CHIP-AML22/Quizartinib: Quizartinib + Chemotherapy in Newly Diagnosed Pediatric FLT3-ITD+ and NPM1wt AML Patients (CHIP-AML22/Q)

A Phase II, Single Arm, Open Label, Study on the Safety, Efficacy, Pharmacokinetics & Pharmacodynamics of Quizartinib + Chemotherapy and as Single-agent After High Dose Therapy in Newly Diagnosed Pediatric FLT3-ITD+ and NPM1wt AML Patients

The CHIP-AML22 Master protocol has the overall aim of increasing the cure rate in newly diagnosed pediatric de novo AML patients, while avoiding unnecessary toxicity. The linked Quizartinib trial (CHIP-AML22/Quizartinib) is a phase II, single arm, open label, study on the safety, efficacy, pharmacokinetics and pharmacodynamics of quizartinib in combination with chemotherapy and as single-agent after high dose therapy in newly diagnosed pediatric AML patients with a FLT3-ITD mutation and NPM1 wild-type.

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia in Children
• Intervention / Treatment: Drug: Quizartinib; Drug: Etoposide; Drug: Dexrazoxane; Drug: Mitoxantrone; Drug: Cytarabine; Drug: Methotrexate; Drug: Daunorubicin; Drug: Fludarabine; Other: allo-SCT

Detailed Description

The CHIP-AML22/Quizartinib study is a single-arm, multinational, multicenter, open-label phase II study, with a safety run-in, aiming to assess the safety, efficacy, pharmacokinetics and pharmacodynamics of quizartinib, a FLT3-inhibitor, as IMP added to standard of care chemotherapy in newly diagnosed FLT3-ITD positive and NPM1 wild-type AML pediatric patients.

This study is a linked trial to the CHIP-AML22/Master protocol. Patients will start in the CHIP-AML22/Master study and if they are FLT3-ITD positive and NPM1 wild-type, can be enrolled in the CHIP-AML22/Quizartinib study.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Renske Benedictus; Phone Number: +31 88 972 72 72; Email: CHIP-AML22@prinsesmaximacentrum.nl

Study Locations

• Netherlands
  • Utrecht, Netherlands, 3584 CS
    • Recruiting
    • Princess Máxima Center for Pediatric Oncology
    • Contact: Gertjan Kaspers, Prof. Dr.
    • Principal Investigator: Bianca Goemans, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

1. Enrollment on CHIP-AML22/Master:

   Patients must be enrolled on the CHIP-AML22/Master prior to enrollment on CHIP-AML/Quizartinib linked-trial, and may have received a diagnostic work-up according to the master protocol. Induction treatment can be started as standard of care.

2. FLT3-ITD+ and wild-type NPM1:

   Presence of FLT3-ITD+ and NPM1 wild type in bone marrow or peripheral blood provided by the local laboratories, as part of standard of care diagnostics. The results of FLT3-ITD testing must be obtained prior to the first dose of quizartinib (e.g., Induction course 1, Day 10).

3. Age:

   Patients must be from 1 month to ≤ 18 years old at initial diagnosis

4. Performance status Karnofsky performance status score of >50% for subjects >16 years of age, and a Lansky performance status score of >50% for subjects ≤16 years of age.

5. Organ function criteria:

   These criteria must be met based on the results before start of any chemotherapy (e.g., MEC) a. Adequate Renal Function Defined as:

   • Calculated eGFR ≥ 50 mL/min/1.73 m2 using the Schwartz formula. b. Adequate Liver Function Defined as:

   • Total or direct (conjugated) bilirubin < 1.5xULN for age (≤ 5xULN if related to leukemic involvement), AND
   • Aspartate transaminase (AST) and alanine transaminase (ALT) <5xULN (<10×ULN if related to leukemic involvement)
6. Life expectancy: > 6 weeks

7. Pregnancy test:

   Serum/urine pregnancy test (for all girls ≥ age of menarche) negative within 2 weeks prior to enrollment on the quizartinib linked-trial.

8. Taking quizartinib:

   Patients must be able to reliably swallow or administer quizartinib by NG tube.

9. Informed consent:

   Written informed consent/assent for the quizartinib linked trial from patients and/or from parents or legal guardians for minor patients, according to local law and regulations.

   General exclusion criteria:

   1. Patients with only extramedullary disease

   2. Uncontrolled or significant cardiovascular disease, including -Diagnosed or suspected congenital long QT syndrome

      -History of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes); any history of arrhythmia will be discussed with sponsor, the national coordinator and C.I.the prior to subject's entry into the study.

      -QT interval corrected >450 ms: QTc interval corrected with Fridericia's formula (QTcF) for subjects ≥ 6 years of age at the time of enrollment.

      -Left ventricular systolic dysfunction (LVSD), defined as ejection fraction (EF) below 55% during the screening for the CHIP-AML22/Master protocol.

      -History of uncontrolled angina pectoris or myocardial infarction within 6 months.

      -History of second (Mobitz II) or third degree heart block (subjects with pacemakers are eligible if they have nohistory of fainting or clinically relevant arrhythmias while using the pacemaker).

      -Heart rate <50 beats/minute on ECG during the screening for the CHIP-AML22/Master protocol (In case,adolescents with a normal sinusoidal rhythm and no evidence of other cardiac dysfunction will be discussed with sponsor, the national coordinator and C.I. the prior to subject's entry into the study.)

      -Uncontrolled hypertension (e.g., systolic blood pressure and /or diastolic blood pressure that is, on repeated measurement, at or above the 95th percentile for sex, age, and height).

      • History of complete left bundle branch block.
      • History of New York Heart Association Class 3 or 4 heart failure.
   3. Known history of HIV or active clinically relevant liver disease (e.g., active hepatitis B or active hepatitis C)
   4. Underlying GI disease that may affect absorption of study drug
   5. Use of strong or moderate CYP3A inducers will be prohibited throughout the duration of the study. Strong CYP3A4 inhibitors will be allowed with a concomitant dose reduction of quizartinib with the exception during the safety run-in.
   6. History of hypersensitivity to any of the study medications or their excipients.
   7. Other serious illnesses or medical conditions, that will likely make it impossible to complete treatment according to protocol (e.g., patients who should not be given any of the study medications based on the SmPC)
   8. Currently participating in other investigational interventional procedures, if it interferes with any endpoints of the quizartinib trial.

2) Additional exclusion criteria during safety run-in:

1. Patients with CNS3 disease
2. Using strong CYP3A4 inhibitors (If patient can stop using strong CYP3A4 inhibitors, he/she will be allowed to enroll. In such case, no washout is required for the strong CYP3A4 inhibitor)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Quizartinib; Quizartinib will be administered for 14 days following the completion of standard of care chemotherapy for up to 3-5 cycles of induction and consolidation. After high dose chemotherapy or allo-Stem Cell Transplantation (allo-SCT), patients will receive continuation treatment with quizartinib for six 28-day courses

Drug: Quizartinib; Quizartinib is a novel oral Class III receptor tyrosine kinase (RTK) inhibitor exhibiting highly potent and selective but reversible inhibition of FMS-like tyrosine kinase FLT3. The dose will be adjusted for the patient's body weight (BW) as measured at the start of each course. Quizartinib will be administered orally once daily and is taken for 14 consecutive days during induction and consolidation courses. Induction course 1: Start on day 13; Induction course 2: Start on day 9; Consolidation course 1: Start on day 6; Consolidation courses 2 and 3 (only if no allo-SCT is done): Start on day 6. Continuation courses 1-6: patients will receive quizartinib for six 28-day courses. For the first 15 days of course 1 a starting dose will be applicable. On course 1 Day 16, the dose will be increased if the average QTc of the triplicate Electrocardiograms is ≤450 msec on course 1 Day 15. Once the dose is increased, the patient may continue on this dose as long as dose reduction is not needed.; Other Names: AC220; Vanflyta; Quizartinib dihydrochoride; Drug: Etoposide; Induction course 1: 150 mg/m2 once daily by Intravenous (IV) infusion over 2 hours (+/- 30 mins) on days 1-5 inclusive (total 5 doses). Induction course 2: 150 mg/m2 once daily by IV infusion over 2 hours (+/- 30 mins) on days 6-8 inclusive (total 3 doses). Consolidation course 2 (only if no allo-SCT is done): 100 mg/m2 once daily by IV infusion over 1 hour (+/- 15 mins) on days 1-5 inclusive (total 5 doses).; Drug: Dexrazoxane; Induction course 1: 250 mg/m2 once daily by 15 mins IV infusion shortly before Mitoxantrone on day 6-10 inclusive (total 5 days), per investigator discretion and per institutional guidelines and availability. Induction course 2: 600 mg/m2 once daily by 15 mins IV infusion shortly before daunorubicin on day 2,4,6 inclusive (total 3 does), per investigator discretion and per institutional guidelines and availability. Consolidation course 1: 500 mg/m2 once daily by 15 mins IV infusion shortly before Mitoxantrone on 3-5 inclusive (total 3 does), per investigator discretion and per institutional guidelines and availability.; Drug: Mitoxantrone; Induction course 1: 5 mg/m2 once daily by IV infusion over 1 hour (+/- 15 mins) on days 6-10 inclusive (total 5 doses). Please note that mitoxantrone and cytarabine should not be given concomitantly. Mitoxantrone should be completed before cytarabine is given. Consolidation course 1: 10 mg/m2 once daily by IV infusion over 1 hour (+/- 15 mins) on days 3-5 inclusive (total 3 doses).; Drug: Cytarabine; Induction course 1: 200 mg/m2 once daily by IV infusion over 12 hours (+/- 1 hour) on days 6-12 inclusive (total 7 doses), following mitoxantrone. Induction course 2: 100 mg/m2 once daily by continuous IV infusion on days 1-2 inclusive. And 100 mg/m2 twice daily as a 30min (+/- 10 mins) IV infusion every 12 hours on days 3-8 inclusive (total 12 doses). Consolidation course 1: 1000 mg/m2 twice daily by IV infusion over 2 hours (+/- 30 min) every 12 hours on days 1-3 inclusive (total 6 doses). Consolidation course 2 (only if no allo-SCT is done): 3000 mg/m2 twice daily by IV infusion over 2 hours (+/- 30 mins) every 12 hours on days 1-3 inclusive (total 6 doses). Consolidation course 3 (only if no allo-SCT is done): 2000 mg/m2 once daily by IV infusion over 3 hours (+/- 1 hour) starting 4 hours after fludarabine on days 1-5 inclusive (total 5 doses), following fludarabine.; Drug: Methotrexate; Induction course 1: Methotrexate (MTX) Intrathecal therapy (IT) prophylaxis is age-adjusted. If MTX is given at diagnosis omit IT therapy on day 6 unless in case of CNS involvement (CNS3). For children with initial CNS involvement (CNS3) MTX IT is replaced with triple IT and given more frequently. For children with CNS2, CSF must be investigated on day 22; if leukemic cells persist, treat as CNS3. Induction course 2, Day 1: MTX (IT) prophylaxis is age-adjusted. For children with initial CNS involvement (CNS3) MTX IT is replaced with triple IT and given more frequently. Consolidation course 1, Day 1: MTX (IT) prophylaxis is age-adjusted. For children with initial CNS involvement (CNS3) MTX IT is replaced with triple IT and given more frequently. Consolidation course 2 and 3, Day 1 (only if no allo-SCT is done): MTX (IT) prophylaxis is age-adjusted. For children with initial CNS involvement (CNS3) MTX IT is replaced with triple IT and given more frequently.; Drug: Daunorubicin; Induction course 2: 60 mg/m2 once daily by IV infusion over 1 hour (+/- 15 mins) on days 2,4,6 inclusive (total 3 doses).; Drug: Fludarabine; Consolidation course 3 (only if no allo-SCT is done): 30 mg/m2 once daily by IV infusion over 30 mins (+/- 10 mins) on days 1-5 inclusive (total 5 doses).; Other: allo-SCT; The SCT procedure is left to the discretion of the investigator and not part of this protocol.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary objective (efficacy)	The percentage of patients with (Minimal Residual Disease) MRD levels <0.1% (MRD negativity) after up to 2 courses of induction chemotherapy plus quizartinib, as measured in the bone marrow using multiparameter flow cytometry (MFCM) before start of consolidation therapy, in the evaluable population for response. o Patients to be evaluated at baseline, end of cycle 1, and end of cycle 2	2 induction courses (maximum of 56+/-2 days per course)
Primary objective (safety)	Incidence of Dose-Limiting Toxicities (DLTs) assessed during Induction course 1 and 2 (until day 56 of each course) for the DLTs evaluable patients.	2 induction courses (maximum of 56+/-2 days per course)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary objectives (efficacy_1)	Morphological overall response rate (ORR)	2 induction courses (maximum of 56+/-2 days per course)
Secondary objectives (efficacy_2)	MRD by multiparameter flow cytometry (MFCM)	Multiple time points, last time point after continuation treatment (1.5 years)
Secondary objectives (efficacy_3)	Event free survival (EFS)	3 years
Secondary objectives (efficacy_4)	Overall survival (OS)	3 years
Secondary objectives (efficacy_5)	Disease free survival (DFS)	3 years
Secondary objectives (efficacy_6)	Duration of response	3 years
Secondary objectives (efficacy_7)	Cumulative incidence of relapse (CIR)	3 years
Secondary objectives (efficacy_8)	Number and percentage of patients actually being treated with hematopoietic stem cell transplantation (HSCT)	1 year
Secondary objectives (efficacy_9)	Number of patients starting and completing continuation treatment post-HSCT.	1.5 years
Secondary objectives (safety) - Adverse Events, Laboratory Abnormalities and cumulative incidence of non-relapse mortality	Safety and tolerability of combining quizartinib with conventional treatment and quizartinib given as single-agent after HSCT.; Adverse events (AEs), as characterized by type, frequency, severity (as graded using CTCAE, v5.0).; Laboratory abnormalities (including time to recovery of ANC and PLT), electrocardiograms and changes in vital signs as characterized by type, frequency, severity and timing will be tabulated, and reported as AEs when considered clinically significant by the investigator.; The cumulative incidence of non-relapse mortality, defined as the cumulative probability of non-relapse mortality, with time calculated between start of study treatment and death due to other causes than relapsed or refractory leukemia, accounting for competing events.	1.5 years
Pharmacokinetics (PK_1)	Population PK analysis to estimate AUC (tau) for quizartinib and AC886	1.5 years
Pharmacokinetics (PK_2)	Population PK analysis to estimate Cmax for quizartinib and AC886	1.5 years
Pharmacokinetics (PK_3)	Population PK analysis to estimate clearance (CL/F) for quizartinib.	1.5 years
Pharmacokinetics (PK_4)	Population PK analysis to estimate volume of distribution (Vss/F) for quizartinib.	1.5 years
Palatability of quizartinib formulations	Patients and/or parents or legal guardians will answer using a Hedonic scale for the taste and ability to swallow the medicine.	1.5 years

Collaborators and Investigators

• Sponsor: Princess Maxima Center for Pediatric Oncology
• Collaborators: Daiichi Sankyo
• Investigators: Study Chair: Gertjan Kaspers, Prof. Dr., Pediatric Oncologist; Study Director: Michel Zwaan, Prof. Dr., Head Trial and Data Center

Study record dates

Study Major Dates

• Study Start (Actual): February 6, 2024
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2032

Study Registration Dates

• First Submitted: January 26, 2024
• First Submitted That Met QC Criteria: February 7, 2024
• First Posted (Actual): February 16, 2024

Study Record Updates

• Last Update Posted (Actual): August 5, 2025
• Last Update Submitted That Met QC Criteria: July 31, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: FLT3-ITD+ NPM1wt AML
• Additional Relevant MeSH Terms: Tyrosine Kinase Inhibitors; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Antirheumatic Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Antimetabolites, Antineoplastic; Antimetabolites; Dermatologic Agents; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors; Sensory System Agents; Antiviral Agents; Protein Kinase Inhibitors; Analgesics; Antimitotic Agents; Mitosis Modulators; Topoisomerase Inhibitors; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Protective Agents; Cardiotonic Agents; Methotrexate; Fludarabine; Cytarabine; Etoposide; Daunorubicin; Mitoxantrone; Dexrazoxane; Razoxane; Quizartinib
• Other Study ID Numbers: MH22CAQ; 2022-002886-14 (EudraCT Number); 2023-505000-27 (Other Identifier: EU CT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All individual participant data will be used to generate a publication
• IPD Sharing Time Frame: Primary CSRs may be completed earlier when the primary objective is completed and may be followed by a final CSR not later than 6 months after the LPLV.
• IPD Sharing Access Criteria: A summary of the study results will be made public via clinicaltrials.gov as well as to Ethical committees/ Health Authorities and all participating patients by providing them through their treating physicians a patient letter with a summary of the results.
• IPD Sharing Supporting Information Type: CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No