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

NCT06262438 | Recruiting Phase 2 DMC FDA Drug

• 3 other identifiers: MH22CAQ2022-002886-142023-505000-27
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Acute Myeloid Leukemia in Children

Keywords

FLT3-ITD+ NPM1wt AML

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (15)

• Secondary objectives (efficacy_1)

  2 induction courses (maximum of 56+/-2 days per course)

• Secondary objectives (efficacy_2)

  Multiple time points, last time point after continuation treatment (1.5 years)

• Secondary objectives (efficacy_3)

  3 years

• Secondary objectives (efficacy_4)

  3 years

• Secondary objectives (efficacy_5)

  3 years

Study Arms (1)

Quizartinib

EXPERIMENTAL

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; Drug: Etoposide; Drug: Dexrazoxane; Drug: Mitoxantrone; Drug: Cytarabine; Drug: Methotrexate; Drug: Daunorubicin; Drug: Fludarabine; Other: allo-SCT

Interventions

Quizartinib DRUG

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.

Also known as: AC220, Quizartinib dihydrochoride, Vanflyta

Quizartinib

Etoposide DRUG

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).

Quizartinib

Dexrazoxane DRUG

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.

Quizartinib

Mitoxantrone DRUG

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).

Quizartinib

Cytarabine DRUG

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.

Quizartinib

Methotrexate DRUG

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.

Quizartinib

Daunorubicin DRUG

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).

Quizartinib

Fludarabine DRUG

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).

Quizartinib

allo-SCT OTHER

The SCT procedure is left to the discretion of the investigator and not part of this protocol.

Quizartinib

Eligibility Criteria

• Age: 1 Month - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.
• 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).
• Age:
• Patients must be from 1 month to ≤ 18 years old at initial diagnosis
• 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.
• 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)
• Life expectancy: \> 6 weeks
• Pregnancy test:
• Serum/urine pregnancy test (for all girls ≥ age of menarche) negative within 2 weeks prior to enrollment on the quizartinib linked-trial.

You may not qualify if:

• Patients with only extramedullary disease
• 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.
• Known history of HIV or active clinically relevant liver disease (e.g., active hepatitis B or active hepatitis C)
• Underlying GI disease that may affect absorption of study drug
• 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.
• History of hypersensitivity to any of the study medications or their excipients.

Sponsors & Collaborators

• Princess Maxima Center for Pediatric Oncology: lead
• Daiichi Sankyo: collaborator

Study Sites (1)

Princess Máxima Center for pediatric oncology

Utrecht, Utrecht, 3584 CS, Netherlands

RECRUITING

MeSH Terms

Interventions

quizartinib; Etoposide; Dexrazoxane; Mitoxantrone; Cytarabine; Methotrexate; Daunorubicin; fludarabine

Intervention Hierarchy (Ancestors)

Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Razoxane; Diketopiperazines; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Anthraquinones; Anthrones; Anthracenes; Quinones; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Anthracyclines; Naphthacenes; Aminoglycosides

Study Officials

• Gertjan Kaspers, Prof. Dr.

  Pediatric Oncologist

  STUDY CHAIR

• Michel Zwaan, Prof. Dr.

  Head Trial and Data Center

  STUDY DIRECTOR

Central Study Contacts

Renske Benedictus

CONTACT

+31 88 972 72 72; CHIP-AML22@prinsesmaximacentrum.nl

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Given the rarity of pediatric subjects with newly diagnosed Acute Myeloid Leukemia (AML) with FLT3-ITD mutations and the slow enrollment in historical studies, it is not feasible to enroll a sufficient number of subjects for an adequately powered randomized study. Therefore, a standard oncology Phase 2 response-rate design has been chosen. One of the exploratory objectives planned is to compare the outcome of patients treated in this study to the outcome of patients treated in the NOPHO-DBH AML-2012 study as historical control.

Study Record Dates

• First Submitted: January 26, 2024
• First Posted: February 16, 2024
• Study Start: February 6, 2024
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2032
• Last Updated: August 5, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: CSR
• 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.
• 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.

Locations

NL (1)