Description:
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.
Title
- Brief Title: 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: 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)
Clinical Trial IDs
- ORG STUDY ID:
CPKC412E2301
- SECONDARY ID:
2017-003540-21
- NCT ID:
NCT03512197
Conditions
- Acute Myeloid Leukemia (AML)
Interventions
| Drug | Synonyms | Arms |
|---|
| Midostaurin | PKC412 | Midostaurin + chemotherapy |
| Midostaurin Placebo | | Midostaurin Placebo + chemotherapy |
| Chemotherapy | | Midostaurin + chemotherapy |
Purpose
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Midostaurin + chemotherapy | Experimental | 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. | |
| Midostaurin Placebo + chemotherapy | Placebo Comparator | 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 | - Midostaurin Placebo
- Chemotherapy
|
Eligibility 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)
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Event Free Survival (EFS) |
| Time Frame: | From date of Randomization up to 5 years of follow-up |
| Safety Issue: | |
| Description: | 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
| Measure: | Overall survival (OS) |
| Time Frame: | Between randomization to date of death up to 5 years of follow-up of last patients |
| Safety Issue: | |
| Description: | 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 |
| Measure: | 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 |
| Safety Issue: | |
| Description: | Assessment will be based on the IWG criteria for AML as per investigator assessment |
| Measure: | Percentage of patients with Minimal Residual Disease (MRD) negative status |
| Time Frame: | Between start and three months after end of treatment |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Disease-free survival (DFS) |
| Time Frame: | From date of CR or CRi with adequate blood count recovery up to 5 years of follow-up |
| Safety Issue: | |
| Description: | 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 |
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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 |
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Plasma concentrations for midostaurin and its metabolitees: CGP52421 and CGP62221 |
| Time Frame: | From date of Randomization up to 1.5 years of follow-up |
| Safety Issue: | |
| Description: | |
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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 |
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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 |
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Percentage of patients with MRD negative status during post-consolidation phase |
| Time Frame: | between start and three months after end of treatment |
| Safety Issue: | |
| Description: | |
| Measure: | Morphologic complete remission without hematopoietic recovery (CRi) with adequate blood count recovery rate |
| Time Frame: | At maximum 93 days from induction therapy start |
| Safety Issue: | |
| Description: | Assessment will be based on the IWG criteria for AML as per investigator assessment |
| Measure: | 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 |
| Safety Issue: | |
| Description: | |
| Measure: | 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 |
| Safety Issue: | |
| Description: | |
| Measure: | 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 |
| Safety Issue: | |
| Description: | |
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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 |
| Measure: | 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 |
| Safety Issue: | |
| Description: | The AUC from time zero to the last measurable concentration sampling time after the first dose |
| Measure: | 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 |
| Safety Issue: | |
| Description: | The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after the first dose administration |
| Measure: | 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 |
| Safety Issue: | |
| Description: | The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration |
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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. |
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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. |
Details
| Phase: | Phase 3 |
| Primary Purpose: | Interventional |
| Overall Status: | Completed |
| Lead Sponsor: | Novartis Pharmaceuticals |
Trial Keywords
- Newly diagnosed FLT3-mutation negative
- PKC412
- midostaurin
- cytarabine
- daunorubicin
- idarubicin
- acute myeloid leukemia
- AML
- FLT3-MN (SR<0.05)
- combination treatment
- induction failure
- event free survival
- EFS
- minimal residual disease
Last Updated
June 15, 2021
