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

• ClinicalTrials.gov Identifier: NCT03591510
• Recruitment Status: Recruiting
• First Posted: July 19, 2018
• Last Update Posted: April 5, 2024
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: June 25, 2018
• First Posted Date: July 19, 2018
• Last Update Posted Date: April 5, 2024
• Actual Study Start Date: March 13, 2019
• Estimated Primary Completion Date: August 18, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 8, 2021)

• 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.
• 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
• 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

Original Primary Outcome Measures (submitted: July 7, 2018)

• 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.
• Part 2 of study for United States: frequency of Adverse events [ 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, AE are collected as well during post treatment follow-up phase
• Part 2 of study for countries outside United States: Event Free Survival ( EFS) [ Time Frame: from the start of treatment up to 5 years follow-up of last patient ]
  Event-free survival (EFS) 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 a 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 patients completed at least 24 months of follow-up

Current Secondary Outcome Measures (submitted: May 15, 2023)

• 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
• 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.
• 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.
• 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.
• 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
• 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
• 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
• 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
• 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

Original Secondary Outcome Measures (submitted: July 7, 2018)

• Part 1: frequency adverse events (AEs) [ Time Frame: from the start of treatment up to 5 years follow-up ]
  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
• 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 ]
  plasma concentration of midostaurin and its 2 metabolites
• Part 2: for United States: Event Free Survival [ Time Frame: from the start of treatment up to 5 years follow-up of last patient ]
  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
• 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 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
• 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 ]
  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
• 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 ]
  OS is defined as the time from Day 1 of chemotherapy to the date of death due to any cause.
• 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 ]
  proportion of patients with a Complete response and Modified CRi at the end of Block 2
• 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 ]
  Time To Response is defined as the time between start of treatment to the date of first onset of CRi or better response
• Part 2: All countries: 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
• 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 ]
  percentage of patient with MRD negative status by multiparameter flow cytometry
• 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 ]
  palatability is assessed through questionnaires- Palatability PRO and obsPRO
• 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 ]
  Bone marrow and peripheral blood parameters and extramedullar involvement at the end of induction block 1 and block 2
• 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 ]
  plasma concentration of midostaurin and its 2 metabolites
• 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 ]
  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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• Brief Summary: 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.

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, 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: FLT3-mutated Acute Myeloid Leukemia

Intervention

• Drug: Midostaurin
  midostaurin 30mg/m2 bid
  Other Name: PKC412
• Drug: Fludarabine
  30mg/m2/day on D1-D5 of Block 2 FLADx
  Other Name: Part 1 Block 2 induction FLADx
• Drug: Cytarabine

  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
• Drug: Daunorubicin or idarubicin
  daunorubicin 60 mg/m2/day OR idarubicin 12mg/m2/day On D2, D4, D6 of Block 2 FLADx
  Other Name: Part 1 Block 2 induction FLADx
• Drug: Mitoxantrone
  10mg/m2/day D3 and D4
  Other Names:

  • Part 1:
  • Block 3 consolidation HAM
  • Part 2:
  • Block 2 induction HAM
  • Block 4 consolidation HAM
• Drug: Etoposide
  100mg/m2/day D1 to D5
  Other Names:

  • Part 1:
  • Block 4 consolidation HA3E
  • Part 2:
  • Block 3 consolidation HA3E

Study Arms

Experimental: Chemotherapy followed by Midostaurin

In Part 1, midostaurin with standard induction (Block 1 induction according to local practice, Block 2 induction containing fludarabine, cytarabine, daunorubicin/idarubicin) and consolidation (Block 3: cytarabine + mitoxantrone, Block 4: cytarabine + etoposide, Block 5: cytarabine) followed by single agent midostaurin post-consolidation therapy.

In Part 2, midostaurin with standard induction (Block 1 induction according to local practice, Block 2 induction containing cytarabine + mitoxantrone) and consolidation (Block 3: cytarabine + etoposide, Block 4: cytarabine + mitoxantrone, Block 5: cytarabine) followed by single agent midostaurin post-consolidation therapy.

Interventions:

• Drug: Midostaurin
• Drug: Fludarabine
• Drug: Cytarabine
• Drug: Daunorubicin or idarubicin
• Drug: Mitoxantrone
• Drug: Etoposide

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 15, 2022): 23
• Original Estimated Enrollment (submitted: July 7, 2018): 50
• Estimated Study Completion Date: February 15, 2029
• Estimated Primary Completion Date: August 18, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 3 Months to 17 Years (Child)
• Accepts Healthy Volunteers: No

Contacts

Contact: Novartis Pharmaceuticals; 1-888-669-6682; novartis.email@novartis.com

Contact: Novartis Pharmaceuticals; +41613241111

• Listed Location Countries: Austria, Czechia, Germany, Greece, Italy, Japan, Jordan, Korea, Republic of, Poland, Russian Federation, Slovenia, Turkey, United States

Administrative Information

• NCT Number: NCT03591510
• Other Study ID Numbers: CPKC412A2218; 2017-004830-28 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: April 2024