Clinical Trials List
Protocol NumberCPKC412E2301
NCT Number(ClinicalTrials.gov Identfier)NCT03512197
2018-07-20 - 2021-02-12
Phase III
Terminated4
ICD-10C92.00
Acute myeloblastic leukemia, not having achieved remission
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)
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Trial Applicant
NOVARTIS (TAIWAN) CO., LTD.
-
Sponsor
Novartis Pharmaceuticals
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Trial scale
Multi-Regional Multi-Center
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Update
2025/08/20
Investigators and Locations
The Actual Total Number of Participants Enrolled
0 Stop recruiting
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Co-Principal Investigator
- 高小雯 Division of Hematology & Oncology
- Tung-Liang Lin Division of Hematology & Oncology
- Hung Chang Division of Hematology & Oncology
- Ming-Chung Kao Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Audit
None
Co-Principal Investigator
- Chien-Chin Lin Division of General Internal Medicine
- CHENG-HONG TSAI Division of General Internal Medicine
- SHAN-CHI YU Division of Others -
- Wen-Chien Chou Division of General Internal Medicine
- Huai-Hsuan Huang Division of General Internal Medicine
- 田豐銘 Division of General Internal Medicine
- Tai-Chung Huang Division of General Internal Medicine
- Chieh-Lung Cheng Division of General Internal Medicine
- 林建廷 Division of General Internal Medicine
- MING YAO Division of General Internal Medicine
- - - Division of General Internal Medicine
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Audit
None
Condition/Disease
Acute Myeloid Leukemia (AML)
Objectives
Primary Objective: To determine if the addition of midostaurin to standard
induction and consolidation therapy, followed by single agent postconsolidation therapy improves event-free survival (EFS) in patients with
newly diagnosed FLT3-MN (SR<0.05) AML.
Key Secondary Objective: To determine if the addition of midostaurin to
standard induction and consolidation therapy, followed by single agent postconsolidation therapy improves overall survival (OS) in patients with newly
diagnosed FLT3-MN (SR<0.05) AML.
Test Drug
Rydapt
Active Ingredient
Midostaurin (PKC412)
Dosage Form
Capsule
Dosage
25
Endpoints
Primary Outcome Measures :
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 :
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.
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 :
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.
Inclution Criteria
Patients eligible for inclusion in this study have to meet all of the following
criteria:
1. Diagnosis of AML (≥20% blasts in the bone marrow based on World
Health Organization (WHO) 2016 classification). Patients with acute
promyelocytic leukemia APL with a PML-RARA rearrangement are not
eligible.
2. Suitability for intensive induction chemotherapy in the judgment of the
investigator based on patient’s performance status and comorbidities
3. Documented absence of an internal tandem duplication (ITD) and
tyrosine kinase domain (TKD) activating mutation at codons D835 and
I836 in the FLT3 gene, with clinical cutoff of 0.05 mutant to wild type
signal ratio.
4. Age ≥ 20 years
5. Laboratory values that indicate adequate organ function assessed locally
at the screening visit:
• Aspartate aminotransferase (AST) ≤ 3 times upper limit of normal
(ULN)
• Alanine aminotransferase (ALT) ≤ 3 times ULN
• Serum total bilirubin ≤ 1.5 times ULN, except in the setting of isolated
Gilbert syndrome
• Estimated (by Cockcroft-Gault) creatinine clearance ≥ 30ml/min
6. Written informed consent
criteria:
1. Diagnosis of AML (≥20% blasts in the bone marrow based on World
Health Organization (WHO) 2016 classification). Patients with acute
promyelocytic leukemia APL with a PML-RARA rearrangement are not
eligible.
2. Suitability for intensive induction chemotherapy in the judgment of the
investigator based on patient’s performance status and comorbidities
3. Documented absence of an internal tandem duplication (ITD) and
tyrosine kinase domain (TKD) activating mutation at codons D835 and
I836 in the FLT3 gene, with clinical cutoff of 0.05 mutant to wild type
signal ratio.
4. Age ≥ 20 years
5. Laboratory values that indicate adequate organ function assessed locally
at the screening visit:
• Aspartate aminotransferase (AST) ≤ 3 times upper limit of normal
(ULN)
• Alanine aminotransferase (ALT) ≤ 3 times ULN
• Serum total bilirubin ≤ 1.5 times ULN, except in the setting of isolated
Gilbert syndrome
• Estimated (by Cockcroft-Gault) creatinine clearance ≥ 30ml/min
6. Written informed consent
Exclusion Criteria
Patients eligible for this study must not meet any of the following criteria:
1. Central nervous system (CNS) leukemia
2. Therapy-related secondary AML
3. Isolated extramedullary leukemia
4. Prior therapy for leukemia or myelodysplasia with the following
exceptions:
a. Emergency leukapheresis
b. Emergency treatment for hyperleukocytosis with hydroxyurea or
low-dose cytarabine for ≤ 7 days
c. Cranial radiotherapy (RT) for CNS leukostasis (one dose only)
d. Hematopoietic Growth factor/cytokine support
e. Other supportive therapy including antibiotics at the discretion of the
investigator
5. AML after antecedent myelodysplasia (MDS) with prior cytotoxic
treatment (e.g., azacytidine or decitabine)
6. Any investigational agent within 30 days or 5 half-lives, whichever is
greater
7. Prior treatment with a FLT3 inhibitor
8. Strong CYP3A4/5 enzyme inducing drugs (see Appendix 1) unless they
can be discontinued or replaced prior to enrollment.
9. Any other known disease or concurrent severe and/or uncontrolled
medical condition that could compromise participation in the study.
10. Abnormal chest X-ray with corresponding clinical symptoms or
findings that indicate an active infection, or other pulmonary conditions
that are currently clinically significant.
11. Intestinal malabsorption
12. Known human immunodeficiency virus (HIV) infection or active viral
hepatitis
13. Cardiovascular abnormalities, including any of the following:
• History of myocardial infarction (MI), angina pectoris, coronary
artery bypass graft (CABG) within 6 months prior to starting study
treatment
• Clinically uncontrolled cardiac arrhythmias (e.g., ventricular
tachycardia), complete left bundle branch block, high-grade
atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II
and third degree AV block)
• Uncontrolled congestive heart failure
• Left ventricular ejection fraction of <50%
• Poorly controlled hypertension
14. Pregnant or nursing (lactating) women
15. Women of child-bearing potential, defined as all women physiologically
capable of becoming pregnant, unless they are using highly effective
methods of contraception during dosing and for at least 4 months after
stopping medication.
16. Sexually active males unless they use a condom during intercourse
17. Unwillingness or inability to comply with the protocol.
1. Central nervous system (CNS) leukemia
2. Therapy-related secondary AML
3. Isolated extramedullary leukemia
4. Prior therapy for leukemia or myelodysplasia with the following
exceptions:
a. Emergency leukapheresis
b. Emergency treatment for hyperleukocytosis with hydroxyurea or
low-dose cytarabine for ≤ 7 days
c. Cranial radiotherapy (RT) for CNS leukostasis (one dose only)
d. Hematopoietic Growth factor/cytokine support
e. Other supportive therapy including antibiotics at the discretion of the
investigator
5. AML after antecedent myelodysplasia (MDS) with prior cytotoxic
treatment (e.g., azacytidine or decitabine)
6. Any investigational agent within 30 days or 5 half-lives, whichever is
greater
7. Prior treatment with a FLT3 inhibitor
8. Strong CYP3A4/5 enzyme inducing drugs (see Appendix 1) unless they
can be discontinued or replaced prior to enrollment.
9. Any other known disease or concurrent severe and/or uncontrolled
medical condition that could compromise participation in the study.
10. Abnormal chest X-ray with corresponding clinical symptoms or
findings that indicate an active infection, or other pulmonary conditions
that are currently clinically significant.
11. Intestinal malabsorption
12. Known human immunodeficiency virus (HIV) infection or active viral
hepatitis
13. Cardiovascular abnormalities, including any of the following:
• History of myocardial infarction (MI), angina pectoris, coronary
artery bypass graft (CABG) within 6 months prior to starting study
treatment
• Clinically uncontrolled cardiac arrhythmias (e.g., ventricular
tachycardia), complete left bundle branch block, high-grade
atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II
and third degree AV block)
• Uncontrolled congestive heart failure
• Left ventricular ejection fraction of <50%
• Poorly controlled hypertension
14. Pregnant or nursing (lactating) women
15. Women of child-bearing potential, defined as all women physiologically
capable of becoming pregnant, unless they are using highly effective
methods of contraception during dosing and for at least 4 months after
stopping medication.
16. Sexually active males unless they use a condom during intercourse
17. Unwillingness or inability to comply with the protocol.
The Estimated Number of Participants
-
Taiwan
20 participants
-
Global
502 participants
