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

In the CLL2-BZAG trial will be included a total of 40 patients with relapsed or refractory CLL in need of treatment. This trial will evaluate a debulking with two cycles bendamustine (only for patients with a high tumor load), followed by an induction and maintenance treatment with obinutuzumab, zanubrutinib and venetoclax in patients with relapsed/refractory CLL. Thus, this trial combines one established (chemotherapy) and three novel, synergistic (antibody, Bruton's tyrosine kinase(BTK)-inhibitor and Bcl-2 antagonist) principles of action in order to achieve deep and long lasting remissions with a short duration of treatment. Additionally, this trial has an extensive accompanying scientific program aiming at a better understanding of the kinetics of response and clonal evolution of CLL.

Inclusion criteria

• Relapsed/refractory CLL in need of treatment according to International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria

In case of a recent previous treatment, patients must have recovered from acute toxicities and treatment regimen must be stopped within the following time periods before 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 have to be reduced to an equivalent of ≤ 20mg prednisolone per day during treatment Please note: Patients with a progression during previous treatment with venetoclax, ibrutinib or another BTK inhibitor, as well as patients with a known resistance mutation (e.g. BTK-/PLCg2) are excluded from study participation. However, patients who progressed after termination of treatment with venetoclax, ibrutinib, other BTK inhibitors and/or obinutuzumab or who stopped treatment due to intolerance to ibrutinib are eligible for participation.
• Adequate renal function, as indicated by a creatinine clearance ≥30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24 hr. urine collection
• Adequate hematologic function as indicated by a neutrophil count ≥ 1.0 x 109/L, a hemoglobin value ≥8.0 g/dL and a platelet count ≥ 25 x 109/L, unless directly attributable to the patient´s CLL (e.g. bone marrow infiltration), in this case, platelet count should be ≥ 10 × 109/L.
• Adequate liver function as indicated by a total bilirubin ≤2x, AST/ALT ≤2.5x the institutional ULN value, unless directly attributable to the patient's CLL or to Gilbert's Syndrome
• 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 last dosage of GA101 (obinutuzumab) or until the last dose of zanubrutinib, whichever occurs later), negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration
• Age ≥ 18 years
• Eastern Cooperative Oncology Group Performance Status (ECOG) 0 - 2, ECOG 3 is only permitted if related to CLL (e.g. due to anemia or severe constitutional symptoms)
• Life expectancy ≥ 6 months
• Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements

Exclusion criteria

• (Suspicion of) transformation of CLL (i.e. Richter's transformation, pro-lymphocytic leukemia) or central nervous system (CNS) involvement
• 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)
• Confirmed progressive multifocal leukoencephalopathy (PML)
• Malignancies other than CLL currently requiring systemic therapies
• Uncontrolled infection requiring systemic treatment
• 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)
• 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.
• Requirement of therapy with strong CYP3A4 inhibitors/inducers or anticoagulant with phenprocoumon (marcumar) or other vitamin K-antagonists
• 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).
• 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
• Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment)
• 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.
• Vaccination with a live vaccine ≤ 28 days prior to registration
• Legal incapacity
• Prisoners or subjects who are institutionalized by regulatory or court order
• Persons who are in dependence to the sponsor or an investigator