A Multi-Center, Open Label, Uncontrolled, Phase 2a Clinical Trial Evaluating the Safety and Efficacy of the Addition of Ibrutinib to Venetoclax Through a MRD-guided Approach in Relapsed/Refractory Patients With Chronic Lymphocytic Leukemia (CLL)

Venetoclax will be administered, initially as single agent, orally once daily (QD), starting with 20 mg on Day 1, followed by weekly dose escalation up to 400 mg, if well tolerated [Ramp-up Period, according to the modified Venetoclax schedule in Phase 2 and 3 clinical trials] and continued thereafter. At Cycle 12 Day 1, disease status, renal function and risk of bleeding will be assessed. Minimal residual disease (MRD) in the peripheral blood will be evaluated in patients with CR or PR by flow cytometry. All MRD negative subjects (defined as those with MRD level in the PB <10-4 in the PB and in the BM aspirate) will discontinue venetoclax at the end of Cycle 12 (i.e. Cycle 12 Day 28). All MRD positive subjects (defined as those with MRD level in the PB >10-4) and patients with stable disease without any contraindications to ibrutinib treatment will continue venetoclax and start treatment with ibrutinib at the standard dose for CLL of 420 mg QD. Venetoclax will be administered until unacceptable toxicity or disease progression or for a maximum of 2 years and ibrutinib will be continued until unacceptable toxicity, confirmed MRD negativity, or disease progression.

MRD will be assessed every 3 months starting 3 months after treatment initiation; MRD negativity at Cycle 12 Day 1 will be evaluated in PB BM aspirate.

Patients experiencing clinical disease progression will discontinue study treatment and will be followed up for survival status and subsequent anti-cancer therapy.

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

a. Absolute neutrophil count (ANC) ≥1.0 x 109/L (growth factors administration is allowed) b. Platelets ≥30 x 109/L. If thrombocytopenia due to BM involvement, platelets should be ≥ 20 x 109/L c. Hemoglobin value ≥8.0 g/dl exclusion criteria