Rationale and Design of GnG-Trial: A Randomized Phase-III Study to Compare Two Schedules of Gemtuzumab Ozogamicin as Adjunct to Intensive Induction Therapy and to Compare Double-Blinded Intensive Postremission Therapy with or Without Glasdegib in Older Patients with Newly Diagnosed AML
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摘要
Abstract BackgroundOverall survival remains poor in older patients with acute myeloid leukemia (AML) with less than 10% being alive after five years. In recent studies, a significant improvement in event-free, relapse-free and overall survival was shown by adding gemtuzumab ozogamicin (GO), a humanized antibody-drug conjugate directed against CD33, to intensive induction therapy once or in a sequential dosing schedule. Glasdegib, the small-molecule inhibitor of smoothened (SMO), also showed improved overall survival in patients not eligible for intensive chemotherapy when combined with low-dose cytarabine compared to low-dose cytarabine alone. These findings warrant further investigations in the phase III GnG trial.Methods/DesignThis is a randomized phase III trial with measurable residual disease (MRD) after induction therapy and event-free survival (EFS) as primary endpoints. The two research questions are addressed in a 2 by 2 factorial design. Patients age 60 years and older are upfront randomized 1:1 in one of the two induction arms: GO administered to intensive induction therapy on days 1,4 and 7 versus GO administered once on day 1 (GO-147 versus GO-1), and double-blinded 1:1 in one of the subsequent treatment arms glasdegib vs. placebo as adjunct to consolidation therapy and as single-agent maintenance therapy for six months. Chemotherapy backbone for induction therapy consists of standard 7+3 schedule with cytarabine 200mg/m² continuously days 1 to 7, daunorubicin 60mg/m² days 1, 2 and 3 and high-dose cytarabine (1g/m², bi-daily, days 1,2,3) for consolidation therapy. Addressing two primary endpoints, MRD-negativity after induction therapy and event-free survival (EFS), 252 evaluable patients are needed to reject each of the two null hypotheses at a two-sided significance level of 2.5% with a power of at least 85%. ETHICS AND DISSEMINATION: Ethical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings.TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04093505; EudraCT Number: 2019-003913-32.TRIAL REGISTRATION DATE: October 30, 2018
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关键词
gemtuzumab ozogamicin,intensive postremission therapy,intensive induction therapy,older patients,gng-trial,phase-iii,double-blinded
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