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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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ClinicalTrials.gov Identifier: NCT03591510
Recruitment Status : Recruiting
First Posted : July 19, 2018
Last Update Posted : May 12, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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.

Condition or disease Intervention/treatment Phase
FLT3-mutated Acute Myeloid Leukemia Drug: Midostaurin Drug: Fludarabine Drug: Cytarabine Drug: Daunorubicin or idarubicin Drug: Mitoxantrone Drug: Etoposide Phase 2

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 23 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : March 13, 2019
Estimated Primary Completion Date : August 18, 2025
Estimated Study Completion Date : February 15, 2029


Arm Intervention/treatment
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.

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




Primary Outcome Measures :
  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 Measures :
  1. Percentage of participants with complete response (CR or modified 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 complete response and modified CRi at the end of Block 2

  2. 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 CRi or better response.

    Response duration is defined as the time from CR/modified CRi to relapse or death due to AML.


  3. 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. 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. 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. 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. 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, Cycle 1, Cycle 3, Cycle 5, Cycle 7, Cycle 9, Cycle 11 post consolidation (each block could last up to 42 days) ]
    Palatability is assessed through questionnaires- Palatability PRO and obsPRO

  8. 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. 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, Day 1 of Cycle (C)2, C3, C5, C7, C9 and C12 of post-consolidation (each block could last up to 42 days, each cycle = 28 days) ]
    Plasma concentration of midostaurin and its 2 metabolites



Information from the National Library of Medicine

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Ages Eligible for Study:   3 Months to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03591510


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
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United States, Colorado
Childrens Hospital Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact    720-777-1234      
Principal Investigator: Anna Franklin         
United States, Florida
Miami Children s Hospital Recruiting
Miami, Florida, United States, 33155
Contact: Fabian Castillo    305-668-5576    Fabian.Castillo@Nicklaushealth.org   
Principal Investigator: Guillermo DeAngulo         
Czechia
Novartis Investigative Site Recruiting
Brno, Czechia, 613 00
Novartis Investigative Site Recruiting
Praha 5, Czechia, 150 06
Italy
Novartis Investigative Site Recruiting
Bologna, BO, Italy, 40138
Novartis Investigative Site Recruiting
Roma, RM, Italy, 00165
Novartis Investigative Site Recruiting
Napoli, Italy, 80100
Japan
Novartis Investigative Site Recruiting
Kobe-city, Hyogo, Japan, 650-0047
Novartis Investigative Site Recruiting
Setagaya-ku, Tokyo, Japan, 157-8535
Novartis Investigative Site Recruiting
Osaka, Japan, 534-0021
Novartis Investigative Site Recruiting
Saitama, Japan, 330 8777
Novartis Investigative Site Recruiting
Shizuoka, Japan, 420 8660
Jordan
Novartis Investigative Site Recruiting
Amman, Jordan, 11941
Korea, Republic of
Novartis Investigative Site Recruiting
Seoul, Korea, Republic of, 03080
Novartis Investigative Site Recruiting
Seoul, Korea, Republic of, 05505
Poland
Novartis Investigative Site Recruiting
Gdansk, Poland, 80 952
Novartis Investigative Site Recruiting
Krakow, Poland
Russian Federation
Novartis Investigative Site Recruiting
Moscow, Russian Federation, 117198
Slovenia
Novartis Investigative Site Recruiting
Ljubljana, Slovenia, 1000
Turkey
Novartis Investigative Site Recruiting
Antalya, Turkey, 07070
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03591510    
Other Study ID Numbers: CPKC412A2218
2017-004830-28 ( EudraCT Number )
First Posted: July 19, 2018    Key Record Dates
Last Update Posted: May 12, 2021
Last Verified: May 2021
Individual Participant Data (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.


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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
PKC412
Acute Myeloid Leukemia
AML
FLT3-mutated
pediatric population
midostaurin
midostaurin combined with standard chemotherapy
single agent post-consolidation therapy
untreated FLT3-mutated AML
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Fludarabine
Etoposide
Daunorubicin
Mitoxantrone
Idarubicin
Midostaurin
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antiviral Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Protein Kinase Inhibitors