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

Official title

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

Overview

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.

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.

Interventions

• 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
• 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 bef
• 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). Co
• 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 inv
• 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.

Primary outcome measures

• Primary objective (efficacy) [Time frame: 2 induction courses (maximum of 56+/-2 days per course)]
• Primary objective (safety) [Time frame: 2 induction courses (maximum of 56+/-2 days per course)]

Secondary outcome measures (12)

• Secondary objectives (efficacy_1) [Time frame: 2 induction courses (maximum of 56+/-2 days per course)]
• Secondary objectives (efficacy_2) [Time frame: Multiple time points, last time point after continuation treatment (1.5 years)]
• Secondary objectives (efficacy_3) [Time frame: 3 years]
• Secondary objectives (efficacy_4) [Time frame: 3 years]
• Secondary objectives (efficacy_5) [Time frame: 3 years]
• Secondary objectives (efficacy_6) [Time frame: 3 years]
• Secondary objectives (efficacy_7) [Time frame: 3 years]
• Secondary objectives (efficacy_8) [Time frame: 1 year]
• Secondary objectives (efficacy_9) [Time frame: 1.5 years]
• Secondary objectives (safety) - Adverse Events, Laboratory Abnormalities and cumulative incidence of non-relapse mortality [Time frame: 1.5 years]
• Pharmacokinetics (PK_1) [Time frame: 1.5 years]
• Pharmacokinetics (PK_2) [Time frame: 1.5 years]

Eligibility criteria

Inclusion criteria

• 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.

• Taking quizartinib:

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

• 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:

• 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.
• 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)
• 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:

• Patients with CNS3 disease
• 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)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Netherlands · 1 center

• Princess Máxima Center for pediatric oncology — Utrecht

Publications

• Kaspers GJL, van Hamel M, Abrahamsson J, Arad-Cohen N, Benedictus R, Scheidegger N, Castillo L, Ka Leung Cheuk D, Costa V, Duong Y, Fernandez Navarro JM, Fogelstrand L, Goemans BF, Ishimaru S, Jonsson OG, Juul-Dam KL, Karu M, Koedijk JB, Kovalova Z, De Moerloose B, Munthe-Kaas MC, Palmu S, Pasauliene R, Tierens A, van Tinteren H, Turkiewicz D, Valerio DG, Wijnen N, Zwaan CM, Pronk CJ. CHIP-AML22: PMID 42321916

Identifiers

NCT: NCT06262438 · MH22CAQ · 2022-002886-14 · 2023-505000-27

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗