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

Inclusion Criteria:

1. Relapsed/refractory CLL in need of treatment according to International Workshop onChronic Lymphocytic Leukemia (iwCLL) criteria In case of a recent previous treatment, patients must have recovered from acutetoxicities and treatment regimen must be stopped within the following time periodsbefore start of the study treatment in the CLL2-BZAG trial:

• chemotherapy ≥ 28 days

• antibody treatment ≥ 14 days

• kinase inhibitors, BCL2-antagonists or immunomodulatory agents ≥ 3 days

• corticosteroids may be applied until the start of the BZAG-regimen, these haveto be reduced to an equivalent of ≤ 20mg prednisolone per day during treatmentPlease note: Patients with a progression during previous treatment withvenetoclax, ibrutinib or another BTK inhibitor, as well as patients with aknown resistance mutation (e.g. BTK-/PLCg2) are excluded from studyparticipation. However, patients who progressed after termination of treatmentwith venetoclax, ibrutinib, other BTK inhibitors and/or obinutuzumab or whostopped treatment due to intolerance to ibrutinib are eligible forparticipation.

2. Adequate renal function, as indicated by a creatinine clearance ≥30ml/min calculatedaccording to the modified formula of Cockcroft and Gault or directly measured with 24 hr. urine collection

3. Adequate hematologic function as indicated by a neutrophil count ≥ 1.0 x 109/L, ahemoglobin value ≥8.0 g/dL and a platelet count ≥ 25 x 109/L, unless directlyattributable to the patient´s CLL (e.g. bone marrow infiltration), in this case,platelet count should be ≥ 10 × 109/L.

4. Adequate liver function as indicated by a total bilirubin ≤2x, AST/ALT ≤2.5x theinstitutional ULN value, unless directly attributable to the patient's CLL or toGilbert's Syndrome

5. Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative,patients positive for anti-HBc may be included if PCR for Hepatitis B Virus (HBV)DNA is negative and HBV-DNA PCR is performed every 4 weeks until one year after lastdosage of GA101 (obinutuzumab) or until the last dose of zanubrutinib, whicheveroccurs later), negative testing for hepatitis-C RNA and negative HIV test within 6weeks prior to registration

6. Age ≥ 18 years

7. Eastern Cooperative Oncology Group Performance Status (ECOG) 0 - 2, ECOG 3 is onlypermitted if related to CLL (e.g. due to anemia or severe constitutional symptoms)

8. Life expectancy ≥ 6 months

9. Ability and willingness to provide written informed consent and to adhere to thestudy visit schedule and other protocol requirements

Exclusion Criteria:

1. (Suspicion of) transformation of CLL (i.e. Richter's transformation, pro-lymphocyticleukemia) or central nervous system (CNS) involvement

2. Progression during previous treatment with venetoclax, ibrutinib or another BTKinhibitor, 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 RatingScale (CIRS) score of 4, excluding the eyes/ears/nose/throat/larynx organ system orany other life-threatening illness, medical condition or organ system dysfunctionthat - in the investigator´s opinion - could compromise the patients safety orinterfere with the absorption or metabolism of the study drugs (e.g, inability toswallow 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 withphenprocoumon (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 accordancewith 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 knownhypersensitivity to bendamustine are allowed to participate but will not receive adebulking with bendamustine

11. Pregnant women and nursing mothers (a negative pregnancy test is required for allwomen 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 highlyeffective (Pearl Index <1) and one additional effective (barrier) method duringstudy 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