Q-HAM: a multicenter upfront randomized phase II trial of quizartinib and high-dose Ara-C plus mitoxantrone in relapsed/refractory AML with FLT3-ITD

• Published in: Current controlled trials in cardiovascular medicine 2023-09, Vol.24 (1), p.591-591, Article 591
• Main Authors: Jaramillo, Sonia, Le Cornet, Lucian, Kratzmann, Markus, Krisam, Johannes, Görner, Martin, Hänel, Mathias, Röllig, Christoph, Wass, Maxi, Scholl, Sebastian, Ringhoffer, Mark, Reichart, Alexander, Steffen, Björn, Kayser, Sabine, Mikesch, Jan-Henrik, Schaefer-Eckart, Kerstin, Schubert, Jörg, Geer, Thomas, Martin, Sonja, Kieser, Meinhard, Sauer, Tim, Kriegsmann, Katharina, Hundemer, Michael, Serve, Hubert, Bornhäuser, Martin, Müller-Tidow, Carsten, Schlenk, Richard F
• Format: Article
• Language: English
• Subjects: Acute myeloid leukemia; Biometrics; Chemotherapy; Cytarabine; Dosage and administration; Drug dosages; Hospitals; Induction therapy; Informatics; Internal medicine; Matched threshold crossing approach; Measurable residual disease; Medical prognosis; Mitoxantrone hydrochloride; Mutation; Neutropenia; Patients; Quizartinib; Refractory; Relapse; Remission (Medicine); Response rates; Study Protocol; Testing; Toxicity
• ISSN: 1745-6215; 1745-6215
• DOI: 10.1186/s13063-023-07421-x

Background About 50% of older patients with acute myeloid leukemia (AML) fail to attain complete remission (CR) following cytarabine plus anthracycline-based induction therapy. Salvage chemotherapy regimens are based on high-dose cytarabine (HiDAC), which is frequently combined with mitoxantrone (HAM regimen). However, CR rates remain low, with less than one-third of the patients achieving a CR. FLT3-ITD has consistently been identified as an unfavorable molecular marker in both relapsed and refractory (r/r)-AML. One-quarter of patients who received midostaurin are refractory to induction therapy and relapse rate at 2 years exceeds 40%. The oral second-generation bis-aryl urea tyrosine kinase inhibitor quizartinib is a very selective FLT3 inhibitor, has a high capacity for sustained FLT3 inhibition, and has an acceptable toxicity profile. Methods In this multicenter, upfront randomized phase II trial, all patients receive quizartinib combined with HAM (cytarabine 3g/m.sup.2 bidaily day one to day three, mitoxantrone 10mg/m.sup.2 days two and three) during salvage therapy. Efficacy is assessed by comparison to historical controls based on the matched threshold crossing approach with achievement of CR, complete remission with incomplete hematologic recovery (CRi), or complete remission with partial recovery of peripheral blood counts (CRh) as primary endpoint. During consolidation therapy (chemotherapy and allogeneic hematopoietic cell transplantation), patients receive either prophylactic quizartinib therapy or measurable residual disease (MRD)-triggered preemptive continuation therapy with quizartinib according to up-front randomization. The matched threshold crossing approach is a novel study-design to enhance the classic single-arm trial design by including matched historical controls from previous clinical studies. It overcomes common disadvantages of single-armed and small randomized studies, since the expected outcome of the observed study population can be adjusted based on the matched controls with a comparable distribution of known prognostic and predictive factors. Furthermore, balanced treatment groups lead to stable statistical models. However, one of the limitations of our study is the inability to adjust for unobserved or unknown confounders. Addressing the primary endpoint, CR/CRi/CRh after salvage therapy, the maximal sample size of 80 patients is assessed generating a desirable power of the used adaptive design, assuming a logistic regressi