A Phase-3-trial of Acalabrutinib, Obinutuzumab & Venetoclax Compared to Obinutuzumab and Venetoclax in Previously Untreated Patients With High Risk CLL
A Prospective, Open-label, Multicentre, Randomized, Phase-3-trial of Acalabrutinib, Obinutuzumab and Venetoclax (GAVE) Compared to Obinutuzumab and Venetoclax (GVE) in Previously Untreated Patients With High Risk Chronic Lymphocytic Leukemia (CLL)
German CLL Study Group
202 participants
Apr 19, 2022
INTERVENTIONAL
Conditions
Summary
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).
Eligibility
Inclusion Criteria10
- 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
- Adequate bone marrow function indicated by a platelet count \>30 x10\^9/l
- Creatinine clearance ≥ 30ml/min
- Adequate liver function as indicated by a total bilirubin ≤ 2 x, AST/ ALT ≤ 2.5 x the institutional ULN value, unless directly attributable to the patient's CLL or to Gilbert's Syndrome
- Negative testing for hepatitis B (HbsAg negative 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 month until 12 months after last treatment cycle),or hepatitis C (negative testing for hepatitis C RNA within 6 wee
- ks prior to registration for study screening (i.e. PCR only required when serology was positive))
- ECOG (Eastern Cooperative Oncology Group Performance Status) status 0-2
Exclusion Criteria8
- 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)
- Malignancies other than CLL currently requiring systemic therapies
- Uncontrolled or active infection of HIV/PML or any other active infection
- Anticoagulant therapy with warfarin or phenoprocoumon
- Pregnant women and nursing mothers
Interventions
Obinutuzumab 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 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)
Cycles 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).
Locations(30)
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NCT05197192