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NCT Number: NCT03591510

A Global Study of Midostaurin in Combination With Chemotherapy to Evaluate Safety, Efficacy and Pharmacokinetics in Newly Diagnosed Pediatric Patients With FLT3 Mutated AML

This study will evaluate the safety, efficacy and pharmacokinetics of midostaurin in combination with standard chemotherapy in pediatrics patients with newly diagnosed FLT3-mutated Acute Myeloid Leukemia. The study has two parts: Part 1 to define the Recommended Phase 2 Dose, and Part 2 to evaluate safety and tolerability and efficacy of midostaurin. Both parts will consist of 2 induction blocks, 3 consolidation blocks, 12 cycles of post-consolidation consisting of continuous therapy with midostaurin, and a follow-up phase.

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Key information

Conditions

FLT3-mutated Acute Myeloid Leukemia Hematologic Diseases Hemic and Lymphatic Diseases Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Neoplasms Neoplasms by Histologic Type

Age range

3 month–17 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Novartis Investigative Site, Prague, Czechia

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About this study

This trial is an open label, multi center single arm study to evaluate twice daily oral midostaurin with standard induction, consolidation chemotherapy with sequential midostaurin therapy for 5 treatment blocks (2 induction blocks, 3 consolidation blocks, followed by single agent midostaurin post consolidation therapy for 12 cycles).

The total maximum planned duration on treatment is 17 cycles (5 blocks and 12 cycles). A block is defined as the time from start of study treatment to the time of hematopoietic recovery, at the latest at Day (D) 42, or determination of persistent disease, whichever occur first.

In both Part 1 and Part 2, patients will receive the first course of induction chemotherapy according to local standard and duration is from 8 to 12 days. Upon FLT3 mutation confirmation, patients will receive midostaurin for 14 days. After determination of remission and hematopoietic recovery, patients will receive Block 2.

In Part 1:

  • Block 2 FLADx treatment duration is D1 to D6, and midostaurin from D8 to D21. Patients who achieve documented CR (and hematopoietic recovery at the latest at D42 from the first day of Block 2) will receive Block 3.
  • Block 3 consolidation HAM treatment duration is D1 to D4, followed by midostaurin D8 to D21. Patients who achieve hematopoietic recovery at the latest at D42 from the first day of Block 3 will receive Block 4. Patients who relapse will discontinue further study treatment.
  • Block 4 HA3E treatment duration is D1 to D5 followed by midostaurin D8 to D21. Patients who achieve hematopoietic recovery at the latest at D42 from the first day of Block 4 will receive Block 5.
  • Block 5 HiDAC treatment duration is D1 to D3 followed by midostaurin D8 to D21. Patients who relapse will discontinue further study treatment.

Patients in continuous remission with hematopoietic recovery will receive continuous post consolidation therapy of midostaurin, during 12 cycles (28 days per cycle).

In Part 1 of the study, patients in cohorts of 3 will receive sequential midostaurin administered at 30mg/m2bid. If the 30mg/m2 bid is well tolerated as measured by the Dose Limited Toxicity (DLT) rate during Bock 1, additional patients in cohort of 3 will be treated with sequential midostaurin at 60mg/m2 bid. When the recommended phase 2 dose (RP2D) is confirmed, subsequent patients will be treated in Part 2 of the study at the RP2D.

In Part 2:

  • Block 2 HAM treatment duration is D1 to D4 and midostaurin from D8 to D21. Patients who achieve documented CR (and hematopoietic recovery at the latest at D42 from the first day of Block 2) will receive Block 3.
  • Block 3 consolidation HA3E treatment duration is D1 to D5, followed by midostaurin D8 to D21. Patients who achieve hematopoietic recovery at the latest at D42 from the first day of Block 3 will receive Block 4. Patients who relapse will discontinue further study treatment.
  • Block 4 HAM treatment duration is D1 to D4 followed by midostaurin D8 to D21. Patients who achieve hematopoietic recovery at the latest at D42 from the first day of Block 4 will receive Block 5.
  • Block 5 HiDAC treatment duration is D1 to D3 followed by midostaurin D8 to D21. Patients who relapse will discontinue further study treatment.

Patients in continuous remission with hematopoietic recovery will receive continuous post consolidation therapy of midostaurin, during 12 cycles (28 days per cycle). Patients who relapse will discontinue further study treatment.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Documented Diagnosis of previously untreated de novo AML according to WHO 2016 criteria
  • Presence of a FLT3 mutation status as measured/confirmed by a designated lab with results available prior first dose of Midostaurin
  • Patients with Lansky or Karnofsky performance status equal or superior to 60
  • Patient with the following laboratory value : AST and ALT ≤ 3times ULN
  • Serum Total bilirubin ≤ 1.5times ULN
  • Estimated creatinine clearance ≥30ml/min

Exclusion criteria

  • Any concurrent malignancy, AML with Philadelphia Chromosome, AML-DS, JMML
  • Symptomatic leukemic CNS involvement
  • Isolated extramedullary leukemia, secondary AML and MDS
  • Acute Promyelocytic Leukemia with the PML RARA rearrangement
  • Patient who have received prior treatment with a FLT3 inhibitor. However, up to 1 week of FLT3 inhibitor (except midostaurin) exposure prior to study enrollment is permissible.

Other protocol-defined inclusion/exclusion criteria may apply

Treatment and study plan

Midostaurin

Drug

midostaurin 30mg/m2 bid

Other names: PKC412

Fludarabine

Drug

30mg/m2/day on D1-D5 of Block 2 FLADx

Other names: Part 1 Block 2 induction FLADx

Cytarabine

Drug

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

Other names: 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

Daunorubicin or Idarubicin

Drug

daunorubicin 60 mg/m2/day OR idarubicin 12mg/m2/day On D2, D4, D6 of Block 2 FLADx

Other names: Part 1 Block 2 induction FLADx

Mitoxantrone

Drug

10mg/m2/day D3 and D4

Other names: Part 1:, Block 3 consolidation HAM, Part 2:, Block 2 induction HAM, Block 4 consolidation HAM

etoposide

Drug

100mg/m2/day D1 to D5

Other names: Part 1:, Block 4 consolidation HA3E, Part 2:, Block 3 consolidation HA3E

Primary outcomes

  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 outcomes

  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

Sponsors and collaborators

Lead sponsor

Novartis Pharmaceuticals

Industry

Registry information

Official study title

A Phase II, Open-label, Single Arm Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Twice Daily Midostaurin (PKC412) Combined With Standard Chemotherapy and as a Single Agent Post-consolidation Therapy in Children With Untreated FLT3-mutated AML

Important dates

Study start
2019
Primary completion
2029
Study completion
2029
First posted
Jul 19, 2018
Registry last updated
Jul 9, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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