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
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
The aim of the current trial is to evaluate if combination treatment with venetoclax +
 ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia (RR CLL) can
 lead to MRD negativity, which may induce long lasting remissions for MRD-negative patients
 randomized to stopping treatment after 15 induction cycles.
Inclusion Criteria:

 -  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 /μL 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) ≥ 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) ≤ 3.0 x
 upper limit of normal (ULN)

 -  Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or
 of nonhepatic 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.

 Exclusion Criteria:

 -  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.