CHIP-AML22: a complex clinical trial in de novo pediatric AML patients, including a gemtuzumab ozogamicin randomization and targeted therapy with quizartinib in eligible subgroups, within the NOPHO-DB-SHIP consortium

Abstract

Background: The overall survival of children with newly diagnosed acute myeloid leukemia (AML) in high-income countries has increased to 80% over the past decades. Nevertheless, a significant subset of patients experiences relapse and treatment is associated with both short- and long-term toxicities. The CHIP-AML22 protocol includes an updated standard-of-care treatment for children with AML within the NOPHO-DB-SHIP consortium. Targeted therapies are offered to specific subsets of patients and measures to reduce toxicity are being investigated. Methods: CHIP-AML22 is a multinational complex clinical trial in newly diagnosed de novo AML patients up to and including 18 years of age, sponsored by the Princess Máxima Center. The primary aim is to improve event-free survival. To achieve this, (1) FLT3-ITD+/NPM1wt patients can participate in a linked-trial assessing safety and efficacy of quizartinib, in addition to conventional chemotherapy during induction and consolidation therapy and as continuation monotherapy after allogeneic hematopoietic stem cell transplantation; (2) a randomization study is incorporated on the use of two doses of 3 mg/m2 gemtuzumab ozogamicin during induction therapy in CD33-positive patients; and (3) updated criteria are used for the identification of high-risk patients, based both on flow measurable residual disease (MRD) and (cyto)genetic profiling. The design allows for introduction of new treatment options in the future. Furthermore, a randomization is included aiming to demonstrate non-inferiority in disease-free survival after two versus three consolidation courses in standard-risk patients. Additionally, the use of the cardioprotective drug dexrazoxane is recommended in all patients. Interim analyses will be conducted to assess safety and efficacy in the linked trial and randomization studies. Based on power calculations, we aim to recruit a total of 905 patients in the Master protocol and 60 patients in the linked Quizartinib trial. Discussion: The risk-based approach and use of targeted therapies in CHIP-AML22 illustrate a shift toward more personalized treatment. Besides improving event-free survival, this study aims to contribute to the international consensus on strategies to reduce toxicity for all patients. The design of this study provides a dynamic framework, allowing for the potential introduction of emerging therapeutic options in the future. Trial registration: CHIP-AML22 Master protocol: EU CT 2023-504999-25-00, Clinicaltrials.gov NCT05994690. Registered on 16-08-2023 Quizartinib linked-trial: EU CT 2023-505000-27-01, Clinicaltrials.gov NCT06262438.