearance (CrCL) ¡Ý 30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24hr urine collection.

♦ Adequate liver function as indicated

- Serum aspartate transaminase (AST) or alanine transaminase (ALT) ¡Ü 3.0 x upper limit of normal (ULN)

- Bilirubin ¡Ü1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)

- Prothrombin time (PT)/International normal ratio (INR) <1.5 x ULN and PTT (activated partial thromboplastin time [aPTT]) <1.5 x ULN (unless abnormalities are related to coagulopathy or bleeding disorder).

♦ 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.

♦ WHO/ECOG performance status 0-3 (appendix C), stage 3 only if attributable to CLL.

♦ Negative pregnancy test at study entry (for women of childbearing potential).

♦ Male and female subjects of reproductive potential must agree to use both a highly effective method of birth control (e.g. implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence , or sterilized partner) and a barrier method (e.g., condoms, cervical ring, sponge, etc.) during the period of therapy and for 90 days after the last dose of study drug.

♦ Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.

♦ Written informed consent.

♦ Any prior therapy with ibrutinib and/or venetoclax.

♦ Transformation of CLL (Richter¡¯s transformation).

♦ 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.

♦ Known bleeding disorders (e.g., von Willebrand¡¯s disease or hemophilia).

♦ Uncontrolled or active infection.

♦ Patients requiring treatment with a strong cytochrome P450 (CYP) 3A inhibitor (see appendix K). 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.

♦ 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.

♦ Pregnant women and nursing mothers.

♦ Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.