Sequential Regimen of Bendamustine Followed by Obinutuzumab (GA101), Zanubrutinib (BGB-3111) and Venetoclax (ABT-199) in Patients With Relapsed/Refractory CLL

Exclusion Criteria

• •1. (Suspicion of) transformation of CLL (i.e. Richter's transformation, pro-lymphocytic leukemia) or central nervous system (CNS) involvement
• •2. Progression during previous treatment with venetoclax, ibrutinib or another BTK inhibitor, and/or presence of known mutations associated with resistance to therapy, e.g. Bruton´s Tyrosine Kinase and Phospholipase C Gamma 2 (PLCg2)
• •3. Confirmed progressive multifocal leukoencephalopathy (PML)
• •4. Malignancies other than CLL currently requiring systemic therapies
• •5. Uncontrolled infection requiring systemic treatment
• •6. Any comorbidity or organ system impairment rated with a Cumulative Illness Rating Scale (CIRS) score of 4, excluding the eyes/ears/nose/throat/larynx organ system or any other life-threatening illness, medical condition or organ system dysfunction that - in the investigator´s opinion - could compromise the patients safety or interfere with the absorption or metabolism of the study drugs (e.g, inability to swallow tablets or impaired resorption in the gastrointestinal tract)
• •7. Significantly increased risk of bleeding according to the investigator´s evaluation, e.g. due known bleeding diathesis (e.g. von-Willebrandt´s disease or hemophilia), major surgical procedure ≤ 4 weeks or stroke/intracranial hemorrhage ≤ 6 months.
• •8. Requirement of therapy with strong CYP3A4 inhibitors/inducers or anticoagulant with phenprocoumon (marcumar) or other vitamin K-antagonists
• •9. Use of investigational agents ≤ 28 days prior to start of study treatment, however, kinase inhibitors, BCL2-antagonists and antibody treatment are allowed in accordance with inclusion criterion number 1 (see above).
• •10. Known hypersensitivity to obinutuzumab (GA101), venetoclax (ABT-199), zanubrutinib (BGB-3111) or any of the excipients Please note: Patients with a known hypersensitivity to bendamustine are allowed to participate but will not receive a debulking with bendamustine
• •11. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment)
• •12. Fertile men or women of childbearing potential unless:
• •* surgically sterile or ≥ 2 years after the onset of menopause, or
• •* willing to use two methods of reliable contraception including one highly effective (Pearl Index \<1) and one additional effective (barrier) method during study treatment and for 18 months after end of study treatment.
• •13. Vaccination with a live vaccine ≤ 28 days prior to registration
• •14. Legal incapacity
• •15. Prisoners or subjects who are institutionalized by regulatory or court order
• •16. Persons who are in dependence to the sponsor or an investigator