Venetoclax for Chronic lymphocytic leukemia | Relapsed/refractory chronic lymphocytic leukemia

Inclusion criteria

• {"criterion_text":"- Relapsed/refractory CLL in need of treatment according to 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 immuno-modulatory 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.\n- 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\n- Adequate hematologic function as indicated by a neutro-phil 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\n- Adequate liver function as indicated by a total bilirubin ≤2x, AST/ALT ≤2.5x the institutional ULN value, unless di-rectly attributable to the patient’s CLL or to Gilbert’s Syn-drome\n- Negative serological testing for hepatitis B (HBsAg nega-tive and anti-HBc negative, patients positive for anti-HBc may be included if PCR for 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\n- Age ≥ 18 years\n- ECOG 0 to 2, ECOG 3 is only permitted if related to CLL (e.g. due to anemia or severe constitutional symptoms)\n- Life expectancy ≥ 6 months\n- Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements"}

Exclusion criteria

• {"criterion_text":"- (Suspicion of) transformation of CLL (i.e. Richter’s transformation, pro-lymphocytic leukemia) or central nervous system (CNS) involvement\n- Known hypersensitivity to obinutuzumab (GA101), ve-netoclax (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\n- Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment)\n- Fertile men or women of childbearing potential unless: -\tsurgically sterile or ≥ 2 years after the onset of menopause, or -\twilling 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.\n- Vaccination with a live vaccine ≤ 28 days prior to registra-tion\n- Legal incapacity\n- Prisoners or subjects who are institutionalized by regulatory or court order\n- Persons who are in dependence to the sponsor or an in-vestigator\n- 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)\n- Confirmed progressive multifocal leukoencephalopathy (PML)\n- Malignancies other than CLL currently requiring systemic therapies\n- Uncontrolled infection requiring systemic treatment\n- Any comorbidity or organ system impairment rated with a CIRS (cumulative illness rating scale) 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 gastroin-testinal tract)\n- Significantly increased risk of bleeding according to the investigator´s evaluation, e.g. due known bleeding diathe-sis (e.g. von-Willebrandt´s disease or hemophilia), major surgical procedure ≤ 4 weeks or stroke/intracranial hem-orrhage ≤ 6 months.\n- Requirement of therapy with strong CYP3A4 inhibitors/inducers or anticoagulant with phenprocoumon (marcumar) or other vitamin K-antagonists\n- Use of investigational agents ≤ 28 days prior to start of study treatment, however, kinase inhibitors, BCL2-antagonists and antibody treatment are allowed in ac-cordance with inclusion criterion number 1 (see above)."}

Primary endpoints

• {"endpoint_text":"- Negativity rate of minimal residual disease (MRD) in peripher-al blood (PB) measured by multi-color flow cytometry at final restaging (RE) at the end of induction treatment (12 weeks after the start of the last induction cycle)","definition_or_measurement_approach":"MRD negativity measured in peripheral blood by multi-color flow cytometry at final restaging (RE), defined at the end of induction treatment (12 weeks after the start of the last induction cycle)."}

Secondary endpoints

• {"endpoint_text":"- Overall response rate (ORR) according to iwCLL criteria at RE 12 weeks after the start of the last cycle of induction ther-apy including all patients achieving: -\ta complete response (CR), -\tCR with incomplete recovery of the bone marrow (CRi), or -\ta partial response (PR)","definition_or_measurement_approach":"ORR assessed per iwCLL criteria at re-staging (RE) 12 weeks after start of the last induction cycle; includes CR, CRi, PR."}
• {"endpoint_text":"- CR/CRi rate at RE 12 weeks after the start of the last cycle of induction therapy","definition_or_measurement_approach":"CR/CRi assessed per iwCLL criteria at RE 12 weeks after the start of the last induction cycle."}
• {"endpoint_text":"- Safety parameters: Type, frequency, severity, and relation-ship to study treatment of -\tadverse events (AE), -\tserious adverse events (SAE) and -\tadverse events of particular/special interest (AEPI/AESI)","definition_or_measurement_approach":"Safety assessed by collection and classification of AEs, SAEs and AEPIs/AESIs including type, frequency, severity and relationship to study treatment."}
• {"endpoint_text":"- MRD in PB measured by 4-color flow cytometry to guide the duration of maintenance therapy at: -\tRE 12 weeks after the start of the last cycle of induc-tion therapy in all patients responding to study treat-ment and -\tevery 12 weeks (= approx. 3 months) during the maintenance phase -\tevery 24 weeks (= approx. 6 months) during the fol-low-up","definition_or_measurement_approach":"MRD in peripheral blood measured by 4-color flow cytometry; results used to guide maintenance therapy duration; schedule: at RE 12 weeks after last induction cycle, every 12 weeks during maintenance, every 24 weeks during follow-up."}
• {"endpoint_text":"- and MRD in PB measured by 4-color flow cytometry for the assessment of the kinetics of response to the different treat-ment phases at: -\tscreening/baseline -\tstaging after debulking (if applicable) -\tbefore start with zanubrutinib (cycle 2, d1) -\tbefore start with venetoclax (cycle 3, d1) -\tinterim staging (after 3 induction cycles) -\tinitial response assessment (after 6 induction cycles)","definition_or_measurement_approach":"MRD kinetics assessed by 4-color flow cytometry at defined timepoints: screening/baseline, post-debulking (if applicable), before cycle 2 day 1, before cycle 3 day 1, after 3 induction cycles (interim), after 6 induction cycles (initial response)."}
• {"endpoint_text":"- MRD in bone marrow measured by 4-color flow cytometry op-tionally in patients with (clin.) CR/CRi (or PR almost fulfilling CR criteria, e.g. with residual splenomegaly) 12 weeks after achievement of MRD negativity in PB","definition_or_measurement_approach":"Optional bone marrow MRD measured by 4-color flow cytometry in patients with (clinical) CR/CRi or PR almost fulfilling CR, performed 12 weeks after MRD negativity in peripheral blood."}
• {"endpoint_text":"- Best response rate (BRR) until 6 months after RE","definition_or_measurement_approach":"Best overall response up to 6 months after RE per iwCLL criteria."}
• {"endpoint_text":"- ORR after debulking","definition_or_measurement_approach":"Overall response rate measured after debulking phase per iwCLL criteria."}
• {"endpoint_text":"- ORR after end of maintenance treatment","definition_or_measurement_approach":"Overall response rate measured at end of maintenance treatment per iwCLL criteria."}
• {"endpoint_text":"- Progression-free survival (PFS)","definition_or_measurement_approach":"Time from defined baseline to disease progression or death."}
• {"endpoint_text":"- Event-free survival (EFS)","definition_or_measurement_approach":"Time from baseline to occurrence of a defined event (progression, treatment discontinuation, or death) as per protocol."}
• {"endpoint_text":"- Overall survival (OS)","definition_or_measurement_approach":"Time from baseline to death from any cause."}
• {"endpoint_text":"- Duration of response in patients with -\ta complete response (CR), -\ta CR with incomplete recovery of the bone marrow (CRi), -\ta partial response (PR)","definition_or_measurement_approach":"Duration measured from first documented response to progression or relapse."}
• {"endpoint_text":"- Treatment-free survival (TFS) and time to next CLL treatment (TTNT)","definition_or_measurement_approach":"TFS and TTNT measured per protocol-defined timepoints and events."}

Germany

Earliest CTIS Part Ii Submission Date

13-05-2024

Latest Decision Or Authorization Date

30-03-2026

Processing Time Days

686

Number Of Sites

5

Number Of Participants

42

Primary sponsor

Full Name

University Of Cologne

Organisation Type

Educational Institution

Country Of Registered Address

Germany

Third parties

• {"country":"Germany","full_name":"Universitaetsklinikum Carl Gustav Carus Dresden an der Technischen Universitaet Dresden AöR","duties_or_roles":"4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"University Hospital Cologne AöR","duties_or_roles":"1","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"University Hospital Cologne AöR","duties_or_roles":"4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"University Hospital Cologne AöR","duties_or_roles":"4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"University Hospital Cologne AöR","duties_or_roles":"4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"Universitaetsklinikum Ulm AöR","duties_or_roles":"4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"Universitaetsklinikum Schleswig-Holstein AöR","duties_or_roles":"4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"University Hospital Cologne AöR","duties_or_roles":"10,11,12,13,5,6,8","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"Universitaetsklinikum Heidelberg AöR","duties_or_roles":"14","organisation_type":"Hospital/Clinic/Other health care facility"}