CHIP-AML22/Quizartinib sub-study: study of the safety and efficacy of quizartinib in children and adolescents with FLT3-ITD positive AML with normal NPM1.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Prinses Maxima Centrum voor Kinderoncologie B.V.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

29 Dec 2023 → ongoing

Decision date (initial)

2024-10-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Daiichi Sankyo

External identifiers

EU CT number

2023-505000-27-01

EudraCT number

2022-002886-14

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Therapy, Safety, Pharmacodynamic

Primary Objective (Efficacy): To assess the clinical benefit of quizartinib as measured by the MRD-negativity rate (defined as <0.1% using flow-cytometry) after up to two courses of conventional chemotherapy plus quizartinib, in newly diagnosed pediatric de novo AML with a FLT3-ITD and without a concurrent NPM1 mutation.
Primary Objective (Safety): During the safety run-in, the co-primary objective will be to determine the Recommended Phase 2 Dose (RP2D) of quizartinib for newly diagnosed pediatric AML patients with a FLT3-ITD and without a concurrent NPM1 mutation, based on the safety and tolerability profile of quizartinib observed at dose levels.

Secondary objectives 4

1. Efficacy: To explore the added anti-leukemic effect of quizartinib based on other measures of response, as defined as secondary endpoints, including morphological overall response rate (ORR), MRD by MFCM, event free survival (EFS), overall survival (OS), disease free survival (DFS), duration of response, cumulative incidence of relapse (CIR), number and percentage of patients actually being treated with hematopoietic stem cell transplantation (HSCT), number of patients starting and completing continuation treatment post-HSCT.
2. Safety: To describe the safety and tolerability of combining quizartinib with conventional treatment and quizartinib given as single-agent after HSCT
3. Pharmacokinetics (PK): To characterize the pharmacokinetics of quizartinib and its main circulating active metabolite AC886
4. Palatability of quizartinib formulations: To assess the palatability of quizartinib formulations.

Conditions and MedDRA coding

newly diagnosed pediatric FLT3-ITD positive and NPM1 wild-type AML

Study design 1 period

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Enrollment on CHIP-AML22/Master
2. FLT3-ITD+ and wild-type NPM1
3. Age from 1 month to ≤ 18 years old at initial diagnosis
4. Karnofsky Performance status 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: a. Adequate Renal Function Defined as: • Calculated eGFR ≥ 50 mL/min/1.73 m2 b. Adequate Liver Function Defined as: • Total or direct (conjugated) bilirubin <1.5 × ULN 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 negative within 2 weeks prior to enrollment on the quizartinib linked-trial.
8. Patients must be able to reliably swallow or administer quizartinib by NG tube.
9. 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.

Exclusion criteria 9

1. Patients with only extramedullary disease
2. Uncontrolled or significant cardiovascular disease, including i. Diagnosed or suspected congenital long QT syndrome ii. 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. iii. QT interval corrected >450 ms: - QTc interval corrected with Fridericia’s formula (QTcF) for subjects ≥ 6 years of age at the time of enrollment. iv. Left ventricular systolic dysfunction (LVSD), defined as ejection fraction (EF) below 55% during the screening for the CHIP-AML22/Master protocol. v. History of uncontrolled angina pectoris or myocardial infarction within 6 months. vi. History of second (Mobitz II) or third degree heart block (subjects with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker). vii. Heart rate <50 beats/minute on ECG during the screening for the CHIPAML22/ 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.) viii. 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). ix. History of complete left bundle branch block. x. 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
9. Additional exclusion criteria during safety run-in a. Patients with CNS3 disease b. 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)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Efficacy: The percentage of patients with 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. 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.

Secondary endpoints 15

1. Efficacy: Other measurements of treatment response: o Proportion of subjects with a complete remission (CR) rate without evidence of MRD after 1 and after 2 induction courses (including CR and remission with incomplete blood count or platelet recovery)
2. Efficacy: Other measurements of treatment response: o Bone marrow blast counts by morphology and MFCM after induction course 1 and induction course 2 and before allo-SCT; CRc (CR and CRi) and morphologic leukemia-free state (MLFS) rates after induction course 1 and 2; MRD negativity (<0.1%), after course 1 and 2 and before allo-HSCT; Absolute MRD levels after induction course 1 and 2, and before allo-HSCT;
3. Efficacy: Other measurements of treatment response: o Bone marrow blast counts by morphology and MFCM at other timepoints (The disease assessments at other time-points (e.g., After consolidation course 2, 3, before/during continuation treatment)
4. Efficacy: Other measurements of treatment response: o Event-free survival (EFS) probability, at least at 1, 2 and 3 years Time from the start of treatment until an event, defined as 1) not achieving CR/CRi because of early death or with refractory disease (ie: treatment failure); 2) morphological relapse; 3) second malignancy; 4) death in complete remission due to any cause.
5. Efficacy: Other measurements of treatment response: o Overall survival (OS) probability, at least at 1, 2 and 3 years. o Time from the start of treatment until death, due to any cause.
6. Efficacy: Other measurements of treatment response: o Disease free survival (DFS) probability, at least at 1, 2 and 3 years. o Time from CR/CRi until morphological relapse or death due to any cause
7. Efficacy: Other measurements of treatment response: o Duration of complete response. o Time from CR until morphological relapse or death due to any cause
8. Efficacy: Other measurements of treatment response: o Cumulative incidence of morphological relapse (CIR) probability, at least at 1,2 and 3 years
9. Efficacy: Other measurements of treatment response: o Number and percentage of patients proceeding to HSCT
10. Efficacy: Other measurements of treatment response: o Number of patients starting and completing continuation treatment post-HSCT
11. Safety o Adverse events (AEs), as characterized by type, frequency, severity (as graded using CTCAE, v5.0).
12. Safety: o 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.
13. Safety: 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.
14. Pharmacokinetics (PK): Population PK analysis to estimate AUC (tau) and Cmax for quizartinib and AC886, clearance (CL/F) and volume of distribution (Vss/F) for quizartinib.
15. Palatability: Patients and/or parents or legal guardians will answer using a Hedonic scale for the taste and ability to swallow the medicine.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Prinses Maxima Centrum voor Kinderoncologie B.V.

Sponsor organisation

Prinses Maxima Centrum voor Kinderoncologie B.V.

Address

Heidelberglaan 25

City

Utrecht

Postcode

3584 CS

Country

Netherlands

Scientific contact point

Organisation

Prinses Maxima Centrum voor Kinderoncologie B.V.

Contact name

Prof. Dr. Gertjan J.L. Kaspers

Public contact point

Organisation

Prinses Maxima Centrum voor Kinderoncologie B.V.

Contact name

Secretariat TDC

Locations

12 EU/EEA countries · 50 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 2 · Art. 52 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 158 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

18 submissions — initial application plus substantial / non-substantial modifications