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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

NCT03591510

Description:

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 the Part 2 to evaluate efficacy and safety of midostaurin. All patients will follow the same treatment regimen consisting in 2 Induction blocks, 3 consolidation blocks, 12 cycles of post-consolidation consisting of continuous therapy with midostaurin, and a follow-up phase.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: CPKC412A2218
  • SECONDARY ID: 2017-004830-28
  • NCT ID: NCT03591510

Conditions

  • FLT3-mutated Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
MidostaurinPKC412Chemotherapy followed by Midostaurin
FLUDARABINEBlock 2 induction FLADxChemotherapy followed by Midostaurin
cytarabineblock 2 induction FLADx, block 3 consolidation HAM, block 4 consolidation HA3E, block 5 consolidation HIDACChemotherapy followed by Midostaurin
Daunorubicin liposomal or daunorubicin or idarubicinblock 2 induction FLADxChemotherapy followed by Midostaurin
MitoxantroneBlock 3 consolidation HAMChemotherapy followed by Midostaurin
EtoposideBlock 4 consolidation HA3EChemotherapy followed by Midostaurin

Purpose

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 the Part 2 to evaluate efficacy and safety of midostaurin. All patients will follow the same treatment regimen consisting in 2 Induction blocks, 3 consolidation blocks, 12 cycles of post-consolidation consisting of continuous therapy with midostaurin, and a follow-up phase.

Detailed Description

      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, which occur
      first.

      patient will receive the firs course of induction chemotherapy according to local standard
      and duration is from 8 to 12 days. Upon FLT3 mutation is confirmed, patient will receive
      midostaurin for 14 days. After determination of remission and hematopoietic recovery, patient
      will receive Block 2.

      Block 2 FLADx treatment duration is D1 to D6, and midostaurin from D8 to D21. patient who
      achieve hematopoietic recovery at the latest at D42 from the first day of block 2 will
      receive block 3.

      Block3 consolidation HAM treatment duration is D1 to D4, followed by midostaurin D8 to D21
      .patient who achieve hematopoietic recovery at the latest at D42 from the first day of block
      3 will receive block 4.

      Block 4 HA3E treatment duration is D1 to D5 followed by midostaurin D8 to D21. Patient who
      achieve hematopoietic recovery at the latest at D42 from the first day of block 4will receive
      block 5.

      Block 5 HiDAC treatment duration is D1 to D3 followed by midostaurin D8 to D21. Patient 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 cohort 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 block 1, additional patients in cohort of 3 will be
      treated with sequential midostaurin at 60mg/m2 bid.

      when the recommended 2 dose (RP2D) is confirmed, subsequent patients will be treated in the
      part 2 of the study at the RP2D.
    

Trial Arms

NameTypeDescriptionInterventions
Chemotherapy followed by MidostaurinExperimentalMidostaurin with standard induction (Block 1 induction according to local practice, Block 2 induction containing Fludarabine, cytarabine, daunorubicin/daunorubicin liposomal(idarubicin ) and consolidation (Block 3: cytarabine+ mitoxantrone, Block 4:cytarabine + etoposide, Block 5:Cytarabine) chemotherapy followed by single agent midostaurin post-consolidation therapy
  • Midostaurin
  • FLUDARABINE
  • cytarabine
  • Daunorubicin liposomal or daunorubicin or idarubicin
  • Mitoxantrone
  • Etoposide

Eligibility Criteria

        Inclusion Criteria:

          -  Documented Diagnosis of previously untreated de novo AML according to WHO 2016
             criteria

          -  Presence of a FLT3 mutation status 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.

        Other protocol-defined inclusion/exclusion criteria may apply
      
Maximum Eligible Age:17 Years
Minimum Eligible Age:3 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Part 1: frequency adverse events (AEs)
Time Frame:from the start of treatment up to 5 years follow-up
Safety Issue:
Description:Safety profile includes type, frequency and severity of adverse events, during the induction, consolidation and post consolidation phase, AE are collected as well during post treatment follow-up phase
Measure:Part 1: Plasma concentrations for midostaurin and its metabolites
Time Frame:Day 1 after end of local chemotherapy-induction block 1, Day 21 Block 2 to Block 5, Day 1 of Cycle 2, Cycle 3, Cycle 5, Cycle 7, Cycle 9
Safety Issue:
Description:plasma concentration of midostaurin and its 2 metabolites
Measure:Part 2: for United States: Event Free Survival
Time Frame:from the start of treatment up to 5 years follow-up of last patient
Safety Issue:
Description:EFS is defined as a failure to obtain CR/Modified CR within induction, relapse after CR/modified CRFi, or death due to any cause, whichever occurs first. EFS will be measured after all patients completed at least 24 months of follow-up
Measure:Part 2 for countries outside United States: Frequency of AE
Time Frame:from the start of treatment up to 5 years follow-up of last patient
Safety Issue:
Description:Safety profile includes type, frequency and severity of adverse events, during the induction, consolidation and post consolidation phase, AE are collected as well during post treatment follow-up phase
Measure:Part 2: All countries: EFS rate censored for HSCT
Time Frame:from the start of treatment up to 5 years follow-up of last patient
Safety Issue:
Description:Event Free Survival ( EFS) . EFS is defined as a failure to obtain CR/Modified CR within induction, relapse after CR/modified CRFi, or death due to any cause, whichever occurs first Patient are censored at the date of HSCT if occured before the EFS event. EFS will be measured after the last patient treated has completed up to 24 months
Measure:Part 2: All countries: Overall Survival
Time Frame:at each visit, every 3 months after last follow-up visit and up to 5 years after last patient first treatment
Safety Issue:
Description:OS is defined as the time from Day 1 of chemotherapy to the date of death due to any cause.
Measure:Part 2: All countries:proportion of patient with Complete response
Time Frame:from the start of treatment up to 5 years follow-up of last patient
Safety Issue:
Description:proportion of patients with a Complete response and Modified CRi at the end of Block 2
Measure:Part 2: All countries : Number of day from treatment start to documented CR/CRi -
Time Frame:from the start of treatment up to 5 years follow-up of last patient
Safety Issue:
Description:Time To Response is defined as the time between start of treatment to the date of first onset of CRi or better response
Measure:Part 2: All countries: Disease free survival ( DFS)
Time Frame:from the start of treatment up to 5 years follow-up of last patient
Safety Issue:
Description:DFS is defined as the time from CR/modified CRi in induction to relapse or death due to any cause
Measure:Part 2: All countries: •Percentage of patients with MRD negative status during post-consolidation phase
Time Frame:MRD is evaluated at Day 14 after end of chemotherapy induction block 1, at Day 21 block 2 to block 5, Cycle 7 during post consolidation phase
Safety Issue:
Description:percentage of patient with MRD negative status by multiparameter flow cytometry
Measure:Part 2: All countries: palatability of oral solution of Midostaurin
Time Frame:14 Day after end of chemotherapy induction block 1, Day 21 for block 2 to block 5, Cycle 1, Cycle 3, Cycle 5, Cycle 7, Cycle 9, Cycle 11 post consolidation
Safety Issue:
Description:palatability is assessed through questionnaires- Palatability PRO and obsPRO
Measure:Part 2: All countries: percentage of Blast on 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
Safety Issue:
Description:Bone marrow and peripheral blood parameters and extramedullar involvement at the end of induction block 1 and block 2
Measure:Part 2: All countries :•Plasma concentrations for midostaurin and its metabolites
Time Frame:Day 1 after end of local chemotherapy-induction block 1, Day 21 Block 2 to Block 5, Day 1 of Cycle 2, Cycle 3, Cycle 5, Cycle 7, Cycle 9
Safety Issue:
Description:plasma concentration of midostaurin and its 2 metabolites
Measure:Part 2: All countries: Cumulative Incidence of Relapse (CIR)
Time Frame:From date of complete response (CR) or CRi with adequate blood count recovery up to 5 years of follow-up
Safety Issue:
Description:Cumulative Incidence of Relapse (CIR) is defined for patients with CR or modified CRi and is time from achieving the CR or modified CRi in induction until the onset of relapse from CR or modified CRi. Patients without relapse are censored at the last adequate response assessment. Patients who died without relapse are counted as a competing cause of failure. Kaplan-Meier product-limit estimates will be used to describe the CIR.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

  • PKC412
  • Acute Myeloid Leukemia
  • AML
  • FLT3-mutated
  • pediatric population
  • midostaurin
  • midostaurin combined with standard chemotherapy
  • single agent post-consolidation therapy
  • untreated FLT3-mutated AML

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