Phase 1/2 Study of Quizartinib in Combination with Chemotherapy in Pediatric and Young Adult Patients with FLT3-ITD Mutated Relapsed/Refractory Acute Myeloid Leukemia

The primary objective of this study is to determine the recommended Phase 2 dose (**RP2D**) of **quizartinib** in combination with chemotherapy for pediatric subjects with **Acute Myeloid Leukemia** (AML) who have relapsed or are refractory. This is crucial for optimizing therapeutic efficacy and minimizing toxicity in both older (≥1 year to ≤21 years) and younger (≥1 month to <12 months) age groups. Additionally, the study aims to determine the composite complete remission (**CRc**) rate, which includes complete remission (**CR**) and CR with incomplete recovery (**CRi**), after up to two re-induction cycles. The safety and cumulative toxicity of quizartinib, when administered with re-induction chemotherapy and as a single-agent continuation therapy, will also be evaluated. Furthermore, the study will estimate individual pharmacokinetic parameters of quizartinib and its metabolite AC886.

Secondary objectives include:

• Determining the CR and CRi rate after up to two re-induction cycles and the duration of CRi, CRc, and CR.
• Assessing time to relapse, relapse rates after 1, 2, and 3 years, and cumulative incidence of relapse at the end of treatment.
• Determining CR, CRi, and CRc rates after completion of the first re-induction cycle.
• Assessing overall survival (**OS**) and event-free survival (**EFS**) at 1, 2, and 3 years.
• Evaluating the number of subjects proceeding to high-dose conditioning therapy/hematopoietic stem cell transplantation (**HSCT**).
• Assessing the activity of quizartinib on **FLT3-ITD** autophosphorylation activity during re-induction, continuation, and at relapse.
• Evaluating the **FLT-ITD/FLT3-wild-type (WT)** allelic ratio at screening, during re-induction, and at relapse.
• Evaluating somatic mutations in blasts at screening and at refractory disease or relapse.
• Assessing the rate of CRc without **FLT3-ITD** minimal residual disease (**MRD**) using next-generation sequencing.
• Assessing the acceptability, including palatability, of quizartinib formulations.

The clinical trial involves a total of **2 participants** diagnosed with **Acute Myeloid Leukemia** (AML) according to the World Health Organization 2008 classification. The study population includes both male and female subjects, ranging in age from 1 month to 21 years. Participants were selected based on specific criteria, including the presence of the FLT3-ITD activating mutation in bone marrow or peripheral blood, and a protocol-defined adequate performance status score. The trial population is characterized by individuals who have experienced a first relapse or are refractory to first-line high-dose chemotherapy, with no more than one attempt at remission induction. Participants must have fully recovered from acute clinically significant toxicity effects of previous anti-cancer therapy prior to the start of the re-induction cycle. The study includes vulnerable populations, and participants are required to adhere to specific reproductive health guidelines, such as the use of highly effective birth control during and after the treatment period. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is a **Phase 1/2**, multicenter, dose-escalating study designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of **Quizartinib** administered in combination with re-induction chemotherapy and as a single-agent continuation therapy in pediatric subjects with relapsed or refractory **Acute Myeloid Leukemia** (AML) with FLT3-ITD mutations. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial is from August 15, 2018, to May 1, 2027.

Participants will undergo a sequence of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, diagnosis, and previous treatment history. Following successful screening, participants will enter the treatment phase, which includes up to two re-induction cycles with optional consolidation therapy and a single-agent continuation therapy over a maximum of 12 cycles. Follow-up visits will be scheduled to monitor safety, efficacy, and pharmacokinetic parameters. The end-of-study visit will conclude the participant's involvement, assessing the overall outcomes and any long-term effects.

The expected length of participant involvement varies depending on individual response and tolerance to the treatment, with a maximum duration extending to the end of the study. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or failure to comply with study protocols. The primary endpoints focus on the composite complete remission rate and safety profile, while secondary endpoints include various efficacy measures, such as complete remission rates and duration, as well as pharmacodynamic and biomarker assessments.

The clinical trial involves the administration of **Quizartinib**, an investigational medication, which is a **Class III receptor tyrosine kinase inhibitor**. The active substance in this medication is **quizartinib dihydrochloride**, and it is provided in the form of an **oral solution**. The pharmaceutical form is specifically designed for oral administration. Quizartinib is not a pediatric formulation, and it is manufactured by Daiichi Sankyo, Inc. The medication is administered orally, and the dosing schedule is determined based on the phase of the trial and the specific cohort of participants. The trial aims to establish the recommended Phase 2 dose (RP2D) of quizartinib in combination with chemotherapy for different age groups, as well as to evaluate its safety, pharmacokinetics, pharmacodynamics, and efficacy.

In addition to the experimental treatment with quizartinib, participants may receive standard re-induction chemotherapy as part of the study protocol. The chemotherapy regimen is used in combination with quizartinib during the re-induction phase, and quizartinib is also administered as a single-agent continuation therapy. The trial includes monitoring of participant compliance with the dosing schedule, and assessments are conducted to evaluate the composite complete remission rate, safety, and cumulative toxicity of the treatment regimen. The study is designed to include pediatric subjects with relapsed or refractory acute myeloid leukemia (AML) who have FLT3-ITD mutations, as well as young adults up to 21 years of age.

Efficacy in this clinical trial will be assessed primarily through the **composite complete remission (CRc) rate**, which includes complete remission (CR) and CR with incomplete recovery (CRi) after the completion of up to two Re-Induction Cycles. This primary endpoint will be evaluated based on the investigator's assessment. Secondary efficacy endpoints include the CR rate, CRi rate, duration of CR, duration of CRi, and duration of CRc, all measured after the completion of up to two Re-Induction Cycles. Additionally, the trial will assess the time to relapse, rate of relapse after 1, 2, and 3 years, cumulative incidence of relapse at the end of the study, overall survival (OS), and event-free survival (EFS). Pharmacodynamic assessments will include the inhibition of FLT3-ITD autophosphorylation activity and the FLT3-ITD to FLT3-WT allelic ratio at various stages of the trial. Biomarker analysis will focus on the rate of CRc without minimal residual disease (MRD) using next-generation sequencing. These efficacy parameters will be collected and analyzed at specified time points throughout the trial to determine the therapeutic impact of Quizartinib in pediatric subjects with relapsed/refractory acute myeloid leukemia (AML) with FLT3-ITD mutations.