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Trial record 64 of 324 for:    CYTARABINE AND DAUNORUBICIN

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)

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ClinicalTrials.gov Identifier: NCT03512197
Recruitment Status : Recruiting
First Posted : April 30, 2018
Last Update Posted : October 15, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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.


Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia (AML) Drug: Midostaurin Drug: Midostaurin Placebo Drug: Chemotherapy Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 502 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : January 3, 2018
Estimated Primary Completion Date : October 15, 2019
Estimated Study Completion Date : April 29, 2026


Arm Intervention/treatment
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.
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: Chemotherapy
Along with the study drug/placebo, chemotherapy will be give as welll: either Daunorubicin or Idarubicin and Cytarabine al take by i.v.

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
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.




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. Plasma concentrations for midostaurin and its metabolitees: CGP52421 and CGP62221 [ Time Frame: From date of Randomization up to 1.5 years of follow-up ]
  8. 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

  9. 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

  10. 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

  11. Percentage of patients with MRD negative status during post-consolidation phase [ Time Frame: between start and three months after end of treatment ]
  12. 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

  13. 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 ]
  14. 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 ]
  15. 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 ]
  16. 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

  17. 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

  18. 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

  19. 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

  20. 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.

  21. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)

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): NCT03512197


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.emai@novarti.som
Contact: Novartis Pharmaceuticals +41613241111

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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: NCT03512197     History of Changes
Other Study ID Numbers: CPKC412E2301
2017-003540-21 ( EudraCT Number )
First Posted: April 30, 2018    Key Record Dates
Last Update Posted: October 15, 2019
Last Verified: October 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.


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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 ):
cytarabine
daunorubicin
Newly diagnosed FLT3-mutation negative
PKC412
midostaurin
idarubicin
acute myeloid leukemia
AML
FLT3-MN (SR<0.05)
combination treatment
induction failure
event free survival
EFS
minimal residual disease
Additional relevant MeSH terms:
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Cytarabine
Daunorubicin
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Idarubicin
Midostaurin
Staurosporine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Protein Kinase Inhibitors