Clinical Study With Ibrutinib and Venetoclax for Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia

Inclusion criteria

1. ≥ 18 years of age
2. Documented CLL requiring treatment according to the IWCLL criteria (Hallek M et al, 2008)
3. Relapsed/refractory CLL patients who received at least 1 prior therapy
4. Adequate bone marrow function without transfusion \< 2 weeks of screening as follows:

   1. Absolute neutrophil count (ANC) ≥1.0 x 109/L (growth factors administration is allowed)
   2. Platelets ≥30 x 109/L. If thrombocytopenia due to BM involvement, platelets should be ≥ 20 x 109/L
   3. Hemoglobin value ≥8.0 g/dl
5. The patient has adequate renal and hepatic function per local reference laboratory reference ranges as follows:

   1. Renal: patient has a creatinine clearance (CrCl) ≥ 30 mL/min
   2. Hepatic: AST and ALT ≤ 3 × the upper normal limit (ULN) of institution's normal range and bilirubin ≤ 1.5 × ULN. Patients with AIHA and Gilbert's syndrome may have a bilirubin \> 1.5 × ULN, but these conditions must be clearly documented in clinical records.
6. Female patients of childbearing potential and non-sterile male patients must practice at least one of method of birth control with partner(s) beginning with initial treatment administration and continuing to 30 days after the last dose of study treatment. Female of child bearing potential must have a negative serum pregnancy test upon study entry
7. Male patient must agree to refrain from sperm donation, from initial treatment administration until 90 days after the last dose of treatment
8. Ability to provide written informed consent and to understand and comply with the requirements of the study

Exclusion criteria

1. Transformation of CLL to aggressive NHL (Richter's transformation or pro-lymphocytic leukemia)
2. Known central nervous system (CNS) involvement
3. Inadequate renal function: CrCl \<30 mL/min
4. Previous treatment with BTK and/or BCL2 inhibitors (patients previously treated with PI3K inhibitors are eligible)
5. Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia
6. Requires the use of warfarin, marcumar, or phenprocoumon (potential drug-drug interaction increasing exposure of warfarin or phenprocoumon): low molecular weight drugs e.g. heparin are acceptable
7. Treatment, administration or consumption of any of the following within 3 days prior to the first dose of venetoclax (see also Appendix G):

   1. Strong Cytochrome P450 3A (CYP3A) inhibitors
   2. Moderate CYP3A inhibitors
   3. Moderate or strong CYP3A inducers
   4. PI3K inhibitor (e.g. Idelalisib);
   5. Grapefruit or grapefruit products
   6. Seville oranges (including marmalade containing Seville oranges)
   7. Star fruit
8. Known history of human immunodeficiency virus (HIV) or active with hepatitis B virus (HBV) or hepatitis C virus (HCV). Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded.
9. Known hypersensitivity to one or more study drugs
10. Known bleeding disorders (e.g. von Willebrand's disease) or hemophilia
11. History of stroke or intracranial hemorrhage within 6 months prior to enrollment
12. Major surgery within 4 weeks of the first dose of study drug
13. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach, or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
14. Any uncontrolled active systemic infection or infection requiring systemic treatment that was completed ≤7 days before planned treatment start date
15. Prior allogeneic stem cell transplant
16. Lactating or pregnant
17. Unable to understand the purpose and the risks of the study and to provide a signed and dated informed consent (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations)
18. History of other malignancies, except:

    1. Malignancy treated with curative intent and with no known active disease present for ≥3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician.
    2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
    3. Adequately treated carcinoma in situ without current evidence of disease.