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A Global Study of the Efficacy and Safety of Midostaurin + Chemotherapy in Newly Diagnosed Patients With FLT3 Mutation Negative (FLT3-MN) Acute Myeloid Leukemia (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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03512197
Recruitment Status : Active, not recruiting
First Posted : April 30, 2018
Last Update Posted : October 22, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE March 26, 2018
First Posted Date  ICMJE April 30, 2018
Last Update Posted Date October 22, 2020
Actual Study Start Date  ICMJE August 25, 2010
Estimated Primary Completion Date January 25, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 18, 2018)
Event Free Survival (EFS) [ Time Frame: From date of Randomization up to 5 years of follow-up ]
EFS is defined as the time from randomization to failure to obtain a Complete Remission (CR) or Morphologic Complete Remission without hematopoietic recovery (CRi) with adequate blood count recovery(adequate for treatment continuation) in induction, relapse after CR or CRi with adequate blood count recovery or death due to any cause, whichever occurs first as assessed by the investigator
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 18, 2018)
  • Overall survival (OS) [ Time Frame: Between randomization to date of death up to 5 years of follow-up of last patients ]
    OS is defined as the time from randomization to date of death due to any cause. Patients will enter the survival follow-up phase once they complete the safety follow up period (30 days after the last dose of midostaurin/placebo) in case of induction failure or have relapse during post-treatment follow-up. Patients will then be contacted by telephone every 3 months +/- 2 weeks or have a visit to follow up on their survival status
  • Complete Remission (CR) with adequate blood count recovery rate [ Time Frame: Between randomization to date of death up to 5 years of follow-up of last patients ]
    Assessment will be based on the IWG criteria for AML as per investigator assessment
  • Percentage of patients with Minimal Residual Disease (MRD) negative status [ Time Frame: Between start and three months after end of treatment ]
    Comparisons of the MRD levels between the end of the consolidation phase during the post-consolidation phase. The time to MRD negative status is defined as the time from randomization to first occurrence of MRD negativity
  • Disease-free survival (DFS) [ Time Frame: From date of CR or CRi with adequate blood count recovery up to 5 years of follow-up ]
    DFS is defined as the time from CR or CRi with adequate blood count recovery to relapse or death due to any cause. Patient who did not relapse nor die will be censored at the last adequate response assessment. Assessment will be based on the IWG criteria for AML as per investigator assessment
  • Number of days from the first day of a chemotherapy cycle to first day neutrophils ≥0.5 x 10^9/L [ Time Frame: At maximum 93 days from induction therapy start ]
    The time to neutrophil recovery will be assessed for the following criteria: number of days from start of treatment to the first day neutrophils ≥0.5 x 10^9/L, Number of days from start of treatment to the first day neutrophils ≥1.0 x 10^9/L
  • Number of days from the first day of a chemotherapy cycle to first day platelets ≥50 x 10^9/L [ Time Frame: At maximum 93 days from induction therapy start ]
    Time to platelet recovery will be assessed for the following criteria: Number of days from start of treatment to the first day platelets ≥50 x 10^9/L, Number of days from start of treatment to the first day platelets ≥100 x 10^9/L
  • Plasma concentrations for midostaurin and its metabolitees: CGP52421 and CGP62221 [ Time Frame: From date of Randomization up to 1.5 years of follow-up ]
  • Cumulative incidence of relapse (CIR) [ Time Frame: From date of CR or CRi with adequate blood count recovery up to 5 years of follow-up ]
    CIR is defined for patients with CR or CRi with adequate blood count recovery and is time from achieving CR or CRi with adequate blood count recovery until the onset of relapse from CR or CRi with adequate blood recovery. Patients without relapse are censored at the last adequate response assessment. Patients who died without relapse are counted as a competing cause of failure. Assessment will be based on the IWG criteria for AML as per investigator assessment
  • Cumulative incidence of death (CID) [ Time Frame: From date of CR or CRi with adequate blood count recovery up to 5 years of follow-up ]
    CID is defined for all patients achieving CR or CRi with adequate blood count recovery measured from the date of achievement of CR or CRi until the date of death due to any reason. Patients not known to have died are censored on the last contact date. Patients who experienced relapse are counted as a competing cause of failure. Assessment will be based on the IWG criteria for AML as per investigator assessment
  • Number of days from date of randomization to first documented CR or CRi with adequate blood count recovery [ Time Frame: At maximum 93 days from induction therapy start ]
    Time to CR or CRi with adequate blood count recovery is defined as the time from randomization to CR or CRi with adequate blood count recovery whichever occurs first
  • Percentage of patients with MRD negative status during post-consolidation phase [ Time Frame: between start and three months after end of treatment ]
  • Morphologic complete remission without hematopoietic recovery (CRi) with adequate blood count recovery rate [ Time Frame: At maximum 93 days from induction therapy start ]
    Assessment will be based on the IWG criteria for AML as per investigator assessment
  • Number of days from day 1 of commencing induction therapy to first day neutrophils ≥1.0 x 10^9/L [ Time Frame: At maximum 93 days from induction therapy start ]
  • Number of days from day 1 of commencing induction therapy to first day platelets ≥100 x 10^9/L [ Time Frame: From date of Randomization up to 5 years of follow-up ]
  • Number of days from date of randomization to first documented MRD negativity [ Time Frame: From date of Randomization up to 5 years of follow-up ]
  • AUC0-t: Pharmacokinetic (PK) parameter for midostaurin and its metabolites: CGP52421 and CGP62221 [ Time Frame: From date of Randomization up to 1.5 years of follow-up ]
    The AUC from time zero to a measurable concentration sampling time (t) (mass x time x volume-1). Note: as the last sampling time is at 12 h, AUC0-12h will be determined after the first dose
  • AUClast: Pharmacokinetic (PK) parameter for midostaurin and its metabolites: CGP52421 and CGP62221 [ Time Frame: From date of Randomization up to 1.5 years of follow-up ]
    The AUC from time zero to the last measurable concentration sampling time after the first dose
  • Cmax: Pharmacokinetic (PK) parameter for midostaurin and its metabolites: CGP52421 and CGP62221 [ Time Frame: From date of Randomization up to 1.5 years of follow-up ]
    The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after the first dose administration
  • Tmax: Pharmacokinetic (PK) parameter for midostaurin and its metabolites: CGP52421 and CGP62221 [ Time Frame: From date of Randomization up to 1.5 years of follow-up ]
    The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration
  • Change from baseline score for each time point for the FACT-Leu [ Time Frame: From date of Randomization up to 5 years of follow-up ]
    The total FACT-Leu score consists of 44 items with total scores ranging from 0 to 176. Higher scores indicate better HRQoL. Negative changes from baseline indicate a worsening of HRQoL while positive changes indicate an improvement in HRQoL.
  • Change from baseline score for each time point for the EQ5D-5L (a visual analogue scale (VAS)) [ Time Frame: From date of Randomization up to 5 years of follow-up ]
    The EQ5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response options (no problems, slight problems, moderate problems, severe problems and extreme problems) that reflect increasing levels of difficulty. The patient is asked to indicate his/her current health state by selecting the most appropriate level in each of the 5 dimensions. The questionnaire also included a Visual Analogue Scale (VAS), where the patient is asked to rate current health status on a scale of 0 to 100, with 0 being the worst imaginable health state.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Global Study of the Efficacy and Safety of Midostaurin + Chemotherapy in Newly Diagnosed Patients With FLT3 Mutation Negative (FLT3-MN) Acute Myeloid Leukemia (AML)
Official Title  ICMJE A Phase III, Randomized, Double-blind Study of Chemotherapy With Daunorubicin or Idarubicin and Cytarabine for Induction and Intermediate Dose Cytarabine for Consolidation Plus Midostaurin (PKC412) or Chemotherapy Plus Placebo in Newly Diagnosed Patients With FLT-3 Mutation Negative Acute Myeloid Leukemia (AML)
Brief Summary

The purpose of this study is to confirm the preliminary evidence from early clinical trials that midostaurin may provide clinical benefit not only to AML patients with the FLT3-mutations but also in FLT3-MN (SR<0.05) AML (FLT3 mutant to wild type signal ratio below the 0.05 clinical cut-off).

This study will evaluate the efficacy and safety of midostaurin in combination with daunorubicin or idarubicin and cytarabine for induction and intermediate-dose cytarabine for consolidation, and midostaurin single agent post-consolidation therapy in newly diagnosed patients with FLT3-MN (SR<0.05) AML.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Acute Myeloid Leukemia (AML)
Intervention  ICMJE
  • Drug: Midostaurin
    After randomization, patients will receive midostaurin twice daily until not achieving CR nor CRi, relapse after CR or CRi, intolerable toxicity, or consent withdrawal
    Other Name: PKC412
  • Drug: Midostaurin Placebo
    After randomization, patients will receive midostaurin placebo twice daily until not achieving CR nor CRi, relapse after CR or CRi, intolerable toxicity, or consent withdrawal
  • Drug: Chemotherapy
    Along with the study drug/placebo, chemotherapy will be give as welll: either Daunorubicin or Idarubicin and Cytarabine al take by i.v.
Study Arms  ICMJE
  • Experimental: Midostaurin + chemotherapy
    Participants will receive Midostaurin 50mg twice a day until not achieving CR nor CRi without adequate hematologic recovery for continuation of treatment, intolerable toxicity, relapse or consent withdrawal plus chemotherapy whichever occurs first during induction and consolidation followed by midostaurin monotherapy for 12 cycles of 28 days cycle duration.Chemotherapy consists of daunorubicin or idarubicin and cytarabine for induction and intermediate dose cytarabine for consolidation.
    Interventions:
    • Drug: Midostaurin
    • Drug: Chemotherapy
  • Placebo Comparator: Midostaurin Placebo + chemotherapy
    Participants will receive matching placebo to midostaurin with same dose, plus chemotherapy. Chemotherapy consists of daunorubicin or idarubicin and cytarabine for induction and intermediate dose cytarabine for consolidation
    Interventions:
    • Drug: Midostaurin Placebo
    • Drug: Chemotherapy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: October 19, 2020)
513
Original Estimated Enrollment  ICMJE
 (submitted: April 18, 2018)
502
Estimated Study Completion Date  ICMJE January 25, 2021
Estimated Primary Completion Date January 25, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Diagnosis of AML (≥20% blasts in the bone marrow based on WHO 2016 classification). Patients with APL with PML-RARA are not eligible.
  2. Suitability for intensive induction chemotherapy in the judgment of the investigator
  3. Documented absence of an ITD and TKD activating mutation at codons D835 and I836 in the FLT3 gene, as determined by analysis in a Novartis designated laboratory using a validated clinical trial assay with clinical cutoff of 0.05 mutant to wild type signal ratio
  4. Age ≥18 years
  5. Laboratory values that indicate adequate organ function assessed locally at the screening visit

Exclusion Criteria:

  1. Central nervous system (CNS) leukemia
  2. Therapy-related secondary AML
  3. Isolated extramedullary leukemia
  4. Prior therapy for leukemia or myelodysplasia
  5. AML after antecedent myelodysplasia (MDS) with prior cytotoxic treatment (e.g., azacytidine or decitabine)
  6. Prior treatment with a FLT3 inhibitor (e.g., midostaurin, quizartinib, sorafenib)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Austria,   Belgium,   Brazil,   Bulgaria,   Czechia,   France,   Germany,   Israel,   Italy,   Japan,   Norway,   Poland,   Portugal,   Spain,   Switzerland,   Taiwan,   Turkey,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03512197
Other Study ID Numbers  ICMJE CPKC412E2301
2017-003540-21 ( 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  ICMJE
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.

Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP