A Global Study of Midostaurin in Combination With Chemotherapy to Evaluate Safety, Efficacy and Pharmacokinetics in Newly Diagnosed Pediatric Patients With FLT3 Mutated AML
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1. Part 1 of the study: Occurence of dose limiting toxicities (DLT) (Time Frame - From the start of midostaurin treatment in Block 1 to the end of Block 2, from Day 1 to Day 84): Dose-limiting toxicity (DLT) is defined as any death due to toxicity related to study treatment (chemotherapy + midostaurin) and/or any CTCAE grade 4 non-hematological adverse event or abnormal laboratory value grade 4 related to study treatment unless the event improves sufficiently by day 42 and therefore does not further delay the next cycle of study treatment.
2. Part 2 of the study: To evaluate Safety of midostaurin (30mg/m2 bid or 1 mg/kg bid for participants <10 kg body weight) in sequential combination with chemotherapy followed by 12 cycles of midostaurin post-consolidation therapy. (Time Frame - From the start of treatment up to 5 years follow-up of last patient): Safety profile includes type, frequency and severity of adverse events during the induction, consolidation and post consolidation phase. AEs are also collected during post treatment follow-up phase
3. Part 2 of the study: To evaluate Tolerability of midostaurin (30mg/m2 bid or 1 mg/kg bid for participants <10 kg body weight) in sequential combination with chemotherapy followed by 12 cycles of midostaurin post-consolidation therapy. (Time Frame - From the start of treatment up to 5 years follow-up of last patient): Number of dose interruptions/reductions and discontinuations due to study drug
Secondary outcome:
1. Part 2 of the study: Percentage of participants with response (CR, CR/modified CRi and CR/CRi) (Time Frame - From the start of treatment in Block 1 to the end of Block 2, from Day 1 up to Day 84): Percentage of participants with a response of CR, CRi or modified CRi at the end of Block 2
2. Part 2 of the study: Time to response (TTR) and response duration (Time Frame - From the start of treatment up to 5 years follow-up of last patient): TTR is defined as the time between start of treatment to the date of first onset of response (CR, CRi or modified CRi).
Response duration is defined as the time from CR, CRi or modified CRi to relapse or death due to any cause.
3. Part 2 of the study: Event Free Survival (EFS) (Time Frame - From the start of treatment to time when all patients have completed at least 18 months of follow up (~ 48 months)): EFS is defined as the time from Day 1 of chemotherapy until an EFS event is observed.
An EFS event is defined as a failure to obtain CR/Modified CRi within induction, relapse after CR/modified CRi, or death due to any cause, whichever occurs first. EFS will be measured after all participants completed at least 18 months of follow-up.
4. Part 2 of the study: Overall Survival (OS) (Time Frame - At each visit, every 3 months after last follow-up visit and up to 5 years after last patient first treatment): OS is defined as the time from Day 1 of chemotherapy to the date of death due to any cause.
5. Part 2 of the study: Disease free survival (DFS) (Time Frame - From the start of treatment up to 5 years follow-up of last patient): DFS is defined as the time from CR/modified CRi in induction to relapse or death due to any cause
6. Part 2 of the study: Percentage of participants with MRD negative status during each study phase (Time Frame - MRD is evaluated at Day 14 after end of chemotherapy induction Block 1, at Day 21 of Blocks 2, 3, 4 and 5, and Cycle 7 during post-consolidation phase (each block could last up to 42 days)): Percentage of patient with MRD negative status by multiparameter flow cytometry
7. Part 2 of the study: Palatability of oral solution of midostaurin (Time Frame - Day 14 after end of chemotherapy induction Block 1, Day 21 of Blocks 2, 3, 4 and 5 (each block can last up to 42 days), post-consolidation Cycle 1, Cycle 3, Cycle 5, Cycle 7, Cycle 9, Cycle 11): Palatability is assessed through questionnaires- Palatability PRO and obsPRO
8. Part 2 of the study: Percentage of blasts in bone marrow and peripheral blood (Time Frame - Parameters are assessed 14 days after end of chemotherapy induction Block 1 and Day 14 induction Block 2): Bone marrow and peripheral blood parameters and extramedullar involvement at the end of induction Block 1 and Block 2
9. Part 1 and Part 2 of the study: Plasma concentrations of midostaurin and its metabolites (Time Frame - Days 1, 7 & 14 after end of local chemotherapy-induction in Block 1, Days 14 & 21 of Block 2, Day 21 of Blocks 3, 4 & 5 (each block can last up to 42 days), in-post consolidation Day 1 of Cycle (C)2, C3, C5, C7, C9 and C12 (each cycle = 28 days)): Plasma concentration of midostaurin and its 2 metabolites
Fludarabine (Part 1 Block 2 induction FLADx): 30mg/m2/day on D1-D5 of Block 2 FLADx
Cytarabine (Part 1: / Block 2 induction FLADx / Block 3 consolidation HAM / Block 4 consolidation HA3E / Block 5 consolidation HIDAC / Part 2: / Block 2 induction HAM / Block 3 consolidation HA3E / Block 4 consolidation HAM / ): Part 1:
2000mg/m2/day D1 to D5 of Block 2 FLADx 1000mg/m2 every 12 hours D1 to D3 Block 3 HAM 3000mg/m2 every 12 hours D1 to D3 Block 4 HA3E 3000mg/m2 every 12 hours D1 to D3 Block 5 HIDAC
Part 2:
1000mg/m2 every 12 hours D1 to D3 Block 2 HAM 3000mg/m2 every 12 hours D1 to D3 Block 3 HA3E 1000mg/m2 every 12 hours D1 to D3 Block 4 HAM 3000mg/m2 every 12 hours D1 to D3 Block 5 HIDAC
Daunorubicin or idarubicin (Part 1 Block 2 induction FLADx): daunorubicin 60 mg/m2/day OR idarubicin 12mg/m2/day On D2, D4, D6 of Block 2 FLADx
Mitoxantrone (Part 1: / Block 3 consolidation HAM / Part 2: / Block 2 induction HAM / Block 4 consolidation HAM / ): 10mg/m2/day D3 and D4
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"A Global Study of Midostaurin in Combination With Chemotherapy to Evaluate Safety, Efficacy and Pharmacokinetics in Newly Diagnosed Pediatric Patients With FLT3 Mutated AML"
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