Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03591510
Recruitment Status : Recruiting
First Posted : July 19, 2018
Last Update Posted : July 31, 2019
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 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.

Condition or disease Intervention/treatment Phase
FLT3-mutated Acute Myeloid Leukemia Drug: Midostaurin Drug: FLUDARABINE Drug: cytarabine Drug: Daunorubicin liposomal or 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, 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.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
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 : May 12, 2022
Estimated Study Completion Date : May 12, 2027


Arm Intervention/treatment
Experimental: Chemotherapy followed by Midostaurin
Midostaurin 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
Drug: Midostaurin
midostaurin titrated from 30mg/m2 bid to 60mg/m2
Other Name: PKC412

Drug: FLUDARABINE
30mg/m2/day on D 1-D5 of block 2 FLADx
Other Name: Block 2 induction FLADx

Drug: cytarabine
2000mg/m2/day D1 to D5 of block 2 FLADx 1000mg/m2 every 12 hours D1 to D3 Block 3 3000mg/m2 every 12 hours D1 to D 3 block 4 3000mg/m2 every 12 hours D1 to D 3 block 5
Other Names:
  • block 2 induction FLADx
  • block 3 consolidation HAM
  • block 4 consolidation HA3E
  • block 5 consolidation HIDAC

Drug: Daunorubicin liposomal or daunorubicin or idarubicin
daunorubicin 60 mg/m2/day OR Idarubicin : 12mg/m2/day On Day 2, D4, D6 block 2 FLADx
Other Name: block 2 induction FLADx

Drug: Mitoxantrone
10mg/m2/days days 3 and 4
Other Name: Block 3 consolidation HAM

Drug: Etoposide
100mg/m2/day Day 1 to Day 5
Other Name: Block 4 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 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

  3. 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



Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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.

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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.




Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
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
Layout table for location contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
Layout table for location information
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
Praha 5, Czechia, 150 06
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
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
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Layout table for investigator information
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

Layout table for additonal information
Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03591510     History of Changes
Other Study ID Numbers: CPKC412A2218
2017-004830-28 ( EudraCT Number )
First Posted: July 19, 2018    Key Record Dates
Last Update Posted: July 31, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
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.


Layout table for additional information
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:
Layout table for MeSH terms
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Fludarabine
Fludarabine phosphate
Etoposide
Daunorubicin
Mitoxantrone
Idarubicin
Midostaurin
Staurosporine
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