Evaluation of Quizartinib in Combination with Chemotherapy for Pediatric FLT3-ITD Positive, NPM1 Wild-Type Acute Myeloid Leukemia

The primary objective of this study is to evaluate the **clinical benefit** of quizartinib in newly diagnosed pediatric patients with FLT3-ITD positive and NPM1 wild-type acute myeloid leukemia (AML). This is measured by the rate of minimal residual disease (MRD) negativity, defined as less than 0.1% using flow-cytometry, after up to two courses of conventional chemotherapy combined with quizartinib. Additionally, during the safety run-in phase, the co-primary objective is to determine the Recommended Phase 2 Dose (RP2D) of quizartinib for these patients, based on its safety and tolerability profile at various dose levels. These objectives are clinically relevant as they aim to establish the efficacy and optimal dosing of quizartinib, potentially improving treatment outcomes for this specific pediatric AML population.

Secondary objectives include: - **Efficacy**: To explore the added anti-leukemic effect of quizartinib through various response measures such as morphological overall response rate (ORR), MRD by multiparameter flow cytometry (MFCM), event-free survival (EFS), overall survival (OS), disease-free survival (DFS), duration of response, cumulative incidence of relapse (CIR), and the number and percentage of patients undergoing hematopoietic stem cell transplantation (HSCT) and completing post-HSCT treatment. - **Safety**: To describe the safety and tolerability of quizartinib when combined with conventional treatment and as a single-agent post-HSCT. - **Pharmacokinetics (PK)**: To characterize the pharmacokinetics of quizartinib and its main circulating active metabolite, AC886. - **Palatability**: To assess the palatability of quizartinib formulations.

The clinical trial involves a total of **8 participants** who are newly diagnosed with pediatric **FLT3-ITD positive and NPM1 wild-type acute myeloid leukemia (AML)**. The study population includes both male and female subjects, ranging in age from 1 month to 18 years at the time of initial diagnosis. Participants were selected based on specific criteria, including a Karnofsky Performance status of greater than 50% for those over 16 years of age, and a Lansky performance status score of greater than 50% for those 16 years or younger. The trial population is characterized by adequate renal and liver function, as well as a life expectancy of more than 6 weeks. Participants must be able to swallow or administer quizartinib via a nasogastric tube. The study includes a vulnerable population, and informed consent was obtained from patients or their legal guardians. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **phase II**, single-arm, open-label study to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of **quizartinib** in combination with chemotherapy and as a single agent following high-dose therapy in newly diagnosed pediatric patients with FLT3-ITD positive and NPM1 wild-type acute myeloid leukemia (AML). The trial aims to assess the clinical benefit of quizartinib by measuring the minimal residual disease (MRD) negativity rate, defined as less than 0.1% using flow cytometry, after up to two courses of conventional chemotherapy plus quizartinib. The study will also determine the recommended phase 2 dose (RP2D) of quizartinib based on its safety and tolerability profile.

Participants will be involved in the trial for a maximum treatment period of 238 days. The trial will include several study visits, starting with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, organ function, and life expectancy. Follow-up visits will occur at baseline, the end of cycle 1, and the end of cycle 2 to evaluate MRD levels and dose-limiting toxicities. The end-of-study visit will assess the overall response and safety outcomes. Participants may be terminated early from the study if they experience unacceptable toxicity, withdraw consent, or if the investigator deems it in the participant's best interest.

The trial is expected to conclude by December 31, 2031, with recruitment starting on December 31, 2023. The primary endpoints include the percentage of patients achieving MRD negativity and the incidence of dose-limiting toxicities. Secondary endpoints will evaluate additional efficacy measures such as complete remission rates, event-free survival, and overall survival, as well as safety outcomes like adverse events and laboratory abnormalities. Pharmacokinetic analysis will estimate parameters such as area under the curve (AUC) and maximum concentration (Cmax) for quizartinib. The study will also assess the palatability of the oral solution formulation of quizartinib.

The clinical trial involves the administration of **Quizartinib**, an investigational medication, in the form of an **oral solution**. The active substance in this medication is **quizartinib dihydrochloride**, a chemical compound. The pharmaceutical form is designed for **oral use**, ensuring ease of administration in the pediatric population. The maximum daily dose of Quizartinib is 60 mg, with a total maximum dose of 14,280 mg over the course of the treatment period, which spans up to 238 days. The medication is administered as part of a single-arm, open-label study, focusing on its safety, efficacy, pharmacokinetics, and pharmacodynamics in newly diagnosed pediatric patients with FLT3-ITD positive and NPM1 wild-type acute myeloid leukemia (AML).

In addition to the experimental treatment with Quizartinib, participants will receive standard chemotherapy as part of the study protocol. The trial does not include a placebo or comparator treatment, as it is designed to evaluate the effects of Quizartinib in combination with chemotherapy and as a single agent following high-dose therapy. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment regimen and to assess the safety and tolerability of the investigational medication. The study aims to determine the Recommended Phase 2 Dose (RP2D) of Quizartinib based on the observed safety profile at various dose levels.

The efficacy of the clinical trial will be assessed primarily by measuring the **MRD-negativity rate** in newly diagnosed pediatric patients with acute myeloid leukemia (AML) who are FLT3-ITD positive and NPM1 wild-type. This will be determined using multiparameter flow cytometry (MFCM) to evaluate the percentage of patients achieving minimal residual disease (MRD) levels of less than 0.1% after up to two courses of induction chemotherapy combined with quizartinib. Efficacy assessments will occur at baseline, the end of cycle 1, and the end of cycle 2, before the start of consolidation therapy.

Secondary efficacy endpoints include various measurements of treatment response, such as the proportion of subjects achieving complete remission (CR) without evidence of MRD after one and two induction courses. Additional assessments will involve bone marrow blast counts by morphology and MFCM, event-free survival (EFS), overall survival (OS), disease-free survival (DFS), duration of complete response, and cumulative incidence of morphological relapse (CIR). These parameters will be evaluated at specified timepoints, including after induction courses and during continuation treatment.

Other efficacy measures include the number and percentage of patients proceeding to hematopoietic stem cell transplantation (HSCT) and the number of patients starting and completing continuation treatment post-HSCT. The trial will also assess pharmacokinetics (PK) through population PK analysis to estimate parameters such as AUC (tau), Cmax, clearance (CL/F), and volume of distribution (Vss/F) for quizartinib. Palatability will be evaluated using a Hedonic scale for taste and the ability to swallow the medicine, as reported by patients and/or their parents or legal guardians.