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.
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.
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
Patients with only extramedullary disease
Uncontrolled or significant cardiovascular disease, including -Diagnosed or suspected congenital long QT syndrome
History of complete left bundle branch block.
History of New York Heart Association Class 3 or 4 heart failure.
Single group
Quizartinib
DrugQuizartinib 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.
Etoposide
DrugInduction 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).
Dexrazoxane
DrugInduction 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.
Mitoxantrone
DrugInduction 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).
Cytarabine
DrugInduction 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.
Methotrexate
DrugInduction 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.
Daunorubicin
DrugInduction course 2: 60 mg/m2 once daily by IV infusion over 1 hour (+/- 15 mins) on days 2,4,6 inclusive (total 3 doses).
Fludarabine
DrugConsolidation 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).
allo-SCT
Other interventionThe SCT procedure is left to the discretion of the investigator and not part of this protocol.
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
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.
Secondary objectives (efficacy_1)
Morphological overall response rate (ORR)
Secondary objectives (efficacy_2)
MRD by multiparameter flow cytometry (MFCM)
Secondary objectives (efficacy_3)
Event free survival (EFS)
Secondary objectives (efficacy_4)
Overall survival (OS)
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Princess Maxima Center for Pediatric Oncology
Lead sponsor
Daiichi Sankyo
Collaborator
