This multicenter, prospective, open-label, randomized, superiority phase 3 study is designed to demonstrate that treatment with a triple combination of acalabrutinib, obinutuzumab and venetoclax (GAVe) prolong the progression-free survival (PFS) as compared to treatment with the combination of obinutuzumab and venetoclax (GVe) in pa-tients with high risk CLL (defined as having at least one of the follow-ing risk factors: 17p-deletion, TP53-mutation, complex karyotype or an unmutated IGHV-gene status).
Documented CLL/SLL requiring treatment according to iwCLL criteria
Age at least 18 years
At least one of the following risk factors: 17p-deletion, TP53-mutation, complex karyotype (defined as defined as the presence of 3 or more chromosomal aberrations in 2 or more metaphases) or an unmutated IGHV gene status.
Life expectancy ≥ six months
Any prior CLL-specific therapies (except corticosteroid treatment administered due to necessary immediate intervention; within the last 10 days before start of study treatment, only dose equivalents up to 20 mg prednisolone are permitted)
Absence of high risk disease (17p-deletion, TP53-mutation complex karyotype
An individual organ/system impairment score of 4 as assessed by the CIRS definition (e.g. advanced cardiac disease (NYHA class 3 or 4) limiting the ability to receive the study treatment 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)
Transformation of CLL (Richter transformation)
Parallel
Obinutuzumab
DrugObinutuzumab i.v. infusion: Cycle 1 Day 1: Obinutuzumab 100 mg i.v. Cycle 1 Day 1 (or 2): Obinutuzumab 900 mg i.v. Cycle 1 Day 8: Obinutuzumab 1000 mg i.v. Cycle 1 Day 15: Obinutuzumab 1000 mg i.v. Cycles 2-6: Day 1: Obinutuzumab 1000 mg i.v.
Venetoclax
DrugVenetoclax p.o.: Cycle 1: Days 22-28: Venetoclax 20 mg (2 x 10 mg) Cycle 2: Days 1-7: Venetoclax 50 mg (1 x 50 mg) Cycle 2:Days 8-14: Venetoclax 100 mg (1 x 100 mg) Cycle 2:Days: 15-21: Venetoclax 200 mg (2 x 100 mg) Cycle 2:Days: 22-28: Venetoclax 400 mg (4 x 100 mg) Cycles 3-12: Days 1-28: Venetoclax 400 mg (4 x 100 mg)
Acalabrutinib
DrugCycles 15-24: Days 1-28: 100 mg acalabrutinib twice daily p.o. approx. every 12 hrs (corresponding to a total daily dose of 200 mg).
Progression-free survival (PFS)
The study is designed to demonstrate that 14 cycles of treatment with GAVe followed by up to 10 cycles maintenance with acalabrutinib for patients with detectable MRD at cycle 14 day 14 prolong PFS as compared to 12 cycles of treatment with GVe in patients with high risk CLL (defined as hav-ing at least one of the following risk factors: 17p-deletion, TP53- mutation or complex karyotype).
Minimal residual disease (MRD) levels
Minimal residual disease (MRD) levels in the peripheral blood (PB) and in the bone marrow (BM) at final restaging ((Staging 5) cycle 15 day 1 for patients in GVe study arm, cycle 14 day 14 for patients in GAVe study arm)
MRD in PB at cycle 27 day 1
MRD in PB at cycle 27 day 1 for all patients (end of maintenance for patients in GAVe study arm, who had detectable MRD levels after 14 cycles of GAVe-treatment)
Overall response rate
Overall response rate (ORR; as per iwCLL guidelines) at cycle 15
Complete response rate
Complete response rate (CRR; as per iwCLL guidelines) at cycle 15
Correlation between MRD in PB/BM and PFS/OS
Time-to-event analyses will be calculated accordiung to MRD levels in peripheral bloos and bone marrow respectively.
MRD by methods other than flow cytometry (ddPCR)
New methods of MRD measurements (ddPCR) will be compared with the standard method (flow cytometry )
Correlation between MRD in PB and BM
MRD levels in the peripheral blood and in the bone marrow will be statistically compared.
Longitudinal Analysis of European Organisation for Research and Treatment of Cancer(EORTC): Quality of Life Questionnaire (QLQ-C30) at defined timepoints
Outcome measure: scores of EORTC QLQ-C30 and QLQ-CLL17 Questionnaires at defined timepoints will be analyzed and compared to baseline level for each patient. Scoring of the QLQ-C30 is performed according to QLQ-C30 Scoring manual. All of the scales and single-item measures range in score from 0 to 100. Higher score for the functioning scales and global health status denote a better level of functioning (i.e. a better state of the patient), while higher scores on the symptom and single-item scales indicate a higher level of symptoms (i.e. a worse state of the patient)
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German CLL Study Group
Lead sponsor
AstraZeneca
Collaborator
