Conditions: Acute Myeloid Leukemia (AML)
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
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 511
Healthy volunteers: no

Brief summary:
The purpose of this study was 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 evaluated 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:
This was a multi-center, multinational, randomized, double-blind Phase III study using a group sequential design. Subjects were stratified according to age (\<60 vs. ≥ 60 years). Subjects within each stratum were randomized in a 1:1 ratio into one of two treatment arms: Midostaurin + chemotherapy 'or' Placebo + chemotherapy.

The study consisted of the following phases:

Screening/randomization phase: Subjects had to sign informed consent form before screening for enrollment. Subjects started chemotherapy at day 1 and were randomized at day 8.

Induction phase: All subjects received at least one cycle (28 days) of induction therapy with continuous infusion cytarabine (D1 - D7) and daunorubicin or idarubicin (D1 - D3) (induction 1). Subjects who did not achieve CR or CRi with adequate blood count recovery after Induction 1 received a second cycle with intermediate-dose cytarabine (D1 - D3) and daunorubicin or idarubicin (D1 - D3) (induction 2). Subjects who did not achieve CR or CRi with adequate blood recovery after induction 2 discontinued study treatment and were followed for survival.

Consolidation phase: Subjects who achieved CR or CRi with adequate blood count recovery after induction with one or two cycles of induction proceeded to consolidation therapy with either 3 or 4 cycles respectively of intermediate-dose cytarabine (D1 - D3), or to Hematopoietic Stem Cells Transplantation (HSCT) with or without preceding consolidation cycles.

Post-consolidation phase: Subjects who maintained CR or CRi with adequate blood count recovery at the end of the consolidation phase received 12 cycles (28 days/cycle) of continuous therapy with midostaurin or placebo twice daily at 50 mg. Subjects who underwent HSCT after achieving CR or CRi with adequate blood count recovery received midostaurin or placebo twice daily 50 mg post-transplant therapy, continuously, for up to 12 cycles (28 days/cycle). Post HSCT post-consolidation therapy began \>30 days but not later than 100 days following HSCT.

Follow-up phase: All enrolled subjects were followed through the treatment period and until relapse/treatment failure, thereafter for start of new line of therapy and survival.

Arms:
arm 1: Participants received Midostaurin in Induction 50mg twice daily on Day 8 until 48 hrs before start of next cycle. During Induction 2 and consolidation 50mg twice daily on Day 4 until 48 hrs before start of next cycle. During post-consolidation 50mg twice daily for 28 consecutive days of each 28-day treatment cycle up to 12 cycles. For participants who could not tolerate the protocol-specified dosing schedule, dose interruptions and/or reductions were either recommended or mandated allowing participants to continue the study treatment. Chemotherapy consisted of daunorubicin or idarubicin and cytarabine for induction and intermediate dose cytarabine for consolidation. arm 2: Participants received matching placebo to midostaurin with same dose, plus chemotherapy. Chemotherapy consisted of daunorubicin or idarubicin and cytarabine for induction and intermediate dose cytarabine for consolidation

Interventions: intervention 1: Midostaurin intervention 2: Placebo intervention 3: Chemotherapy
Intervention descriptions: intervention 1: Midostaurin was provided as 25 mg capsules 8PC, was supplied as double-blind in blister packs and taken orally. intervention 2: Placebo was provided as 25 mg soft gelatin capsules 8PC, was supplied as double-blind in blister packs and taken orally. intervention 3: Along with the study drug/placebo, chemotherapy was given as well: either Daunorubicin or Idarubicin and Cytarabine - all taken by i.v.

Protocol document:
Prot_000.pdf: 
Oncology Global Development Unit
PKC412 (Midostaurin)
Clinical Protocol CPKC412E2301 / NCT03512197
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)
Document type
Oncology Clinical Trial Protocol (Clean)
EUDRACT number
2017-003540-21
Version number
01 (Amended Protocol)
Development phase
III
Document status
Final
Release date
08-Jun-2018
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template version 06-Apr-2017


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Table of contents
Table of contents .................................................................................................................2
List of Figures......................................................................................................................7
List of tables ........................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................13
Protocol summary:.............................................................................................................14
Amendment 1 (08-Jun-2018) ............................................................................................22
1
Background........................................................................................................................24
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............24
1.2
Introduction to investigational treatment(s) and other study treatment(s).............25
1.2.1
Overview of Midostaurin......................................................................25
2
Rationale............................................................................................................................32
2.1
Study rationale and purpose...................................................................................32
2.2
Rationale for the study design ...............................................................................33
2.2.1
Midostaurin post-consolidation therapy in AML: disease 
considerations........................................................................................33
2.2.2
Benefit of midostaurin post-consolidation therapy...............................33
2.3
Rationale for dose and regimen selection..............................................................35
2.4
Rationale for choice of combination drugs............................................................35
2.5
Rationale for choice of comparators drugs............................................................38
2.6
Rationale for MRD assessment .............................................................................38
38
2.8
Risk and benefit .....................................................................................................39
3
Objectives and endpoints...................................................................................................41
4
Study design ......................................................................................................................45
4.1
Description of study design ...................................................................................45
4.2
Study phase (details of dosing in section 6) ..........................................................46
4.2.1
Induction phase .....................................................................................46
4.2.2
Consolidation phase ..............................................................................47
4.2.3
Post-consolidation phase.......................................................................47
4.2.4
Follow-up phase....................................................................................47
4.3
Timing of interim analyses and design adaptations...............................................48
4.4
Definition of end of study......................................................................................48
4.5
Early study termination..........................................................................................48
5
Population..........................................................................................................................48


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5.1
Patient population..................................................................................................48
5.2
Inclusion criteria ....................................................................................................49
5.3
Exclusion criteria...................................................................................................49
6
Treatment...........................................................................................................................51
6.1
Study treatment......................................................................................................51
6.1.1
Dosing regimen.....................................................................................51
6.1.2
Ancillary treatments..............................................................................56
6.1.3
Rescue medication ................................................................................56
6.1.4
Guidelines for continuation of treatment ..............................................56
6.1.5
Treatment duration................................................................................56
6.2
Dose escalation guidelines.....................................................................................57
6.3
Dose modifications................................................................................................57
6.3.1
Dose modification and dose delay ........................................................57
6.3.2
Dose adjustments for QTcF prolongation.............................................62
6.3.3
Follow-up for toxicities.........................................................................62
6.4
Concomitant medications ......................................................................................63
6.4.1
Permitted concomitant therapy .............................................................63
6.4.2
Permitted concomitant therapy requiring caution and/or action...........64
6.4.3
Prohibited concomitant therapy ............................................................64
6.4.4
Use of Bisphosphonates (or other concomitant agents)........................65
6.5
Patient numbering, treatment assignment or randomization .................................65
6.5.1
Patient numbering .................................................................................65
6.5.2
Treatment assignment or randomization...............................................65
6.5.3
Treatment blinding................................................................................66
6.6
Study drug preparation and dispensation...............................................................66
6.6.1
Study treatment packaging and labeling ...............................................67
6.6.2
Drug supply and storage........................................................................67
6.6.3
Study drug compliance and accountability ...........................................68
6.6.4
Disposal and destruction .......................................................................68
7
Visit schedule and assessments .........................................................................................69
7.1
Study flow and visit schedule................................................................................69
7.1.1
Molecular pre-screening........................................................................90
7.1.2
Screening...............................................................................................90
7.1.3
Treatment period...................................................................................92
7.1.4
Discontinuation of study treatment .......................................................93
7.1.5
Withdrawal of consent ..........................................................................94


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7.1.6
Follow up for safety evaluations...........................................................94
7.1.7
Follow up for efficacy evaluations........................................................94
7.1.8
Survival follow up.................................................................................95
7.1.9
Lost to follow-up...................................................................................95
7.2
Assessment types...................................................................................................95
7.2.1
Efficacy assessments.............................................................................95
7.2.2
Safety and tolerability assessments.....................................................100
7.2.3
Pharmacokinetics ................................................................................107
7.2.4
Biomarkers..........................................................................................111
113
7.2.6
Patient reported outcomes...................................................................113
8
Safety monitoring and reporting......................................................................................114
8.1
Adverse events.....................................................................................................114
8.1.1
Definitions and reporting ....................................................................114
8.1.2
Laboratory test abnormalities..............................................................116
8.1.3
Adverse events of special interest.......................................................116
8.2
Serious adverse events.........................................................................................116
8.2.1
Definitions...........................................................................................116
8.2.2
Reporting.............................................................................................117
8.3
Emergency unblinding of treatment assignment .................................................118
8.4
Pregnancies..........................................................................................................118
8.5
Warnings and precautions....................................................................................119
8.6
Data Monitoring Committee................................................................................119
8.7
Steering Committee .............................................................................................120
9
Data collection and management.....................................................................................120
9.1
Data confidentiality .............................................................................................120
9.2
Site monitoring ....................................................................................................121
9.3
Data collection.....................................................................................................121
9.4
Database management and quality control..........................................................122
10 Statistical methods and data analysis ..............................................................................122
10.1
Analysis sets ........................................................................................................123
10.1.1
Full Analysis Set .................................................................................123
10.1.2
Safety set .............................................................................................123
10.1.3
Per-Protocol set ...................................................................................123
10.1.4
Pharmacokinetic analysis set...............................................................123
10.2
Patient demographics/other baseline characteristics ...........................................124


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10.3
Treatments (study treatment, concomitant therapies, compliance) .....................124
10.4
Primary objective.................................................................................................124
10.4.1
Statistical hypothesis, model, and method of analysis........................125
10.4.2
Handling of missing values/censoring/discontinuations.....................125
10.4.3
Supportive analyses.............................................................................125
10.5
Secondary objectives ...........................................................................................126
10.5.1
Key secondary objective(s).................................................................126
10.5.2
Other secondary efficacy objectives ...................................................127
10.5.3
Safety objectives .................................................................................129
10.5.4
Pharmacokinetics ................................................................................131
10.5.5
Patient-reported outcomes...................................................................132
133
133
133
133
135
10.7
Interim analyses...................................................................................................135
10.7.1
Event free survival (EFS)....................................................................135
10.7.2
Key secondary endpoint: Overall survival (OS).................................137
10.8
Sample size calculation........................................................................................139
10.9
Power for analysis of key secondary endpoint ....................................................139
11 Ethical considerations and administrative procedures ....................................................139
11.1
Regulatory and ethical compliance......................................................................139
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................140
11.3
Informed consent procedures...............................................................................140
11.4
Discontinuation of the study................................................................................140
11.5
Publication of study protocol and results.............................................................141
11.6
Study documentation, record keeping and retention of documents.....................141
11.7
Confidentiality of study documents and patient records .....................................142
11.8
Audits and inspections.........................................................................................142
11.9
Financial disclosures............................................................................................142
12 Protocol adherence ..........................................................................................................142
12.1
Amendments to the protocol................................................................................142
13 References (available upon request)................................................................................144
14 Appendices ......................................................................................................................147
14.1
Appendix 1 – Concomitant medications..............................................................147


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14.1.1
List of prohibited medications ............................................................147
14.1.2
Permitted medications to be used with caution...................................147
14.2
Appendix 2 – FACT-Leu questionnaire ..............................................................149
14.3
Appendix 3 – EQ-5D-5L questionnaire...............................................................152


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List of Figures
Figure 4-1
Study Design .........................................................................................45
List of tables
Table 3-1
Objectives and related endpoints ..........................................................41
Table 6-1
Dose and treatment schedule.................................................................54
Table 6-2
Criteria for dose reduction/interruption and re-initiation of 
midostaurin/placebo, daunorubicin/idarubicin and cytarabine 
treatment for adverse drug reactions.....................................................59
Table 6-3
Dispensing and preparation...................................................................67
Table 6-4
Supply and storage of study treatments ................................................68
Table 7-1
Visit evaluation schedule ......................................................................70
Table 7-2
Response classification in AML at a given evaluation time (Cheson 
2003, ELN 2017 / Döhner et al 2017)...................................................95
Table 7-3
Flow cytometry MRD sample collection plan ......................................99
Table 7-4
ECOG performance status scale..........................................................101
Table 7-5
Clinical laboratory parameters collection plan ...................................102
Table 7-6
Standard hematologic diagnostics.......................................................103
Table 7-7
Local ECG assessment monitoring schedule ......................................106
Table 7-8
Pharmacokinetic blood collection log for Midostaurin, CGP52421 
and CGP62221 – Full PK collection (N=60)......................................107
Table 7-9
Pharmacokinetic blood collection log for Midostaurin, CGP52421 
and CGP62221 – Sparse PK collection...............................................109
110
Table 7-11
Biomarker sample collection plan.......................................................111
Table 10-1
Noncompartmental pharmacokinetic parameters................................132
Table 10-2
Simulated cumulative probabilities to stop for efficacy or futility 
by the 1st interim (IA1), the 2nd interim (IA2) or the final EFS (FA) 
analyses ...............................................................................................137
Table 10-3
Simulated probabilities to stop for efficacy on overall survival at 
2nd EFS interim (1st OS interim (IAOS1)), final EFS (2nd OS 
interim (IAOS2)) analysis or final OS analysis (FAOS) ....................138


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List of abbreviations
ADR
Adverse Drug Reaction
AdSM
Advanced systemic mastocytosis
AE
Adverse Event
AESI
Adverse event of special interest
AHNMD
Associated hematologic non-mast cell lineage disorder
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AML
Acute myeloid leukemia
ANC
Absolute Neutrophil Count
APL
acute promyelocytic leukemia
AR
Allelic Ratio
ASM
Aggressive systemic mastocytosis
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
Area under the curve
AV
Atrioventricular
BCRP
Breast cancer resistant protein
BCS
Biopharmaceutics classification system
BM
Bone Marrow
BMA
Bone marrow aspirate
BSA
Body Surface Area
CABG
Coronary artery bypass graft
CALGB
Cancer and Leukemia Group B
CBF
Core binding factor
CID
Cumulative incidence of death
CIR
Cumulative incidence of relapse
CIVI
Continuous intravenous infusion 
CMO&PS
Chief Medical Office and Patient 
CMV
Cytomegalovirus
CNS
Central Nervous System


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CPO
Country Pharma Organization
CR
Complete remission
CRi
Morphologic complete remission without hematopoietic recovery
eCRF
Electronic Case Report/Record Form; the term CRF can be applied to either EDC
or Paper
CRO
Contract Research Organization
CSF
Cerebrospinal fluid
CSR
Clinical study report
CSR addendumAn addendum to Clinical Study Report (CSR) that captures all the additional 
information that is not included in the CSR
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
CYP3A4
cytochrome P450 3A4 enzyme
DILI
Drug-induced liver injury
DFS
Disease-free survival
DMC
Data Monitoring Committee
EBV
Epstein-Barr Virus
EC
Ethic committee
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
EDD
Expected Delivery Date
EFS
Event-free survival
ELN
European LeukemiaNet
EOT
End of Treatment
EQ-5D
EuroQol- 5 Dimension
EQ VAS
EQ visual analogue scale
FAB
French American British
FACT-G
Functional assessment of cancer therapy-general
FACT-Leu
Functional assessment of cancer therapy-leukemia
FAS
Full analysis set


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FDA
Food and drug administration
FGFR
Fibroblast growth factor receptor
FLT3
FMS-like tyrosine kinase
FLT-3 MN (SR<0.05) FLT-3 Mutation Negative (FLT-3 mutant to wild type signal ratio below
the 0.05 clinical cut-off
FLT3-WT
FLT3 wild type
GGT
Gamma-glutamyltransferase
GI
Gastrointestinal
HIV
Human Immunodeficiency Virus
HR
Hazard Ratio
HSCT
Hematopoietic Stem Cell Transplantation
HSV
Herpes simplex virus
IB
Investigator’s Brochure
ICF
Inform consent form
ICH
International Conference on Harmonization
ICMJE
International Committee of Medical Journal Editors
IDAC
Intermediate dose of Ara-C/Cytarabine
IEC
Independent Ethics Committee
IN
Investigator notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology that includes Interactive Voice Response System
and Interactive Web Response System
ITD
Internal Tandem duplication
IUD
Intrauterine Device
IUS
Intrauterine System
I.V
Intravenous(ly)
IWG
International Working Group
LAIP
Leukemia-Associated ImmunoPhenotypes
LFT
Liver function tests
LPLV
Last patient last visit
LLOQ
Lower limit of quantitation 


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LVEF
Left Ventricular Ejection Fraction
MAR
Missing-at-random
MCL
Mast cell leukemia
MDS
Myelodysplastic Syndrome
MedDRA
Medical dictionary for regulatory activities
MFC
multi-parameter flow cytometry 
MI
Myocardial Infarction
MMRM
Mixed models for repeated measures
MR
Minor Response
MRD
Minimal/Measurable Residual Disease
MRP2
Multi-drug resistance associated protein 2
MUGA
Multigated Acquisition Scan
NCA
Non-compartmental analysis
NCCI
National Comprehensive Cancer Network
NCI
National cancer institute
NOEL
number of observable effect level
OS
Overall Survival
PAS
Pharmacokinetic Analysis Set
PD
Pharmacodynamic
PDGFR
Platelet-derived growth factor receptor
P-gp
P-glycoprotein
PHI
Protected Health Information
 
PK
Pharmacokinetic
PML-RARA
Promyelocyte Leukemia - Retinoic Acid Receptor Alpha Rearrangement
p.o.
per os/by mouth/orally
PopPK
Population pharmacokinetic analysis
PPS
Per-Protocol Set
PR
Partial remission
PRO
Patient reported outcome
PT
Prothrombin time


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aPTT
activated partial thromboplastin time
QT/QTcF
QT interval/QT interval corrected with Fridericia’s formula
RATIFY 
Randomized AML Trial In FLT3+ patients <60 Years (Study A2301)
REB
Research Ethics Board
RT
Radiotherapy
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Steering Committee
SD
Standard deviation
SDAC
Standard dose of Ara-C/Cytarabine
SM
Systemic Mastocytosis
SR
Signal Ratio
SS
Safety set
SSD
Study specification document
SUSAR
Suspected unexpected serious adverse reations
TBIL
Total bilirubin
TdP
Torsades de Pointes
TKD
Tyrosine Kinase Domain
ULN
Upper limit of normal
VAP
Validation and planning
VAS
Visual analogue scale
VEGFR
Vascular endothelial growth factor
WBC
White blood cell
WHO
World Health Organization


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), bone 
marrow, saliva, tissue, urine, stool, etc. taken from a study subject or study 
patient
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g.: 28 days)
Enrollment
Point/time of patient entry into the study; the point at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described in the 
protocol)
FLT3-Mutation Negative (MN)
For the purpose of this study FLT3-MN is defined as the absence of ITD 
mutation and absence of TKD activating mutation at codons D835 and I836 in 
the FLT3 gene (FMS-like tyrosine kinase 3 gene), based on mutant to wild 
type signal ratio below the 0.05 clinical cutoff.
Investigational drug
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug.”
Investigational treatment
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when applicable). This also 
includes approved drugs used outside of their indication/approved dosage, or 
that are tested in a fixed combination. Investigational treatment generally does 
not include other study treatments administered as concomitant background 
therapy required or allowed by the protocol when used in within approved 
indication/dosage
Medication number
A unique identifier on the label of each study treatment package which is 
linked to one of the treatment groups of a study
Other study treatment
Any drug administered to the patient as part of the required study procedures 
that is not included in the investigational treatment
Subject number (Subject No.)
A unique identifying number assigned to each patient/subject/healthy 
volunteer who enrolls in the study
Period
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, induction, consolidation, post-consolidation, 
follow-up for efficacy or survival.
Personal Data
Subject information collected by the Investigator that is transferred to Novartis 
for the purpose of the clinical trial. This data includes subject identifier 
information, study information and biological samples.
Randomization number
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when 
study treatment was discontinued whichever is later
Study treatment
Midostaurin or placebo in sequential combination with daunorubicin/idarubicin 
and cytarabine induction, in sequential combination with intermediate dose 
cytarabine consolidation, and as single agent post-consolidation therapy.
Study treatment discontinuation
Point/time when patient permanently stops taking study treatment for any 
reason
Treatment group
A treatment group defines the dose and regimen of the combination.
Variable
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints.
Withdrawal of consent
Withdrawal of consent from the study occurs only when a subject does not 
want to participate in the study any longer, and does not allow any further 
collection of personal data


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Protocol summary:
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 FLT3-mutation negative acute myeloid leukemia (AML) 
Brief title
A global study of the efficacy and safety of midostaurin + chemotherapy in newly 
diagnosed patients with FLT3-MN AML
Sponsor and clinical 
phase
Novartis,  Phase III
Investigation type
Drug
Study type
Interventional
Purpose and rationale
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.
Primary objective(s) 
and key secondary 
objective
Primary Objective: To determine if the addition of midostaurin to standard induction and 
consolidation therapy, followed by single agent post-consolidation 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 post-consolidation 
therapy improves overall survival (OS) in patients with newly diagnosed FLT3-MN 
(SR<0.05) AML.
Secondary objectives
Objective 1: To compare the rate of complete remission (CR + CRi with adequate blood 
count recovery) in the two treatment groups.
Objective 2: To compare the percentage of patients who reached MRD negative status 
in the two treatment groups.
Objective 3: To compare the percentage of patients with MRD negative status in the 
post-consolidation phase in the two treatment groups.
Objective 4: To compare the time to MRD negative status bone marrow between the 
two treatment groups.
Objective 5: To compare disease-free survival (DFS), as well as the cumulative 
incidence of relapse (CIR) and cumulative incidence of death (CID) in the two treatment 
groups.
Objective 6: To compare the time to CR or CRi with adequate blood count recovery in 
the two treatment groups.
Objective 7: To compare the time to neutrophil recovery in the two treatment groups.
Objective 8: To compare the time to platelet recovery in the two treatment groups.
Objective 9: To assess the safety and tolerability of midostaurin in combination with 
chemotherapy and as monotherapy during post-consolidation.
Objective 10: To further characterize the pharmacokinetics of midostaurin, CGP52421 
and CGP62221.
Objective 11: To assess the impact of midostaurin on health related quality of life and 
AML symptom reduction.
 
 


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Protocol No. CPKC412E2301
 
 
 
Study design
This is a multi-center, multinational, randomized, double-blind Phase III study using a 
group sequential design with two interim analyses.  The primary endpoint is EFS as per 
investigator assessment and is defined as the time from randomization to failure to 
achieve CR or CRi with adequate blood count recovery (i.e., neutrophils ≥1.0 x 109/L 
and platelets ≥50 x 109/L) in induction phase, relapse from CR or CRi with adequate
blood count recovery or death due to any cause whichever occurs first.
Overall survival (OS) is the key secondary endpoint and is defined as the time from 
randomization to death due to any cause. OS will be hierarchically tested if the EFS 
shows significant improvement in the second interim analysis or in the final analysis.
Patients will be stratified according to 
Age (<60 vs. ≥60 years)
Patients within each stratum will be randomized in a 1:1 ratio into one of two treatment 
arms:
Midostaurin + chemotherapy
or
Placebo + chemotherapy
The study will consist of the following phases:
Screening/randomization phase:
Patients having signed informed consent will be screened for eligibility criteria. 
Patients will start treatment with chemotherapy at day 1 and will be randomized at day 
8.
Induction phase:
All patients will receive at least one cycle of induction therapy with continuous infusion 
cytarabine and daunorubicin or idarubicin (induction 1). Patients not achieving CR or 
CRi with adequate blood count recovery after Induction 1 will receive a second cycle 
with intermediate-dose cytarabine and daunorubicin or idarubicin (induction 2).
Patients not achieving CR or CRi with adequate blood recovery after induction 2 will 
discontinue study treatment and will be followed for survival.
Patients achieving CR or CRi with adequate blood count recovery after induction 2 will 
enter the consolidation phase.
Consolidation phase : 
Patients achieving CR or CRi with adequate blood count recovery after induction with 
one or two cycles will proceed to consolidation therapy with either 3 or 4 cycles of 
intermediate-dose cytarabine, or to Hematopoietic Stem Cells Transplantation (HSCT)
with or without preceding consolidation cycles.
Post-consolidation phase: 
Patients achieving CR or CRi with adequate blood count recovery at the end of the 
consolidation phase will receive 12 cycles (28 days/cycle) of continuous therapy with 
midostaurin or placebo twice daily at 50 mg.
Patients who underwent HSCT after achieving CR or CRi with adequate blood count
recovery will receive midostaurin or placebo twice daily 50 mg post-transplant therapy, 
continuously, for up to 12 cycles (28 days/cycle). Post HSCT post-consolidation therapy 
will begin >30 days but not later than 100 days following HSCT.
Follow-up phase:


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All patients enrolled to the study will be followed through the treatment period and until 
relapse/treatment failure, thereafter for start of new line of therapy and survival. 
Population
The study will include 502 adult (male and female) patients 18 years with newly 
diagnosed FLT3-MN (SR<0.05) AML.
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
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.
Suitability for intensive induction chemotherapy in the judgment of the investigator
based on patient’s performance status and comorbidities
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.
Age 18 years 
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
Written informed consent 
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
Central nervous system (CNS) leukemia
Therapy-related secondary AML 
Isolated extramedullary leukemia
Prior therapy for leukemia or myelodysplasia with the following exceptions:
Emergency leukapheresis
Emergency treatment for hyperleukocytosis with hydroxyurea or low-dose cytarabine
for 7 days
Cranial radiotherapy (RT) for CNS leukostasis (one dose only)
Hematopoietic Growth factor/cytokine support
Other supportive therapy including antibiotics at the discretion of the investigator
AML after antecedent myelodysplasia (MDS) with prior cytotoxic treatment (e.g., 
azacytidine or decitabine)
Any investigational agent within 30 days or 5 half-lives, whichever is greater
Prior treatment with a FLT3 inhibitor
Strong CYP3A4/5 enzyme inducing drugs (see Appendix 1) unless they can be 
discontinued or replaced prior to enrollment. 
Any other known disease or concurrent severe and/or uncontrolled medical condition 
that could compromise participation in the study.
Abnormal chest X-ray with corresponding clinical symptoms or findings that indicate an 
active infection, or other pulmonary conditions that are currently clinically significant. 
Intestinal malabsorption
Known human immunodeficiency virus (HIV) infection or active viral hepatitis
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


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Left ventricular ejection fraction of <50%
Poorly controlled hypertension
Pregnant or nursing (lactating) women
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.
Sexually active males unless they use a condom during intercourse 
Unwillingness or inability to comply with the protocol.
Known hypersensitivity to midostaurin, cytarabine or idarubicin / daunorubicin or to any 
of the excipients of midostaurin/placebo, cytarabine or idarubicin / daunorubicin.
Investigational and 
reference therapy
Midostaurin or placebo in sequential combination with daunorubicin/idarubicin and 
cytarabine induction, in sequential combination with intermediate dose cytarabine 
consolidation, and as single agent post-consolidation therapy. Treatment switching is 
not an option in this trial.
Efficacy assessments
Efficacy assessment will be determined by the following parameters:
Blast count in bone marrow, peripheral blood specimens (platelet count, neutrophils 
and blasts), evaluation of extramedullary disease and assessment of red blood cell and 
platelet transfusion. 
Entry of response evaluations in the case report form (CRF) will be according to the 
International Working Group (IWG) criteria for AML (Cheson et al., 2003, ELN 2017 / 
Döhner et al 2017) as per investigator assessment. The response to treatment and 
relapse will not require confirmation by a repeated test.
Response assessment will be done at the following time points:
End of each induction cycle, end of each consolidation cycle, every cycle during post-
consolidation phase and every 3 months during follow-up phase.
Patients moving to HSCT will have a response assessment documented before start of 
HSCT. 
Patients with CRi without adequate blood count recovery at end of each cycle, will have 
a response assessment performed (for a maximum of 2-3 additional weeks) upon blood 
recovery.
Moreover, disease assessment will be performed any time in case of suspected 
relapse.
For details please see Section 7.2.1.
Safety assessments
Safety assessment will include AEs with severity, relationship to study treatment and 
seriousness, physical examination, Eastern cooperative oncology group (ECOG) PS, 
vital signs, 12-lead electrocardiogram (ECG), local measurements of QTc≥480ms will 
be centrally verified on a copy of a high quality recording that includes time and voltage 
scales, multigated acquisition scan (MUGA), echocardiogram (ECHO) and laboratory 
assessments including hematology, chemistry, coagulation and urinalysis
Other assessments
PK parameters 
Plasma concentrations of midostaurin and its active metabolites CGP62221 and
CGP52421 
 
 
 
Patient reported outcome assessment using EuroQol- 5 Dimension (EQ-5D), Functional 
assessment of cancer therapy-general (FACT-G) with FACT-leukemia (FACT-Leu)
 


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Statistical methods and 
data analyses
Populations:
The Full Analysis Set (FAS) comprises all patients to whom study drug has been 
assigned by randomization. According to the intent to treat principle, patients will be 
analyzed according to the treatment and stratum they have been assigned to during the 
randomization procedure.
The Safety Set (SS) includes all patients who received at least one dose of study 
treatment starting at day 1, were randomized and took at least one dose of midostaurin 
or placebo. Patients will be analyzed according to the study treatment received, where 
treatment received is defined as the randomized treatment if the patient took at least 
one dose of that treatment. 
Primary efficacy and key secondary endpoints:
EFS and OS are the primary and key secondary endpoints, respectively. Therefore, 
family wise type I error rate associated with efficacy analyses for testing EFS and OS 
will be controlled by using hierarchical testing procedure. 
Event Free Survival (EFS):
The study is designed to test the following statistical hypothesis for EFS using a 
stratified log-rank test (stratified according to randomization stratification factor of age 
(<60 vs. ≥ 60 years)) at the one-sided 2.5% level of significance: 
H01: θ1 ≥ 1 vs. Ha1: θ1 < 1
Where θ1 is the hazard ratio (Midostaurin treatment arm vs. placebo arm) of EFS.
The primary efficacy endpoint EFS will be analyzed at the interim looks and final look of 
a group sequential design based on the FAS population according to the treatment 
group patients were randomized and the strata they were assigned at randomization 
(i.e. age < 60 vs. >=60 years). EFS will be estimated using the Kaplan-Meier method. 
The median EFS along with 95% confidence intervals will be presented by treatment 
group. 
Under the proportional hazards assumption, a test based on the stratified log-rank test 
provides an asymptotically equivalent result as that of the stratified Cox regression 
model which will be used to estimate the hazard ratio (HR) of EFS, along with 95% 
confidence interval (using the same strata information as above). 
The final analysis will be performed when there are approximately 285 EFS events. 
Two interim analyses will be performed when approximately 114 and 214 of the 285 
EFS events (approximately 40% and 75% information fraction respectively) have been 
documented.
These analyses are expected to take place around 12 and 20 months respectively from 
the date of first patient randomized in the study assuming an increasing recruitment 
rate to reach 30 patients / month in month 6. The primary intent of the first interim 
analysis is to allow the study to stop early for lack of efficacy (futility). There is no intent 
to carry out an analysis to declare superior efficacy at the time of the first interim 
analysis. At least, 283 patients (56%) are expected to be randomized at the time of the 
interim futility analysis, i.e., when approximately 114 EFS events have occurred. The 
2nd interim analysis will allow the study to stop early for outstanding efficacy. The 2nd
interim analysis will only be carried out after all patients have been randomized.
A user-defined gamma spending function (γ = -1.2) will be used as a beta-spending 
function to determine the non-binding futility boundary at the time of the 1st interim 
analysis. The futility boundary at the first interim is calculated as hazard ratio of 0.97. 
The observed (i.e., nominal) p-value has to be greater than p=0.44 (one-sided) to 
conclude futility. Since the observed number of EFS events at the interim analyses may 
not exactly be equal to the planned number of events, the futility boundary will need to 
be re-calculated (or updated) based on the actual number of observed events. 
Therefore, the observed p-value (or Z-test statistic) at the first interim analysis will be 
compared with the updated futility boundary.
A Haybittle-Peto stopping boundary will be used for efficacy interim and final EFS 
analyses (Peto et al 1976). At the second interim analysis, the observed p-value has to 
be less than p=0.0001 (i.e. HR<0.601) in order to conclude superior efficacy. If the 
study continues, the final analysis will be performed when approximately 285 EFS 
events have been documented or 5 years after the end of the study treatment for the 
last patient whichever occurs first. The final analysis criteria will be determined based 


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on the actual number of events observed such that the overall significance level across 
all analyses is maintained at 0.025. It is estimated that the observed hazard ratio (HR)
needs be less than 0.793 to declare statistical significance at the final EFS analysis.
The following table represents the operational characteristics of this design. These are 
based on simulations in the software package East version 6.4. The following are a few 
key operational characteristics: The cumulative probability to detect an efficacious 
treatment by the primary analysis is 90%; while the cumulative probability of 
erroneously detecting a non-efficacious treatment by the final analysis is 2.4%. If the 
null hypothesis is true then cumulative probability to stop the trial at the first interim 
analysis for lack of efficacy is 55.8%.
Hazard 
ratio
Analysis
Avera
ge 
sampl
e size
EFS 
(information 
fraction)
Average
Time
(months)
Simulated cum. Prob 
stop due to
Efficacy
Futility
0.675
IA 1
IA 2
FA
282
502
502
114 (40%)
223 (78%)
285 (100%)
11.9
20
38.8
0.0149*
0.1983
0.900
0.025
NA
NA
0.8375
IA1
IA2
FA
264
502
502
123 (43%)
240 (84%)
285 (100%)
11.3
20
31
0.0003*
0.009
0.312
0.213
NA
NA
1.0
IA1
IA2
FA
249
502
502
114 (40%)
255 (89%)
285 (100%)
10.8
20
26.5
0
0.0001
0.024
0.558
NA
NA
*Although the probability to stop for efficacy at IA1 is provided, there is no intent to stop 
for efficacy at IA1.
Overall Survival (OS):
OS is the key secondary endpoint. A hierarchical testing procedure will be adopted and 
analysis of OS will be performed only if the primary null hypothesis for EFS is rejected. 
The analysis of OS will be based on FAS following a separate group-sequential plan.
Two interim analyses and a final analysis for OS may be performed in this study. A 
Haybittle-Peto boundary (Peto et al 1976), independent of the Haybittle-Peto boundary 
used for EFS, along with the testing strategy outlined below will be used to maintain the 
overall type I error probability. Timing of two interim OS analyses will be at the same 
time as the second interim and final EFS analyses. The OS analysis will compare 
midostaurin+chemotherapy with placebo+chemotherapy (H02: θ2 ≥1 vs. Ha2: θ2 < 1 
Where θ2 is the hazard ratio (midostaurin treatment arm vs. placebo arm) of OS). The 
median OS in the control treatment arm is expected to be around 30 months. It is 
hypothesized that midostaurin treatment arm will result in a 28.6% reduction in the 
hazard rate for overall survival (corresponding to an increase in median survival by 12 
months (from 30 to to 42 months) under the exponential model assumption). If the true 
hazard ratio is 0.714, a total of 278 deaths are needed to be observed to have 80% 
power at an one-sided overall 2.5% level of significance to reject the null hypotheses 
(HR≥1) using a log-rank test and a 3-look group sequential design. Under the 
assumptions mentioned above, approximately 79 and 190 survival events (28% and 
68% information fraction respectively) are expected to occur at the time of the first and 
second interim OS analysis, respectively. The final analysis for OS will be conducted 
when 278 deaths have occurred.
It is estimated that these 278 deaths will be observed at approximately 64 months from 
the date of first patient to be randomized. 
The following table provides expected time at which interim and final analyses for EFS 
and OS will be performed.  These estimates are based on the assumptions used for 
determining the study design:


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Analysis
Expected 
number of 
randomized 
patients
Number of events
Expected 
time***
(month)
EFS
(information 
fraction)
OS**
(information 
fraction)
EFS First interim
283
114 (40%)
-
12
Second EFS 
interim/first OS 
interim
502
223 (78%)
79 (28%)
20
EFS final/Second 
OS interim
502
285 (100%)
190 (68%)
39
OS final
502
-
278 (100%)
64
** Analyses performed in case EFS is significant
*** Expected time after FPFV.
The interim analyses for EFS and the first interim analysis of OS will be performed by 
an independent statistician. 
Results from the EFS interim analysis will not be communicated to clinical team, the 
study steering committee (SC) or any party involved in the study conduct (apart from 
the independent statistician and independent data monitoring committee (DMC)
members) or external parties including Health Authority and investigators until EFS is 
found to be significant or study needs to be terminated due to safety or lack of efficacy. 
Unblinded results from the OS interim analysis will not be communicated to clinical 
team or any party involved in the study conduct (apart from the independent statistician 
and DMC members) or external parties, until OS is found to be significant or until the 
final OS analysis or the study needs to be terminated due to any cause.  Note that the 
DMC will also conduct regular safety looks which may include on-study deaths.
Other secondary endpoints:
Other secondary efficacy variables include CR or CRi with adequate blood count 
recovery rate, DFS, Cumulative Incidence of Relapse (CIR), and Cumulative Incidence 
of Death (CID). The assessment of these endpoints will be based on the IWG for AML 
(Cheson et al 2003, ELN 2017 / Döhner et al 2017), per investigator assessment. 
CR or CRi with adequate blood count recovery rates will be analyzed using Cochran-
Mantel-Haenszel test based on strata at randomization. Estimated CR or CRi with 
adequate blood count recovery rates along with corresponding 95% confidence 
intervals will be presented by treatment group.
Median DFS, Time to CR or CRi with adequate blood count recovery, Cumulative 
Incidence of Relapse (CIR) and Cumulative Incidence of Death (CID) along with 
corresponding 95% confidence intervals will be presented by treatment group.
The rate of CR or CRi with adequate blood count recovery and time to CR or CRi with 
adequate blood count recovery will be analyzed based on the FAS. However, DFS, 
Cumulative Incidence of Relapse (CIR) and Cumulative Incidence Death (CID) will be 
analyzed based on data from responders (CR or CRi with adequate blood count 
recovery) in the FAS. Assessment of relapse from CR or from CRi with adequate blood 
count recovery, DFS, Cumulative Incidence of Relapse (CIR), and Cumulative
Incidence of Death (CID) will not consider whether a patient received HSCT.
The median time to platelet and to neutrophil recovery along with their corresponding 
95% confidence intervals will be presented by treatment group.
In addition safety, pharmacokinetic, patient reported outcome (PRO) data will be 
analyzed.  For PRO, The FACT-Leu will be scored.  For each treatment group, 
calculated score and change from baseline will be analyzed.  Effects of treatment on 
overall HRQL will be assessed.  
Sample size
The assumption of median EFS of 12.0 months for the control treatment arm for sample 
size calculations is based on available data for patients with FLT-MN Hoenekopp
(Bacher et al 2008). It is expected that treatment with test treatment arm will result in a 


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37.5% reduction in the hazard rate (corresponding to an increase in median PFS from 
12.0 months to 17.8 months under the exponential model assumption. 
If the true hazard ratio is 0.675, a total of 285 EFS events are required to have 90% 
power at an one-sided overall 2.5% level of significance to reject the null hypothesis 
(HR=1) using a log-rank test and a 3-look group sequential design with Haybittle-Peto 
boundary to determine efficacy boundary and gamma spending function (γ = -1.2) to 
determine the non-binding futility boundary. Considering a recruitment period of 
approximately 20 months assuming an increasing recruitment rate to reach 30 patients 
/ month in month 6, 502 patients will need to be randomized to the two treatment arms 
in a 1:1 ratio. Assuming about 10% patients will be lost to follow-up for EFS, a total of 
502 patients will need to be randomized. Given the above assumptions, it is estimated 
that the 285th EFS event will be observed at approximately 39 months from the date of 
first patient randomized in the study. The sample size calculation was conducted with 
software package East 6.4.
For details of the statistical methods, please see section 10.
Key words
PKC412, midostaurin, cytarabine, daunorubicin, idarubicin, acute myeloid leukemia, 
FLT3-MN (SR<0.05), combination treatment, induction failure, event free survival, 
measurable residual disease.


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Amendment 1 (08-Jun-2018)
Amendment rationale
At the time of this protocol amendment, patients have not yet been enrolled in the trial.  
Due to the implementation of the Global Data Protection Regulation (GDPR) on 25-May-
2018, corresponding changes have been made to the ICF and protocol. 
Additional text has been added to the screening section in order to clarify that at sites that also 
participate in the CPKC412A2220 (A2220) trial (aiming at patients with FLT3 mutated AML), 
patients who are screened in the A2220 trial and confirmed to be FLT3 mutation negative 
(SR<0.05) may be offered the opportunity to join the E2301 trial provided they also meet all 
other inclusion criteria. As the majority of patients diagnosed with AML are FLT3 mutation 
negative, this will allow that a considerable number of patients, who have gone through 
complex screening procedures and who would remain without study treatment, can be offered 
the opportunity to be treated within the E2301 clinical trial.
Further text has been added to outline that blood will be taken to collect information on some 
enzyme activity (pharmacogenomic analysis) to understand how the drug is broken down, and 
to address a Regulatory Authority request.
Additional changes were implemented based on Health Authority recommendations. 
Changes to the protocol 
Minor typos and grammatical errors were updated throughout the protocol. 
1. List of Abbreviations updated. 
2. Glossary of terms: Updated ‘Personal data’ and ‘withdrawal of consent’ to coincide with 
GDPR guidelines.
3. All: Correction of typos and formatting to include Pgp to P-gp, 109/L to 109. Bone 
marrow samples ‘on’ day 21-28 changed to “between” day 21-28. Updated to CTCAE 
version 5.0.
4. Section 2.2.2: Analyses of OS updated ‘indicates’ to ‘suggests’.
5. Section 4.2.2: Updated timing for Study treatment interruption before HSCT.
6. Section 4.4: Clarified the time to End of study.
7. Section 4.5: Further defined early termination.
8. Section 5.3: Exclusion criterion #16 updated.
9. Section 5.3: Exclusion criterion #18 added ‘Known hypersensitivity to IMP’.
10. Section 6.1.1.1: Clarification on study drug characteristics.
11. Section 6.3.2 and Table 6.2: Clarified dose modifications.
12. Table 6.2: Dose modifications for idarubicin included.
13. Section 6.4.2: Permitted Concomitant medication updated. 
14. Table 7.1 and Table 7.6: Cytogenetics updated to reflect new AML testing guidelines.
15. Table 7.1: Update 30 day follow up assessments.


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16. Section 7.1.2: Screening section updated to capture inclusion of A2220 FLT3 mutation 
negative patients and to clarify the sample collection and timing of AML diagnosis. 
17. Section 7.1.2.2: Clarification on FLT3 data collection. 
18. Section 7.1.3: Updated duration of each cycle length. 
19. Section 7.1.5: Withdrawal of consent updated to align with GDPR.
20. Section 7.2.2.1: Physical exam definition updated.  
21. Section 7.2.2.5 and 11.3: Fertility information updated.
23. Section 7.2.4 and Table 7.11: Biomarker tests clarified. 
24. Section 10.5.2.2: MRD negative status updated.
25. Section 10.5.4 and Table 10-1: Updated pharmacokinetics and PK parameters. 
26. References: Addition of ‘Thiede et al 2002’ citation.
27. Appendix 1: Prohibited concomitant medication updated for clarity.  
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Acute myeloid leukemia (AML) is one of the most common types of leukemia in adults. It is a 
heterogeneous disease that is characterized by the presence of acquired mutations as well as 
cytogenetic and epigenetic alterations that influence disease prognosis. Risk stratification in 
AML is evolving as a consequence of characterizing cytogenetic abnormalities and mutational 
profiling, and the latter is especially important in patients lacking karyotypic abnormalities 
(Döhner et al 2017).
Currently, the most generally recognized approach to classifying AML and predicting its 
prognosis considers the (co)occurrence of specific cytogenetic abnormalities together with 
mutations such as NPM1, FLT3-ITD and CEBPA. However other mutations such as 
DNMT3A and TP53 are also increasingly recognized to impact clinical outcome 
(Papaemmanuil et al 2016; Arber et al 2016). The European LeukemiaNet (ELN) guidelines 
have provided updated recommendations for prognostic determination (Döhner et al 2017). 
Favorable prognosis AML includes that with FLT3-ITDlow allelic ratio or FLT3-ITD-negative 
genotype combined with a NPM1-mutation, or the presence of core binding factor (CBF) 
alterations. Adverse prognosis is associated with karyotypes such as monosomy 5 or 
monosomy 7, NPM1-WT genotype with FLT3-ITDhigh allelic ratio, or the t(6;9) or t(9;22) 
translocations, among others. The remainder is classified as intermediate risk disease. For the 
complete ELN risk groups including all genetic and genomic risk markers please refer to the 
2017 guidelines (Döhner et al 2017).
Approximately 30% of patients with newly diagnosed AML have an activating mutation in 
the FLT3 gene, usually either an ITD mutation, in approximately 20% of AML patients, or an 
activating point mutation in the activating loop of the TKD, approximately 6-8% of AML 
patients) (Kayser and Levis 2014); rarely, both occur in the same leukemia. The FLT3 gene 
encodes a protein in the class III tyrosine kinase receptor family, and it serves a key role in the 
proliferation and differentiation of normal hematopoietic progenitor cells. FLT3-ITD 
mutations, particularly when they are present at a high allelic ratio relative to FLT3-MN 
(FLT3-wildype), are associated with poor prognosis (Kottaridis et al 2001, Bacher et al 2008, 
Thiede et al 2002, Pratcorona et al 2013). In patients with newly diagnosed AML, the 
complete remission (CR) rates in patients with FLT3 mutations are generally similar, or only 
slightly lower, than in those without FLT3 mutations. However, FLT3-ITD mutations have 
been shown to be associated with inferior DFS and OS, with a higher risk of relapse 
(Kottaridis et al 2001, Bacher et al 2008, Thiede et al 2002). The prognostic significance of 
the FLT3-TKD mutation has not been consistent in reports.
Initial therapy for AML in younger patients (<60 years) to induce remission has changed little 
in the past three decades, and for patients with an adequate performance status it frequently 
comprises the “7 + 3” remission induction regimen with daunorubicin and cytarabine, 
followed by high dose cytarabine for remission consolidation. The 5-year survival rate with 


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this approach is 30 to 40% in patients under the age of 60 years, and less than 15% in older 
patients (Stone et al 2005).
Patients with poor prognostic features of AML are recommended to enroll into clinical trials 
and/or to undergo HSCT following achievement of remission with standard induction 
chemotherapy (Schiller 2014). Significant improvements in OS and DFS for AML patients 
harboring FLT3-ITD mutations have been reported with allo-HSCT compared to 
chemotherapy or autologous HSCT (DeZern et al 2011, Brunet et al 2013), especially for 
patients with high FLT3-ITD allelic ratios (Schlenk et al 2014). However, these patients 
remain at high risk of relapse post-HSCT compared to patients without FLT3-ITD mutations, 
with a higher 2-year relapse incidence (30% vs 16%; p=0.006) and lower leukemia free 
survival (58% vs 71%; p=0.04), respectively (Brunet et al 2012).
The ability to delay or prevent relapses in transplant candidates who experience complete 
remission could allow more eligible patients to undergo a HSCT. This benefit of a longer time 
window in remission would particularly apply to those patients who require an unrelated 
donor, because 3 to 6 months is generally required for the donor search alone. In addition, 
midostaurin may reduce the rate of relapses after HSCT. Overall, these effects may contribute 
to a longer EFS and OS. In AML patients with mutated FLT3 the interim analysis of a study 
that investigates the safety and efficacy of post-transplant treatment with midostaurin suggest 
an improved EFS when comparing with historical controls. 
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of Midostaurin
Midostaurin (Rydapt®, PKC412, CGP41251) is an orally bioavailable staurosporine analog 
with potent activity against both ITD- and TKD-mutant as well as against FLT3-MN, and 
these observations informed the decision to pursue its development in patients with FLT3-
mutated AML. In addition, it inhibits other molecular targets including several isoforms of 
protein kinase C, KIT, vascular endothelial growth factor receptor (VEGFR-2), platelet-
derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and 
multi-drug resistance gene products, which are thought to be important for the pathogenesis of 
AML or its sensitivity to standard therapies. Furthermore, midostaurin inhibits kinases with 
mutations that confer resistance to other tyrosine kinase inhibitors such as imatinib.
The anti-proliferative effects of midostaurin were demonstrated in in vitro assays with cells 
expressing FLT3-ITD or FLT3-TKD mutations (Weisberg et al 2002). Synergistic inhibitory 
activity of midostaurin in combination with daunorubicin or cytarabine was observed in AML 
patient cell lines. Moreover, a related FLT3 inhibitor provided enhanced but sequence 
dependent cell cytotoxicity when administered simultaneously with or immediately following 
cytarabine, and the combinatorial activity of the FLT3 inhibitor with daunorubicin was also 
demonstrated (Levis et al 2004).
The potential clinical activity of midostaurin in patients with FLT3-Wildtype AML is 
supported by enzymatic and cell-based studies. Midostaurin potently inhibits the activity of 
the purified FLT3-MN tyrosine kinase with an IC50 of 19.8 nM, and it binds to the purified 


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FLT3-MN kinase with a dissociation constant of 11 nM. Midostaurin inhibits the proliferation 
of the M07e leukemia cell line (FLT3-MN) with an IC50 of 183 16 nM (Novartis internal 
data). Moreover, midostaurin inhibits protein tyrosine phosphorylation of FLT3-MN-
expressing Ba/F3 hematopoietic cells stimulated with FLT-ligand at midostaurin doses in the 
range of 0.01-1 µM (Weisberg et al 2002).
1.2.1.1
Non-clinical experience 
Pharmacokinetics and drug metabolism in animals
The oral absorption of [14C]midostaurin in all species was moderate to high, and the 
bioavailability was low to moderate. Given midostaurin’s low aqueous solubility (<0.001 
mg/mL) and its high absorption in human (>90%), midostaurin is classified as a 
Biopharmaceutics classification system (BCS) II drug. In rats, dogs and rabbits, the total 
systemic plasma clearance (0.24 - 0.98 L/h/kg) and the volume of distribution at steady state 
(1.20 - 3.77 L/kg) were moderate. The half-life was relatively short in animals (3.2-7.3 h). In 
human the apparent terminal half-life was relatively long (~20 h) following a single oral dose.
Radioactivity derived from [14C]midostaurin was extensively distributed into tissues in the rat. 
The concentrations in most tissues were higher than that in blood. Radioactivity crossed the 
blood brain barrier. After multiple doses, the radioactivity in tissues was 2-10-fold higher than 
that after a single dose. [14C]midostaurin showed a high protein binding in the rat, dog and 
human (>98-99%). The protein binding was independent of concentration in animals. In 
human, a concentration dependent increase in fraction unbound was observed over a 
concentration range of 100-20,000 ng/mL. The two major metabolites of midostaurin, 
[14C]CGP52421 and [3H]CGP62221, showed a similar plasma protein binding to midostaurin.
Midostaurin was extensively metabolized in the rat, dog, rabbit and human. The primary 
biotransformation pathways observed included hydroxylation, O-demethylation, N-
demethylation and amide hydrolysis. The major circulating components were midostaurin and 
CGP52421 (two epimers) in all species. CGP62221 (the O-demethylation product) was also a 
major human circulating metabolite and detectable in the dog and rabbit. The total recovery of 
radioactivity was high in the rat, rabbit, dog and human (81.5% - 99.4%). In all these species, 
radioactivity was mainly excreted via fecal excretion. Renal excretion was apparently very 
minor (<4%).
Based on recombinant enzymes and human liver microsomes, the CYP3A4 is the major 
enzyme involved in midostaurin oxidative metabolism. Midostaurin, CGP52421 and 
CGP62221 were found to inhibit the following cytochromes in-vitro: CYP1A2, CYP2B6, 
CYP2C8, CYP2C9, CYP2D6, CYP2E1 and CYP3A4. It also induces the following 
cytochromes: CYP1A2, CYP2C8, CYP2C9, CYP2B6 and CYP3A4. The results of the net 
effect model suggest that an impact of midostaurin and/or CGP52421 and CGP62221 is 
expected on the following CYP: CYP3A4, CYP2C8 and CYP2B6. 
In vitro experiments demonstrated as well that midostaurin, CGP52421 and CPG62221 can 
potentially inhibit P-glycoprotein (P-gp) inhibitor with an IC50 value of 1.7 M, breast cancer 
resistant protein (BCRP) (IC50=0.23 M) and OATP1B1 (IC50=1.25 M). Thus, its 
concomitant use with P-gp, BCRP or OATP1B1 substrates could lead to clinical drug-drug 


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interactions. Midostaurin drug transport inhibition experiments indicated that midostaurin is 
not likely to be a substrate of P-gp, multi-drug resistance associated protein 2 (MRP2), and is 
not actively taken up into the liver.
Preclinical toxicology
Midostaurin has been extensively evaluated in various in vitro systems and in vivo models. 
Studies relevant to clinical dosing of midostaurin include repeat dose toxicology studies with 
durations of up to 52 weeks, genetic toxicology, reproductive and developmental toxicity, 
juvenile toxicity and safety pharmacology studies. Additional toxicology studies have been 
performed with the combination of midostaurin and daunorubicin/cytarabine. No 
carcinogenicity studies have been performed.
Overall, the effects of treatment with midostaurin observed in the toxicology studies have 
been essentially limited to those expected from an inhibitor of cell proliferation. The no 
observable effect level (NOEL) in the 12-month toxicity studies was 3 mg/kg in rat and 1 
mg/kg in dog. In-vitro and in-vivo mutagenicity tests revealed no genotoxicity. There was no 
teratogenic effect noted from embryo-fetal development studies in rats and rabbits. 
Developmental toxicity was seen at 10 mg/kg or higher. NOEL for fertility and general 
reproductive toxicity was defined at 30 mg/kg.
Treatment with midostaurin at doses ≥3 mg/kg in dogs and ≥10 mg/kg in rats at durations up 
to 12 months was associated with effects on proliferating tissues, especially the intestine 
(mucosal alteration), testes (degenerated spermatogonia), and bone marrow (hypocellularity). 
The effect on the bone marrow was accompanied by hematological changes (decreased total 
white cells, lymphocytes and erythrocytic parameters).
Please, refer to the Investigators Brochure for additional information.
1.2.1.2
Clinical experience
Clinical pharmacokinetics
PK characteristics
Midostaurin is a BCL class II compound with good absorption and poor solubility. Two of its 
metabolites demonstrated pharmacological activities (CGP52421 and CGP62221). Following 
multiple doses, the PK of midostaurin and CGP62221 was time-dependent with an initial 
increase observed the first week followed by a decline of concentrations until reaching a 
steady-state on D28. CGP52421 concentrations do not appear to decline significantly as for 
midostaurin and CGP62221. Midostaurin is rapidly absorbed after oral administration, with 
peak plasma concentrations observed at 1-3 hours post dose. Midostaurin has an apparent 
volume of distribution of 95 L and is highly bound to protein, including albumin, alpha-
glycoprotein and lipoprotein, with a free fraction of about 2%. 
Midostaurin is predominantly metabolized by CYP3A4 into two major active circulating 
metabolites, CGP62221 (via O-demethylation) and CGP52421 (via hydroxylation). The major 
circulating components in plasma are CGP52421, CGP62221 and midostaurin, accounting for 
38, 28, and 22% of area under the curve AUC0-168h, respectively. The compound related 
materials are mainly distributed to plasma, and minimally to red blood cells. The median 


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terminal half-lives of midostaurin-, CGP62221 and CGP52421 in plasma are approximately 
20.5, 32.3 and 471 hours, respectively. The midostaurin mean apparent plasma clearance 
(CL/F) was 2.4-3.1 L/h in healthy subjects. In AML and advanced systemic mastocytosis (SM)
patients, popPK estimates for clearance of midostaurin at steady-state was 5.9 L/h and 4.4 L/h, 
respectively. The Human Mass Balance study results indicated that faecal excretion is the 
major route of excretion (78% of the dose), and mostly as metabolites (73% of the dose), 
while unchanged midostaurin accounts for 3% of the dose. Only 4% of the dose is recovered 
in urine.
Drug-drug interactions
Strong CYP3A4 inhibitors 
Overall, strong CYP3A4 inhibitors increase exposure of midostaurin. The potential impact of
these agents on the pharmacokinetics of midostaurin was assessed across the midostaurin 
clinical program since many of these agents are commonly used as standard of care antifungal 
prophylaxis in patients with AML.
In the Phase 3 study A2301, a high proportion of patients received a strong CYP3A4 inhibitor 
mostly during induction chemotherapy (62%), and using routine antifungal prophylaxis. 
Patients receiving concomitant strong CYP3A4 inhibitors had 1.44-fold higher exposure to 
midostaurin compared to patients not receiving strong CYP3A4 Inhibitors. However, 
increases in midostaurin exposure following co-administration of strong CYP3A4 inhibitors 
were off-set by reductions in exposure to the active metabolites, resulting in relatively small 
changes in the exposure to the sum of active moieties at steady state, consisting of 1.22 fold 
higher exposure in patients receiving strong CYP3A4 inhibitors. Analysis of the grade 3-4 
AEs demonstrated that although differences were noted between patients treated with strong 
CYP3A4 inhibitors compared to those without, there was no definite pattern. For example, for 
patients treated with strong CYP3A4 inhibitors, a slightly higher incidence of sepsis and 
febrile neutropenia was observed; yet patients who did not receive strong CYP3A4 inhibitors 
had a slightly higher incidence of neutropenic infection Nevertheless, different approaches 
were taken to further assess the impact of strong CYP3A4 inhibitors on the PK of midostaurin. 
In a pooled analysis across advanced systemic mastocytosis (AdSM) and AML patients 
receiving midostaurin as single –agent therapy, there was maximum of 2.7-fold increase of 
midostaurin exposure (Cmin) at steady state upon co-administration with strong CYP3A4 
inhibitors. When exposure to the sum of active moieties was compared, the geometric mean 
Cmin increased by 76% upon co -administration with CYP3A4 inhibitors. In Study A2104E2, 
AML patients who were concomitantly administered the strong CYP3A4 inhibitor 
itraconazole (n=7) with midostaurin 50 mg (twice daily) in the combination arm had a 2.09 -
fold increase in midostaurin Cmin at steady state compared to when they received midostaurin 
50 mg twice daily alone, CGP52421, CGP62221 and the sum of the active moieties were 
increased by 16%, 33% and 18% respectively. A similar finding was confirmed through 
popPK analysis for AML patients.
Of note, in the Phase III Study A2301, no dose-reduction of midostaurin/placebo was 
recommended with concomitant strong CYP3A4 inhibitors. Based on these data, no dose 
adjustment is required when midostaurin is co-administered with CYP3A4 inhibitors. 
However, caution should be advised when administering medicinal products that are strong 


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inhibitors of CYP3A4 concomitantly with midostaurin, and alternative therapeutics that do 
not strongly inhibit CYP3A4 activity should be considered. In situations where satisfactory
therapeutic alternatives do not exist -for example with the use of routine antifungal
prophylaxis with azole antifungals during induction/consolidation chemotherapy for AML, 
patients should be closely monitored due to the potential for increase in exposure.
Strong CYP3A4 inducers: In the healthy volunteer study A2110, midostaurin concentrations 
decreased by approximately 10-fold (90% decrease) when co-administered with rifampicin, a 
CYP3A4 inducer. In the single-agent midostaurin studies D2201, A2213 and A2104E1, there 
were no difference in plasma Cmin between patients who received CYP3A4 inducers and 
those who did not for any of the active moieties or sum of active moieties. Of note, none of 
the patients were administered a strong CYP3A4 inducers at least 7 days prior to a PK sample.
Therefore, concomitant administration of medicinal products that are strong inducers of 
CYP3A4 with midostaurin should be avoided, and alternative therapeutics that do not strongly 
induce CYP3A4 should be considered.
CYP3A4 induction related to midostaurin administration: The PK of a single dose of 
midazolam (sensitive CYP3A4 probe substrate) was not affected in a clinically meaningful 
manner following four dosing days of midostaurin administration in healthy subjects (Study 
A2112). The geomean Cmax and AUCinf of midazolam decreased by 9% and 5%, 
respectively. However, it cannot be excluded that midostaurin may be an inducer of CYP3A4, 
as the dose of midazolam was administered only after four dosing days of midostaurin and not 
at steady state. Based on a physiologically-based PK analysis, the simulated results indicate 
that the midazolam geometric mean ratio of AUC could be reduced by 25% at steady-state 
levels of midostaurin, as compared to the value observed in Study A2112 (Day 8).
Medicinal products with a narrow therapeutic range that are CYP3A4 substrates should be
used with caution when administered concomitantly with midostaurin, and may need dose
adjustment to maintain optimal exposure.
Clinical efficacy in AML
Irrespective of activating mutations of FLT3 which are present in 30%, FLT3 is constitutively 
overexpressed in 70% or more of AML patients. As detailed in section 1.2.1 the potential 
clinical activity of midostaurin in patients with FLT3-MN AML is supported by enzymatic 
and cell-based studies (Weisberg et al 2002). Accordingly, some of the early clinical trials 
with midostaurin in AML included not only patients with FLT3 mutated AML but also 
patients with FLT3-MN AML.
The [CPKC412A2104-E1] phase II trial evaluated midostaurin (single agent) in patients with 
AML or high-risk MDS with either FLT3-mutated or FLT3-MN disease. Among the 57 
patients with FLT3-MN disease who were enrolled and were evaluable for efficacy, the best 
response was MR in nine (15.8%) patients, and blast reduction (with or without MR) was 
observed in 23 (40.4%) patients. The results overall indicated evidence of clinical activity and 
also supported the evaluation of midostaurin in combination with standard chemotherapy in 
patients with previously untreated AML. In the [CPKC412A2104-E2] phase II trial in the 
same patient population, midostaurin was either dose escalated or combined with itraconazole 
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Of note, one patient in the [CPKC412A2104-E2] trial with FLT3-MN AML who was enrolled 
in the midostaurin+itraconazole arm obtained a minor response with blast reduction from Day 
8 to Day 205, PR on Day 261, and obtained a CR on Day 324. The duration of response was 
1320 days. Both midostaurin and itraconazole were administered until Day 1362, and the 
patient subsequently discontinued the study due to unsatisfactory therapeutic effect. 
The [CPKC412A2106] phase IB trial evaluated midostaurin administered sequentially or 
concomitantly with daunorubicin and cytarabine in 69 patients with AML. Among patients 
treated at 50 mg twice daily, 11/13 (84.6%) patients with FLT3 mutation positive AML and 
16/27 (59.3%) patients with FLT3-MN AML obtained a CR. The median time to CR was 
similar in FLT3-mutated and FLT3-MN patients Kaplan–Meier OS probabilities at 1 and 2 
years, respectively, were 0.85 (95% CI: 0.65–1.0) and 0.62 (95% CI: 0.35–0.88) in patients 
with FLT3-mutated AML, and 0.78 (95% CI: 0.62–0.93) and 0.52 (96% CI: 0.33–0.71) in 
patients with FLT3–WT AML. Kaplan–Meier DFS probabilities at 1 year for FLT3-mutated
and FLT3–WT patients were 0.50 (95% CI: 0.22–0.78) and 0.60 (95% CI: 0.39–0.81), 
respectively. 
The Cancer and Leukemia Group B10603 (CALGB10603) ([CPKC412A2301], RATIFY) 
trial, hereafter referred to as Study [A2301], enrolled patients in North America and Europe < 
60 years of age with newly diagnosed FLT3-mutated acute myeloid leukemia (AML), 
Midostaurin combined with standard induction and consolidation therapy following by single 
agent midostaurin continuation was compared to placebo plus chemotherapy. Study [A2301]
is a randomized, double-blind, multi-center, placebo-controlled Phase III study conducted in 
717 in patients with newly diagnosed FLT3 mutation positive (ITD or TKD) AML according 
to WHO criteria. The primary efficacy endpoint was OS non-censored at the time of HSCT, 
and the key secondary endpoint was EFS non-censored at the time of HSCT. The study met 
its primary endpoint; a significant improvement in OS was demonstrated with a HR of 0.77 
(95% CI: 0.629, 0.953), corresponding to a 23% reduction in risk of death in favor of the 
midostaurin arm. The result was statistically significant with a p-value of 0.0078 at a one-
sided alpha of 0.0239. Because the OS primary analysis was statistically significant, the key 
secondary endpoint EFS was tested in a confirmatory setting. The median EFS was 8.2 
months for patients in the midostaurin arm compared to 3.0 months for patients in the placebo 
arm (HR=0.78; 95% CI 0.662, 0.930); this was statistically significant (p=0.0024) at a one-
sided alpha level of 0.025. Subgroup analysis demonstrated that the benefit in OS and EFS 
was of similar magnitude for FLT3 ITD mutated patients with low allelic ratio (allelic ratio 
AR < 0.7) compared to high allelic ratio (> 0.7). In addition the OS & EFS benefit for FLT3 
TKD mutated patients, who have disease prognosis closer to wild type patients also showed a 
similar benefit compared to FLT3 ITD with AR > 0.7, suggesting that the observed treatment 
benefit may not only be driven by the action on the FLT3 mutated AML clones but 
midostaurin may have activities on FLT3 WT AML.
Based on data from the [A2301] study, midostaurin has been approved by US food and drug 
administration (FDA) for the treatment of patients with newly diagnosed FLT3 mutated AML, 
in combination with standard cytarabine and daunorubicin induction and cytarabine 
consolidation.
The multi-kinase inhibitor sorafenib inhibits FLT3 and other kinases. In a phase III evaluation 
of sorafenib versus placebo added to standard chemotherapy in patients with newly diagnosed 


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AML, patients with either FLT3-MN or FLT3-mutated AML were enrolled. Although full 
quantitative information about mutation subgroups has not been presented publicly, an 
analysis in which patients with FLT3-ITD mutations were excluded showed that increases in 
EFS and RFS remained statistically significant; however, an analysis of patients with FLT3-
MN disease was not reported (Röllig et al 2015). These data suggest that multikinase 
inhibition may be useful in AML more broadly and not just among patients with FLT3-
mutated AML.
Summary of safety in clinical studies
Midostaurin has been extensively studied in both oncology and non-oncology indications as 
well as in a large number of healthy volunteers over the past two decades. Taken together, 
midostaurin has been evaluated in an extensive clinical program including more than 1800 
subjects, including one large, placebo-controlled study of midostaurin in combination with 
chemotherapy in FLT3-mutated AML, two Phase 2 studies in advanced SM, nine Phase 1-2 
studies conducted in various indications, and 11 clinical pharmacology studies
The safety profile of midostaurin is well characterized, with predictable, primary 
gastrointestinal (nausea, vomiting) events and cytopenias that are generally manageable with 
the use of anti-emetic therapy and dose adjustment/temporary interruption. 
The largest portion of the midostaurin clinical safety experience has been in two indications:

As a single agent in patients with AdSM [formerly aggressive systemic mastocytosis 
(ASM) or mast cell leukemia (MCL) with or without an associated hematologic non-mast 
cell lineage disorder (AHNMD)]

In combination with standard chemotherapy in patients with newly diagnosed FLT3-
mutated AML
When administered to AML patients in combination with standard “7+3” chemotherapy in the 
pivotal phase III [A2301] trial, most of the AEs, AEs suspected to be related to study drug, 
serious adverse events (SAEs) and AEs leading to discontinuation occurred at similar 
frequencies in both midostaurin and placebo control groups. The most frequent adverse events 
reported in the combination setting included predominantly cytopenias (thrombocytopenia, 
anemia, neutropenia) and gastrointestinal events (nausea, vomiting) compared with patients 
receiving midostaurin monotherapy, as expected from the known toxicities of the backbone 
“7+3” chemotherapy regimen.
In Study [A2301], the safety profile (overall) for both the midostaurin and placebo groups was 
consistent. The median duration of exposure to midostaurin and placebo was 42.0 days (range
2-576 days) and 34.0 days (range 1-465 days), respectively. As expected, the most frequent 
grade 3/4 AEs in both groups were related to myelosuppression (neutropenia, anemia, 
thrombocytopenia, febrile neutropenia) and occurred in nearly all patients during the 
induction/consolidation phases. The addition of midostaurin did not prolong the time to 
platelet or neutrophil recovery in the induction and consolidation phases.
The most frequent non-hematologic grade 3/4 AEs in the midostaurin group were infections 
(device-related), diarrhea, and exfoliative dermatitis; and for the placebo arm, hypokalemia, 
diarrhea, and pneumonia. AEs were generally balanced between the two arms, with the 
exception of exfoliative dermatitis and transaminase elevations, which occurred more 


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frequently in midostaurin-treated patients. Please refer to the Investigators Brochure for 
additional information.
2
Rationale
2.1
Study rationale and purpose
The available preclinical and clinical evidence suggesting a potential clinical activity of 
midostaurin in patients with FLT3-MN AML is summarized in Section 1.2.
A [A2301] subgroup analysis compared the benefit in OS and EFS in patients with different 
ratios of FLT3-mutated and FLT3-MN (allelic ratio). This subgroup analysis demonstrated 
that the benefit in OS and EFS was of similar magnitude for FLT3 ITD mutated patients with 
low allelic ratio (AR < 0.7 and AR < 0.5) compared to high allelic ratio (≥0.7). In addition 
the OS and EFS benefit for FLT3 TKD mutated patients, who have disease prognosis closer to 
wild type patients also showed a similar benefit compared to FLT3 ITD with AR ≥0.7, 
suggesting that the observed treatment benefit may not be driven by FLT3-inhibition alone
but could be driven by other factors, such as the inhibition of the tyrosine-kinase activity of 
overexpressed FLT3-MN. Midostaurin is an ATP-competitive inhibitor of multiple kinases 
including FLT3, KIT, protein kinase C, VEGFR, PDGFR and FGFR. These are molecular
targets implicated in the pathogenesis of AML and a variety of other diseases. The relative 
contribution to efficacy of the different mechanisms of action of midostaurin is currently not 
fully understood.
The efficacy of currently available treatments is dissatisfying in both, AML with FLT3-
mutated as well as FLT3-MN AML. Despite multiple attempts, little improvement of the 
available therapy for AML was achieved during several decades of preclinical and clinical 
research. Approximately 35% to 40% of patients younger than 60 years of age may obtain 
long-term survival with current forms of treatment. However, there is a wide variation in 
outcome among genetically distinguishable subsets of the disease, with some subtypes having 
a notoriously poor outcome such as patients with genetic abnormalities that indicate adverse 
prognosis like monosomies, complex cytogenetic abnormalities, p53 mutations, RUNX1 
mutations, ASXL1 mutations and others. Also, in older patients, the overall prognosis has 
remained highly unsatisfactory. E.g. a clinical study of intensive chemotherapy in 998 older 
patients with a median age of 71 years (range, 65–89 years) demonstrated a CR rate of 45%, a 
death rate in induction of 29% and a median survival of 5.4 months. The 1- and 2-year 
survival rates were 30% and 16%, respectively (Kantarjian et al 2006).  Thus; there is an 
urgent unmet need for therapeutic improvements. 
This study is designed to confirm the preliminary evidence from early clinical trials that 
midostaurin may provide clinical benefit not only to AML patients with the FLT3-mutation 
but also in FLT3-MN (SR<0.05) AML. If midostaurin is active in this subgroup, patients 
could derive clinical benefit in multiple ways. For example, a higher CR rate or a longer 
remission time that would widen the time window to search for an allogeneic HSCT donor or 
midostaurin may prolong the time in remission and overall survival in patients with and 
without HSCT. This study will also allow an increase in the preliminary understanding of the 


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prognostic potential of MRD assessments during treatment and follow-up and may contribute 
to the standardization of the required assays.
2.2
Rationale for the study design
The efficacy of midostaurin at a dose of 50 mg twice daily in combination with the 7+3 
chemotherapy regimen for induction and with intermediate-dose cytarabine for consolidation 
will be evaluated in a 1:1 randomized double-blind study using placebo plus chemotherapy as 
a comparator. The justification for randomization is that it will provide the most robust 
assessment of safety and efficacy of midostaurin in this patient population when used in 
combination with frequently used standard chemotherapy regimens. Randomization will be 
stratified according to age (<60 vs. 60 years).
After completion of consolidation therapy or after allogeneic HSCT, patients will receive 
post-consolidation therapy with midostaurin/placebo alone for twelve 28-day cycles. 
2.2.1
Midostaurin post-consolidation therapy in AML: disease 
considerations
The incorporation of post-consolidation therapy in the study is based on high incidence of 
relapse after the completion of induction and consolidation chemotherapy. Additionally, in the 
[A2301] study, there was a trend for a reduction in the rate of relapses during the maintenance 
phase, followed by a peak of early relapse observed among patients who discontinued or 
completed 12 cycles of midostaurin continuation therapy [A2301] (see Section 2.4, below). 
This observation is consistent with the mechanistic observation that midostaurin, effective at 
blast reduction in the relapsed refractory setting, may play a role, through its blast reduction 
of preventing the reappearance of clinical disease after the completion of consolidation 
treatment with intensive induction chemotherapy. The selection of a 12-month period of 
midostaurin/placebo post-consolidation was deemed appropriate based on the considerable 
risk of relapse during this period even among patients who remained in CR through the 
induction and consolidation treatment phases. The 12-month duration is also consistent with 
the safety experience with single-agent midostaurin. 
In summary, patients who still have measurable residual disease experience rapid relapse once 
chemotherapy is completed. Thus, the continued administration of an oral, non-cytotoxic drug 
such as midostaurin after completion of chemotherapy might continue to inhibit the outgrowth 
or even eliminate residual leukemic blasts that are present at the end of a routine course of 
chemotherapy, potentially prolonging DFS. The observation of anti-leukemic activity when 
midostaurin was used as a single agent in patients with relapsed/refractory FLT3-mutated and 
FLT3-MN AML provided a supporting rationale.
2.2.2
Benefit of midostaurin post-consolidation therapy
Data from Study [A2301] in patients with FLT3-mutated AML suggest that single agent post-
consolidation therapy for 12 cycles was an important factor in the overall success of the study.
However, A2301 evaluated patients with AML with FLT3 mutations and the results of 2301 
cannot be extrapolated to AML with FLT3-MN (SR<0.05). 
The results of MRD 
measurements during the post-consolidation phase of Study [E2301] may support the 


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hypothesis that post-consolidation treatment with midostaurin in AML with FLT3-MN 
(SR<0.05) is effective as well.
In A2301, the analysis of OS (non-censored for HSCT) from the start of the post-
consolidation phase shows a survival benefit for patients treated with midostaurin compared 
to placebo (HR=0.802, 95% CI: 0.504, 1.276). This analysis included 205 patients (120 
patients in the midostaurin arm, and 85 patients in the placebo arms). A comparison of 
baseline demographic and disease characteristics for these patients did not identify any 
imbalance between the midostaurin and placebo groups that would have influenced the OS 
assessment. Of note, the study was not sufficiently powered to test for statistical significance
[AML Summary of Clinical Efficacy-Section 3.2.5].
The OS Kaplan-Meier curves show clear separation between midostaurin and placebo during 
the first 18 months after start of post-consolidation, before getting closer together. This is 
consistent with the data below for DFS, which suggest a protective effect during the 12 
months of midostaurin post-consolidation therapy.
To determine the treatment benefit whilst on post-consolidation therapy, DFS was analyzed 
for the subset of patients who entered the post-consolidation phase in CR (194 patients; 115 in 
the midostaurin arm and 79 in the placebo arm). Patients were censored at the end of the 12-
month post-consolidation phase. In this analysis, the HR was 0.714 (95% CI 0.430, 1.184), 
showing benefit for midostaurin post-consolidation therapy over placebo.
Taken together, the analyses of OS from the start of post-consolidation and DFS during post-
consolidation are consistent, and suggest a treatment benefit of post-consolidation therapy. Of 
note, the observations above do not follow a secondary randomization and rely on few events, 
so conclusions must be drawn cautiously.
2.2.2.1
Safety and tolerability of midostaurin post-consolidation therapy
When the post-consolidation phase (single agent midostaurin or placebo) was assessed 
separately, a difference in the type and severity of adverse drug reactions (ADRs) was 
observed compared to the phases of combined treatment with chemotherapy i.e. induction and 
consolidation phase. The overall incidence of ADRs during the post-consolidation phase was 
generally lower. ADR during the post-consolidation phase with at least ≥5% difference 
between the midostaurin and placebo arms were: nausea (46.4% vs 17.9%), hyperglycaemia 
(20.2% vs 12.5%), vomiting (19% vs 5.4%) and lymphopenia (16.7% vs 8.9%). Most of the 
hematological abnormalities reported occurred during the induction and consolidation phase 
when the patients received midostaurin or placebo in combination with chemotherapy. The 
most frequent grade 3/4 hematological abnormalities reported in patients during the post-
consolidation phase with midostaurin and placebo respectively were absolute neutrophil count 
decrease (20.8% vs 18.9%) and leukopenia (7.5% vs 5.9%). Overall, ADRs reported during 
the post-consolidation phase were of mild to moderate intensity and led to very few 
discontinuations (8.1% for midostaurin arm and 5.4% for placebo arm). The median duration 
of exposure in the post-consolidation phase was the same in both treatment groups (336 days) 
[Study A2301-Table 12-2], demonstrating the tolerability of midostaurin monotherapy 
following chemotherapy for previously untreated AML. 


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2.3
Rationale for dose and regimen selection
The recommended dose of midostaurin 50 mg twice daily combined sequentially with
intensive standard chemotherapy for AML was established in the clinical trials described in
Section 2.4.
The currently approved midostaurin dosing regimen in FLT3 positive AML patients during 
the induction/consolidation cycles is 50 mg twice daily at day 8 – 21, i.e., the midostaurin 
regimen that was evaluated in [A2301]. In E2301, midostaurin will be dosed at 50 mg twice 
daily from day 8 to 48h prior to the first day of the subsequent cycle of chemotherapy. The 
reasons for this change are detailed below. 
An exposure-response analysis of the pivotal study [A2301] showed a positive relationship of 
dose intensity of midostaurin with efficacy endpoints including complete response rates in 
cycle 1, EFS and OS. Although a modest increase of the probability of grade 3/4 clinically 
notable adverse events was observed there was no relationship between an increased 
midostaurin exposure with the frequency of study drug discontinuation. Hence a higher 
exposure with midostaurin was associated with an increased efficacy as measured with 
clinically relevant endpoints but not at the expense of a clinically concerning increase of 
adverse events. No association of the plasma exposures of midostaurin, the pharmacologic 
active metabolites CGP62221 and CGP52421 with the duration of neutropenia was found. 
Most importantly an increased exposure with the active metabolite CGP62221 was associated 
with an increased survival. Further considering that CGP62221 is a stronger inhibitor of 
mutated as opposed to wild type FLT3 a higher exposure with midostaurin in AML without 
FLT3 mutation is expected to be clinically beneficial in this indication. 
The proposed longer midostaurin dosing regimen is being used in study ADE02 (newly 
diagnosed AML with FLT3 mutation). The analysis of interim ADE02 results from the first 
245 patients enrolled (median age: 53.6 years old, range 20 – 69) showed that an increased 
dose intensity of midostaurin can be safely achieved by increasing the number of dosing days 
per treatment cycle compared to the [A2301] trial. Overall the safety and tolerability of the 
treatment in ADE02T was very similar compared to [A2301]. Most importantly, the rate of 
death in patients up to 60 years old during induction and consolidation therapy was low in 
both trials (death during induction therapy was 3.4% and 3% in [A2301]  and ADE02T 
respectively). Therefore, in order to further optimize the risk-benefit relationship of the 
treatment of AML without FLT3 mutation the same dosing regimen of midostaurin will be 
applied in E2301 as was used in ADE02T.
2.4
Rationale for choice of combination drugs
For patients with newly diagnosed AML regardless of cytogenetic and molecular markers 
(except acute promyelocytic leukemia), and who are judged to be fit, the most frequently used 
therapy has been the ‘7 + 3’ remission induction regimen with cytarabine and daunorubicin, 
followed by high dose cytarabine for remission consolidation. Studies showed that 
modifications of the components of the chemotherapy regimen and their timing and dosing 
resulted in little incremental benefit for patients of all risk categories, including patients with 
and without FLT3-mutations. Therefore, minor modifications or variants of this standard 
treatment approach that better reflect the existing variants of current standard of care and that 


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are not expected to jeopardize the treatment homogeneity in the study are allowed such as 
replacement of daunorubicin with an equivalent dose of idarubicin or the omission of a second 
induction chemotherapy cycle in patients who achieved CR already with the first induction 
cycle. Significant improvements in OS and DFS for AML patients have been reported with 
HSCT compared to consolidation chemotherapy (Kayser et al 2010, DeZern et al 2011).
Therefore, patients in this study are allowed to undergo allogeneic or autologous HSCT at any 
time after induction therapy and can thereafter resume treatment with the study drug during
the post-consolidation phase of the study.
Midostaurin will be administered sequentially with chemotherapy during each induction and 
consolidation treatment cycle. Midostaurin will be dosed at 50 mg twice daily. Study 
[CPKC412A2106] showed that in combination with chemotherapy the 50 mg twice daily.
midostaurin dose was better tolerated than was the 100 mg twice daily. dose, and the 
sequential regimen was better tolerated than was concomitant administration. The safety of 
intensive chemotherapy combined with midostaurin was confirmed in the phase III study 
A2301 as described in section 1.2.1.2. Moreover, in a leukemia cell culture model a related 
FLT3 tyrosine kinase inhibitor was shown to synergize with cytarabine when administered 
following this chemotherapy but antagonized anti-leukemic cytotoxicity when administered 
before cytarabine (Levis et al 2004).
Data suggest that the detection of measurable residual disease in AML patients predicts rapid 
relapse once chemotherapy is completed. The continued administration of an oral, non-
cytotoxic drug such as midostaurin following chemotherapy might continue to inhibit growth 
or even kill residual blasts present at the end of a routine course of chemotherapy, potentially 
prolonging DFS
(Ivey et al). Studies [CPKC412A2104], [CPKC412A2104E1]
and 
[CPKC412A2104E2] showed that midostaurin has single agent activity in relapsed or 
refractory AML even in FLT3-MN cases. 
In addition, the analysis of [A2301] study suggests a protective effect against relapse during 
the 12 months of midostaurin continuation therapy and a contribution to the sustained overall 
survival benefit. More details are summarized in section 2.2.2. To determine the treatment 
benefit whilst on maintenance therapy, DFS was analyzed for the subset of patients who 
entered the maintenance phase in CR (194 patients; 115 in the midostaurin arm and 79 in the 
placebo arm). Patients were censored at the end of the 12-month maintenance phase. In this 
analysis, the HR was 0.714 (95% CI 0.430, 1.184), showing benefit for midostaurin 
maintenance therapy over placebo. DFS after completion of the maintenance phase was 
analyzed using the subset of patients who remained in CR after completing the maintenance
phase. The DFS events (all relapses) in the midostaurin arm occurred early (primarily within 
the first 6 months after stopping therapy), whereas in the placebo arm, the events were more 
distributed over time. The findings show that even after the completion of maintenance
therapy, the risk of disease relapse is substantial and it is supportive of the hypothesis that 
continued suppression of leukemic cell clones that survived induction and consolidation 
therapy is important even after completion of cytotoxic chemotherapy administration. The 
observations above do not follow a secondary randomization and rely on few events, so 
conclusions must be drawn cautiously. However, taken together, the analyses of OS from the 
start of maintenance, DFS during maintenance, and DFS after maintenance, are consistent, 
and indicate a clear treatment benefit of maintenance therapy in AML with mutated FLT-3. 


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Similarly, suppression of the kinase activity in residual leukemic blasts in AML with non-
mutated but overexpressed FLT3 during 12 month maintenance treatment with midostaurin 
may improve the DFS after completion of the induction and consolidation therapy. During the
maintenance phase patients will be followed in 3-months intervals for MRD as well as 3 
months after completion of the maintenance therapy. Since a strong relationship between the 
presence of MRD and subsequent relapse was demonstrated in several studies in AML MRD 
might be a surrogate marker of the likelihood of relapse during and after maintenance and 
quantitative changes of MRD may indicate effectiveness of maintenance therapy.
It has been demonstrated that allogeneic HSCT does not cure all patients with AML with or 
without mutated FLT3 as MRD may persist and relapses occur at substantial frequencies 
(Christopeit et al 2014). The interim analysis of a single arm study in AML FLT3-mutated 
demonstrated that midostaurin can be safely administered after allogeneic transplant. Patients 
received midostaurin during induction, consolidation and after transplant. EFS at 2 years after 
start of treatment was substantially improved from 25% to 34.6% compared to historical 
controls. The relative contribution of each phase of treatment (induction, consolidation if 
applicable, HSCT and post-consolidation) could not be determined (PKC412ADE02T Interim 
Study Report June 2016, on file). In this study patients can start post-consolidation treatment
after allogeneic HSCT and recovery from the procedure. MRD measurements during and after 
post-consolidation treatment may help to determine whether midostaurin can reduce the 
residual leukemic disease load in MRD-positive patients after allogeneic transplant and 
convert the MRD status to negative and/or reduce the rate of molecular and hematologic 
relapses in MRD-negative transplanted patients. Such findings would support the hypothesis 
that midostaurin after allogeneic HSCT could ultimately result in a longer DFS after 
transplant.
The study design will assess the use of midostaurin in combination with standard remission 
induction chemotherapy, with intermediate dose cytarabine during consolidation, and as a 
single agent during 12 cycles of post-consolidation therapy. Patients who have AML without 
a FLT3 mutation (neither ITD nor TKD per clinical cut-off SR<0.05) will be randomly 
assigned in a 1:1 ratio to midostaurin or placebo arm. 
Patients will be treated with one or two cycles of remission induction therapy with cytarabine 
and daunorubicin or idarubicin, followed by sequential midostaurin or placebo. Patients who 
demonstrate a CR or CRi with adequate blood count recovery (neutrophils ≥1.0 x 109/L and 
platelets ≥50 x 109/L) will receive in consolidation therapy three or four cycles of 
intermediate-dose cytarabine chemotherapy with sequential midostaurin/placebo as assigned. 
If a patient continues to be in remission, post-consolidation therapy for up to twelve 28-day 
cycles will be administered with midostaurin/placebo as assigned. Patients who receive HSCT 
can stay in the study and will start midostaurin/placebo post-consolidation therapy but will 
interrupt midostaurin during the procedure and recovery.
The safety of the chemotherapy regimen combined with midostaurin was demonstrated in the
[A2301] study (Stone et al 2017). This study will comprise the first randomized placebo-
controlled evaluation of safety and efficacy of midostaurin chemotherapy regimen in FLT-
MN AML. 


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2.5
Rationale for choice of comparators drugs 
Midostaurin will be added to the 7+3 standard combination regimen with daunorubicin (or 
idarubicin) and cytarabine for induction and intermediate dose cytarabine for consolidation. 
Because no standard treatment that combines chemotherapy with a kinase inhibitor exist, 
placebo added to the standard chemotherapy 7+3 will serve as comparator.
2.6
Rationale for MRD assessment
MRD in AML refers to the presence of leukemic cells at a sensitivity of detection below the 
threshold of conventional morphologic methods. Patients who experience a CR or CRi 
according to morphologic assessments (<5% blasts in the bone marrow), can potentially still 
harbor a large number of leukemic cells in the bone marrow (up to 1010) which can confer a 
poor outcome. Detection of MRD (usually <0.1% bone marrow blasts) has shown prognostic 
relevance in several studies (Terwijn et al 2013; Ivey A et al, 2016), indicating that depth of 
leukemic clearance should be considered as a relevant prognostic endpoint in AML. The most 
frequently used methods for MRD assessment in AML include multi-parameter flow 
cytometry (MFC) to detect abnormal immunophenotypes and PCR assays to detect molecular 
alterations, including NPM1 mutations or genomic translocations (Hourigan CS et al, 2017). 
While molecular methods are generally more sensitive than MFC, they are currently only 
suitably to monitor MRD in the subset of patients harboring those genomic aberrations (40-
60% of all patients). In contrast, MFC is suitable for MRD monitoring in ~90% of all AML 
patients, making it the most adequate technology currently available to test the prognostic 
impact of MRD status in this trial.
MRD will be assessed during and after treatment using MFC for secondary endpoint, to 
determine the treatment benefit of midostaurin. Flow cytometry assessments for leukemia-
associated immunophenotypes (LAIP) will be used to monitor MRD at a sensitivity of 0.1% 
in bone marrow aspirates. 
 
 
Monitoring of MRD will be performed at baseline, during treatment (including induction, 
consolidation and post-consolidation), post treatment and at relapse to sensitively assess the 
depth and duration of response and to provide prognostic information on risk of relapse.
 
 
 
 
 
 
 


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2.8
Risk and benefit
The data available for midostaurin in AML, taken from early stage single agent and 
combination trials, indicated a favorable benefit-risk profile. This was confirmed in the 
randomized phase III [A2301] trial, which met its primary endpoint of overall survival, 
whereby patients receiving midostaurin had a 23% reduced risk of death compared to the 
placebo arm. The secondary endpoints of CR rate, EFS and DFS were all superior in the 
midostaurin arm, with generally balanced toxicities and no impact of midostaurin treatment 
on time to hematologic recovery, infections or bleeding. The challenge in evaluating toxicities 
with this compound is separating out those associated with background chemotherapy seen in 
patients in trials, multiple concomitant medications or confounding factors due to 
complications of underlying disease. Pooled data from completed studies indicated 
gastrointestinal events, consisting of nausea, vomiting and diarrhea are the most prevalent 
adverse events, and the most common causes for drug discontinuation. These events tended to 
be grades 1 or 2, and resolved upon discontinuing study medication. The data thus 
demonstrate a positive benefit-risk balance for midostaurin in combination with standard 


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chemotherapy followed by 12 months of continuation therapy in patients with FLT3-mutated 
AML.
This study E2301 may demonstrate similar benefits as seen in [A2301], i.e., prolongation of 
the overall survival, event free survival and disease free survival compared to standard 
therapy. Since there is no other approved FLT3-inhibitor available for AML with FLT3WT 
current standard intensive induction and consolidation chemotherapy with or without HSCT is 
the relevant alternative treatment for comparison of the benefit and risks of the study 
treatment. Moreover it is regarded unlikely that the safety and tolerability of Midostaurin in 
AML with FLT3-MN (SR<0.05) AML will significantly differ from those observed in 
[A2301] in FLT3-mutated AML. The risks of the study treatment during induction and 
consolidation are expected to reflect mainly those associated with the chemotherapy backbone 
and to be similar compared to standard chemotherapy as was seen in the [A2301] trial. During 
the post-consolidation phase with midostaurin monotherapy the adverse events expected to be 
observed more frequently compared to placebo are mainly grade 1 or 2 gastrointestinal events, 
including nausea, vomiting and diarrhea and the most common causes for drug 
discontinuation. Overall it appears plausible that the risk profile associated with the study 
treatment in patients with AML with FLT3-MN (SR<0.05) will not be significantly different 
from the risks in AML-mutated.
No diagnostic procedures that are different from those in standard of care will be performed in 
E2301.
Appropriate eligibility criteria as well as specific dose modification and stopping rules, are 
included in this protocol. Recommended guidelines for prophylactic or supportive 
management of study-drug induced adverse events are provided in Section 6.3. The risk to 
subjects in this trial may be minimized by compliance with the eligibility criteria and study 
procedures, as well as, close clinical monitoring, dose reduction recommendations for toxicity, 
stopping rules and supportive therapy according to clinical standard of care. For the most 
current overview of known risks refer to the latest Investigator’s Brochure. There may be 
unforeseen risks which could be serious. In the large Phase III study [A2301] in FLT3-
mutated AML, midostaurin at a dose of 50 mg twice daily was overall well tolerated in 
combination
In summary, the collectively available clinical data support a positive benefit risk assessment 
addressing important unmet medical needs in in patients with AML-FLT3-MN (SR<0.05).


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3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.
Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
To determine if the addition of midostaurin to 
standard induction and consolidation therapy, 
followed by single agent post-consolidation
therapy improves EFS in patients with newly 
diagnosed FLT3-MN (SR<0.05) AML.
EFS is defined as the time from randomization to failure to obtain a CR or 
CRi with adequate blood count recovery 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.  
Key secondary
Refer to Section 10.5.1
To determine if the addition of midostaurin to 
standard induction and consolidation therapy, 
followed by single agent post-consolidation 
therapy improves OS in patients with newly 
diagnosed FLT3-MN (SR<0.05) AML.
Overall survival is defined as the time from randomization to date of 
death due to any cause. 
Other secondary
To compare CR + CRi with adequate blood count 
recovery rate in the two treatment groups.
CR and CRi with adequate blood count recovery rate according to the 
International Working Group (IWG) for AML (Cheson et al 2003, ELN 
2017 / Döhner et al 2017) as per investigator assessment.
Refer to Section 10.5.2.1
To compare the percentage of patients who 
reached MRD negative status in the two 
treatment groups.
Percentage of patients with MRD negative status.
Refer to Section 10.5.2.2


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Objective
Endpoint
Analysis
To compare the percentage of patients with MRD 
negative status in the post-consolidation phase
in the two treatment groups.
Percentage of patients with MRD negative status during post-
consolidation phase
To compare the time to MRD negative bone 
marrow between the two treatment arms in the 
two treatment groups.
Number of days from date of randomization to first documented MRD-
To compare DFS, as well as the Cumulative 
Incidence of Relapse (CIR) and Cumulative 
Incidence of Death (CID) in the two treatment 
groups.
DFS, as measured from the date of first CR or CRi with adequate blood 
count recovery to relapse or death from any cause, whichever occurs 
first. 
CIR is defined for patients with CR or CRi with adequate blood count 
recovery: time from achieving CR or CRi with adequate blood count 
recovery until onset of relapse. Patients without relapse are censored at 
the last adequate response assessment. Patients who died without 
relapse are counted as a competing cause of failure. 
CID is defined for patients with CR or CRi with adequate blood count 
recovery: time from achieving CR or CRi with adequate blood count 
recovery until death. Patients who did not die are censored at the last 
contact date. Patients who relapsed are counted as a competing cause of 
failure. 
Refer to Section 10.5.2.1
To compare the time to CR or CRi with adequate 
blood count recovery in the two treatment 
groups.
Number of days from date of randomization to first documented CR or 
CRi with adequate blood count recovery. 
Refer to Section 10.5.2.1
To compare the time to neutrophil recovery in the 
two treatment groups.
Number of days from the first day of a chemotherapy cycle to first day 
neutrophils ≥0.5 x 109/L.
Number of days from day 1 of commencing induction therapy to first day 
neutrophils ≥1.0 x 109/L.
Refer to Section 
10.5.2.2


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Objective
Endpoint
Analysis
To compare the time to platelet recovery in the 
two treatment groups.
Number of days from the first day of a chemotherapy cycle to first day 
platelets ≥50 x 109/L.
Number of days from day 1 of commencing induction therapy to first day 
platelets ≥100 x 109/L.
To 
assess 
the 
safety 
and 
tolerability 
of 
midostaurin in combination with chemotherapy 
and as monotherapy during post-consolidation. 
Frequency/severity of AEs, and laboratory abnormalities.
Refer to Section 10.5.3
To further characterize the pharmacokinetics of 
midostaurin, CGP52421 and CGP62221.
Plasma concentrations and pharmacokinetic parameters for midostaurin, 
CGP52421 and CGP62221.
Refer to Section 10.5.4
To assess the impact of midostaurin on health 
related quality of life and AML symptom 
reduction. 
Change from baseline score for each time point for the FACT-Leu and 
the EQ5D-5L (visual analogue scale (VAS)) by treatment arm.
Refer to Section 10.5.5
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Objective
Endpoint
Analysis
 
 
 
 
 
 
 


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4
Study design
4.1
Description of study design
This is a randomized, double-blind, multi-center, placebo-controlled phase III study of 
midostaurin (PKC412) or placebo in combination with idarubicin/daunorubicin and 
cytarabine for induction therapy, intermediate-dose cytarabine for consolidation therapy, 
followed by post-consolidation therapy with midostaurin or placebo in adult patients with 
newly diagnosed FLT3-MN (SR<0.05) AML, i.e., FLT3 mutant to wild type signal ratio 
below the 0.05 clinical cut-off. The study is designed to evaluate the efficacy and safety of 
midostaurin combined with intensive chemotherapy in this indication. 502 adult patients with 
newly diagnosed AML demonstrating FLT3-MN (SR<0.05) as determined by a Novartis
designated laboratory will be enrolled at approximately 150-180 sites worldwide.
Figure 4-1
Study Design
Eligible and consented patients are allowed to start with the 7+3 chemotherapy immediately 
after the unequivocal diagnosis of AML; the day of the first dose of chemotherapy is defined 
as Day 1.
Patients will be tested for the absence of FLT3-ITD and FLT-TKD mutations, using a 
validated clinical trial assay in a Novartis designated laboratory. Absence of mutation is 
defined as ITD and TKD activating mutations at codons D835 and I836 in the FLT3 gene, 
below the clinical cutoff of 0.05 mutant to wild type signal ratio.


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Patients with confirmed FLT3-MN (SR<0.05) AML will be randomly assigned 1:1 to 
midostaurin or placebo by using a stratified randomization according to age (<60 vs. 60 
years), Patients will be randomized on Day 8, i.e., the day of the first dose of midostaurin or 
placebo. Patients with a FLT3 mutation or with an unknown FLT3 mutation status by study 
Day 8 will be considered as molecular screening failures and cannot be randomized.
Provided that FLT3-MN (SR<0.05) status has been confirmed, patients meeting all other 
eligibility criteria will start the administration of midostaurin or placebo on Day 8.
4.2
Study phase (details of dosing in section 6)
The study contains three treatment phases:

Induction treatment phase

Consolidation treatment phase and,

Post-consolidation treatment phase
A patient has to meet the following criteria to continue with the next treatment phase:

A patient achieves CR at end of any treatment phase OR patient achieves CRi at end of 
any treatment phase with adequate blood count recovery defined as the following:

Complete Recovery in neutrophil count (1 x 10E9/L)

Minimal recovery in platelet count (50 x 10E9/L)
Of note, a patient not meeting the above criteria up to 93 days after start of induction phase is 
considered as “induction failure”. For details please see Section 7.2.1.1.
The planned duration of an induction and consolidation cycle is 28 days.  Upon adequate 
blood count recovery after day 28, midostaurin is stopped immediately (e.g., the evening dose 
of midostaurin or placebo on that day is not taken).  Forty-eight hours thereafter is Day 1 (and 
start of chemotherapy) of the next cycle (Induction 2, Consolidation 1-4).  At the end of the 
last consolidation cycle, i.e., prior to start of the post-consolidation cycle 1, midostaurin or 
placebo will not be interrupted. The duration of each post-consolidation cycle is 28 days.
4.2.1
Induction phase
All patients will receive at least one cycle of induction therapy with continuous infusion 
cytarabine and idarubicin/daunorubicin. Patients not achieving CR nor CRi with adequate 
blood count recovery after induction 1 will receive a second cycle with intermediate-dose 
cytarabine and daunorubicin/idarubicin (the latter only in patients under 60 years of age).
Daunorubicin may be replaced by an equivalent dose of idarubicin. 
The dose of idarubicin would be one fifth of the planned daunorubicin dose. Midostaurin will 
start on day 8 of the first induction cycle and last until 48 hours before the start of the next 
chemotherapy cycle which is either a second induction or the first consolidation cycle. 
Patients achieving CR or CRi with adequate blood count recovery with induction cycle 1 will
go directly to consolidation therapy (4 cycles) without a second cycle of induction therapy.
Patients who do not achieve CR nor CRi with adequate blood count recovery with one cycle 


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of induction will receive a second induction cycle with intermediate dose cytarabine and 
daunorubicin/idarubicin.
Patients achieving CR or CRi with adequate blood count recovery with 2 cycles of induction 
will go directly to consolidation therapy (3 cycles).
Patients not achieving CR nor CRi with adequate blood count recovery after induction 2 (i.e. 
up to 93 days after start of induction phase) will discontinue study treatment and will be 
followed for survival. 
4.2.2
Consolidation phase
Patients achieving CR or CRi with adequate blood count recovery after induction with one or 
two cycles of induction therapy will proceed to consolidation therapy with either 3 or 4 cycles 
of intermediate-dose cytarabine respectively, or to HSCT with or without preceding 
consolidation cycles. Patients may undergo transplantation at the discretion of the Investigator 
(refer to 2017 ELN and 2016 National Comprehensive Cancer Network (NCCI)
recommendations). In patients who are treated with allogeneic HSCT instead of consolidation 
therapy or after start of consolidation therapy the conditioning regimen and management after 
transplantation will be according to local institutional standards. Study treatment will be 
interrupted at least 48 hours before the initiation of the transplant conditioning regimen.
Patients with transplantation and recovery from the procedure will not receive further cycles 
of consolidation treatment but receive post-consolidation treatment with study drug. They can 
start the post-consolidation therapy not earlier than 30 days after transplant but not later than 
100 days after transplant.
Patients will receive midostaurin (two 25 mg capsules) or placebo (2 capsules) twice daily 
orally from day 4 until 48 hours prior to the start of the next consolidation cycle.
4.2.3
Post-consolidation phase
After adequate blood count recovery following the final cycle of consolidation therapy, 
patients will receive 12 cycles (28 days/cycle) of continuous therapy with midostaurin or 
placebo twice daily at 50 mg. 
Patients who underwent HSCT after achieving CR or CRi with adequate blood count recovery 
will receive midostaurin or placebo 50 mg twice daily as post-consolidation therapy, 
continuously, for up to 12 cycles (28 days/cycle). Post HSCT post-consolidation therapy will 
begin >30 days but not later than 100 days following HSCT.
4.2.4
Follow-up phase
Patients who discontinue study treatment will continue to have response assessments 
performed every 12 weeks until documented relapse, and thereafter will be followed every 3 
months for survival except those who are lost to follow-up. Data on anti-neoplastic therapies 
will be collected as well.


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4.3
Timing of interim analyses and design adaptations 
Two interim analyses are planned when approximately 114 and 214 of the 285 EFS events 
targeted for the primary analysis (approximately 40% and 75% information fraction, 
respectively) have been documented. The first interim analysis is planned for a futility 
assessment. The study can be stopped for efficacy at the second interim analysis. These 
analyses are expected to take place around 12 and 20 months, respectively, from the date of 
first patient randomized in the study assuming an increasing recruitment rate to reach 30 
patients/month 6 months after start of the study. Please refer to Section 10.7 for detailed 
information.
4.4
Definition of end of study
The end of study will occur when approximately 278 deaths have been documented (it is 
estimated that these 278 deaths will be observed at approximately 64 months from the date of
randomization of the first patient) or 5 years after the end of the study treatment for the last 
patient whichever occurs first. At this time, the final OS analysis will be performed. All 
patients will remain in treatment, post-treatment or survival follow-up until the data cut-off 
date and all available data up to this cut-off date will be analyzed.
4.5
Early study termination 
The study may be terminated at any time for any reason by Novartis. This may include 
reasons related to the benefit/ risk assessment of participating in the study, practical reasons 
(including slow enrollment), or for regulatory or medical reasons. In taking this decision to 
terminate, Novartis will always consider the subject’s welfare and safety. Should this be 
necessary, patients should be seen as soon as possible for the End of Treatment (EOT) visit, 
and assessments for EOT as described in Section 7 should be performed for discontinued or 
withdrawn patients. The investigator may be informed of additional procedures to be followed 
in order to ensure that adequate consideration is given to the protection of the patient’s 
interests. The investigator will be responsible for informing institutional review boards (IRBs)
and/or ethics committees (ECs) of the early termination of the trial.
In the event that the study is terminated prematurely, e.g., due to futility or overwhelming 
efficacy, patients still receiving study treatment and who, according to investigator assessment, 
continue to benefit from the treatment, will be offered to complete study treatment as per 
protocol.
5
Population
5.1
Patient population
The study population will be comprised of male and female patients 18 years of age with 
newly diagnosed FLT3-MN (SR<0.05) (no ITD in the juxtamembrane domain or TKD 
activating mutation as defined in inclusion criteria) AML who are deemed by the investigator 
to be suitable for treatment with intensive induction and consolidation chemotherapy.


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All data for the Inclusion/Exclusion criteria must be verifiable in the patient’s source 
documents.
5.2
Inclusion 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 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:

AST ≤ 3 times ULN

Alanine aminotransferase (ALT) ≤ 3 times ULN

Serum total bilirubin ≤ 1.5 times ULN, unless in case of hyperbilirubinemia due to an 
isolated Gilbert syndrome

Estimated (by Cockcroft-Gault) creatinine clearance ≥30ml/min
6. Written informed consent must be obtained prior to any screening procedures.
5.3
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 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, prior to Day 
1. An investigational agent is defined as an agent with no approved medical use in adults 
or in pediatric patients.
7. Prior treatment with a FLT3 inhibitor (e.g., midostaurin, quizartinib, sorafenib)
8. Strong CYP3A4/5 enzyme inducing drugs (see Appendix 1) unless they can be 
discontinued or replaced prior to enrollment. 


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9. Any other known disease or concurrent severe and/or uncontrolled medical condition (e.g., 
cardiovascular disease including congestive heart failure or active uncontrolled infection) 
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. Impairment of gastrointestinal (GI) function or GI disease that might alter significantly the 
absorption of midostaurin.
12. Known confirmed diagnosis of HIV infection or active viral hepatitis (testing is not 
mandatory to exclude these viral infections).
13. Cardiovascular abnormalities, including any of the following:

History of MI, angina pectoris, CABG within 6 months prior to starting study 
treatment

Clinically uncontrolled cardiac arrhythmias (e.g., ventricular tachycardia), complete 
left bundle branch block, high-grade 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. Highly effective 
contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). The vasectomized male 
partner should be the sole partner for that subject

Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception.

Midostaurin may reduce the effectiveness of hormonal contraceptives; therefore, 
females using systemically active hormonal contraceptives should add a barrier 
method of contraception. 
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(i.e., age appropriate, history of vasomotor symptoms) or have had surgical bilateral 


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oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at 
least six weeks ago. In the case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment is she 
considered not of child bearing potential.
16. Sexually active males unless they use a condom during intercourse while taking the drug 
during treatment, and for at least 4 months after stopping treatment and should not father a 
child in this period. A condom is required to be used also by vasectomized men as well as 
during intercourse with a male partner in order to prevent delivery of the drug via semen.
17. Unwillingness or inability to comply with the protocol.
18. Known hypersensitivity to midostaurin, cytarabine or daunorubicin/idarubicin or to any of 
the excipients of midostaurin/placebo, cytarabine or daunorubicin /idarubicin.
6
Treatment
6.1
Study treatment
In this study, the term “Study drug” refers to midostaurin/placebo labeled as PKC412/placebo 
provided as 25 mg capsules which are packaged in blister packs and supplied by Novartis as 
double-blind supplies.
The term “Study treatment” will indicate treatment with daunorubicin/idarubicin, cytarabine, 
or midostaurin/placebo. 
Induction chemotherapy will start on Day 1 and the randomization and treatment start with 
midostaurin/placebo will be done on Day 8 when (molecular) eligibility has been confirmed 
based on the absence of a FLT3 mutation as determined by a Novartis designated laboratory. 
If the patient does not have FLT3 test results qualifying for eligibility by Day 8 then the 
patient will be considered as a molecular screening failure and cannot be randomized.
6.1.1
Dosing regimen
On Day 1 of study treatment, the first dose of induction chemotherapy will be administered.
Daunorubicin/ idarubicin and cytarabine are approved drugs and will be sourced either 
according to local practice or centrally. Please refer to the Package Insert for complete 
guidelines for administration and for safety monitoring guidelines.
The dosage of daunorubicin/idarubicin and cytarabine will be adjusted based on body surface 
area (BSA) calculated before administration. To calculate BSA, the height at baseline and 
weight on the first day of the respective treatment cycle will be used.
Dose modification for obese patients: 
There is no clearly documented adverse impact of treatment of obese patients when dosing is 
performed according to actual body weight. Therefore, all dosing is to be determined solely 
by the patient’s BSA as calculated from actual weight. This will eliminate the risk of 
calculation error and the possible introduction of variability in dose administration. 


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6.1.1.1 Treatment regimen:
First Induction:

Cytarabine 200 mg/m2/day will be administered by continuous intravenous infusion 
(CIVI) on Days 1-7 (168 hour infusion).

Daunorubicin 60 mg/m2/day or idarubicin 12 mg/m2/day will be administered 
intravenously by IV push (IVP) or short (30 minutes) infusion on Day 1-3.

Study drug (midostaurin 50 mg [two 25 mg capsules] or placebo [2 capsules]) will be 
administered twice per day by mouth from Day 8 until 48 hrs prior to the start of next 
cycle (i.e. the morning of Day 27 if hematopoiesis recovers timely (cycle length of 28
days) or later if the cycle needs to be prolonged for blood count recovery). Patients should 
take their doses at approximately the same time each day, and approximately 12 hours 
should elapse between the morning and evening doses. On days that PK samples are 
obtained, the patient should take study drug during the clinic visit after the pre-dose PK 
sample and prior to post-dose PK samples, when instructed by the study staff. Each daily 
dose should be given with food and a glass of water (~240 mL). Patients should be 
instructed to swallow capsules whole and not chew capsules. If vomiting occurs, no re-
dosing is allowed prior to the next scheduled dose. The soft capsules should be removed 
from the blister pack only shortly prior to administration. The capsules may have an 
unpleasant odor, which disappears a few seconds after the blister foil is opened.
A bone marrow aspiration will be performed in all patients between Day 21-28 to determine 
the need for a second induction cycle. If the bone marrow aspirate is insufficient to make a 
determination of remission, then the bone marrow assessment should be repeated after about 
one week. 
A disease assessment will be performed at the end of induction 1 based on bone marrow and 
peripheral blood assessments. If the response is CR or CRi with adequate blood recovery the 
patient will proceed to the consolidation phase. If the response is CRi without adequate blood 
count recovery, the patient will continue to be treated with Midostaurin/Placebo and observed 
up to 2 weeks to get the platelet ≥50 x 109/L and neutrophil ≥1 x 109/L (i.e., adequate blood 
count recovery) to be able to move to consolidation. In such cases a response assessment will 
be performed at day 42 (28 days plus the time window of 2 weeks for adequate blood count 
recovery)
If patients after induction 1 therapy still show ≥5% blasts (i.e., no CR or CRi) in their D21-
D28 bone marrow, then they require a second induction treatment. Dosing of 
midostaurin/placebo should be stopped immediately after knowledge of ≥5% blasts
persistence. 48 hours thereafter the second induction treatment should start.
Of note, Physicians should consider earlier bone marrow exams in patients whose peripheral 
blood counts are not recovering or recovering in an unexpectedly slow manner. 
Second Induction:
Patients who still have more than ≥5% blasts in their bone marrow (no CR or CRi) after 
induction cycle 1 require a second induction treatment. Dosing of midostaurin/placebo should 
be stopped immediately. 48 hours thereafter the second induction treatment should start. 


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
Intermediate-dose cytarabine (IDAC) 1500 mg/m2 will be administered by intravenous 
infusion over 3 hours every 12 hours on Day 1 to 3. Serial neurologic evaluations will be 
performed before and following the infusion of intermediate-dose cytarabine. For 
patients of age 60 years or older at the time of study entry a dose of 1000 mg/m2 will 
be administered.

Daunorubicin 50 mg/m2/day or idarubicin 10 mg/m2/day will be administered 
intravenously by IV push (IVP) or short (30 minute) infusion on Day 1-3 for patients <60 
years only. Patients 60 years at the time of study entry will not be given 
daunorubicin or idarubicin 

Study drug (midostaurin 50 mg [two 25 mg capsules] or placebo [2 capsules]) will be 
administered twice per day by mouth from Day 4 until 48 hrs prior to start of next cycle
(i.e. the morning of Day 27 if hematopoiesis recovers timely (cycle length of 28 days) or 
later if the cycle needs to be prolonged for blood count recovery).).
A bone marrow aspiration will be performed in all patients between Day 21-28 to determine if 
the patient can move to consolidation phase. If the response is CR, the patient will proceed 
immediately after Day 28 to the consolidation phase. If the response is CRi without adequate 
blood count recovery, the patient will continue to be treated with Midostaurin/Placebo and 
observed 3 additional weeks for an adequate blood recovery to be able to move to 
consolidation. If no adequate blood count recovery will be achieved after these 3 additional 
weeks, the patient will be discontinued from treatment and followed for survival. Otherwise, 
the patient will move to consolidation. A response assessment will be performed at day 49 (28 
days plus the time window of 3 weeks for adequate blood count recovery).Patients who 
failed to achieve CR or CRi with adequate blood count recovery after a second induction 
will be discontinued from protocol therapy and followed for survival and post-study-
treatment therapies (Section 7.1).
Consolidation (3 or 4 cycles)
Patients achieving a CR or CRi with adequate blood count recovery after induction 1 will 
receive 4 cycles of consolidation therapy with midostaurin/placebo + chemotherapy. 
Patients achieving a CR or CRi with adequate blood count recovery only after induction 2 will 
receive 3 cycles of consolidation therapy with midostaurin/placebo and chemotherapy.
A bone marrow examination must be performed at each cycle of the consolidation phase to 
evaluate for relapsed AML. 

Intermediate-dose cytarabine (IDAC) 1500 mg/m2 will be administered by intravenous 
infusion over 3 hours every 12 hours on Days 1 to 3. Serial neurologic evaluations will be 
performed before and following the infusion of intermediate-dose cytarabine. For 
patients of age 60 years or older at the time of study entry a dose of 1000 mg/m2 will 
be administered .

Study drug (midostaurin 50 mg [two 25 mg capsules] or placebo [2 capsules]) will be 
administered twice per day by mouth on Days 4 until 48 hrs prior to start of next 
consolidation cycle (i.e. the morning of Day 27 if hematopoiesis recovers timely (cycle 
length of 28 days) or later if the cycle needs to be prolonged for blood count recovery). . 


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Post-consolidation therapy (12 cycles)
Patients who maintain CR or CRi with adequate blood recovery (by bone marrow 
aspirate/biopsy and peripheral blood evaluation) after completing consolidation therapy will 
receive 12 cycles (28 days/cycle) of midostaurin/placebo post-consolidation therapy.
Prior to initiation of midostaurin/placebo post-consolidation therapy, all significant acute 
toxicity from consolidation therapy must have resolved to <grade 2 or be stable except 
alopecia of any grade. Midostaurin/placebo post-consolidation therapy will begin after partial 
platelet recovery (platelets ≥ 50,000/µL) from remission consolidation.

Study drug (midostaurin 50 mg [two 25 mg capsules] or placebo [2 capsules]) will be 
administered twice per day by mouth for 28 consecutive days. Patients should take their 
doses at approximately the same time each day, and approximately 12 hours should elapse 
between the morning and evening doses. On days that PK samples are obtained, the 
patient should take midostaurin/placebo during the clinic visit after the pre-dose PK 
samples and prior to post-dose PK samples, when instructed by the study staff. 
Hematopoietic stem cell transplantation
Patients who underwent HSCT after achieving CR or CRi with adequate blood count recovery
will receive midostaurin or placebo 50 mg twice daily as post-consolidation therapy, 
continuously, for up to 12 cycles (28 days/cycle). Post HSCT post-consolidation therapy will 
begin >30 days following HSCT and adequate blood count recovery but not later than 100 
days following HSCT.
Table 6-1
Dose and treatment schedule
Study phase
Study 
treatments
Pharmaceutical 
form and route of 
administration
Dose
Frequency 
and/or Regimen
Induction 1 
Cytarabine
CIVI 
200 mg/m2/day
Day 1-7 (168 hour 
infusion)
Daunorubicin
Or Idarubicin
Intravenously by IV 
push or short (30 
minute) infusion
Intravenously by IV 
push or short (30 
minute) infusion
60 mg/m2/day
(irrespective of 
age)
12 mg/m2/day
(irrespective of 
age)
Day 1-3
Day 1-3
Midostaurin/
Placebo
Capsules for oral 
use
50 mg/dose
Twice daily on 
Day 8 until 48 hrs 
before start of 
next cycle  (i.e. 
the last dose of 
Midostaurin/Place
bo to be 
administered in 
the morning of 
Day 27 if the cycle 


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Study phase
Study 
treatments
Pharmaceutical 
form and route of 
administration
Dose
Frequency 
and/or Regimen
length is 28 days
or later if the cycle 
needs to be 
prolonged for 
blood count 
recovery).
Induction 2 for 
patients without 
CR/CRi with 
adequate 
recovery after 
Induction 1
Cytarabine
Intravenously over 3 
hours
1500 
mg/m2/dose for 
pts <60  years 
1000 
mg/m2/dose for 
pts 60  years 
12-hour intervals 
on Day 1-3
Daunorubicin
Or Idarubicin
No 
daunorubicin 
or Idarubicin
for 
pts 
60 
years
Intravenously by IV 
push or short (30 
minute) infusion
Intravenously by IV 
push or short (30 
minute) infusion
50 mg/m2/day
10 mg/m2/day
Day 1-3
Day 1-3
Midostaurin/
Placebo
Capsules for oral 
use
50 mg/dose
Twice daily on 
Day 4 until 48 hrs 
before start of 
next cycle (i.e. the 
last dose of 
Midostaurin/Place
bo to be 
administered in 
the morning of 
Day 27 if the cycle 
length is 28 days
or later if the cycle 
needs to be 
prolonged for 
blood count 
recovery)
Consolidation 
phase
Cytarabine
Intravenously over 3 
hours
1500 
mg/m2/dose for 
pts <60  years 
1000 
mg/m2/dose for 
pts 60  years
12-hour intervals 
on Day 1-3


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Study phase
Study 
treatments
Pharmaceutical 
form and route of 
administration
Dose
Frequency 
and/or Regimen
Midostaurin/
Placebo
Capsules for oral 
use
50 mg/dose
Twice daily on 
Day 4 until 48 hrs 
before start of 
next 
chemotherapy 
cycle (i.e. the last 
dose of 
Midostaurin/Place
bo to be 
administered in 
the morning of 
Day 27 if the cycle 
length is 28 days
or later if the cycle 
needs to be 
prolonged for 
blood count 
recovery)
Post-
consolidation  
phase
Midostaurin/
Placebo
Capsules for oral 
use
50 mg/dose
Twice daily for 28 
consecutive days 
of each 28-day 
treatment cycle up 
to 12 cycles
No interruption 
between post-
consolidation 
cycles required
6.1.2
Ancillary treatments 
Not applicable.
6.1.3
Rescue medication 
Not applicable.
6.1.4
Guidelines for continuation of treatment 
See Section 6.3
6.1.5
Treatment duration
The treatment consists of 3 treatment phases and the maximum planned duration of treatment 
is 17 cycles. Planned durations of each treatment phase are:

Induction phase: 1 or 2 cycles (daunorubicin/idarubicin, cytarabine and 
midostaurin/placebo). The maximum length of the first induction cycle is 43 days (28 days 
plus potentially up to 14 additional days for adequate blood count recovery plus 1 day 
prior to the start of the next cycle. Patients not achieving CR or CRi after Induction 1 will 


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get a second cycle of Induction. The maximum length of the second induction cycle is 50 
days (28 days plus potentially up to 21 additional days for adequate blood count recovery
plus 1 day prior to the start of the next cycle).

Consolidation phase: Patients who achieved CR or CRi with adequate blood count 
recovery after induction 1 therapy will receive 4 cycles of consolidation (intermediate-
dose cytarabine and midostaurin/placebo). Patients achieving CR or CRi with adequate 
blood count recovery only after induction 2 therapy will receive 3 cycles of consolidation.
One cycle length is planned to be 28 days whereas the maximum length of each 
consolidation cycle is 50 days (28 days plus potentially up to 21 additional days for 
adequate blood count recovery plus 1 day prior to the start of the next cycle). 

Post-consolidation phase : 12 cycles (midostaurin/placebo). Each cycle is 28 days.
Patients may be discontinued from treatment prior to completion of study therapy for reasons 
of unacceptable toxicity, induction failure, relapse from CR/CRi with adequate blood count 
recovery, withdrawal of consent, failure to abide by the protocol, or at the discretion of the 
investigator.
6.2
Dose escalation guidelines 
Not applicable.
6.3
Dose modifications
6.3.1
Dose modification and dose delay
For patients who do not tolerate the protocol-specified dosing schedule, dose interruptions 
and/or reductions are either recommended or mandated in order to allow patients to continue 
the study treatment.
These dose modifications are summarized in Table 6-2. Deviations to mandatory dose 
interruptions and/or reductions are not allowed. Permanent treatment discontinuation is 
mandatory for specific events indicated as such in Table 6-2.
These dose changes must be recorded on the appropriate CRF.
Study drug (midostaurin/placebo)
Table 6-2 describes toxicities (i.e., adverse drug reactions), laboratory values, or other 
assessments that require interruption or dose modification of study drug. Whether an AE that 
is not considered to be caused by the study treatment requires modifications needs to be 
assessed by the investigator. The need for modification in case of non-drug related AEs 
depends on the type of these AEs.
During induction and consolidation therapies, modifications must be done in case of non-
hematologic toxicities, i.e., ADRs (pulmonary, cardiac or other non-hematologic toxicities).
During post-consolidation therapy, modifications must be done in case of hematologic and 
non-hematologic toxicities (pulmonary, cardiac or other non-hematologic toxicities).
If interruptions occur, missed doses of study drug will not be made up.


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Study drug interruptions of greater than 28 consecutive days will require discontinuation from 
study treatment, unless the patient undergoes HSCT as in that case the drug interruption can 
be longer than 28 consecutive days (please refer to section 6.1.1 for more detailed 
information).
Cytarabine
Doses will be modified only during the consolidation phase with intermediate-dose cytarabine 
and in case of neurotoxicity, hematology and non-hematology toxicity. Please refer to Table 
6-2.
Idarubicin/ Daunorubicin
Doses will be modified during induction phase in case of hepatotoxicity, hematology and non-
hematology toxicity. Please refer to Table 6-2.


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Table 6-2
Criteria for dose reduction/interruption and re-initiation of midostaurin/placebo, daunorubicin/idarubicin and 
cytarabine treatment for adverse drug reactions
Dose modifications for midostaurin/placebo
Hematologic toxicities
During induction and consolidation 
cycles
No dose modifications are required for hematologic toxicity due to midostaurin/placebo during induction and 
consolidation therapy.
During post-consolidation cycles
In the presence of grade 4 neutropenia during post-consolidation therapy, midostaurin/placebo must be held until 
Absolute Neutrophil Count (ANC) ≥ 1.0 x 109/L.
Once ANC ≥ 1.0 x 109/L, then resume midostaurin/placebo at the previous dose. 
If neutropenia persists for more than two weeks, then discontinue midostaurin/placebo protocol therapy.
Non-Hematologic toxicities: 

Pulmonary toxicities
During induction, consolidation and 
post-consolidation cycles
For ≥ grade 3 pulmonary infiltrate, midostaurin/placebo must be interrupted for the remainder of the cycle. 
Resume midostaurin/placebo at the same dose when infiltrate resolves to ≤grade 1.
Missed doses of midostaurin/placebo will not be made up. If there is no improvement after 28 days, the patient 
must be discontinued from study drug.

Cardiac Toxicity
During induction, consolidation and 
post-consolidation cycles

For QTcF interval > 470 ms and ≤ 500 ms, check magnesium and potassium levels and correct any 
abnormalities. If possible, stop any medications that may prolong the QTcF interval. Decrease 
midostaurin/placebo to 50 mg once daily for the remainder of the cycle. Resume midostaurin/placebo at the 
initial dose in the next cycle provided that QTcF interval improves to ≤ 470 ms at the start of that cycle. 
Otherwise continue midostaurin/placebo 50 mg once daily.

For QTcF interval > 500 ms and/or QTcF prolongation >60 ms from baseline, check magnesium and 
potassium levels and correct any abnormalities. Hold or interrupt midostaurin/placebo for the remainder of the 
cycle, and, if possible, stop any medications that may prolong the QTcF interval. If QTcF improves to ≤ 470 ms 
just prior to the next cycle, resume midostaurin/placebo at the initial dose. If QTcF interval is not improved to ≤ 
470 ms in time to start the next cycle, midostaurin/placebo may be held up to 28 days. If there is no 
improvement after 28 days, the patient must be discontinued from study drug.

Other Non-Hematologic toxicity


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During induction and consolidation 
cycles

Grade 1/2: No dose modifications for any grade 1 or 2 non-hematologic toxicity.

Grade 3/4: If a patient experiences other grade 3/4 non-hematologic toxicity considered related to 
midostaurin/placebo, midostaurin/placebo will be interrupted until toxicity resolves to ≤ grade 1. If the toxicity 
resolves prior to day 21, then restart at same dose to complete current cycle. Missed doses of 
midostaurin/placebo will not be made up. A study drug interruption in excess of 28 days will require 
discontinuation of study treatment.
During post-consolidation cycles

Grade 1/2: Persistent grade 1 or 2 toxicity during post-consolidation therapy that patients deem to be 
unacceptable may prompt a study drug interruption for as long as 28 days. A study drug interruption in excess 
of 28 days will require discontinuation of study treatment.

Grade 3/4: For other grade 3/4 non-hematologic toxicities that are considered to be related to 
midostaurin/placebo, interrupt midostaurin/placebo. Resume midostaurin/placebo at the same dose when 
toxicity resolves to ≤grade 2. If midostaurin/placebo is held for more than 28 days, then discontinue 
midostaurin/placebo post-consolidation therapy.
Dose modifications for intermediate-dose cytarabine (IDAC) induction 2 if applicable and consolidation therapy
During Induction 2 if applicable and
consolidation cycles
Dose reduction according to institutional guidelines except in case of neurotoxicity dose modifications as below:
Contributions of concomitant medications to neurotoxicity should be assessed and other medications discontinued 
if possible.
For neurotoxicity ≥ grade 2 due to intermediate-dose cytarabine, discontinue cytarabine for the remainder of the 
cycle. Intermediate-dose cytarabine may be considered at the next consolidation therapy cycle with a dose 
modification from 1500mg/m2 to 1000mg in patients <60 years of age and from 1000mg/m2 to 600mg/mg2 in 
patients ≥60 of age if the toxicity has resolved to ≤ grade 1.
For a second occurrence of neurotoxicity ≥ grade 2, intermediate-dose cytarabine should be permanently 
discontinued.


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Dose modifications for daunorubicin 
Dose reduction according to institutional guidelines except in case of hepatotoxicity dose modifications as below:
During induction cycles
Total Bilirubin (mg/dL)
% daunorubicin dose to administer
≤ 1.2
100%
> 1.2 – ≤ 3.0
75% (25% dose reduction)
> 3.0
50% (50% dose reduction)
Dose modifications for idarubicin
Dose reduction according to Prescribing Information: 
Idarubicin should not be administered if the serum bilirubin level exceeds 5 mg/100 ml. 
In patients with hepatic and/or renal impairment, a dose reduction of idarubicin should be considered.
Patients with serum creatinine concentrations of greater than 3 mg/dL should receive 50% of the usual daily daunorubicin dose.
All dose modifications should be based on the worst preceding toxicity. Common Toxicity Criteria for Adverse Events (CTCAE Version 5.0)


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6.3.2
Dose adjustments for QTcF prolongation
In case of QTcF >500 ms, (or QTcF prolongation >60 ms from baseline)
1. Assess the quality of the ECG recording and the QT value and repeat if needed
2. Interrupt study treatment
3. Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia). If 
abnormal, correct abnormalities before resuming study drug treatment.
4. Review concomitant medication associated with QT prolongation, including drugs with a 
“Known”, “Possible”, or “Conditional risk of Torsades de Pointes”, and drugs with the 
potential to increase the risk of study drug exposure related QT prolongation 
5. Check study drug dosing schedule and treatment compliance
6. Consider collecting a time-matched PK sample, and record time and date of last study 
drug intake.
7. Note that measurements of QTcF ≥480ms shall be centrally verified on a copy of the 
original high quality recording that includes time and voltage scales
After confirming ECG reading at site, if QTcF > 500 ms

Interrupt study treatment

Repeat ECG and confirm ECG diagnosis by a cardiologist 

If QTcF confirmed > 500 ms:

Correct electrolytes, eliminate culprit concomitant treatments, and identify and 
address clinical conditions that could potentially prolong the QT 

Consult with a cardiologist (or qualified specialist)

Increase cardiac monitoring as indicated, until the QTcF returns to ≤ 470 ms.

After resolution to ≤ 470 ms, consider re-introducing treatment at reduced dose, and 
increase ECG monitoring for the next treatment(s):

If QTcF remains ≤ 500 ms after dose reduction, continue planned ECG monitoring 
during subsequent treatment

If QTcF recurs > 500 ms after dose reduction, discontinue patient from study drug.
6.3.3
Follow-up for toxicities
Please refer to IB for AEs of special interest.
6.3.3.1
Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with total bilirubin (TBIL) increase may be 
indicative of potential DILI, and should be considered as clinically important events.
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:

For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN


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
For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or 
elevation of ALP liver fraction in patients with bone metastasis.
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury).
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat liver function testing (LFT) as soon as possible, preferably within 
48 hours from the awareness of the abnormal results. The evaluation should include 
laboratory tests, detailed history, physical assessment and the possibility of liver metastasis or 
new liver lesions, obstructions/compressions, etc.
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, gamma-glutamyl transferase (GGT), prothrombin time 
(PT)/international normalized ratio (INR) and alkaline phosphatase.
2 . A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted.
4. Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is 
performed in the study.
5. Additional testing for other hepatotropic viral infection (cytomegalovirus (CMV), Epstein-
Barr virus (EBV) or herpes simplex virus (HSV)), autoimmune hepatitis or liver biopsy 
may be considered as clinically indicated or after consultation with specialist/hepatologist.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the 
term “potential drug-induced liver injury”. All events should be followed up with the outcome 
clearly documented.
6.4
Concomitant medications 
Administration of certain concomitant medications may lead to the requirement for subject to 
be discontinued. Such cases should be discussed with the sponsor on a case by case basis.
6.4.1
Permitted concomitant therapy
Supportive therapy including prophylactic antibiotic and antifungal treatments, transfusions, 
growth factors etc. will be administered at the discretion of the investigators according to 
standard of care.


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The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy, herbal/natural medications and blood 
transfusions) administered during the study must be listed on the Prior or Concomitant non-
drug therapies/procedures CRF.
6.4.2
Permitted concomitant therapy requiring caution and/or action 
Strong CYP3A4 inhibitors should be used with caution due to potential increase in 
midostaurin exposure. Alternative medicinal products that do not strongly inhibit CYP3A4 
activity should be considered. In situations where satisfactory therapeutic alternatives do not 
exist, patients should be closely monitored for midostaurin-related toxicity. 
Based on in vitro data, midostaurin and its active metabolites may have the potential to inhibit 
P-glycoprotein (P-gp), BCRP, and OATP1B1. Midostaurin, CGP62221 and CGP52421 can 
potentially induce the following CYPs: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP3A4 and inhibit the following ones: CYP1A2, CYP2C8, CYP2C9, CYP2D6, CYP2E1, 
CYP3A4/5. In absence of clinical data medicinal products with a narrow therapeutic range 
that are substrates of these CYPs should be used with caution when administered 
concomitantly with midostaurin, and may need dose adjustment to maintain optimal exposure.
Therefore medicinal products with a narrow therapeutic range that are substrates of CYP1A2, 
CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4/5, P-gp, BCRP or OATP1B1 
should be used with caution when administered concomitantly with midostaurin and may need 
dose adjustment to maintain optimal exposure.
A list of strong CYP3A4 inhibitors, substrates with narrow therapeutic index for CYP1A2, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A and P-gp and 
substrates of BCRP and OATP1B1 is available in Appendix 1.
6.4.3
Prohibited concomitant therapy
Strong CYP3A4 inducers: Concomitant use of midostaurin/placebo with strong inducers of 
CYP3A4 should be avoided. Strong CYP3A4 inducers decrease exposure of midostaurin and 
its active metabolites (CGP52421 and CGP62221). In a study in healthy subjects, 
coadministration of the strong CYP3A4 inducer rifampicin (rifampin, 600 mg daily) to steady 
state with a single dose of midostaurin decreased midostaurin Cmax by 73% and -AUCinf by 
96% in average, respectively. CGP62221 exhibited a similar pattern. The mean AUClast of 
CGP52421 decreased by 60%. In absence of clinical data, the impact of strong CYP3A4 
inducers on midostaurin exposure at steady-state was investigated based on physiologically-
based PK models. Exposure was predicted to be decreased by 60%.
A list of strong inducers of CYP3A4 is available in Appendix 1.
Other prohibited concomitant medications: If concomitant administration of drugs with a 
“known risk of torsades de pointes (TdP)” is required and cannot be avoided, then the study 
drug must be interrupted. If, based on the investigator assessment and clinical need, study 
treatment is resumed, close ECG monitoring is advised. Note that measurements of 
QTc≥480ms shall be centrally verified on a copy of a high quality recording that includes time 
and voltage scales.


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If during the course of the study, concomitant administration of a drug with ¨Possible risk of 
TdP ¨ or ¨Conditional risk of TdP¨ is required, based on the investigator assessment and 
clinical need, study treatment may be continued with close ECG monitoring to ensure patient 
safety. A list of drugs associated with QT prolongation and/or TdP is available online at 
[www.qtdrugs.org].
As far as possible avoid co-administering drugs with a “Known”, “Possible”, or “Conditional” 
risk of TdP during the course of the study:

If concomitant administration of drugs with a “Known risk of TdP” is required and cannot 
be avoided, study drug must be interrupted. If, based on the investigator assessment and 
clinical need, study treatment is resumed, close ECG monitoring is advised. 

If during the course of the study, concomitant administration of a drug with ¨Possible risk¨ 
or ¨Conditional risk of TdP¨ is required, based on the investigator assessment and clinical 
need, study treatment may be continued under close ECG monitoring to ensure patient 
safety.
A list of drugs associated with QT prolongation and/or TdP is available online at 
[www.qtdrugs.org]
6.4.4
Use of Bisphosphonates (or other concomitant agents) 
Not Applicable.
6.5
Patient numbering, treatment assignment or randomization
6.5.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned 
when the patient is first enrolled for screening and is retained as the primary identifier for the 
patient throughout his/her entire participation in the trial. The Subject No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a 
sequential subject number suffixed to it, so that each subject is numbered uniquely across the 
entire database. Upon signing the informed consent form, the patient is assigned to the next 
sequential Subject No. available to the investigator through the Clinical Data Management 
System interface.
The investigator or designated staff will contact Interactive Response Technology (IRT) and 
provide the requested identifying information for the patient to register them into IRT. Once 
assigned, the Subject No. must not be reused for any other subject and the Subject No. for that 
individual must not be changed, even if the patient is re-screened. If the patient fails to be 
randomized or start treatment for any reason, the reason will be entered into the Disposition 
page.
IRT must be notified within 2 days that the patient was not randomized.
6.5.2
Treatment assignment or randomization
Patients will be assigned to one of the 2 treatment arms, midostaurin or placebo (Section 4.1
and Section 6.1) in a ratio of 1:1. 


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Randomization will be stratified by age (<60 versus 60 years).
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and is concealed from patients and investigator staff. A 
patient randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication randomization list will be produced by or under 
the responsibility of Novartis Drug Supply Management using a validated system that 
automates the random assignment of medication numbers to medication packs containing 
each of the study treatments.
On study Day 8, all patients who fulfill all inclusion/exclusion criteria, including
demonstrated FLT3-NM AML as confirmed by a Novartis-designated laboratory, and who 
have begun induction chemotherapy will be randomized via IRT to one of the treatment arms. 
The investigator or delegate will call or log on to the IRT and confirm that the patient fulfills 
all the inclusion/exclusion criteria. The IRT will assign a randomization number to the patient, 
which will be used to link the patient to a treatment arm and will specify a unique medication 
number for the first package of study drug to be dispensed to the patient. The randomization 
number will not be communicated to the caller.
6.5.3
Treatment blinding
Patients, investigators, site personnel, study team members, and anyone involved in the study 
conduct will remain blinded to the identity of the study drug from the time of randomization 
until database lock for the EFS analysis.
Randomization data will be kept strictly confidential until the time of unblinding and will not 
be accessible to anyone involved in the conduct of the study except for the independent 
biostatistician who will perform the interim analysis and the bioanalyst to avoid the 
unnecessary analysis of placebo samples. The identity of the study drug will be concealed by 
the use of study drug (midostaurin or placebo) that is identical in packaging, labeling, 
schedule of administration, appearance, and odor. Confidentiality of randomization data is 
required to limit the occurrence of potential bias arising from the influence that the knowledge 
of treatment may have on the recruitment and allocation of patients.
Unblinding of study drug assignment will only occur in the case of patient emergencies
(Section 8.3), at the time of the interim analysis (see Section 10.7), for regulatory reporting 
purposes and at the conclusion of the study. 
In rare cases when unblinding occurs because of emergency patient management, the actual
treatment arm will not be communicated to any Novartis employee involved in the trial 
conduct in order to maintain their blinded status.
6.6
Study drug preparation and dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the appropriate CRF.


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Study drug provided is midostaurin 25 mg and matching placebo control. Study drug will be 
supplied by Novartis as capsules and will be packaged in child-resistant blisters. Each blister 
pack contains eight capsules, and each medication kit contains eight blisters for a total of 
sixty-four capsules per kit.
Study treatment provided is daunorubicin/ idarubicin and cytarabine. They will be procured 
locally according to local practice and regulation, or supplied by Novartis (or its designee).
Table 6-3
Dispensing and preparation
Study treatments
Dispensing
Preparation
Midostaurin or 
Placebo
Capsules 
including 
instructions 
for 
administration are dispensed by study 
personnel on an outpatient basis.
Patients will be provided with adequate 
supply 
of 
study 
drug 
for 
self-
administration at home until at least 
their next scheduled study visit.
Not applicable
Daunorubicin or 
Idarubicin
Not applicable
Refer to product information
Cytarabine
Not applicable
Refer to product information
6.6.1
Study treatment packaging and labeling
Study drug: midostaurin/placebo:
Midostaurin/placebo will be provided as global clinical blinded supply and will be packed and 
labeled under the responsibility of Novartis Drug Supply Management. 
Labels for midostaurin/placebo will comply with the legal requirements of each country and 
will include storage conditions and a unique medication number (corresponding to study 
treatment and strength).  Responsible site personnel will identify the study drug package(s) to 
be dispensed by the medication number(s) assigned by IRT to the patient. Site personnel will 
add the subject number on the label. The label has 2-parts (base plus tear-off label); 
immediately before dispensing the package to the patient, site personnel will detach the outer 
part of the label from the package and affix it to the patient’s source document.
Chemotherapy: daunorubicin/idarubicin and cytarabine:
Daunorubicin/idarubicin and cytarabine will be procured locally according to local practice 
and regulation, or supplied by Novartis (or its designee).
6.6.2
Drug supply and storage
Study treatments must be received by designated personnel at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator and 
designated site personnel have access. Upon receipt, the study treatment should be stored 
according to the instructions specified on the drug labels and in the Investigator’s Brochure 
for midostaurin/placebo or the package insert for daunorubicin/idarubicin and cytarabine.
These instructions should be made clear to the patient for storage and self-administration of 
midostaurin/placebo at home.


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Site staff will be responsible for managing re-supplies for the chemotherapy 
(daunorubicin/idarubicin and cytarabine) 
Midostaurin/placebo will be managed by IRT system. 
Table 6-4
Supply and storage of study treatments
Study treatments
Supply
Storage
Midostaurin/Placebo
Centrally supplied by Novartis
Refer to study drug label
Daunorubicin/Idarubicin
Cytarabine
Procured locally according to 
local practice and regulation, 
or supplied by Novartis (or its 
designee).
Refer to local product information
6.6.3
Study drug compliance and accountability
6.6.3.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each patient visit, 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
patient visit.
6.6.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis (or Contract Research Organization (CRO)) 
monitor or to the Novartis address provided in the investigator folder at each site.
6.6.3.3
Handling of other study treatment
Not applicable.
6.6.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. Arrange for drug supply to be destroyed at the site only if 
permitted by local regulations and authorized by Novartis in a prior agreement.
Drug supplies will be destroyed only after the approval of monitor and after the completion of 
drug accountability reconciliation. 


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7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation.
The table indicates which assessments produce data to be entered into the clinical database (D) 
or remain in source documents only (S) (“Category” column). No CRF will be used as a 
source document. 
Allowed visit windows are specified as follows: 

Screening assessments listed below, must occur within 14 days prior to Day 1 as per Table 
7-1. 

During each induction and consolidation cycle, PK and ECG assessments must be 
performed on the specified day. Local measurements of QTc≥480ms will be centrally 
verified on a copy of a high quality recording that includes time and voltage scales.

All other assessments should not exceed a 5 day window to take into account scheduling 
over public holidays if not explicitly specified otherwise. 
Every effort should be made to follow the schedule outlined in Table 7-1.


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Table 7-1
Visit evaluation schedule
A: Screening until end of consolidation phase
Category
Protocol Section 
Screening Phase
Induction Phase
Cycle 1 -2
End of Induction 
Phase / EOT
Prior to each cycle of
Consolidation phase
Consolidation Phase/HSCT
Cycle 1-4
End of Consolidation 
Phase / EOT
Visit name
D
S
C
R
INDUCTION C1-C2
IND 
DISPOSI
TION
CONSOLIDATION C1- C4
CON 
DISPO
SITION
Day of cycle 
-14 to -1
1
2
3
4
5
7
8
11
15
18
21
24
27
28
1
2
3
4
8
11
15
17
21
27
28
Informed 
consent
Obtain 
study  
Informed 
Consent 
D
x
IRT
Registration
D
x
Randomizat
ion:
I1, D8: 
when FLT3 
mutation 
status is 
confirmed
D
x
I 1


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Category
Protocol Section 
Screening Phase
Induction Phase
Cycle 1 -2
End of Induction 
Phase / EOT
Prior to each cycle of
Consolidation phase
Consolidation Phase/HSCT
Cycle 1-4
End of Consolidation 
Phase / EOT
Visit name
D
S
C
R
INDUCTION C1-C2
IND 
DISPOSI
TION
CONSOLIDATION C1- C4
CON 
DISPO
SITION
Day of cycle 
-14 to -1
1
2
3
4
5
7
8
11
15
18
21
24
27
28
1
2
3
4
8
11
15
17
21
27
28
Patient 
history
Diagnosis 
D
x
Disease 
history 
D
x
Demograph
y
D
x
Inclusion/ 
exclusion 
criteria
D
x
Eligibility 
checklist
I1,D8
D
x
x
FLT3 
mutation 
status
D
x
Cytogenetic
s 
D
x
Medical 
History 
D
x


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Category
Protocol Section 
Screening Phase
Induction Phase
Cycle 1 -2
End of Induction 
Phase / EOT
Prior to each cycle of
Consolidation phase
Consolidation Phase/HSCT
Cycle 1-4
End of Consolidation 
Phase / EOT
Visit name
D
S
C
R
INDUCTION C1-C2
IND 
DISPOSI
TION
CONSOLIDATION C1- C4
CON 
DISPO
SITION
Day of cycle 
-14 to -1
1
2
3
4
5
7
8
11
15
18
21
24
27
28
1
2
3
4
8
11
15
17
21
27
28
Prior 
antineoplast
ic 
medications 
D
x
Prior/ 
concomitant 
medications 
and 
procedures 
including 
blood 
transfusions
.
D
x
Continuous


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Category
Protocol Section 
Screening Phase
Induction Phase
Cycle 1 -2
End of Induction 
Phase / EOT
Prior to each cycle of
Consolidation phase
Consolidation Phase/HSCT
Cycle 1-4
End of Consolidation 
Phase / EOT
Visit name
D
S
C
R
INDUCTION C1-C2
IND 
DISPOSI
TION
CONSOLIDATION C1- C4
CON 
DISPO
SITION
Day of cycle 
-14 to -1
1
2
3
4
5
7
8
11
15
18
21
24
27
28
1
2
3
4
8
11
15
17
21
27
28
Physical examination 
(7.2.2.1)
Performanc
e status
D
7.2.
2.4
x
x
x (at 
EOT)
x
x
x
x (at 
EOT)
Height 
D
7.2.
2.3
x
Weight  
D
7.2.
2.3
x
x
x (at 
EOT)
x
x (at 
EOT)
Vital signs
D
7.2.
2.2
x
x
x
x
x
x
x (at 
EOT)
x
x
x
x
x
x
x (at 
EOT)
Physical 
examination
S
7.2.
2.1
x
x
x
x
x
x
x
x
x
x
x (at 
EOT)
x
x
x
x
x
x
x (at 
EOT)
Lab assessments
(see Table 7-5 )
Hematology
D
7.2.
2.5.
1
x
x
x
x
x
x
x
x
x
x
x (at 
EOT)
x
x
x
x
x
x
x (at 
EOT)
Chemistry
B: Tot 
Bilirubin 
only
D
7.2.
2.5.
2
x
x
x
B
x
B
x
x
x
x (at 
EOT)
x
x
x
x
x
x (at 
EOT)


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Category
Protocol Section 
Screening Phase
Induction Phase
Cycle 1 -2
End of Induction 
Phase / EOT
Prior to each cycle of
Consolidation phase
Consolidation Phase/HSCT
Cycle 1-4
End of Consolidation 
Phase / EOT
Visit name
D
S
C
R
INDUCTION C1-C2
IND 
DISPOSI
TION
CONSOLIDATION C1- C4
CON 
DISPO
SITION
Day of cycle 
-14 to -1
1
2
3
4
5
7
8
11
15
18
21
24
27
28
1
2
3
4
8
11
15
17
21
27
28
Coagulation
D
7.2.
2.5.
3
x
x
x
x
x
x
Other 
hepatic 
tests in 
case of 
suspected 
DILI 
D
6.3.
3.1
If clinically indicated
Urinalysis 
dipstick and 
sediment
D
7.2.
2.5.
4
x
If clinically indicated
If clinically indicated
Serum (S) 
or Urine (U) 
Pregnancy 
test 
S
7.2.
2.5.
5
x
S
x
U
x (U at 
EOT)
x
U
x (U at 
EOT)
Imaging/other 
assessments
Chest X-ray 
D
7.2.
2.6
x
If clinically indicated
ECG (Table 
7-7)
D
7.2.
2.7.
1
x
x
I1 
x
I1 
x
I1 
x (at 
EOT)
x
x
x (at 
EOT)
Cardiac 
D
7.2.
x
If clinically indicated


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Page 75
Amended Oncology Protocol Version No. 01 (Clean)
Protocol No. CPKC412E2301
Category
Protocol Section 
Screening Phase
Induction Phase
Cycle 1 -2
End of Induction 
Phase / EOT
Prior to each cycle of
Consolidation phase
Consolidation Phase/HSCT
Cycle 1-4
End of Consolidation 
Phase / EOT
Visit name
D
S
C
R
INDUCTION C1-C2
IND 
DISPOSI
TION
CONSOLIDATION C1- C4
CON 
DISPO
SITION
Day of cycle 
-14 to -1
1
2
3
4
5
7
8
11
15
18
21
24
27
28
1
2
3
4
8
11
15
17
21
27
28
MUGA/
ECHO
2.7.
2
Efficacy/ disease assessments  (see Section 7.2.1 for details)
Microscopic 
peripheral 
blood exam 
incl. full 
differential 
count
D
x
x
(and up to 2 and 
3 weeks after day 
28 for induction1 
and 2 respectively 
for patients in CRi 
without adequate 
blood count 
recovery)
x 
(at time 
of 
relapse)
x
(and up to 
3 weeks 
after day 
28 for 
patients in 
CRi 
without 
adequate 
blood 
count 
recovery)
x 
(at 
time 
relaps
e)


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Amended Oncology Protocol Version No. 01 (Clean)
Protocol No. CPKC412E2301
Category
Protocol Section 
Screening Phase
Induction Phase
Cycle 1 -2
End of Induction 
Phase / EOT
Prior to each cycle of
Consolidation phase
Consolidation Phase/HSCT
Cycle 1-4
End of Consolidation 
Phase / EOT
Visit name
D
S
C
R
INDUCTION C1-C2
IND 
DISPOSI
TION
CONSOLIDATION C1- C4
CON 
DISPO
SITION
Day of cycle 
-14 to -1
1
2
3
4
5
7
8
11
15
18
21
24
27
28
1
2
3
4
8
11
15
17
21
27
28
Microscopic 
exam of 
bone 
marrow 
aspirate/ 
biopsy for 
morphology 
& bone 
marrow 
differential 
count
D
x
x
x 
(at time 
of 
relapse)
x
x 
(at 
time of 
relaps
e)
Extramedull
ary disease 
assessment 
(physical 
exam and 
CNS 
symptom 
assessment
) 
D
x
x
x
x
Investigator 
assessment 
of Disease 
Response 
D
x
(and up to 2 and 
3 weeks after day 
28 for induction1 
and 2 respectively 
for patients in CRi 
x
x
x
(and up to 
3 weeks 
after day 
28 for 
patients in 
x


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Amended Oncology Protocol Version No. 01 (Clean)
Protocol No. CPKC412E2301
Category
Protocol Section 
Screening Phase
Induction Phase
Cycle 1 -2
End of Induction 
Phase / EOT
Prior to each cycle of
Consolidation phase
Consolidation Phase/HSCT
Cycle 1-4
End of Consolidation 
Phase / EOT
Visit name
D
S
C
R
INDUCTION C1-C2
IND 
DISPOSI
TION
CONSOLIDATION C1- C4
CON 
DISPO
SITION
Day of cycle 
-14 to -1
1
2
3
4
5
7
8
11
15
18
21
24
27
28
1
2
3
4
8
11
15
17
21
27
28
without adequate 
blood count 
recovery)
CRi 
without 
adequate 
blood 
count 
recovery)
BMA for 
Flow 
cytometry 
MRD
D
x
x
x 
(at time 
of 
relapse)
x
(C1 only)
x
(at 
time of 
relaps
e)
Safety
Adverse 
events
D
8.1
x
Continuous
Pharmaco
kinetics
PK 
sampling 
(Tables 7-8
& 7-9)
D
7.2.
3
x
I 1
x
I 1
x
I 1
x
I 1
x
I 1
x 
C
1
&
3
x
C
1
&
3


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Amended Oncology Protocol Version No. 01 (Clean)
Protocol No. CPKC412E2301
Category
Protocol Section 
Screening Phase
Induction Phase
Cycle 1 -2
End of Induction 
Phase / EOT
Prior to each cycle of
Consolidation phase
Consolidation Phase/HSCT
Cycle 1-4
End of Consolidation 
Phase / EOT
Visit name
D
S
C
R
INDUCTION C1-C2
IND 
DISPOSI
TION
CONSOLIDATION C1- C4
CON 
DISPO
SITION
Day of cycle 
-14 to -1
1
2
3
4
5
7
8
11
15
18
21
24
27
28
1
2
3
4
8
11
15
17
21
27
28


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Amended Oncology Protocol Version No. 01 (Clean)
Protocol No. CPKC412E2301
Category
Protocol Section 
Screening Phase
Induction Phase
Cycle 1 -2
End of Induction 
Phase / EOT
Prior to each cycle of
Consolidation phase
Consolidation Phase/HSCT
Cycle 1-4
End of Consolidation 
Phase / EOT
Visit name
D
S
C
R
INDUCTION C1-C2
IND 
DISPOSI
TION
CONSOLIDATION C1- C4
CON 
DISPO
SITION
Day of cycle 
-14 to -1
1
2
3
4
5
7
8
11
15
18
21
24
27
28
1
2
3
4
8
11
15
17
21
27
28
  Biomarkers (7.2.4) (for detailed biomarker collection plan, 
please refer to Table 7-11)
BMA for 
DNA, and 
RNA 
analysis 
(MRD 
 
D
x
x
x 
(at time 
of 
relapse)
x
(C1 only)
x
(at 
time of 
relaps
e)
Whole 
blood for 
DNA and 
RNA 
analysis 
(MRD 
 
D
x
x
x
(at EOT)
x
(C1 and 
C3) 
x
(at 
EOT)


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Amended Oncology Protocol Version No. 01 (Clean)
Protocol No. CPKC412E2301
Category
Protocol Section 
Screening Phase
Induction Phase
Cycle 1 -2
End of Induction 
Phase / EOT
Prior to each cycle of
Consolidation phase
Consolidation Phase/HSCT
Cycle 1-4
End of Consolidation 
Phase / EOT
Visit name
D
S
C
R
INDUCTION C1-C2
IND 
DISPOSI
TION
CONSOLIDATION C1- C4
CON 
DISPO
SITION
Day of cycle 
-14 to -1
1
2
3
4
5
7
8
11
15
18
21
24
27
28
1
2
3
4
8
11
15
17
21
27
28
Patient reported outcomes
FACT-G
with FACT-
Leu
EQ-5D-5L
D
7.2.
6
x
x
x (at 
EOT)
x
x (at 
EOT)


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Amended Oncology Protocol Version No. 01 (Clean)
Protocol No. CPKC412E2301
Category
Protocol Section 
Screening Phase
Induction Phase
Cycle 1 -2
End of Induction 
Phase / EOT
Prior to each cycle of
Consolidation phase
Consolidation Phase/HSCT
Cycle 1-4
End of Consolidation 
Phase / EOT
Visit name
D
S
C
R
INDUCTION C1-C2
IND 
DISPOSI
TION
CONSOLIDATION C1- C4
CON 
DISPO
SITION
Day of cycle 
-14 to -1
1
2
3
4
5
7
8
11
15
18
21
24
27
28
1
2
3
4
8
11
15
17
21
27
28
Disposition 
D
x
x
x
IRT
Dispensatio
n 
Midostaurin/
Placebo
D
x
(I
2 
on
ly)
x
(I
1 
on
ly)
x
Treatment 
Discontinua
tion
D
x (at 
EOT)
x (at 
EOT)
Study treatment 
administration
Midostaurin 
/ Placebo  
D
Induction 1: Continuous twice daily Day 8 until 48 hrs 
prior to start of next cycle
Induction 2: Continuous twice daily Day 4 until 48 hrs 
prior to start of next cycle
Continuous twice daily Day 4 until 48 hrs prior to start of next 
cycle
Daunorubici
n/ Idarubicin 
I 2 <60 
years only
D
6.1
x
x
x
Cytarabine
D
6.1
x
x
x
x
I 1
x
I 1
x
I 1
x
x
x


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Amended Oncology Protocol Version No. 01 (Clean)
Protocol No. CPKC412E2301
B: End of consolidation phase until end of study
Category
Protocol Section
Prior to 1st
cycle of post-
consolidation 
Phase
Post-consolidation Phase 
Cycle 1-12
End of post-
consolidation Phase 
/EoT
30 
day 
safety
follow 
up 
Post 
treatment 
follow up
(until 5 
years after 
the last day 
of study 
treatment of 
the last 
patient,  
failure, 
relapse or 
death 
whichever 
occurs first)
Surviva
l follow 
up (until 
5 years 
after last 
day of 
study 
treatme
nt  of 
the last 
patient)
Visit name 
D  
Post-Consolidation C1-C12
Day of cycle 
1
15
Patient history
Prior/concomitant medications 
and procedures including blood 
transfusions.
D
continuous
Antineoplastic therapies after 
discontinuation of study treatment 
D
x
Every 3 
months
Every  3 
months 
Transplant after discontinuation of 
study treatment
D
x
Every 3 
months
Every 3
months
Physical examination
Performance status
D
7.2.2.4
x
x
x
x
Weight 
D
7.2.2.3
x
x
x
Vital signs
D
7.2.2.2
x
x
x
x


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Amended Oncology Protocol Version No. 01 (Clean)
Protocol No. CPKC412E2301
Category
Protocol Section
Prior to 1st
cycle of post-
consolidation 
Phase
Post-consolidation Phase 
Cycle 1-12
End of post-
consolidation Phase 
/EoT
30 
day 
safety
follow 
up 
Post 
treatment 
follow up
(until 5 
years after 
the last day 
of study 
treatment of 
the last 
patient,  
failure, 
relapse or 
death 
whichever 
occurs first)
Surviva
l follow 
up (until 
5 years 
after last 
day of 
study 
treatme
nt  of 
the last 
patient)
Visit name 
D  
Post-Consolidation C1-C12
Day of cycle 
1
15
Physical examination 
S
7.2.2.1
x
x
x
x
Lab assessments (see Table 7-5)
Hematology
D
7.2.2.5.1
x
x
x
(C1 and C2 
post-
consolidation 
only if no 
grade 2 or 
higher 
anemia, 
thrombocyto
penia, or 
neutropenia )
x
Every 3 
months until 
relapse
Chemistry
D
7.2.2.5.2
x
x
x
Other hepatic tests in case of 
suspected DILI
D
6.3.3.1
If clinically indicated
Urinalysis dipstick and sediment
D
7.2.2.5.4
If clinically indicated


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Amended Oncology Protocol Version No. 01 (Clean)
Protocol No. CPKC412E2301
Category
Protocol Section
Prior to 1st
cycle of post-
consolidation 
Phase
Post-consolidation Phase 
Cycle 1-12
End of post-
consolidation Phase 
/EoT
30 
day 
safety
follow 
up 
Post 
treatment 
follow up
(until 5 
years after 
the last day 
of study 
treatment of 
the last 
patient,  
failure, 
relapse or 
death 
whichever 
occurs first)
Surviva
l follow 
up (until 
5 years 
after last 
day of 
study 
treatme
nt  of 
the last 
patient)
Visit name 
D  
Post-Consolidation C1-C12
Day of cycle 
1
15
Urine  Pregnancy test
S
7.2.2.5.5
x
x
x
Imaging/other assessments
Chest X-ray 
D
7.2.2.6
If clinically indicated
ECG (Table 7-6)
D
7.2.2.7.1
x
x
(C 2 to C 12)
Completion of C12 or at 
EOT
x
Cardiac
MUGA/ECHO
D
7.2.2.7.2
If clinically indicated
x
Safety
Adverse events
D
8.1
Continuous
Pharmacokinetics
PK sampling (see Tables 7-8 & 7-
9)
D
7.2.3
x
C4, C7, C10
Completion of C12


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Amended Oncology Protocol Version No. 01 (Clean)
Protocol No. CPKC412E2301
Category
Protocol Section
Prior to 1st
cycle of post-
consolidation 
Phase
Post-consolidation Phase 
Cycle 1-12
End of post-
consolidation Phase 
/EoT
30 
day 
safety
follow 
up 
Post 
treatment 
follow up
(until 5 
years after 
the last day 
of study 
treatment of 
the last 
patient,  
failure, 
relapse or 
death 
whichever 
occurs first)
Surviva
l follow 
up (until 
5 years 
after last 
day of 
study 
treatme
nt  of 
the last 
patient)
Visit name 
D  
Post-Consolidation C1-C12
Day of cycle 
1
15
Biomarkers (7.2.4) (for detailed biomarker collection plan, please refer to Table 7-11)
Bone marrow aspirate for DNA
and RNA analysis (MRD 
 
)
D
x
C4, C7, C10
Completion of C12/ at 
relapse
3 months 
after end of 
post-
consolidatio
n  therapy 
and at 
relapse
Whole blood for DNA and RNA 
analysis (MRD 
 
)
D
x
C4, C7, C10
Completion of C12/ at EOT
Every 3 
months 
during years 
1 and 2 and 
then yearly


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Page 86
Amended Oncology Protocol Version No. 01 (Clean)
Protocol No. CPKC412E2301
Category
Protocol Section
Prior to 1st
cycle of post-
consolidation 
Phase
Post-consolidation Phase 
Cycle 1-12
End of post-
consolidation Phase 
/EoT
30 
day 
safety
follow 
up 
Post 
treatment 
follow up
(until 5 
years after 
the last day 
of study 
treatment of 
the last 
patient,  
failure, 
relapse or 
death 
whichever 
occurs first)
Surviva
l follow 
up (until 
5 years 
after last 
day of 
study 
treatme
nt  of 
the last 
patient)
Visit name 
D  
Post-Consolidation C1-C12
Day of cycle 
1
15
Efficacy/ disease assessments (see Section 7.2.1 for details)
Microscopic peripheral blood 
exam incl. full differential count
D
x
C1-C12
Completion of C12/ at 
relapse
Every 3 
months until 
relapse and 
when 
clinically 
indicated
Microscopic exam of Bone 
marrow aspirate/ biopsy for 
morphology & Bone marrow 
differential count
D
x
C4, C7, C10
Completion of C12/ at 
relapse
3 months 
after end of 
post-
consolidatio
n  therapy
and at 
relapse and
when 
clinically 
indicated
Extramedullary disease 
assessment (physical exam and 
D
x
C1-C12
Completion of C12/ at 
relapse
3 months 
after end of 


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Page 87
Amended Oncology Protocol Version No. 01 (Clean)
Protocol No. CPKC412E2301
Category
Protocol Section
Prior to 1st
cycle of post-
consolidation 
Phase
Post-consolidation Phase 
Cycle 1-12
End of post-
consolidation Phase 
/EoT
30 
day 
safety
follow 
up 
Post 
treatment 
follow up
(until 5 
years after 
the last day 
of study 
treatment of 
the last 
patient,  
failure, 
relapse or 
death 
whichever 
occurs first)
Surviva
l follow 
up (until 
5 years 
after last 
day of 
study 
treatme
nt  of 
the last 
patient)
Visit name 
D  
Post-Consolidation C1-C12
Day of cycle 
1
15
CNS symptom assessment)
post-
consolidatio
n  therapy 
and at 
relapse and
when 
clinically 
indicated
Investigator assessment of 
Disease Response 
D
x
C1-C12
Completion of C12/ at 
relapse
Every 3 
months until 
relapse or 
death
BMA for flow cytometry MRD
D
x
C4, C7, C10
Completion of C12/ at 
relapse
3 months 
after end of 
post-
consolidatio
n  therapy 
and at 
relapse


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Confidential
Page 88
Amended Oncology Protocol Version No. 01 (Clean)
Protocol No. CPKC412E2301
Category
Protocol Section
Prior to 1st
cycle of post-
consolidation 
Phase
Post-consolidation Phase 
Cycle 1-12
End of post-
consolidation Phase 
/EoT
30 
day 
safety
follow 
up 
Post 
treatment 
follow up
(until 5 
years after 
the last day 
of study 
treatment of 
the last 
patient,  
failure, 
relapse or 
death 
whichever 
occurs first)
Surviva
l follow 
up (until 
5 years 
after last 
day of 
study 
treatme
nt  of 
the last 
patient)
Visit name 
D  
Post-Consolidation C1-C12
Day of cycle 
1
15
Patient reported outcomes
FACT-G with FACT-Leu
EQ5D-5L
D
7.2.6
x
x
x
Every 6 
months for 
the first 2 
years and 
then yearly
Disposition 
D
x
x
IRT
Dispensation Midostaurin/ 
Placebo
D
x
Treatment Discontinuation
D
x
Study treatment  administration


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Amended Oncology Protocol Version No. 01 (Clean)
Protocol No. CPKC412E2301
Category
Protocol Section
Prior to 1st
cycle of post-
consolidation 
Phase
Post-consolidation Phase 
Cycle 1-12
End of post-
consolidation Phase 
/EoT
30 
day 
safety
follow 
up 
Post 
treatment 
follow up
(until 5 
years after 
the last day 
of study 
treatment of 
the last 
patient,  
failure, 
relapse or 
death 
whichever 
occurs first)
Surviva
l follow 
up (until 
5 years 
after last 
day of 
study 
treatme
nt  of 
the last 
patient)
Visit name 
D  
Post-Consolidation C1-C12
Day of cycle 
1
15
Midostaurin/ Placebo  
D
continuous twice daily (from 
D1 to D28)
Follow-up
Efficacy Follow-up
D
every 3 
months
Survival Follow-up
D
every 3 
months


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Amended Oncology Protocol Version No. 01 (Clean)
Protocol No. CPKC412E2301
7.1.1
Molecular pre-screening
Not applicable
7.1.2
Screening
Written informed consent must be obtained prior to any screening procedures. Screening 
assessments to confirm eligibility into the study should be performed as per visit evaluation 
schedule between Day-14 and Day-1. Serum pregnancy test must be conducted within 72 
hours prior to start of study treatment and must be confirmed negative before the first dose of 
study treatment. ECG should be obtained within 3 days prior to start of study treatment. Local 
measurements of QTc≥480ms will be centrally verified on a copy of a high quality recording 
that includes time and voltage scales.
As part of screening procedures, a bone marrow aspirate or a whole blood sample will be 
collected and shipped immediately to a Novartis designated laboratory for FLT3 mutation 
assessment. In case both sample types are collected/available, FLT3 screening will be 
preferentially performed only on the bone marrow sample; and the peripheral blood sample 
will be banked for future testing.   
Assessments done within four days prior to Day 1 (start of chemotherapy) as per local 
practice or under a local protocol, prior to signing the study specific informed consent form 
and start of screening for the study, will not have to be repeated and results can be used for the 
study. At the discretion of the investigator, the final diagnosis of AML by bone marrow 
aspirate can be confirmed after the informed consent form has been signed for the study.
In some specific cases (and with Novartis’ prior approval), the FLT3 status may have been 
determined prior to screening in a Novartis validated laboratory. In such cases, this previously 
obtained FLT3 result will be used for the study. Part of the remaining bone marrow sample 
should be provided to Novartis for further analyses defined in the protocol.
 
 
At sites that also participate in the CPKC412A2220 (A2220) trial (aiming at patients with 
FLT3 mutated AML), patients who are screened in the A2220 trial and confirmed to be FLT3 
mutation negative (SR<0.05) may be offered the opportunity to join the E2301 trial provided 
they also meet all other inclusion criteria. To allow this, patients screened as part of A2220 
trial may be offered to sign E2301 informed consent at the same time as the one for A2220. 
Screening, baseline and the start of the first induction cycle will be performed under the 
A2220 protocol. All information obtained during that period will then be used for the E2301 
trial, samples collected under the A2220 trial would be used for further E2301 assessments. 
Some additional assessments will have to be performed for the E2301 trial, such as MRD flow 
cytometry and ePROs. Patients are only considered for the E2301 trial if, under the A2220 
protocol, they are treated with the “RATIFY regimen” (i.e., daunorubicin or idarubicin/
cytarabine dosing regimen as described for the E2301 trial) during the first induction cycle
and are FLT3-MN.
Re-screening is not allowed, and a patient who does not meet all inclusion/exclusion criteria 
will be considered to be a screen failure and cannot be randomized.


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Amended Oncology Protocol Version No. 01 (Clean)
Protocol No. CPKC412E2301
7.1.2.1
Eligibility screening 
Dosing with chemotherapy may begin while FLT3 mutation results are pending. FLT3 
mutation results from the central laboratory must be received by Day 8 and will be used to 
determine if the subject is eligible for randomization and to receive midostaurin/placebo.
Following registering in the IRT for screening, patient eligibility will be checked once all 
screening procedures are completed (except FLT3 status). The eligibility check will be 
embedded in the IRT system. 
Please refer and comply with detailed guidelines in the IRT manual.
7.1.2.2
Information to be collected on screening failures
A patient who signs an informed consent but fails to begin chemotherapy for any reason will 
be considered as a screen failure. The reason for not being started on chemotherapy will be 
entered on the Disposition CRF. The demographic information, informed consent, and 
Inclusion/Exclusion CRF must also be completed for Screen Failure patients. FLT3 data will 
be collected for all patients including screen failures. No other data will be entered into the 
clinical database for patients who are screen failures, unless the patient experienced a Serious 
Adverse Event during the Screening Phase (see Section 8 for SAE reporting details).  If the 
patient fails to be randomized, the IRT must be notified within 2 days of the screen fail that 
the patient was not randomized.
Information to be collected on patients who failed to be randomized
Patients who are determined to have a positive or unknown FLT3 mutation status at Day 8 of 
the 1st cycle of induction will not be randomized and will then be discontinued from the study.
In addition to data collected at screening, the reason for not being randomized will be entered 
on the disposition CRF, and AEs/SAEs will also be collected, if applicable.
No other data will be collected for those patients.
7.1.2.3
Patient demographics and other baseline characteristics
The data to be collected on subject characteristics at screening includes:

Diagnosis and extent of cancer (WHO and French American British (FAB) classification)

Demography (Age, gender, race and ethnicity, or as allowed by local regulations)

Cytogenetics

Medical history

Prior antineoplastic medications

Prior and concomitant medications
Assessments to be performed at screening/baseline include:

Physical examination (i.e., performance status Eastern Cooperative Oncology Group 
(ECOG), height, weight, vital signs)

Extramedullary involvement


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Amended Oncology Protocol Version No. 01 (Clean)
Protocol No. CPKC412E2301

Laboratory assessments (i.e., hematology, chemistry, coagulation, urinalysis, serum 
pregnancy test)

Cardiovascular assessments (i.e., ECG; ECHO or MUGA)

Chest x-ray

Assessment of disease (in blood and bone marrow)

Biomarker assessments in blood and bone marrow (for FLT3 mutation status 
 
)
7.1.3
Treatment period
Patients will be assigned on Cycle 1 Day 8 of induction therapy to midostaurin or placebo 
using a stratified randomization according to age.

Study treatment will begin on Day 1 of Cycle 1 with chemotherapy: daunorubicin from 
Day 1 to Day 3 and cytarabine from Day 1 to Day 7. Study treatment will continue on Day 
8 with midostaurin/placebo until 48 hours prior to start of next cycle.

Chemotherapy and midostaurin/placebo will be administered as indicated in Table 7-1 and 
until the subject experiences any of the following: persistent disease, relapse as 
determined by investigator, unacceptable toxicity that precludes further treatment, 
pregnancy, start of non-protocol anti-cancer therapy, discontinuation at the discretion of 
the Investigator or patient, loss to follow-up, death, or study termination by the Sponsor. 
Visit frequency

Induction phase cycle 1: most assessments will be scheduled once or twice per week until 
hematology recovery. This cycle may be longer than 28 days (until hematology recovery 
occurs), and the assessments will be performed accordingly but cannot be longer than 43
days (28 days plus up to 14 additional days for blood count recovery) in total. If the 
patient has evidence of persistent leukemia on a bone marrow evaluation at the end of the 
first induction cycle, then a second cycle of induction therapy will be administered.

Induction phase cycle 2: assessments will be the same as for Cycle 1, except for the PK 
and study drug dispensation. The maximum length of 
induction cycle 2 is 50 days (28 days plus up to 21 additional days for blood count
recovery). For details of assessments in induction Cycles 1 and 2, refer to Table 7-1.

Patients who achieve a CR or CRi with adequate blood count recovery will continue with 
consolidation therapy for 3 to 4 cycles with a maximum length of 50 days (28 days plus up 
to 21 additional days for  blood count recovery) each. Patients achieving CR/CRi with 
adequate blood count recovery after induction cycle 1 will have 4 cycles of consolidation 
therapy and patients achieving CR or CRi with adequate blood count recovery after the 
second cycle of Induction will have 3 cycles of consolidation therapy.

Patients who remain in CR or CRi with adequate blood count recovery after consolidation 
therapy will begin post-consolidation therapy for up to 12 cycles of 28 days each. Post-
consolidation therapy will begin immediately (i.e. up to 48 hours) after the last dose of 
midostaurin/placebo during the last cycle of consolidation therapy and no later than 50 
days after the start of the last consolidation cycle. Patients who remain in remission after 
12 cycles of post-consolidation therapy will continue in post-treatment follow-up.


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
Patients in CR or CRi with adequate blood count recovery may proceed to HSCT and will
enter the post-consolidation phase within 48 hours after the end of the consolidation phase.
Time windows for scheduling assessments

Every effort should be made to follow the schedule of assessments as described in the 
protocol and especially during the induction and consolidation cycles for PK and ECG 
assessments.

All other assessments have a ± 5 days window, unless otherwise indicated.

Patients who discontinue study treatment must have an End of Treatment (EOT) visit 
performed ≤ 7 days after stopping study treatment.
7.1.4
Discontinuation of study treatment
Patients may voluntarily discontinue from the study treatment for any reason at any time. If 
a patient decides to discontinue from the study treatment, the investigator should make a 
reasonable effort (e.g., telephone, e-mail, letter) to understand the primary reason for this 
decision and record this information in the patient’s chart and on the appropriate CRF pages.  
They may be considered withdrawn if they state an intention to withdraw, fail to return for 
visits, or become lost to follow-up for any other reason.
The investigator may discontinue study treatment for a given patient if he/she believes that 
continuation would be detrimental to the patient’s well-being.
Study treatment must be discontinued under the following circumstances: 

Emergence of specific adverse events or laboratory abnormalities under some 
circumstances outlined in Section 6.3.

Failure to achieve CR or CRi with adequate blood count recovery in induction or relapse 
from CR or CRi with adequate blood count recovery.

Pregnancy (pregnancy will be followed for outcome)

Any other protocol deviation that results in a significant risk to the patient’s safety
The appropriate personnel from the site and Novartis will assess whether study treatment 
should be discontinued for any patient whose treatment code has been broken inadvertently 
for any reason.
Patients who discontinue study treatments should NOT be considered withdrawn from the 
study. They should return for the assessments indicated in Section 7.2.1. If they fail to return 
for these assessments for unknown reasons, every effort (e.g., telephone, email, and letter) 
should be made to contact them as specified in Section 7.1.9.
For patients who discontinue treatment for reasons other than documented failure to achieve 
CR or CRi with adequate blood count recovery in induction phase or relapse from CR or CRi 
with adequate blood recovery, death, loss to follow-up, or withdrawal of consent, will 
continue to be followed for efficacy assessment and survival.
The investigator (or designee) must also contact the IRT to register the patient’s
discontinuation from study treatment.


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7.1.4.1
Replacement policy 
Not applicable
7.1.5
Withdrawal of consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’s samples until their time of withdrawal) according to 
applicable law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form. 
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.
7.1.6
Follow up for safety evaluations
All patients must have safety evaluations for 30 days, after the last dose of study treatment 
(including cytarabine, daunorubicin/idarubicin or midostaurin/placebo).
Data collected should be added to the Adverse Events CRF and the Concomitant Medications 
CRF.
7.1.7
Follow up for efficacy evaluations
Patients who discontinue study treatment for reasons other than death, failure to achieve CR
or CRi with adequate blood count recovery in the induction phase or relapse from CR or CRi
with adequate blood count recovery will continue to have post-treatment assessments as 
outlined in Section 7.1 until relapse or death.
During this phase, the following data will be collected:


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
Antineoplastic therapy/transplantation after discontinuation of treatment: every 3 months
including start of new line, best response, and relapse date etc...
The following assessments will be performed:

Physical examination for extramedullary disease assessment, blood samples for 
hematology 
: every 3 months 

Bone marrow aspirate/biopsy for disease assessment 
: after first 3 months 
after completion of post-consolidation therapy and at relapse.

Questionnaires (EQ5D-5L, FACT with FACT-Leu)
 
 every 6 months during the first two years and then yearly.
Patients will be followed in post-treatment follow up until relapse or end of study, whichever 
occurs first.
7.1.8
Survival follow up
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. Any new 
antineoplastic medications that have been started since the last contact date will also be 
collected during these phone calls or visits.
7.1.9
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition CRF.
7.2
Assessment types
7.2.1
Efficacy assessments
Efficacy assessments will be performed according to the IWG criteria for AML (Cheson et al 
2003, ELN 2017 / Döhner et al 2017). The investigator assessment will be used for the 
efficacy analyses. Response criteria in AML are described in Table 7-2:
Table 7-2
Response classification in AML at a given evaluation time (Cheson 
2003, ELN 2017 / Döhner et al 2017)
Response category
Definition#
Complete remission 
(CR)
Bone marrow 
< 5% blasts 
no blasts with Auer rods 


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Response category
Definition#
Peripheral blood 
neutrophils ≥1.0 x 109/L 
platelets ≥100 x 109/L
no blasts
No evidence of extramedullary disease (such as CNS or soft tissue 
involvement).
Transfusion independent (see Section 7.2.1.6). 
Complete remission 
with incomplete 
hematologic recovery 
(CRi)
Bone marrow 
< 5% blasts
no blasts with Auer rods 
Peripheral blood#
neutrophils < 1.0 x 109/L and/or platelets < 100 x 109/L 
no blasts 
No evidence of extramedullary disease (such as CNS or soft tissue 
involvement).
CRi with adequate blood count recovery is defined as the following:
Bone marrow 
< 5% blasts
no blasts with Auer rods 
Peripheral blood#
Neutrophils >= 1.0 x 109/L and 50 x 109/L <=platelets < 100 x 109/L 
no blasts 
No evidence of extramedullary disease (such as CNS or soft tissue 
involvement).
Partial remission 
(PR)
Bone marrow 
< 5% blasts AND presence of blasts with Auer rods 
OR
≥ 50% decrease from baseline in blasts in bone marrow AND blast count in
bone marrow is 5% to 25%
Peripheral blood 
neutrophils ≥1.0 x 109/L 
platelets ≥100 x 109/L 
no blasts 
No transfusion of neutrophils/platelets within 2 days preceding the 
assessment (see Section 7.2.1.6).
No Response
Failure to attain the criteria needed for any response categories or relapse


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Response category
Definition#
Relapse from CR or 
CRi
Only in patients with a CR or CRi with adequate blood count recovery. Any of 
the following:
Reappearance of blasts in peripheral blood OR 
≥ 5% blasts in bone marrow OR
(Re-)appearance of extramedullary disease
Unknown
In case the response assessment was not done or the assessment was 
incomplete.
# If not defined otherwise, all of the criteria apply.
Response assessment will be performed by investigator between Day 21-28 of each cycle of 
the induction, the consolidation and the post-consolidation phases. Response assessment will 
be re-performed for patients achieving CRi without adequate blood count recovery up to 3 
weeks after day 28 of each cycle. Moreover, patient can be assessed any time if clinically 
indicated.
Treatment failure includes patients who failed to achieve a CR or CRi with adequate blood 
count recovery up to the end of induction cycle 2. The following categories will only be 
assessed in case of induction treatment:
Category
Definition
Primary refractory disease
No CR nor CRi with adequate blood count recovery after 2 cycles of 
induction treatment; excluding patients with death in aplasia or death due 
to indeterminate cause
Death in aplasia
Deaths occurring ≥7 days following completion of induction therapy while 
cytopenic; with an aplastic or hypoplastic bone marrow obtained within 7 
days of death, without evidence of persistent leukemia (< 5% blasts in 
bone marrow, no Auer rods in blasts and/or no extramedullary disease)
Death from indeterminate 
cause
Deaths occurring before completion of therapy, or ,<7 d following its 
completion; or deaths occurring ≥7 d following completion of induction 
therapy with no blasts in the blood, but no bone marrow examination 
available
Induction therapy
Between Day 21-28 of the first induction cycle, a bone marrow aspirate/biopsy will be 
performed to determine the presence of residual leukemia (5% blasts) according to the 
International Working Group (IWG) criteria for AML (Cheson et al 2003, ELN 2017 / 
Döhner et al 2017). If the Day 21-28 bone marrow aspirate/biopsy shows <5% blasts and the 
response assessment is CR or CRi without adequate blood count recovery, then it is not 
necessary to repeat bone marrow aspiration/biopsy while patient is under platelet and/or 
neutrophil recovery but a new blood count assessment will be performed to determine if the 
patient has achieved CR or CRi with adequate blood count recovery to be able to move to 
consolidation phase. If the response is CRi without adequate blood count recovery between
Day 21-28, the cycle will be prolonged up to two weeks for blood count recovery (i.e. day 42). 
If the patient has reached CR or CRi with adequate blood count recovery, the patient will be 


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able to move to consolidation phase. Otherwise, the patient will receive a second cycle of 
induction therapy.
If a patient receives a second course of induction therapy, a bone marrow aspiration/biopsy 
between Day 21-28 of the second induction cycle will be performed to determine if the patient 
has achieved CR or CRi with adequate blood count recovery. If the response is CRi without 
adequate blood count recovery between Day 21-28, the cycle will be prolonged up to three
weeks for blood count recovery. If no adequate blood count recovery is reached, the patient 
will be considered as treatment failure and will be discontinued from study treatment and 
followed for survival and post treatment therapies. Otherwise, the patient will move to 
consolidation phase. Of note, the bone marrow results obtained between Day 21-28 can be 
used retrospectively to determine response level by Day 49 (Day 28 plus 3 weeks).
Therefore, the maximum duration of the induction phase cannot exceed 93 days: 28 days 
(planned duration of cycle 1) + 14 days (i.e. 2 weeks for blood count recovery period)) + plus 
1 day prior to the start of the next cycle + 28 days (planned duration of cycle 2) + 21 days (i.e. 
2 weeks blood count recovery period)) + plus 1 day prior to the start of the next cycle.
7.2.1.1
Consolidation therapy:
A bone marrow and blood count examination will be performed to evaluate for continued 
remission (CR or CRi with adequate blood count recovery) between Day 21-28 of each cycle 
of consolidation. For each cycle, if the patient achieves CR or CRi with adequate blood count 
recovery up to 3 weeks after day 28 of each cycle, the patient will receive the next treatment 
cycle. Of note, the bone marrow results obtained between Day 21-28 can be used 
retrospectively to determine response level by day 49 (Day 28 plus 3 weeks).
7.2.1.2
Post-Consolidation therapy:
A bone marrow examination will be performed to evaluate for continued remission (CR or 
CRi with adequate blood count recovery) prior the start of the post-consolidation therapy, at 
the start of Cycle 4, Cycle 7 and Cycle 10, and at the end of Cycle 12 of post-consolidation 
therapy or at any time at suspected relapse. 
7.2.1.3
Post-treatment follow-up:
A bone marrow examination will be performed to evaluate for continued remission (CR or 
CRi with adequate blood count recovery) 3 months after completion of post-consolidation 
therapy. A bone marrow examination will also be performed at any time of relapse.
7.2.1.4
Assessment of minimum residual disease (MRD) in bone marrow
For the purpose of the secondary MRD endpoint, MRD will be assessed by flow cytometry, 
since this technology can be used for the large majority of AML patients. Assessments will be 
performed at baseline during treatment phases indicated in Table 7-1 and 7-3. Patients with 
leukemic blasts below 0.1% will be considered as MRD-negative based on leukemia-
associated immunophenotype (LAIP). 
 
 
 


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Table 7-3
Flow cytometry MRD sample collection plan
Sample Type
Volume/visit
Visit
Time Point
Bone Marrow Samples 
Bone Marrow 
Aspirate for flow 
cytometry MRD
analysis
6ml*
*First BMA 
pull should be 
used for this 
assessment
Screening
Anytime
Induction Phase 1 Day 21-28
Pre-dose
Induction Phase 2 Day 21-28 
Pre-dose
Consolidation phase C1 Day 21-28
Pre-dose
Prior to 1st cycle of Post-
consolidation Phase
Pre-dose
Post-consolidation Phase C4 Day 1
Pre-dose
Post-consolidation Phase C7 Day 1
Pre-dose
Post-consolidation Phase C10 Day 
1
Pre-dose
Completion of Post-consolidation 
Phase C12 Day 28 
Pre-dose
At relapse (at any phase of the 
study)
Anytime
Post treatment Follow Up: 3 months 
after end of post-consolidation 
therapy, and at relapse 
Anytime
7.2.1.5
Extramedullary disease assessment
Extramedullary involvement is to be assessed at baseline and at each visit for response 
assessment. Presence or absence and physical location of extramedullary disease is to be 
captured in the CRF.
Extramedullary disease is to be assessed via physical examination, cerebrospinal fluid (CSF) 
assessment in case of symptoms suggestive of meningeosis leukemica, and if clinically 
appropriate relevant imaging techniques. In case of extramedullary disease at baseline or (re-) 
appearance during the study, the lesions should be considered for confirmation by imaging or 
biopsy if technically and/or clinically feasible.
7.2.1.6
Evaluation of transfusion dependency
Information on transfusion dependency will be assessed at baseline as well as during the 
course of the trial for all patients. Transfusion of blood products will be recorded in a separate 
module of the CRF. The type of transfusion, start and end date as well as the volume of blood 
product will be captured at each visit with hematologic assessment.


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A period of at least 2 days without any transfusion has been taken as a convention to define 
the status of transfusion independence to assess a CR or CRi with adequate blood count 
recovery.  A patient who has received a blood transfusion within 2 days preceding a response 
assessment (i.e. CR) will be considered transfusion dependent at the time of this response 
assessment.  
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing physical examination, performance status, laboratory 
examinations, ECGs, Echo/MUGA as well as collecting of the adverse events at every visit. 
Local measurements of QTc≥480ms shall be centrally verified on a copy of the original high 
quality recording that includes time and voltage scales. For details on AEs collection and 
reporting, refer to Section 8.
More frequent examinations may be performed at the investigator’s discretion, if clinically 
indicated.
7.2.2.1
Physical examination
Significant findings that were present prior to the signing of informed consent must be 
included in the Medical History page on the patient’s CRF. Significant new findings that 
begin or worsen after informed consent must be recorded on the Adverse Event page of the 
patient’s CRF.
Physical examination will be performed as described in Table 7-1 and will include the 
examination of general appearance, skin, neck (including Thyroid), eyes, ears, nose, throat, 
lungs, heart, abdomen, anus, back, lymph nodes, extremities, vascular and neurological 
assessments.
Information about the physical examination must be present in source documents at the study 
site. Significant findings that were present prior to the signing of informed consent must be 
included in the Medical History CRF. Significant new findings that begin or worsen after 
informed consent must be recorded on the Adverse Events CRF. 
7.2.2.2
Vital signs
Vital signs include blood pressure (supine position preferred), pulse measurement, and body 
temperature and will be measured at screening and at subsequent time points as specified in 
Table 7-1. Data on vital signs will be tabulated and listed, notable values will be flagged.
7.2.2.3
Height and weight
Height in centimeters (cm) will be measured at screening.
Body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but without shoes) will be 
measured at screening and at subsequent time points as specified in Table 7-1.
7.2.2.4
Performance status
ECOG Performance status scale will be performed as described in the Table 7-1. More 
frequent examinations may be performed at the investigator’s discretion, if medically 
indicated. ECOG performance status scale will be used as described in the Table 7-4.


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Table 7-4
ECOG performance status scale
Score 
Performance Status 
0
Fully active, able to carry on all pre disease 
performance without restriction 
1
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light or 
sedentary nature ,light housework, office work 
2
Ambulatory and capable of all self-care but 
unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair 
5
Dead 


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7.2.2.5
Laboratory evaluations
Table 7-5
Clinical laboratory parameters collection plan
Test Category
Test Name
Hematology (Local)
Hgb, white blood cell (WBC) with differential (including basophils, eosinophils, 
lymphocytes, monocytes, neutrophils, bands, metamyelocytes, myelocytes, 
promyelocytes blasts), atypical cells (e.g. LUC, erythroblasts), platelets
Biochemistry (Local)
Albumin, alkaline phosphatase, ALT, AST, LDH, calcium, magnesium, 
phosphorous, sodium, potassium, creatinine, total bilirubin, direct bilirubin, total 
cholesterol, BUN/urea, uric acid, amylase, lipase, glucose 
Coagulation (Local)
International normalized ratio (INR), activated partial thromboplastin time 
(aPTT)
Urinalysis (Local)
Dipstick examination includes specific gravity, pH, glucose, protein, blood, 
bilirubin, ketones and WBC as clinically indicated
Other hepatic tests 
in case of suspected 
DILI (Local)
GGT, alkaline phosphatase, other tests for diagnosis of acute hepatitis A, B, C 
or E infection or testing for hepatotropic viral infection or autoimmune hepatitis
Pregnancy Test 
(Local)
Pregnancy test in serum (at screening) and urine
Clinical laboratory analyses are to be performed by the local laboratory (at the investigational’ 
site) according to the schedule of assessments and collection plan outlined respectively in 
Table 7-1 and Table 7-3. Novartis must be provided with a copy of the local laboratory’s 
certification and a tabulation of the normal ranges and units of each parameters collected in 
the CRF. Any changes regarding normal ranges and units for laboratory values assessed 
during the study must be reported via an updated tabulation indicating the date of revalidation. 
Additionally, if at any time a patient has laboratory parameters obtained from a different 
laboratory, Novartis must be provided with a copy of the certification and a tabulation of the 
normal ranges and units for this laboratory as well. The investigator is responsible for 
reviewing all laboratory reports for patients in the study and evaluating any abnormalities for 
clinical significance.
At any time during the study, abnormal laboratory parameters which are clinically significant 
and require an action to be taken with study treatment (e.g.; require dose modification and/or 
interruption of study treatment, lead to clinical symptoms or signs, or require therapeutic 
intervention), whether specifically requested in the protocol or not will be recorded on the 
Adverse Events CRF. Laboratory data will be summarized using the CTCAE version 5.0. 
Additional laboratory evaluations are left to the discretion of the investigator.
7.2.2.5.1 Hematology
Hematology tests are to be performed by the local laboratory according to the schedule of 
assessments and collection plan outlined respectively in Table 7-1 and Table 7-6. 
More frequent hematology testing may also be performed as medically necessary. Additional 
results from unscheduled hematology lab evaluations should be recorded on the appropriate 
unscheduled visit CRF.


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Table 7-6
Standard hematologic diagnostics
Sample Type
Blood 
volume/visit
Visit
Time Point
Bone marrow by 
biopsy/aspirate
smears for 
cytomorphology 
including differential 
count
6 -8 bone 
marrow 
smears
Screening
Induction Phase 1 Day 21-28
Induction Phase 2 Day 21-28
Consolidation Phase C1 Day 21-28
Consolidation Phase C2 Day 21-28
Consolidation Phase C3 Day 21-28
Consolidation Phase C4 Day 21-28
Consolidation Phase (at time of 
relapse)
Prior to 1st cycle of post-
consolidation Phase
Post-consolidation Phase C4 Day 1
Post-consolidation Phase C7 Day 1
Post-consolidation Phase C10 Day 1 
Completion of  Post-consolidation 
Phase C12 Day 28 
Post-consolidation Phase (at 
relapse)
Post treatment  Follow Up: 3 months 
after end of post-consolidation 
therapy and at relapse
Peripheral blood 
smears for 
cytomorphology 
including microscopic 
differential count
2 peripheral 
blood smears
Screening
Induction Phase 1 Day 21-28
Induction Phase 2 Day 21-28
Consolidation Phase C1 Day 21-28
Consolidation Phase C2 Day 21-28
Consolidation Phase C3 Day 21-28
Consolidation Phase C4 Day 21-28
Consolidation Phase (at time of 
relapse)
Prior to 1st cycle of post-
consolidation Phase
Post-consolidation Phase C2  Day 1
Post-consolidation Phase C3
Day 1
Post-consolidation Phase C4  Day 1
Post-consolidation Phase C5 Day 1
Post-consolidation Phase C6 Day 1
Post-consolidation Phase C7 Day 1
Post-consolidation Phase C8 Day 1


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Sample Type
Blood 
volume/visit
Visit
Time Point
Post-consolidation Phase C9 Day 1
Post-consolidation Phase C10 Day 1
Post-consolidation Phase C11 Day 1
Post-consolidation Phase C12 Day 1
Completion of Post-consolidation 
Phase C12 Day 28 
Post-consolidation Phase (at 
relapse)
Post treatment Follow Up, every 3 
months until relapse and when 
clinically indicated
Bone marrow for 
conventional 
metaphase 
cytogenetics 
5 mL
(minimum)
Screening
Bone marrow for 
immunophenotyping
5mL
Screening
Bone marrow 
(preferably trephine) 
biopsy for histology 
and immunohistology
1-2 cm 
trephine
Screening (mandatory)
Optional in parallel to all bone 
marrow (BM) aspiration for 
cytomorphology (e.g., for the 
purpose of immunohistochemically 
supported blast counting)
7.2.2.5.2 Clinical chemistry
Clinical chemistry tests are to be performed by the local laboratory according to the schedule 
of assessments and collection plan outlined respectively in Table 7-1 and Table 7-5. 
More frequent clinical chemistry testing may also be performed as medically necessary. 
Additional results from unscheduled chemistry lab evaluations should be recorded on the 
appropriate unscheduled visit CRF.
It should be noted in the patient’s CRF if the patient was fasting as the time of blood sampling.
7.2.2.5.3 Coagulation
Coagulation analyses (INR and aPTT) are to be performed by the local laboratory according 
to the schedule of assessments and collection plan outlined respectively in Table 7-1 and 
Table 7-5.
7.2.2.5.4 Urinalysis 
Dipstick analysis (includes specific gravity, pH, glucose, protein, blood, bilirubin, ketones and 
WBC) is to be performed by the local laboratory at screening and during treatment phase if 
clinically indicated.


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Abnormal findings will be followed up with a microscopic analysis and/or additional 
assessments as clinically indicated. 
7.2.2.5.5 Pregnancy and assessments of fertility
Women of child-bearing potential will have serum pregnancy tests at screening. During the 
treatment phases, the absence of pregnancy will be confirmed by urine pregnancy test prior to 
the first dose of study treatment (at day 1 during induction, prior to each consolidation cycle 
and Day 1 during post-consolidation cycles).
Urine pregnancy tests will be required to be performed as well as at the End of Treatment visit
and at 30-day Safety follow up visit. Every effort must be made for the women of child 
bearing potential to return to the site for the final pregnancy test. However if the patient is 
unable to return then the patient will administer the urine pregnancy test at home using the kit 
provided. For all pregnancy test performed at home, the site personnel will follow up with the 
patient via telephone call to collect the date and the test results and document the information 
in the patient’s source documents. 
Women of child-bearing potential will be instructed to contact the site immediately at any 
time during the study (on treatment or during follow-up) should they have a positive 
pregnancy test.
Male patients treated with idarubicin, daunorubicin or cytarabine should receive appropriate 
advice on the risk of infertility and the option of sperm conservation. Midostaurin may impair 
both male and female fertility and this should be communicated to the patients. 
7.2.2.6
Radiological examinations
Chest X-ray will be collected at baseline and during the study if clinically indicated.
7.2.2.7
Cardiac assessments 
7.2.2.7.1 Electrocardiogram (ECG)
A standard triplicate 12 lead ECG each 2 min apart will be performed according to the 
relevant Visit Evaluation Schedule (Table 7-1 and Table 7-7).


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Table 7-7
Local ECG assessment monitoring schedule
Day
Time
ECG Type
Screening
-3 to -1
Pre-dose 
12 Lead 
Induction Phase 1 
Day 8, Day 
11, Day 21
Pre-dose (before PK)
Post-dose at 3 hours ± 0.5 hour (before PK)
12 Lead 
Consolidation 
Phase, each cycle
Day 4, Day 
17
Pre-dose (before PK)
Post-dose at 3 hours ± 0.5 hour (before PK)
12 Lead 
Prior to 1st cycle of 
post-consolidation
Pre-dose (before PK)
12 Lead, 
Post-consolidation, 
cycle 2 to cycle 12
Day 1
Pre-dose (before PK)
12 Lead 
Post-consolidation, 
cycle 12
or 
at EOT (at any 
phase of the study)
Day 28
Pre-dose (before PK)
Anytime
12 Lead 
12 Lead 
Unscheduled sample
Anytime when clinically indicated
12 Lead 
Interpretation of the tracing must be made by a qualified physician and documented on the 
CRF. Each ECG tracing should be labeled with the study number, patient initials (where 
regulations permit), subject number, date, and kept in the source documents at the study site. 
Clinically significant abnormalities present at screening should be reported on the Medical 
History CRF. 
Standard 12 lead ECG recording will be performed after the patient has been resting for 
approximately 10 min prior to each ECG collection time point indicated in Table 7-7 and 
prior to PK samples. Local measurements of QTc≥480ms shall be centrally verified on a copy 
of the original high quality recording that includes time and voltage scales.
Dose adjustments in case of QT prolongation should be performed per Section 6.3.
Clinically significant ECG abnormalities present at screening should be reported on the 
Medical History CRF. New or worsened clinically significant findings occurring after 
informed consent must be recorded on the Adverse Events CRF.
7.2.2.7.2 Cardiac imaging - MUGA (multiple gated acquisition) scan or echocardiogram
Cardiac Imaging will be performed at screening, at the 30 day Safety Follow Up Visit and 
whenever clinically indicated. LVEF needs to be measured and reported at each cardiac 
imaging. Any clinically relevant abnormalities will be reported on the medical history or AE 
page as applicable.
7.2.2.7.3 Cardiac enzymes
Not applicable.


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7.2.3
Pharmacokinetics
Serial PK samples will be collected in all patients to assess the plasma concentrations of 
midostaurin, CGP52421 and CGP62221. To allow a proper description of midostaurin, 
CGP52421 and CGP62221 pharmacokinetics additional PK samples will be collected in a 
subset of the first 60 patients randomized into the trial. Therefore there will be approximately
30 patients receiving midostaurin and contributing to the PK analysis. A detailed description 
of the sample collection is provided in Table 7-8. In this subset of patients, non-
compartmental PK parameters will be derived as described in Section 10.5.4. 
The PK samples in the other patients will be collected according to the sampling scheme 
described in Table 7-9. 
The whole set of concentrations will also be further analyzed using a population PK approach
(Section 10.5.4). 
Table 7-8
Pharmacokinetic blood collection log for Midostaurin, CGP52421 and 
CGP62221 – Full PK collection (N=60)
Dose Reference 
ID (2)
PK Sample 
number
Cycle (Period 
number)
Study day 
for each 
cycle
Time(1)
Blood 
volume 
(mL)
1
101
Induction 1 
Cycle 1*
8
Pre-dose
3 
1
102
Induction 1 
Cycle 1*
8
1h
3 
1
103
Induction 1 
Cycle 1*
8
Post-dose 3hrs 
+- 0.5 hrs
3 
1
104
Induction 1 
Cycle 1*
8
6h
3 
1/ 111(3)
105
Induction 1 
Cycle 1*
8
12h (prior to the 
evening dose of 
Midostaurin/ 
Placebo)
3 
2/201
106
Induction 1 
Cycle 1
11
Pre-dose
3 
2
107
Induction 1 
Cycle 1
11
Post-dose 3hrs 
+- 0.5 hrs
3
3/301
108
Induction 1 
Cycle 1
15
Pre-dose
3 
4/401
109
Induction 1 
Cycle 1
18
Pre-dose
3 
5/501
110
Induction 1 
Cycle 1
21
Pre-dose
3 
5
111
Induction 1 
Cycle 1
21
Post-dose 3hrs 
+- 0.5 hrs
3
6/601
112
Consolidation, 
cycle 1
4
Pre-dose
3 
6
113
Consolidation 
Cycle 1
4
Post-dose 3hrs 
+- 0.5 hrs
3


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Dose Reference 
ID (2)
PK Sample 
number
Cycle (Period 
number)
Study day 
for each 
cycle
Time(1)
Blood 
volume 
(mL)
7/701
114
Consolidation, 
cycle 1
17
Pre-dose
3 
7
115
Consolidation, 
cycle 1
17
Post-dose 3hrs 
+- 0.5 hrs
3
8/801
116
Consolidation, 
cycle 3
4
Pre-dose
3 
8
117
Consolidation, 
cycle 3
4
Post-dose 3hrs 
+- 0.5 hrs
3
9/901
118
Consolidation, 
cycle 3
17
Pre-dose
3 
9
119 
Consolidation, 
cycle 3
17
Post-dose 3hrs 
+- 0.5 hrs
3
10/1001
120 
Prior to 1st of 
Post-
consolidation, 
cycle 1 
Pre-dose 
 
3 
11/1101
121 
Post-
consolidation, 
cycle 4
1
Pre-dose
3 
11
122
Post-
consolidation, 
cycle 4
1
Post-dose 3hrs 
+- 0.5 hrs
3 
12/1201
123 
Post-
consolidation, 
cycle 7
1
Pre-dose
3
13/1301
124 
Post-
consolidation, 
cycle 10
1
Pre-dose
3 
14/1401
125 
End of Post-
consolidation, 
cycle 12
28
Pre-dose
3 
Total volume
Unscheduled samples
NA
100x
NA
NA
Unscheduled
*: When medically feasible full blood sample to be collected
(1): When PK is collected at the same time point as ECG, ECG should be done first. 
(2): Dose reference ID: The first number refers to the administration at the day, the second number 
refers to the administration the day before (The information has to be collected) with an exception on 
Day 1 (see below).
(3) The first number refers to the administration on Day 1 morning dose, the second number refers to 
the administration on Day 1 evening dose.
Unscheduled blood samples will be uniquely, sequentially numbered 1001, 1002, …


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Table 7-9
Pharmacokinetic blood collection log for Midostaurin, CGP52421 and 
CGP62221 – Sparse PK collection
Dose Reference 
ID (2)
PK Sample 
number
Cycle (Period 
number)
Study day 
for each 
cycle
Time(1)
Blood 
volume 
(mL)
1
201
Induction 1 
Cycle 1*
8
Pre-dose
3 
1
202
Induction 1 
Cycle 1*
8
Post-dose 3hrs 
+- 0.5 hrs
3 
2/201
203
Induction 1 
Cycle 1
11
Pre-dose
3 
2
204
Induction 1 
Cycle 1
11
Post-dose 3hrs 
+- 0.5 hrs
3
3/301
205
Induction 1 
Cycle 1
15
Pre-dose
3 
4/401
206
Induction 1 
Cycle 1
18
Pre-dose
3 
5/501
207
Induction 1 
Cycle 1
21
Pre-dose
3 
5
208
Induction 1 
Cycle 1
21
Post-dose 3hrs 
+- 0.5 hrs
3
6/601
209
Consolidation, 
cycle 1
4
Pre-dose
3 
6
210
Consolidation 
Cycle 1
4
Post-dose 3hrs 
+- 0.5 hrs
3
7/701
211
Consolidation, 
cycle 1
17
Pre-dose
3 
7
212
Consolidation, 
cycle 1
17
Post-dose 3hrs 
+- 0.5 hrs
3
8/801
213
Consolidation, 
cycle 3
4
Pre-dose
3 
8
214
Consolidation, 
cycle 3
4
Post-dose 3hrs 
+- 0.5 hrs
3
9/901
215
Consolidation, 
cycle 3
17
Pre-dose
3 
9
216
Consolidation, 
cycle 3
17
Post-dose 3hrs 
+- 0.5 hrs
3
10/1001
217
Prior to 1st of 
Post-
consolidation, 
cycle 1 
Pre-dose 
 
3 
11/1101
218
Post-
consolidation, 
cycle 4
1
Pre-dose
3 
12/1201
219
Post-
consolidation, 
cycle 7
1
Pre-dose
3


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Dose Reference 
ID (2)
PK Sample 
number
Cycle (Period 
number)
Study day 
for each 
cycle
Time(1)
Blood 
volume 
(mL)
13/1301
220
Post-
consolidation, 
cycle 10
1
Pre-dose
3 
14/1401
221
End of Post-
consolidation, 
cycle 12
28
Pre-dose
3 
Total volume
Unscheduled samples
NA
200x
NA
NA
Unscheduled
*: When medically feasible full blood sample to be collected
(1): When PK is collected at the same time point as ECG, ECG should be done first. 
(2): Dose reference ID: The first number refers to the administration at the day, the second number 
refer to the administration the day before (The information has to be collected) 
Unscheduled blood samples will be uniquely, sequentially numbered 2001, 2002, …
Detailed instructions for the collection, handling, and shipment of PK samples will be 
provided in a separate document.
7.2.3.1
Analytical method
Plasma concentrations of midostaurin and its active metabolites CGP62221 and CGP52421 
will be measured using a validated liquid chromatography-tandem mass spectrometry (LC-
MS/MS) assay with a lower limit of quantification (LLOQ) of approximately 10.0 ng/mL. 
Concentrations below the LLOQ will be reported as 0.00 ng/mL and missing samples will be 
labeled accordingly.


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7.2.4
Biomarkers
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 7-11
Biomarker sample collection plan
Sample Type
Blood 
volume/visit
Visit
Time Point
Samples for Molecular Screening
Bone Marrow 
Aspirate for FLT3 
mutational testing *
2 mL
Screening (eligibility confirmation)
Anytime, as early as 
possible after 
patient signed ICF
Peripheral Blood for 
FLT3 mutational 
testing *
6 mL
Screening (eligibility confirmation)
Anytime, as early as 
possible after 
patient signed ICF
*A bone marrow aspirate or a whole blood sample will be collected. In case both sample types 
are collected/available, FLT3 screening will be preferentially performed only on the bone 
marrow sample; and the peripheral blood sample will be banked for future testing
Bone Marrow Samples
Bone Marrow 
Aspirate for RNA, 
DNA (MRD and 
)
6 mL
Screening
Anytime
Induction Phase 1 Day 21-28
Pre-dose
Induction Phase 2 Day 21-28 
Pre-dose
Consolidation phase C1 Day 21-28
Pre-dose
Prior to 1st cycle of Post-consolidation 
Phase
Pre-dose


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Sample Type
Blood 
volume/visit
Visit
Time Point
Post-consolidation Phase C4 Day 1
Pre-dose
Post-consolidation Phase C7 Day 1
Pre-dose
Post-consolidation Phase C10 Day 1
Pre-dose
Completion of Post-consolidation 
Phase C12 Day 28 
Pre-dose
At relapse (at any phase of the study)
Anytime
Post treatment Follow Up: 3 months 
after end of post-consolidation 
therapy, and at relapse 
Anytime
Blood Samples 
Peripheral Blood
for RNA and DNA 
analysis (MRD 
 
)
16 mL
Screening
Anytime
Induction Phase C1 Day 21-28
Pre-dose 
Induction Phase C2 Day 21-28
Pre-dose
Consolidation Phase C1 Day 21-28
Pre-dose
Consolidation Phase C3 Day 21-28
Pre-dose
Prior to 1st cycle of Post-consolidation 
Phase
Pre-dose
Post-consolidation Phase C4 Day 1
Pre-dose
Post-consolidation Phase C7 Day 1
Pre-dose
Post-consolidation Phase C10 Day 1
Pre-dose
Completion of Post-consolidation
Phase C12 Day 28 
Pre-dose
EOT (at any phase of the study)
Anytime
Every 3 months during years 1 and 2 
and then yearly
Anytime


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7.2.4.1
Additional biomarker assessments
 
 
 
 
 
 
 
 
 
 
 
 
 
7.2.6
Patient reported outcomes
Two questionnaires will be used in this study to capture PROs: Functional Assessment of 
Cancer Therapy-Leukemia (FACT-Leu)
and EQ-5D-5L. Brief description of each 
questionnaire is given in the sections below.
The patient should be given the questionnaire(s) to be completed at the scheduled visit before 
other clinical assessments are conducted. Questionnaires should be completed in the language 
the respondent is most familiar with, at the scheduled visit before the patient sees the 
investigator for clinical assessments. The patient should be given sufficient space and time to 
complete the questionnaire. 


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Reason for missing data at scheduled visit will also be captured (‘patient refused due to poor 
health’, ‘patient refused (unrelated to health), ‘study staff felt patient was too ill’, ‘patient 
missed appointment’, ‘other reasons’).
Data from both questionnaires will be captured electronically using dedicated devices. 
Instructions for operating the devices will be available to each study site.  In addition detailed 
instructions relating to the administrative procedures of the questionnaires will be provided to 
the sites in a separate document. Patient’s refusal to complete all or any part of a 
questionnaire should be documented in the study data capture system. 
FACT-Leu
The FACT-Leu is a questionnaire to assess the quality of life in patients with leukemia. It 
consists of a general quality of life instrument (FACT-G) and a condition specific module Leu. 
The FACT-Leu is a fully validated QOL questionnaire applicable for patients with leukemia
and includes a module which assesses specific concerns of patients with leukemia. The 
FACT-G has 27 statements that patients will need to endorse on a five-point scale (not at all, a 
little, somewhat, quite a bit, very much). The statements cover five subscales (Physical Well-
Being, Social/Family Well-Being, Emotional Well-Being, Functional Well-Being and 
Additional Concerns). The Leu module consists of 17 statements patients need to endorse on 
an identical five-point scale. The recall period is “Past 7 days”, and the questionnaire requires 
approximately 5 minutes to complete.
EQ-5D-5L
The EQ-5D is a widely used, self-administered questionnaire designed to assess health status 
in adults. The EQ-5D-5L essentially consists of 2 pages: the EQ-5D descriptive system and 
the EQ visual analogue scale (EQ VAS).  The descriptive system comprises five dimensions: 
mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension 
has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme 
problems.
Patients rate each of these items: no problems, slight problems, moderate problems, severe 
problems and extreme problems. A composite health index is then defined by combining the 
levels for each dimension. The second section of the questionnaire measures self-rated (global) 
health status utilizing a vertically oriented visual analogue scale where 100 represents the 
“best possible health state” and 0 represents the “worst possible health state.” Respondents are 
asked to rate their current health by placing a mark along this continuum. The recall period is 
“today,” and the questionnaire requires approximately 5 minutes to complete.
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained.


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Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History CRF. Adverse event monitoring should be continued for at 
least 30 days following the last dose of study treatment. Adverse events (including lab 
abnormalities that constitute AEs) should be described using a diagnosis whenever possible, 
rather than individual underlying signs and symptoms. When a clear diagnosis cannot be 
identified, each sign or symptom should be reported as a separate Adverse Event.
Adverse events will be assessed and graded according to the CTCAE version 5.0.
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, death related to the AE corresponding respectively to Grades 1 - 5, will 
be used. Information about any deaths (related to an Adverse Event or not) will also be 
collected through a Death form.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
during the screening process after signing informed consent and at each visit during the study. 
Adverse events also may be detected when they are volunteered by the patient during the 
screening process or between visits, or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine:
1. The severity grade (CTCAE Grade 1-5)
2. Its duration (start and end dates) 
3. Its relationship to the study treatment (related, not related)
4. Action taken with respect to study treatment (dose increased, dose not changed, dose 
reduced, drug interrupted, drug withdrawn, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Whether it is serious, where a SAE is defined as in Section 8.2.1 and which seriousness 
criteria have been met
7. Outcome (not recovered/not resolved, recovered/resolved, recovered/resolved with 
sequelae, fatal, unknown) 
8. If the event worsens, the event should be reported a second time in the CRF noting the 
start date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if 
improvement to a lower grade is determined a new entry for this event should be reported 
in the CRF noting the start date when the event improved from having been Grade 3 or 
Grade 4.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 


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necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome.
Treatment failure or relapse (including fatal outcomes), if documented by use of appropriate 
method should not be reported as a serious adverse event.
Adverse events separate from relapse or treatment failure will be reported as per usual 
guidelines used for such events with proper attribution regarding relatedness to the drug.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an AE in their own right (are considered clinically 
significant, induce clinical signs or symptoms, require concomitant therapy or require changes 
in study treatment), should be recorded on the AEs CRF. Whenever possible, a diagnosis, 
rather than a symptom should be provided (e.g. anemia instead of low hemoglobin). 
Laboratory abnormalities that meet the criteria for Adverse Events should be followed until 
they have returned to normal or an adequate explanation of the abnormality is found. When an 
abnormal laboratory or test result corresponds to a sign/symptom of an already reported 
adverse event, it is not necessary to separately record the lab/test result as an additional event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 Event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such.
8.1.3
Adverse events of special interest
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to Midostaurin, for which ongoing 
monitoring and rapid communication by the investigator to the sponsor should be appropriate. 
Such events may require further investigation in order to characterize and understand them.
AESI are defined on the basis of an ongoing review of the safety data. AESI are discussed in 
detail in the Investigator Brochure.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above


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
Requires inpatient hospitalization or prolongation of existing hospitalization, 

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event.
8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence.
Any additional information for the SAE including complications, progression of the initial 
SAE, and recurrent episodes must be reported as follow-up to the original episode within 24 
hours of the investigator receiving the follow-up information. An SAE occurring at a different 
time interval or otherwise considered completely unrelated to a previously reported one 
should be reported separately as a new event.
Any SAEs experienced after the 30 day safety evaluation follow-up period should only be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment.  
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site.
Follow-up information is submitted in the same way as the original SAE Report.  Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis 
Chief Medical Office and Patient Safety (CMO&PS) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 


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Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries.
8.3
Emergency unblinding of treatment assignment
Emergency unblinding should only be undertaken when it is essential for effective treatment 
of the patient. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency code breaks are performed using the IRT. When the investigator 
contacts the IRT to unblind a patient, he/she must provide the requested patient identifying
information and confirm the necessity to unblind the patient. The investigator will then 
receive details of the drug treatment for the specified patient and a fax confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
Study Lead that the code has been broken.
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT in case of emergency. The investigator will inform the patient how to contact 
his/her backup in cases of emergency when he/she is unavailable. The protocol number, study 
treatment name if available, subject number, and instructions for contacting the local Novartis 
country pharma organization (CPO) (or any entity to which it has delegated responsibility for 
emergency code breaks) will be provided to the patient in case emergency unblinding is 
required at a time when the investigator and backup are unavailable. However, if a mechanism 
is already in place to ensure that the investigator and/or back-up can always be reached in case 
of emergency then the procedure above is not required.
The appropriate personnel from the site and Novartis will assess whether study treatment 
should be discontinued for any patient whose treatment code has been broken inadvertently 
for any reason.
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis CMO&PS. Pregnancy follow-up should be recorded on 
the same form and should include an assessment of the possible relationship to the study 
treatment for any pregnancy outcome. Any SAE experienced during pregnancy must be 
reported on the SAE Report Form.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.


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If pregnancy occurs in a patient in the study, the study treatment must be discontinued, 
though the patient may stay in the study and follow the assessments, if she wishes to do so. 
All assessments that are considered as a risk during pregnancy must not be performed. The 
patient may continue all other protocol assessments.
Follow up of the pregnancy (female patient or female partner of patient) should be according 
to the following schedule:

Tracking of pregnancy cases occurs until after Expected Delivery Date (EDD) for all 
prospective pregnancy cases received from clinical studies (including pregnancies where 
the patient was exposed to placebo or comparator and pregnancies due to the conduct of 
the study).

EDD +1 month (mandatory for all cases). Requesting the pregnancy outcome and other 
clinically relevant pregnancy data or changes in data.

EDD+2 month (mandatory if no answer is obtained after request at EDD+1 month). A 
reminder letter for the outcome.

The follow up at EDD+3 months is mandatory for all cases of live birth. Information on 
the status of the baby 3 months after delivery and information on any development issue 
or abnormality that would not be seen at birth must be collected.

The follow up at EDD+12 months is mandatory for all cases of live birth. Information on 
the status of the baby 12 months after delivery and information on any development issue 
or abnormality that would not be seen at birth must be collected.
If the pregnancy case is lost to follow-up (e.g. no response after 3 attempts) this information
must be transferred to the Safety Desk of the CPO.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.6
Data Monitoring Committee 
This study will institute a DMC which will function independently of all other individuals 
associated with the conduct of this clinical trial, including the site investigators participating 
in the study. The DMC will be constituted prior to the randomization of the first patient. The 
DMC will be responsible to review safety data approximately every 6 months (after the first 
randomized patient has started study treatment). The DMC will also be responsible to review 
efficacy and safety data, in the conduct of the interim analysis as defined in the protocol. This 
includes but does not limit the role of the DMC to evaluate these data and to provide 
recommendations to the sponsor to continue, modify or stop the study early.
It is expected that the DMC will consist at a minimum of two physicians with appropriate 
disease area qualifications and one statistician. There will be a meeting with the DMC 


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describing their roles and responsibilities and discussing potential data format and process 
issues prior to the finalization of DMC charter and the interim analysis plan.
It is envisioned that the DMC may make five types of recommendations, namely:

No safety or efficacy issues, ethical to continue the study as planned

Serious safety concerns precluding further study treatment, regardless of efficacy

Overwhelming evidence for efficacy making further participation in the study unethical

Overwhelming evidence for futility, recommend stopping the study.

Recommendation to continue the study but proposing an amendment to the protocol (e.g., 
incorporate an additional safety assessments)
If the study is recommended to continue by the DMC, no details about the results of the 
current interim analysis will be revealed prior to the next scheduled analysis.
8.7
Steering Committee 
The Steering Committee (SC) will be established comprising investigators participating in the 
trial and will not include the independent safety committee or the Novartis representatives 
from the Clinical Trial Team.
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the SC will be defined in a SC charter. The SC will not have access to 
un-blinded trial data prior to the primary analyses.
9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the 
subject experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 


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information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training.
Subject Age will be recorded in the eCRF to establish that the subject satisfies protocol age 
requirements and to enable appropriate age-related normal ranges to be used in assessing 
laboratory test results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan.
9.3
Data collection
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the eCRF. The eCRFs have been built using fully 
validated secure web-enabled software that conforms to 21 CFR Part 11 requirements.
Investigator site staff will not be given access to the EDC system until they have been trained. 
Automatic validation programs check for data discrepancies in the eCRFs and, allow 
modification or verification of the entered data by the investigator staff.
The investigator must certify that the data entered into CRF are complete and accurate and 
that entry and updates are performed in a timely manner.
ECG data will be collected via 12-lead ECG machines and the data will be recorded on the 
CRF. 
PK 
 samples (including FLT3 analytics) drawn during the course of the study 
will be shipped by the site to a Novartis designated laboratory for sample management and/or 
analysis.


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PRO data must be recorded by patients onto the electronic tablet device maintained at the 
study site. Paper questionnaires as back-up might be allowed to use in exceptional cases.
9.4
Database management and quality control
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the 
nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated 
investigator site staff are required to respond promptly to queries and to make any necessary 
changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using 
the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology.
In terms of samples and/or data (e.g. 
 PK) that will be processed centrally the 
results will be sent electronically to Novartis.
PRO data will be entered into an electronic diary by the patient. The system will be supplied 
by a vendor(s), who will also manage the database. The database will be sent electronically to 
Novartis personnel.
Randomization codes and data about all study treatments dispensed to the patient and all IRT 
assigned dosage changes will be tracked using an Interactive Response Technology. The 
system will be supplied by a vendor(s), who will also manage the database. The data will be 
sent electronically to Novartis personnel.
At the conclusion of the study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to Novartis 
personnel (or designated CRO). The occurrence of any protocol violations will be determined. 
After these actions have been completed and the data has been verified to be complete and 
accurate, the database will be declared locked and the treatment codes will be unblinded and 
made available for data analysis. Authorization is required prior to making any database 
changes to locked data, by joint written agreement between the Global Head of Oncology 
Biostatistics, Global Head of Data Management and the Global Head of Clinical Development.
After database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.
10
Statistical methods and data analysis
The final EFS analysis will be performed by Novartis. The interim analyses for the EFS and 
the first interim analyses for OS if EFS statistically significant will be performed by an 
independent external statistician and an independent external programmer (CRO not involved 
with the conduct of the study). The second OS interim analysis at the time of the final EFS 
analysis will be performed by Novartis study team if the final analysis of EFS is statistically 


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significant. Investigators and patients will be kept blinded at the patient level in case the trial 
continues. 
The final EFS analysis will be conducted at the time when approximately 285 EFS events 
have been observed. The final OS analysis will be performed when there are approximately 
278 deaths documented. The safety analysis will be performed approximately every 6 months 
by the iDMC and at the time of EFS or OS analyses.
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study drug has been assigned by 
randomization. According to the intent to treat principle, patients will be analyzed according 
to the treatment and stratum they have been assigned to during the randomization procedure.
10.1.2
Safety set
The Safety Set (SS) includes all patients who received at least one dose of study treatment 
starting at day 1 and being randomized with at least one dose of Midostaurin or placebo. 
Patients will be analyzed according to the study treatment received, where treatment received 
is defined as the randomized treatment if the patient took at least one dose of that treatment. 
Patients who started therapy at day 1 but discontinued prior to randomization at day 8 will be 
listed separately.
10.1.3
Per-Protocol set
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant 
with requirements of the study protocol (i.e., without any major protocol deviation). Protocol 
deviations leading to exclusion from the PPS will be justified and specified in the study 
Specification Document (SSD) and Statistical Analysis Plan (SAP) documents prior to 
database lock.
10.1.4
Pharmacokinetic analysis set
Pharmacokinetic Analysis Set for all (PAS-all)
The Pharmacokinetic analysis set for all (PAS-all) includes all subjects in the safety set, and 
provide at least one evaluable PK concentration.
For a concentration to be evaluable: 

Dosing information must be properly documented (data and time of administration)

the planned dose of midostaurin must be taken prior to sampling,

For pre-dose samples: no vomiting within 4 hours after the midostaurin dose prior to 
sampling, the sample is collected before the next dose administration.

For post-dose samples: no vomiting within 4 hours after midostaurin dosing 
The PAS-all will be the primary population used for all pharmacokinetic analyses using 
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Pharmacokinetic analysis set for full PK profile (PAS-full) 
The Pharmacokinetic analysis set for full PK profiles (PAS-full) includes all subjects in the 
PAS-all, who provide an evaluable PK profile. A profile is considered evaluable if all of the 
following conditions are satisfied:

Subject receives the planned first dose of midostaurin on C1D8 of Induction therapy

Subject did not vomit within 4 hours of the first dose of midostaurin on C1D8 of Induction 
therapy

Subject provides at least one primary PK parameter (Cmax, AUC0-t)
The PAS-full will be the primary population used for all pharmacokinetic analyses based on 
full PK profile data.
Protocol deviations leading to exclusion from the PAS-all and PAS-full will be justified and 
specified in the study Validation and Planning (VAP) and Statistical Analysis Plan (SAP) 
documents.
10.2
Patient demographics/other baseline characteristics
Baseline demographics and disease characteristics data will be summarized descriptively by
treatment group for the FAS. Qualitative data, such as gender, race, etc., will be presented as
frequencies and percentages. Quantitative data, such as age, height, etc., will be summarized 
as mean, standard deviation, median, minimum, and maximum.
10.3
Treatments (study treatment, concomitant therapies, compliance)
Data on the study treatment administration will be summarized by treatment group in the 
safety set. The duration of treatment and relative dose intensity of each of the components of 
study treatment will be summarized using descriptive statistics.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment group.
Any prior concomitant medications or significant non-drug therapies starting and ending prior 
to the start of study treatment will be summarized and listed by treatment group.
10.4
Primary objective
The primary objective of this study is to determine if the addition of midostaurin to standard 
induction and consolidation therapy, followed by single agent post-consolidation therapy
improves EFS in patients with newly diagnosed FLT3-MN (SR<0.05) AML.

The primary endpoint is EFS as per investigator assessment and is defined as the time 
from the date of randomization to failure to obtain CR or CRi with adequate blood count
recovery in induction, relapse after CR or CRi with adequate blood count recovery, or 
death due to any cause, whichever occurs first.


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10.4.1
Statistical hypothesis, model, and method of analysis
The study is designed to test the following statistical hypothesis for EFS using a stratified log-
rank test (stratified according to randomization stratification factor of age (<60 vs. ≥ 60 years)) 
at the one-sided 2.5% level of significance: 
H01: θ1 ≥ 1 vs. Ha1: θ1 < 1
Where θ1 is the hazard ratio (Midostaurin treatment arm vs. placebo arm) of EFS.
The primary efficacy endpoint EFS will be analyzed at the interim looks and final look of a 
group sequential design based on the FAS population according to the treatment group 
patients were randomized and the strata they were assigned at randomization (i.e. age < 60 vs. 
>=60 years). EFS will be estimated using the Kaplan-Meier method. The median EFS along 
with 95% confidence intervals will be presented by treatment group. 
Under the proportional hazards assumption, a test based on the stratified log-rank test 
provides an asymptotically equivalent result as that of the stratified Cox regression model 
which will be used to estimate the hazard ratio (HR) of EFS, along with 95% confidence 
interval (using the same strata information as above). 
10.4.2
Handling of missing values/censoring/discontinuations
In the primary analysis, a patient who had not an EFS event at the date of the analysis cut-off 
would have his/her EFS censored at the time of the last adequate response assessment before 
the cut-off date. 
A patient who failed to achieve CR or CRi with adequate blood count recovery in induction, 
would have his/her EFS event due to induction failure documented at the date of 
randomization.
EFS events documented after the initiation of HSCT or new anti-neoplastic therapy will be 
considered as EFS event for the primary EFS analysis.
If an EFS event is observed after two or more missing or non-adequate response assessments, 
then EFS will be censored at the last adequate response assessment before the EFS event. If 
an EFS event is observed after a single missing or non-adequate response assessment, the 
actual date of event will be used.
An adequate response assessment is considered any disease assessment indicating response 
status apart from “unknown” or “not done”.
10.4.3
Supportive analyses
A supportive analysis on the primary efficacy variable using a stratified Cox’s proportional 
hazards model adjusting for time dependent covariates such as SCT and MRD and other 
potential prognostic factors will be performed. Other potential prognostic factors will be 
specified in the SAP document prior to database lock.
Subgroup analyses based on age and gender etc. will be performed. There will be sensitivity 
analyses for the EFS (e.g., using different censoring techniques, per protocol set analysis, 
etc...). More details on these will be available in SAP.


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10.5
Secondary objectives
The key secondary objective is to determine if the addition of midostaurin to standard 
induction and consolidation therapy, followed by single agent post-consolidation therapy
improves OS in patients with newly diagnosed FLT3-MN (SR<0.05) AML.
Other secondary efficacy objectives are to compare CR or CRi with adequate blood count 
recovery rate, MRD, DFS, Cumulative Incidence of Relapse (CIR), Cumulative Incidence of 
Disease (CID) and health-related quality of life and symptoms of AML in patients treated 
with midostaurin in combination with daunorubicin or idarubicin/cytarabine versus those 
treated with placebo in combination with daunorubicin or idarubicin/cytarabine.
The secondary safety/PK objective is to assess safety, pharmacokinetic of midostaurin in 
combination with daunorubicin or idarubicin/cytarabine versus placebo in combination with 
daunorubicin or idarubicin/cytarabine.
Population and grouping for the analyses
The secondary efficacy variables will be analyzed using the FAS. For all safety analyses, the
safety set will be used. Subgroup analyses will be performed by age (<60 versus ≥60 years) ,
ELN risk group (Favorable/ Intermediate/ Adverse) etc.... All listings and tables will be 
presented by treatment group.
10.5.1
Key secondary objective(s)
The key secondary objective of the study is to determine if the addition of midostaurin to 
standard induction and consolidation therapy, followed by single agent post-consolidation
therapy improves OS in patients with newly diagnosed FLT3-MN (SR<0.05) AML.  
OS is defined as the time from date of randomization to date of death due to any cause. If a 
patient is not known to have died, survival will be censored at the date of last contact. No 
censoring will be done in case of HSCT.
Assuming proportional hazards model for OS, the following statistical hypothesis for OS will 
be tested using a stratified log-rank test (stratified according to randomization stratification 
factor of age) at the one-sided 2.5% level of significance: 
H02: θ2 ≥ 1 vs. Ha2: θ2 < 1
Where θ2 is the hazard ratio (Midostaurin treatment arm vs. placebo arm) of OS.
The analyses for OS will be based on the FAS population according to the treatment group 
patients were randomized and the strata they were assigned at randomization. 
The final OS analysis will not be performed at the time point of the final EFS analysis, but 
after additional follow up. Therefore, a three-look design is considered for OS following a 
separate group-sequential plan.
The OS will be hierarchically tested in the following way: 
1. The first potential time point for OS analysis will be at the time of the 2nd EFS interim 
analysis, where approximately 79 deaths are expected. If EFS is statistically significant at 
this stage, OS will also be tested. If OS is not statistically significant at this stage, the 2nd


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OS analysis will be planned at approximately 190 deaths (i.e. at time of EFS final 
analysis). If OS is not statistically significant at this stage, a final analysis is planned at 
approximately 278 deaths have been recorded. 
2. If EFS is not statistically significant at the time of the interim analysis of EFS, then OS 
will not be tested at the time of the interim analyses of EFS. If EFS is statistically 
significant at the time of the final analysis of EFS, then OS will also be tested. If OS is not 
statistically significant at this stage, the final analysis for OS is planned at approximately 
278 deaths have been recorded. 
3. If EFS is not statistically significant at the final analysis, then OS will not be tested. 
The type I error probability will be controlled by using a separate Haybittle-Peto boundary
independent of the one used for the primary efficacy analysis of EFS at 2.5% level of 
significance. This guarantees the protection of the overall level α = 2.5% (one-sided) across 
the two hypotheses and the repeated testing of the OS hypotheses in the interim and the final 
analyses. 
OS will be estimated using the Kaplan-Meier method. The median OS along with 95%
confidence intervals will be presented by treatment group. The stratified Cox regression 
model will be used to estimate the HR of OS, along with 95% confidence interval. All OS 
analyses will be based on the FAS.
10.5.2
Other secondary efficacy objectives
10.5.2.1 CR/CRi rate, Time to CR or CRi with adequate blood count recovery, 
Disease Free survival (DFS), Cumulative Incidence of Relapse (CIR) 
and Cumulative Incidence of Death (CID)
Other secondary efficacy variables include CR or CRi with adequate blood count recovery
rate, DFS, CIR and CID. The assessment of these endpoints will be based on the IWG criteria
for AML (Cheson et al 2003, ELN 2017 / Döhner et al 2017) as per investigator assessment.
CR/CRi with adequate blood count recovery rate will be analyzed using Cochran-Mantel-
Haenszel test based on strata at randomization. Estimated CR/CRi rate along with 
corresponding 95% confidence intervals will be presented by stratum and overall, and by 
treatment group.
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. 
Patients without experiencing CR, CRi with adequate blood count recovery will be censored 
according to the following events:

Patients experiencing induction failure will be censored at maximum follow-up (i.e. date 
of FPFV to date of LPLV used for the analysis).

Patients not experiencing induction failure and who did not die (any cause) will be 
censored at their last adequate response assessment date which is different from “unknown” 
or “not done”.


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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.
DFS will be estimated using the Kaplan-Meier method. The median DFS along with 95%
confidence intervals will be presented by treatment group. The stratified Cox regression will 
be used to estimate the HR of DFS, along with 95% confidence interval.
Cumulative Incidence of Relapse (CIR) is defined for patients with CR or CRi with adequate 
blood count recovery and is time from achieving the 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.
Cumulative Incidence of Relapse (CIR) will be estimated using the Kaplan-Meier method. 
The median CIR along with 95% confidence intervals will be presented by treatment group. 
The stratified Cox regression will be used to estimate the HR of CIR, along with 95%
confidence interval.
Cumulative Incidence of Death (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.
CID will be estimated using the Kaplan-Meier method. The median CID along with 95%
confidence intervals will be presented by treatment group. The stratified Cox regression will 
be used to estimate the HR of CID, along with 95% confidence interval.
The rate of CR/CRi with adequate blood count recovery will be analyzed based on the FAS. 
However, DFS, Cumulative Incidence of Relapse (CIR) and Cumulative Incidence of Death 
(CID) will be analyzed based on data from responders (CR or CRi with adequate blood count 
recovery) in the FAS. Assessment of relapse from CR or CRi with adequate blood count 
recovery, DFS, CIR and CID will not consider whether a patient received HSCT.
10.5.2.2 MRD negative status
The percentage of patients with MRD negative bone marrow will be summarized along with 
exact 95% CI by treatment group and by treatment phase. Importantly, comparisons of the 
MRD levels between the end of the consolidation phase during the post-consolidation phase 
will be performed by treatment groups.
The time to MRD negative status is defined as the time from randomization to first occurrence
of MRD negativity. Patients without reaching MRD negative status level will be censored 
according to the following events:

Patients experiencing induction failure will be censored at maximum follow-up (i.e. date 
of FPFV to date of LPLV used for the analysis).

Patients not experiencing induction failure and who did not die (any cause) will be 
censored at their last adequate MRD assessment. 


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Moreover, the kinetics of MRD levels will be displayed in terms of boxplot by over time for 
each treatment phase.
10.5.2.3 Time to neutrophil/platelet recovery
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 109/L 

Number of days from start of treatment to the first day neutrophils ≥1.0 x 109/L.
Similarly, the 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 109/L

Number of days from start of treatment to the first day platelets ≥100 x 109/L.
Moreover, the time to adequate blood count recovery will be assessed as:

Number of days from start of treatment to the first day platelets ≥50 x 109/L and the first 
day neutrophils ≥1.0 x 109/L.
In addition, data on transfusion will be summarized by treatment group.
The median time to platelet and to neutrophil recovery along with their corresponding 95% 
confidence intervals will be presented by treatment group.
10.5.3
Safety objectives
10.5.3.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group.
The overall observation period will be divided into three mutually exclusive segments:
1. Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study treatment
2. On-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication
3. Post-treatment period: starting at day 31 after last dose of study medication.
The safety summary tables will include only assessments collected within 30 days after study 
treatment discontinuation and assessments prior to the data cut-off date for ongoing patients, 
unless otherwise specified.
All data, regardless of observation period, will be listed and assessments collected in the 
pretreatment and post-treatment period will be flagged in all the listings. 
10.5.3.2 Adverse events (AEs)
Summary tables for AEs will include only AEs that started or worsened during the on-
treatment period, the treatment-emergent AEs.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades 
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Serious adverse events, non-serious adverse events during the on-treatment period will be 
tabulated.
All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged.
AESI will be analyzed. Such categories consist of one or more well-defined safety events 
which are similar in nature and for which there is a specific clinical interest in connection with 
the investigational treatment(s).
AESI will be defined at the project level and may be regularly updated based on emergent 
data. For each specified AESI, number and percentage of patients with at least one event part 
of the AESI will be reported.
10.5.3.3 Laboratory abnormalities
Grading of laboratory values will be assigned programmatically as per national cancer 
institute (NCI) CTCAE [version 5.0]. The calculation of CTCAE grades will be based on the 
observed laboratory values only, clinical assessments will not be taken into account.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
For laboratory tests where grades are not defined by CTCAE 5.0, results will be categorized 
as low/normal/high based on laboratory normal ranges.
The following by-treatment summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests

Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline.

Shift tables using CTCAE grades to compare baseline to the worst on-treatment value

For laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value.

Listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges.
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots may be 
specified in the SAP
10.5.3.4 Other safety data
ECG values and Vital signs will be listed and summarized by treatment group.
ECG

Listing of ECG evaluations for all patients with at least one abnormality.


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Change from baseline (QTcF and Vital signs)

Shift table baseline to worst on-treatment result.

Table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to this/these post-baseline time points.
10.5.3.5 Supportive analyses for secondary objectives 
Subgroup analyses will be provided for specific secondary variables based on age, gender, 
race, etc. will be performed as appropriate, more details will be provided in the SAP.
10.5.4
Pharmacokinetics
Plasma concentrations: Plasma concentrations will be summarized by treatment part and 
time point. Summary statistics will include n (number of values to be reported), arithmetic and 
geometric mean, median, SD, CV, and geometric CV, minimum and maximum. 
Concentrations below the LLOQ will be treated as zero in summary statistics except for 
geometric mean. Zero concentrations will not be included in the geometric mean calculation. 
For Tmax, the median and range will be provided.
Non-compartmental analysis (NCA): PK parameters for midostaurin and the active 
metabolites will be determined using non-compartmental method(s) using Phoenix 
WinNonlin (Version 6.4 or later- Certara L.P.) for the patients who had full PK sampling on 
Cycle 1 Day 8 of the induction therapy. 
Concentration data from patients who underwent sparse sampling only will be analyzed where 
possible, and relevant NCA parameters determined.
PK parameters listed in Table 10-1 will be estimated and reported, when feasible (dependent 
on sampling scheme, and validity of samples). 
AUC0-t and Cmax are defined as primary parameters (contributing to PAS-full definition). 
All PK parameters will be determined when possible. In addition, and when feasible, analysis 
of data from all subjects (frequently and less frequently sampled) for PK parameters at steady 
state (Table 10-1) will be performed.
NCA PK parameters and all concentrations will be summarized and reported. Summary
statistics will include n (number of values to be reported), arithmetic and geometric mean, 
median, SD, CV, geometric CV, minimum and maximum. 
Population pharmacokinetic (PopPK) analysis: the PK samples of the PAS-all will be 
analyzed using a population PK approach. Comparisons of new data with predicted exposures 
from existing models will be provided through visual predictive checks (VPCs). Further
details of the analysis as well as the results will be reported in a stand-alone analysis plan and 
report independent of this clinical study report. In addition, comparisons of individual 
predicted patient parameters with those observed will be conducted and reported in the CSR. 
Further details will be provided in the SAP.
Exposure-response analyses for relevant efficacy endpoints (including CR, CRi with adequate 
blood count recovery and EFS, plus investigation of further endpoints such as MRD) and 
safety endpoints (including QT and AEs) will be further discussed as appropriate in the SAP.


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Table 10-1
Noncompartmental pharmacokinetic parameters
AUC0-t
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
The AUC from time zero to the last measurable concentration sampling time after the 
first dose (tlast) (mass x time x volume-1)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after the first dose administration (mass x volume-1)
Cmin
Minimal observed pre-dose concentration (when feasible)
C3h
Concentration at 3 hours post-dose (when feasible)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time)
 
 
 
 
 
 
 
 
 
 
10.5.5
Patient-reported outcomes
Responses to the FACT-Leu and EQ5D-5L, will be generated in accordance with the 
respective scoring manual. 
A table of decomposition of patients will be created at each visit depicting the ‘number of 
patients in the analyses’, ‘patients died’, ‘patients achieved CR/CRi’, ‘patient refused data due 
to poor health’, ‘patient refused (unrelated to health), ‘study staff felt patient was too ill’, 
‘patient missed appointment’, ‘other reasons’).
Descriptive statistics (mean, standard deviation, median, minimum, and maximum) will be 
used to summarize the scored scales at each scheduled assessment time point for the FACT-
Leu and EQ5D-5L (VAS) by treatment arm. Additionally, change from baseline in the scores 
at the time of each assessment will be summarized. Patients with an evaluable baseline score 
and at least one evaluable post baseline score during the treatment period will be included in 
the change from baseline analyses. 
Mixed models for repeated measures (MMRM) will be used to estimate the treatment effect 
on the FACT-Leu scores over time. MMRM are commonly used to analyze longitudinal data 
from randomized trials under the missing-at-random (MAR) assumption. The MMRM will 


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include fixed-effect covariates for treatment, study visit (time), and interaction of treatment 
and time; other fixed covariates may include baseline score and randomization stratification 
factors.  A subject-specific random effect will be included in the model.  Change from 
baseline score will serve as the dependent variable. Least squares estimates and 
accompanying 95% CIs for change scores by study arm and visit will be presented. As a 
sensitivity analysis to the MMRM, pattern-mixture models will be used to examine the 
missing mechanism and explore the plausibility of the MAR assumption.  
Analysis will be carried out for all patients as well as excluding those received HSCT.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.7
Interim analyses
10.7.1
Event free survival (EFS)
The efficacy analyses will be based on FAS and are event driven. The final EFS analysis will
be performed when there are approximately 285 EFS events. Two interim analyses will be 
performed when approximately 40% and 75% of 285 EFS events have occurred.
These analyses are expected to take place around 12 and 20 months respectively from the date 
of first patient randomized in the study assuming an increasing recruitment rate to reach 30 
patients / month in month 6. The primary intent of the first interim analysis is to allow the 
study to stop early for lack of efficacy (futility). There is no intent to carry out an analysis to 
declare superior efficacy at the time of the first interim analysis. At least, 283 patients (56%) 
are expected to be randomized at the time of the interim futility analysis, i.e., when 
approximately 114 EFS events have occurred. The 2nd interim analysis will allow the study to 
stop early for outstanding efficacy. The 2nd interim analysis will only be carried out after all 
patients have been randomized.
A user-defined gamma spending function (γ = -1.2) will be used as a beta-spending function 
to determine the non-binding futility boundary at the time of the 1st interim analysis. The 
futility boundary at the first interim is calculated as hazard ratio of 0.97. The observed (i.e.,
nominal) p-value has to be greater than p=0.44 (one-sided) to conclude futility. Since the 
observed number of EFS events at the interim analyses may not exactly be equal to the 


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planned number of events, the futility boundary will need to be re-calculated (or updated) 
based on the actual number of observed events. Therefore, the observed p-value (or Z-test 
statistic) at the first interim analysis will be compared with the updated futility boundary.
A Haybittle-Peto stopping boundary will be used for efficacy interim and final EFS analyses 
(Peto et al 1976). At the second interim analysis, the observed p-value has to be less than 
p=0.0001 (i.e. HR<0.601) in order to conclude superior efficacy. If the study continues, the 
final analysis will be performed when approximately 285 EFS events have been documented 
or 5 years after the end of the study treatment for the last patient whichever occurs first. The 
final analysis criteria will be determined based on the actual number of events observed such 
that the overall significance level across all analyses is maintained at 0.025. It is estimated the 
the observed HR needs to be less than 0.80 to declare statistical significance at the final EFS 
analysis.
Table 10-2 represents the operational characteristics of this design. These are based on 
simulations in the software package East version 6.4. The following are a few key operational 
characteristics: The cumulative probability to detect an efficacious treatment by the primary 
analysis is 90%; while the cumulative probability of erroneously detecting a non-efficacious
treatment by the final analysis is 2.4%. If the null hypothesis is true then cumulative 
probability to stop the trial at the first interim analysis for lack of efficacy is 55.8%.


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Table 10-2
Simulated cumulative probabilities to stop for efficacy or futility by the
1st interim (IA1), the 2nd interim (IA2) or the final EFS (FA) analyses
Hazard 
ratio
Analysis
Average 
sample 
size
Average
Time
(months)
Simulated cum. prob. stop due to
Efficacy
Futility
0.675
IA 1
IA 2
FA
282
502
502
11.9
20
38.8
0.0149
0.1983
0.900
0.025
NA
NA
0.8375
IA1
IA2
FA
264
502
502
11.3
20
31
0.0003
0.009
0.312
0.213
NA
NA
1.0
IA1
IA2
FA
249
502
502
10.8
20
26.5
0
0.0001
0.024
0.558
NA
NA
* In the middle of H0 and HA; cum. prob.: cumulative probability
Note: Simulation is performed with software package [East version 6.4] with number of 
simulations = 10,000 and randomization seed =2301. The interim analyses for EFS will be 
performed by an independent statistician. Results from EFS interim analysis will not be 
communicated to clinical team or any party involved in the study conduct (apart from the 
independent statistician and DMC members) until EFS is found to be significant or study 
needs to be terminated due to safety or lack of efficacy.
10.7.2
Key secondary endpoint: Overall survival (OS)
OS will be compared between the two treatment groups, provided the primary endpoint EFS is 
statistically significant favoring the active treatment group. A hierarchical testing procedure will 
be adopted and the statistical tests for OS will be performed only if the primary efficacy 
endpoint EFS is statistically significant.
Three analyses are planned for OS; at the time of the interim and final EFS analyses (provided 
EFS is significant), at which point a total of approximately 79 and 190 deaths are expected 
(28% and 68% information fraction respectively) and a final OS analysis when approximately 
278 deaths are expected (expected 64 months from date of first patient to be randomized).
A Haybittle-Peto boundary as implemented in East version 6.4 (Peto et al 1976) , independent 
of the Haybittle-Peto boundary used for EFS, along with the testing strategy outlined below will 
be used to maintain the overall type I error probability. This guarantees the protection of the 
(2.5%) overall level of significance across the two hypotheses and the repeated testing of the 
OS hypotheses in the interim and the final analysis (Glimm 2010).
The trial allows for the stopping of the study for a superior OS result, provided the primary 
endpoint EFS has already been shown to be statistically significant favouring the test 


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treatment group. Further, the exact nominal p-values that will need to be observed to declare 
statistical significance at the time of these analyses for OS will depend on the number of OS 
events that have been observed at the time of these analyses and the α for OS already spent at 
the time of earlier analyses. Given the hierarchical testing strategy of EFS and OS, the design 
concerning OS analyses will have the following characteristics based on simulations in
software package [East 6.4]. The probabilities shown in Table 10-3 are conditional
probabilities (conditional on EFS being statistically significant) not marginal probabilities.
Table 10-3
Simulated probabilities to stop for efficacy on overall survival at 2nd
EFS interim (1st OS interim (IAOS1)), final EFS (2nd OS interim (IAOS2))
analysis or final OS analysis (FAOS)
Hazard 
ratio
Analysis
Average 
sample 
size
Average
Time
(months)
Simulated cum. 
prob. stop due to
Efficacy
0.714
IAOS1
IAOS2
FAOS
502
502
502
20
38
64
0.010
0.074
0.799
0.857
IAOS1
IAOS2
FAOS
502
502
502
20
35
58
0.0018
0.0050
0.327
1.0
IAOS1
IAOS2
FAOS
502
502
502
20
34
54
0
0.0001
0.026
* Probabilities are reported as if OS was tested alone, regardless the testing strategy with EFS. The true 
probabilities should take into account the probability of EFS at each look. 
Note: Simulation is performed with software package [East 6.4] with number of simulations = 10,000 and 
randomization seed =2301.
At the time of interim analysis for EFS, an interim analysis for the key secondary endpoint of 
OS will be performed by an independent statistician. Unblinded results from the interim 
analysis for EFS and corresponding interim analysis for OS will not be communicated to the 
Sponsor's clinical team or to any party involved in the study conduct (apart from the 
independent statistician and DMC members) until the DMC has determined that either (i) EFS 
analysis has crossed the pre-specified boundary for efficacy, or (ii) the study needs to be 
terminated due to any cause including futility or safety reasons. Further details will be 
described in the DMC Charter.
At the time of the primary analyses, both EFS and interim OS analysis will be performed by 
the Sponsor's clinical team. Investigators and patients will remain blinded to study treatment 
and all patients will continue to be followed for OS until the final analysis (or earlier if OS 
reaches statistical significance at any of the interim analyses).


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10.8
Sample size calculation
The assumption of median EFS of 12.0 months for the control treatment arm for sample size 
calculations is based on available data for patients with FLT-MN (Bacher et al 2008). It is 
expected that treatment with test treatment arm will result in a 37.5% reduction in the hazard 
rate (corresponding to an increase in median EFS from 12.0 months to 17.8 months under the 
exponential model assumption). 
If the true hazard ratio is 0.675, a total of 285 EFS events are required to have 90% power at 
an one-sided overall 2.5% level of significance to reject the null hypothesis (HR≥1) using a 
log-rank test and a 2-look group sequential design with Haybittle-Peto boundary to determine 
efficacy boundary and gamma spending function (γ = -1.2) to determine the non-binding 
futility boundary. Considering a recruitment period of approximately 20 months assuming an 
increasing recruitment rate to reach 30 patients / month in month 6, 502 patients will need to 
be randomized to the two treatment arms in a 1:1 ratio. Assuming about approximately 10% 
patients will be lost to follow-up for EFS, a total of 502 patients will need to be randomized. 
Given the above assumptions, it is estimated that the 285th EFS event will be observed at 
approximately 40 months from the date of first patient randomized in the study. The sample 
size calculation was conducted with software package [East 6.4].
10.9
Power for analysis of key secondary endpoint
OS will be compared between the two treatment groups, provided that the primary endpoint 
EFS is statistically significant. Based on available data (Gale et al 2008), the median OS in the 
control treatment arm is expected to be around 30 months. It is hypothesized that Midostaurin
treatment arm will result in a 28.6% reduction in the hazard rate for overall survival 
(corresponding to an increase in median survival by 12 months (from 30 to 42 months) under 
the exponential model assumption). If the true hazard ratio is 0.714, a total of 278 deaths are 
needed to be observed to have 80% power at an one-sided overall 2.5% level of significance 
to reject the null hypotheses (HR≥1) using a log-rank test and a 3-look group sequential 
design conditionally to a significant improved EFS before or at the same time of analyses 
testing OS. Based on the same number of patients that are planned to be enrolled in this study 
to detect the primary endpoint, it is estimated that these 278 deaths will be observed at 
approximately 64 months from the date of first patient to be randomized. Therefore the 
estimated time for the final OS evaluation is expected to be approximately 24 months after the 
final EFS analysis have been conducted. The power calculation was conducted with software 
package [East 6.4].
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
international conference on harmonization (ICH) Harmonized Tripartite Guidelines for Good 
Clinical Practice (GCP), with applicable local regulations (including European Directive 
2001/20/EC and US Code of Federal Regulations Title 21), and with the ethical principles laid 
down in the Declaration of Helsinki.


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11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is 
required to sign a protocol signature page confirming his/her agreement to conduct the study 
in accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis (or CRO) monitors, 
auditors, Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents. The date when a subject’s Informed 
Consent was actually obtained will be captured in their CRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis (or CRO) monitor after IRB/IEC/REB 
approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. Male patients treated with idarubicin, daunorubicin or cytarabine should 
receive appropriate advice on the risk of infertility and the option of sperm conservation. 
Midostaurin may impair both male and female fertility and this should be communicated to 
the patients. If there is any question that the patient will not reliably comply, they should not 
be entered in the study.
Additional consent form 
Not applicable.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in Section 
4.4.


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11.5
Publication of study protocol and results
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g., www.clinicaltrials.gov before study
start. In addition, results of interventional clinical trials in adult patients are posted on 
www.novartisclinicaltrials.com, a publicly accessible database of clinical study results within 
1 year of study completion (i.e., last patient last visit (LPLV)), those for interventional clinical 
trials involving pediatric patients within 6 months of study completion.
Novartis follows the International Committee of Medical Journal Editors (ICMJE) authorship 
guidelines (www.icmje.org) and other specific guidelines of the journal or congress to which 
the publication will be submitted
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to
present poster or oral presentation at scientific congress; however, there will be no 
honorarium provided for such presentations.
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable.
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to www.novartis.com.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial.


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Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study CRF is the primary data collection instrument for the 
study. The investigator should ensure the accuracy, completeness, legibility, and timeliness of 
the data reported in the CRFs and all other required reports. Data reported on the CRF, that 
are derived from source documents, should be consistent with the source documents or the 
discrepancies should be explained. All data requested on the CRF must be recorded. Any 
missing data must be explained. For electronic CRFs an audit trail will be maintained by the 
system. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 


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Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, Novartis should be notified of this action and the IRB/IEC at the study 
site should be informed according to local regulations but not later than 10 working days.


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13
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Papaemmanuil E, Gerstung M, Bullinger L, et al (2016) Genomic Classification and 
Prognosis in Acute Myeloid Leukemia. N Engl J Med; 374(23): 2209-21.
Peto R, Pike M, Armitage P, et al (1976) Design and analysis of randomized clinical trials 
requiring prolonged observation of each patient. I. Introduction and design. Br J Cancer; 34(6):
585-612. 
Pratcorona M, Brunet S, Nomded´eu J, et al (2013) Favorable outcome of patients with acute 
myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 
mutation: relevance to post-remission therapy. Blood; 121(14): 2734-38.
Pratz KW and Luger DM (2014) Will FLT3 Inhibitors Fulfill Their Promise in AML? Curr 
Opin Hematol; 21(2): 72–78.
Röllig C, Bornhäuser M, Kramer M, et al (2015) Allogeneic stem-cell transplantation in 
patients with NPM1-mutated acute myeloid leukemia: results from a prospective donor versus 
no-donor analysis of patients after upfront HLA typing within the SAL-AML 2003 trial. J 
Clin Oncol.; 33(13): 1519.
Sato T, Yang X, Knapper S, et al (2011) FLT3 ligand impedes the efficacy of FLT3 inhibitors 
in vitro and in vivo. Blood; 117(12): 3286-3293.
Schiller GJ (2014) Evolving treatment strategies in patients with high-risk acute myeloid 
leukemia. Leuk Lymphoma; 55(11): 2438-48.
Schlenk RF, Kayser S, Bullinger L, et al (2014) Differential impact of allelic ratio and 
insertion site in FLT3-ITD–positive AML with respect to allogeneic transplantation. 
Blood;124: 3441-9.
Stone MR, DeAngelo DJ, Klimek V, et al (2005) Patients with acute myeloid leukemia and an 
activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, 
PKC412. Blood; 105(1): 54-60.
Stone MR, Mandrekar SJ, Sanford BL, et al. (2017) Midostaurin plus chemotherapy for acute 
myeloid leukemia with a FLT3 mutation. N Engl J Med; 377: 454-464.
Steudel C, Mohr B, et al (2002) Analysis of FLT3-activating mutations in 979 patients with 
acute myelogenous leukemia: association with FAB subtypes and identification of subgroups 
with poor prognosis. Blood; 99(12): 4326-35.


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Terwijn M, van Putten WL, et al (2013) High prognostic impact of flow cytometric minimal 
residual disease detection in acute myeloid leukemia: data from the HOVON/SAKK AML 
42A study. J Clin Oncol.;31(31):3889-97.
Thiede C, Steudel C, Mohr B, et al (2002) Analysis of FLT3-activating mutations in 979 
patients with acute myelogenous leukemia: association with FAB subtypes and identification
of subgroups with poor prognosis. Blood: 99(12):4326-4335
Weisberg E, Boulton C, Kelly LM, et al (2002) Inhibition of mutant FLT3 receptors in 
leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell; 1: 433-
443


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Protocol No. CPKC412E2301
14
Appendices
14.1
Appendix 1 – Concomitant medications
The following lists are not comprehensive and are only meant to be used as a guide. The lists 
are based on the Novartis PK Sciences’ guidance, Drug-Drug Interaction and Co-Medication 
Considerations (v07, release date: Jan 2018), which was compiled from the Indiana University 
School 
of 
Medicine’s 
P450 
Drug 
Interaction 
Table 
(http://medicine.iupui.edu/clinpharm/ddis/main-table/) and supplemented with the FDA Draft 
Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis, and 
Implications 
for 
Dosing 
and 
Labeling 
(February 
2012) 
(http://.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm29
2362.pdf), 
and 
the 
University 
of 
Washington’s 
Drug 
Interaction 
Database 
(http://www.druginteractioninfo.org/). 
For current lists of medications that may cause QT prolongation and/or torsades de pointes 
(TdP), refer to the CredibleMeds® website (www.qtdrugs.org/). Please contact the medical 
monitor with any questions.
14.1.1
List of prohibited medications
Strong inducers of CYP3A4
carbamazepine, enzalutamide, lumacaftor, phenobarbital, phenytoin, rifabutin, 
rifampicin (rifampin), mitotane, St. John’s wort (Hypericum perforatum)1
Medications with a known risk 
for QT prolongation2
amidarone, anagrelide, arsenic trioxide, astemizole, azithromycin, chloroquine, 
chlorpromazine, cilostazol, cisapride, citalopram, clarithromycin, disopyramide, 
dofetilide, domperidone, donepezil, dronedarone, droperidol, erythromycin, 
escitalopram, flecainide, fluconazole, gatifloxacin, halofantrine, haloperidol, 
ibutilide, levofloxacin, levomepromazine, levosulpiride, methadone, 
moxifloxacin, ondansetron, oxaliplatin, papaverine HCl (intra-coronary), 
pentamidine, pimozide, procainamide, propofol, quinidine, roxithromycin, 
sevoflurane, sotalol, sulpiride, sultopride, terlipressin, terodiline, thioridazine, 
vandetanib
1 Herbal product
2 The list provided is as of January 2018.Check https www crediblemeds.org/healthcare-providers/drug-list for the 
most updated list. 
14.1.2
Permitted medications to be used with caution
Strong inhibitors of CYP3A
ombitasvir/paritaprevir/dasabuvir/ritonavir (Viekira Pak)1, indinavir/ritonavir1, 
tipranavir/ritonavir1, ritonavir, cobicistat, indinavir, ketoconazole, 
troleandomycin, telaprevir, danoprevir/ritonavir1, elvitegravir/ritonavir1, 
saquinavir/ritonavir1, lopinavir/ritonavir1, itraconazole, voriconazole, mibefradil,  
posaconazole, telithromycin, grapefruit juice2, conivaptan, nefazodone, 
nelfinavir, idelalisib, boceprevir, atazanavir/ritonavir1, darunavir/ritonavir1
Substrates with narrow therapeutic index (NTI)
CYP1A2
theophylline, tizanidine (also sensitive)
CYP2B6
No substrate with narrow therapeutic index known.
CYP2C8
paclitaxel
CYP2C9
(S)-warfarin
CYP2C19
(S)-mephenytoin (also sensitive) 


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CYP2E1
No substrate with narrow therapeutic index known.
CYP3A
alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, sirolimus, 
tacrolimus
Transporter substrates
NTI substrates of P-gp3
cyclosporine, digoxin, fentanyl, paclitaxel, sirolimus, tacrolimus
BCRP substrates
atorvastatin daunorubicin, doxorubicin, hematoporphyrin, imatinib, 
methotrexate, mitoxantrone, pitavastatin, rosuvastatin, SN-38 (irinotecan), 
ethinyl estradiol, simvastatin, sulfasalazine, sofosbuvir, topotecan, 
sulfasalazine, tenofovir, topotecan.
OATP1B1 substrates (including 
OATP1B3, and OATP2B1 
substrates)
aliskiren, ambrisentan, anacetrapib, atenolol, asunaprevir, atrasentan, 
atorvastatin, bosentan, bromociptine, caspofungin, cerivastatin, celiprolol, 
danoprevir, digoxin, docetaxel, eliglustat, epangliflozin, ezetimibe, fimasartan, 
fexofenadine, fluvastatin, glyburide, maraviroc, methotrexate, sn-38, 
rosuvastatin, saquinavir, simvastatin acid, paritaprevir, pitavastatin, 
pravastatin, repaglinide, rosuvastatin, simvastatin, valsartan, olmesartan, 
telmisartan, montelukast, ticlopidine, thyroxine
1 Combination ritonavir-boosted regimens are listed here in the DDI memo as strong CYP3A inhibitors (to avoid 
potential confusion), even though some are considered moderate CYP3A inhibitors in the UW DDI Database. 
2 The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation 
was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation was 
used (e.g., low dose, single strength). 
3 These drugs have both a narrow therapeutic index and an in vivo DDI outcome partly ascribed to P-gp inhibition 
or induction that exceeds 20% change in AUC.


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14.2
Appendix 2 – FACT-Leu questionnaire 
FACT-Leu (Version 4)
English (Universal)
Copyright 1987, 1997
19 November 2007
Page 1 of 3
Below is a list of statements that other people with your illness have said are important. Please select
one number per line to indicate your response as it applies to the past 7 days.
PHYSICAL WELL-BEING
Not
at all
A little
bit
Some-
what
Quite
a bit
Very
much
GP1
I have a lack of energy .......................................................
0
1
2
3
4
GP2
I have nausea ......................................................................
0
1
2
3
4
GP3
Because of my physical condition, I have trouble
meeting the needs of my family.........................................
0
1
2
3
4
GP4
I have pain ..........................................................................
0
1
2
3
4
GP5
I am bothered by side effects of treatment .........................
0
1
2
3
4
GP6
I feel ill ...............................................................................
0
1
2
3
4
GP7
I am forced to spend time in bed........................................
0
1
2
3
4
SOCIAL/FAMILY WELL-BEING
Not
at all
A little
bit
Some-
what
Quite
a bit
Very
much
GS1
I feel close to my friends....................................................
0
1
2
3
4
GS2
I get emotional support from my family ............................
0
1
2
3
4
GS3
I get support from my friends.............................................
0
1
2
3
4
GS4
My family has accepted my illness ....................................
0
1
2
3
4
GS5
I am satisfied with family communication about my
illness..................................................................................
0
1
2
3
4
GS6
I feel close to my partner (or the person who is my main
support) ..............................................................................
0
1
2
3
4
Q1
Regardless of your current level of sexual activity, please
answer the following question. If you prefer not to answer it,
please mark this box
and go to the next section.
GS7
I am satisfied with my sex life ............................................
0
1
2
3
4


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Please select one number per line to indicate your response as it applies to the past 7 days.
EMOTIONAL WELL-BEING
Not
at all
A little
bit
Some-
what
Quite
a bit
Very
much
GE1
I feel sad ..............................................................................
0
1
2
3
4
GE2
I am satisfied with how I am coping with my illness..........
0
1
2
3
4
GE3
I am losing hope in the fight against my illness..................
0
1
2
3
4
GE4
I feel nervous.......................................................................
0
1
2
3
4
GE5
I worry about dying.............................................................
0
1
2
3
4
GE6
I worry that my condition will get worse ............................
0
1
2
3
4
FUNCTIONAL WELL-BEING
Not
at all
A little
bit
Some-
what
Quite
a bit
Very
much
GF1
I am able to work (include work at home) ..........................
0
1
2
3
4
GF2
My work (include work at home) is fulfilling.....................
0
1
2
3
4
GF3
I am able to enjoy life..........................................................
0
1
2
3
4
GF4
I have accepted my illness...................................................
0
1
2
3
4
GF5
I am sleeping well ...............................................................
0
1
2
3
4
GF6
I am enjoying the things I usually do for fun ......................
0
1
2
3
4
GF7
I am content with the quality of my life right now..............
0
1
2
3
4


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Protocol No. CPKC412E2301
Please select one number per line to indicate your response as it applies to the past 7 days.
ADDITIONAL CONCERNS
Not
at all
A little
bit
Some-
what
Quite
a bit
Very
much
BRM3
I am bothered by fevers (episodes of high body
temperature) .......................................................................
0
1
2
3
4
P2
I have certain parts of my body where I experience pain...
0
1
2
3
4
BRM2
I am bothered by the chills.................................................
0
1
2
3
4
ES3
I have night sweats.............................................................
0
1
2
3
4
LEU1
I am bothered by lumps or swelling in certain parts of
my body (e.g., neck, armpits, or groin)..............................
0
1
2
3
4
TH1
I bleed easily.......................................................................
0
1
2
3
4
TH2
I bruise easily .....................................................................
0
1
2
3
4
HI12
I feel weak all over.............................................................
0
1
2
3
4
BMT6
I get tired easily..................................................................
0
1
2
3
4
C2
I am losing weight..............................................................
0
1
2
3
4
C6
I have a good appetite.........................................................
0
1
2
3
4
An7
I am able to do my usual activities.....................................
0
1
2
3
4
N3
I worry about getting infections .........................................
0
1
2
3
4
LEU5
I feel uncertain about my future health ..............................
0
1
2
3
4
LEU6
I worry that I might get new symptoms of my illness........
0
1
2
3
4
BRM9
I have emotional ups and downs ........................................
0
1
2
3
4
LEU7
I feel isolated from others because of my illness or
treatment.............................................................................
0
1
2
3
4


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Protocol No. CPKC412E2301
14.3
Appendix 3 – EQ-5D-5L questionnaire 
Health Questionnaire
English version for the USA
USA (English) © 2009 EuroQol Group. EQ-5D™is a trade mark of the EuroQol Group


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Amended Oncology Protocol Version No. 01 (Clean)
Protocol No. CPKC412E2301
Under each heading, please check the ONE box that best describes your health TODAY
MOBILITY
I have no problems walking

I have slight problems walking

I have moderate problems walking

I have severe problems walking

I am unable to walk

SELF-CARE
I have no problems washing or dressing myself

I have slight problems washing or dressing myself

I have moderate problems washing or dressing myself       
I have severe problems washing or dressing myself

I am unable to wash or dress myself

USUAL ACTIVITIES (e.g. work, study, housework,
family or leisure activities)
I have no problems doing my usual activities

I have slight problems doing my usual activities

I have moderate problems doing my usual activities

I have severe problems doing my usual activities

I am unable to do my usual activities

PAIN / DISCOMFORT
I have no pain or discomfort

I have slight pain or discomfort

I have moderate pain or discomfort

I have severe pain or discomfort

I have extreme pain or discomfort

ANXIETY / DEPRESSION
I am not anxious or depressed

I am slightly anxious or depressed

I am moderately anxious or depressed

I am severely anxious or depressed

I am extremely anxious or depressed



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Amended Oncology Protocol Version No. 01 (Clean)
Protocol No. CPKC412E2301




We would like to know how good or bad your health is
TODAY.

This scale is numbered from 0 to 100.

100 means the best health you can imagine.
0 means the worst health you can imagine.

Mark an X on the scale to indicate how your health is TODAY.

Now, please write the number you marked on the scale in the
box below.
The best health
you can imagine
100
95
90
85
80
75
70
65
60
55
YOUR HEALTH TODAY =
50
45
40
35
30
25
20
15
10
5
0
The worst health
you can imagine

SAP_001.pdf: 


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For business use only
Page 2
Statistical Analysis Plan (SAP) for final CSR
CPKC412E2301
Document History – Changes compared to previous final version of SAP
Date
Time point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
02-Sep-2019
First version
NA
NA
NA
11-Jan-2021
Second version
– SAP for final 
CSR after study 
termination due 
to futility
Futility outcome 
Adjusting 
analyses 
based 
on 
futility 
outcome of the first 
interim analysis.
The censoring rules 
for DFS and CIR 
analyses have been 
adjusted to consider 
all events rather than 
censoring after two or 
more 
missing 
assessments.
All


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Statistical Analysis Plan (SAP) for final CSR
CPKC412E2301
Table of contents
1
Introduction .........................................................................................................................8
2
Study design, objectives and endpoints...............................................................................8
3
General definitions ............................................................................................................12
3.1
Cut-off date used for the analysis ..........................................................................12
3.2
Study drug and study treatment .............................................................................12
3.3
Date of first administration of study drug..............................................................13
3.4
Date of last administration of study drug ..............................................................13
3.5
Date of first administration of study treatment......................................................13
3.6
Date of last administration of study treatment.......................................................13
3.6.1
Baseline.................................................................................................13
3.6.2
On-treatment assessment/event.............................................................14
3.6.3
Study day...............................................................................................14
3.6.4
Screening failure ...................................................................................14
3.7
Last contact date ....................................................................................................15
3.8
Analysis sets ..........................................................................................................15
3.8.1
Full Analysis Set (FAS) ........................................................................15
3.8.2
Safety set (SS).......................................................................................15
3.8.3
Pharmacokinetic analysis set.................................................................16
3.8.4
Stratum information used for analyses..................................................16
3.8.5
Subgroup of interest ..............................................................................16
4
Patient disposition, demographics and other baseline characteristics...............................17
4.1
Baseline demographics ..........................................................................................17
4.2
Disease characteristics of acute myeloid leukemia (AML)...................................17
4.3
Medical history......................................................................................................18
4.4
Concomitant medications with specific impact on the analysis ............................18
4.5
Patient disposition..................................................................................................18
5
Protocol deviations............................................................................................................19
6
Treatments (study treatment, rescue medication, concomitant therapies, compliance)....19
6.1
Study treatment / compliance ................................................................................19
6.2
Cycle definition .....................................................................................................20
6.3
Duration of exposure to Midostaurin/placebo.......................................................20
6.4
Duration of exposure to cytarabine, daunorubicin or Idarubicin in induction 
and consolidation treatment phases .......................................................................20
6.5
Duration of exposure to study treatment ...............................................................20
6.6
Cumulative dose ....................................................................................................20


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Statistical Analysis Plan (SAP) for final CSR
CPKC412E2301
6.7
Planned dose intensity (PDI), Dose intensity (DI) and relative dose intensity 
(RDI) by cycle .......................................................................................................21
6.7.1
Planned cycles lengths ..........................................................................21
6.7.2
Dose Intensity (DI) by cycle analysis ...................................................21
6.7.3
Dose Intensity (DI) over study period...................................................21
6.8
Dose reductions, interruptions or permanent discontinuations..............................22
7
Analysis of the primary objective......................................................................................22
7.1
Primary endpoint - EFS .........................................................................................22
7.2
Statistical hypothesis, model, and method of analysis ..........................................23
7.2.1
Handling of missing values/censoring/discontinuations.......................23
8
Analysis of the key secondary objective: overall survival (OS) .......................................25
8.1
Key secondary endpoint - overall survival (OS) ...................................................25
8.2
Statistical hypothesis, model, and method of analysis ..........................................25
8.3
Analysis of secondary endpoints ...........................................................................26
8.3.1
CR/CRi rate...........................................................................................26
8.3.2
Time to CR or CRi with adequate blood count recovery......................26
8.3.3
Disease Free survival (DFS) .................................................................27
8.3.4
Cumulative Incidence of Relapse (CIR) ...............................................28
8.3.5
Cumulative Incidence of Death (CID)..................................................28
8.3.6
Measurable Residual Disease (MRD) by flowcytometry (LAIP 
approach)...............................................................................................29
8.3.7
Time to neutrophil/platelet recovery.....................................................30
8.3.8
Transfusions ..........................................................................................31
8.3.9
Hematopotic stem cell transplantation (HSCT)....................................31
9
Safety analyses ..................................................................................................................31
9.1
Deaths ....................................................................................................................31
9.2
Adverse events (AEs) ............................................................................................32
9.2.1
Adverse events of special interest (AESI) ............................................33
9.3
Laboratory data......................................................................................................33
9.4
ECG and cardiac imaging data ..............................................................................34
9.5
Vital signs..............................................................................................................34
9.6
Pharmacokinetic endpoints....................................................................................35
9.6.1
Exposure to the sum of active moities ..................................................35
9.6.2
PK parameters .......................................................................................35
9.7
Patient-reported outcomes .....................................................................................36
9.7.1
FACT-Leu.............................................................................................37
38




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Statistical Analysis Plan (SAP) for final CSR
CPKC412E2301
List of abbreviations
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Transaminase
AML
Acute Myeloid Leukemia
AST
Apartate Transaminase
ATC
Anatomical Therapeutic Classification
BP
Blood Pressure
CHMP
Committee for Medicinal Products for Human Use
CI
Confidence Interval
CID
Cumulative Incidence of Death
CIR
Cumulative Incidence of Relapse
CR
Complete Remission
CRi
Morphologic Complete Remission with incomplete hematological recovery
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of Variation
DAR
Dosage Administration Record
DI 
Dose Intensity
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EFS
Event-Free Survival
ELN
European Leukemia Network
EOT
End of Treatment
FAS
Full Analysis Set
FPFV
First Patient First Visit
eCRF
Electronic Case Report Form
IWG
International Working Group
HR
Hazard Ratio
HSCT
Hematopotic Stem Cell Transplantation
IRT
Interactive Response Technology
ITD
internal tandem duplication
LAIP
Leukemia-associated immunophenotypes
LLOQ
Lower Limit of Quantitation 
LPLV
Last Patient Last Visit
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram(s)
MN
Mutation Negative
MRD
Minimal Residual Disease
NCI
National Cancer Institute
NMQ
Novartis MedDRA queries
OS
Overall Survival
PBO
Placebo
PDI
Planned Dose Intensity
PK
Pharmacokinetics
PR
Partial Remission


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Statistical Analysis Plan (SAP) for final CSR
CPKC412E2301
PRO
Patient-reported Outcomes
PT
Preferred Term
QOL
Quality of Life
QUE
Questionnaire compliance part of eCRF
RAP
Report and Analysis Process
RDI
Relative Dose Intensity
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SI
System international
SMQ
Standardized MedDRA Queries
SOC
System Organ Class
SR
Signal Ratio
TKD
Tyrosine Kinase Domain
ULN
Upper limit of normal
WBC
White Blood Cell
WHO
World Health Organization


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Statistical Analysis Plan (SAP) for final CSR
CPKC412E2301
1
Introduction
This statistical analysis plan (SAP) describes all planned analyses for the clinical study report
(CSR) of study CPKC412E2301: a phase III, randomized, double-blind clinical trial of 
chemotherapy with daunorubicin or idarubicin and cytarabine for induction and intermediate 
dose cytarabine for consolidation plus midostaurin (PKC412) or placebo in newly diagnosed 
patients with FLT3-MN (SR<0.05) AML (FLT3 mutant to wild type signal ratio below the 0.05 
clinical cut-off).
The content of this SAP is based on protocol CPKC412E2301 amendment 1. All decisions 
regarding final analysis, have been made prior to final database lock but after unblinding of the 
study data.
The first interim analysis of the primary endpoint (Event Free Survival (EFS)) for futility has 
been performed and the study was stopped due to lack of efficacy on 23-Sep-2019 based on 
DMC recommendation. Subsequently, investigators were notified on the futility outcome and 
study was unblinded not only for Novartis but also the investigators. While majority of patients 
discontinued from the study within subsequent weeks, some patients decided to continue 
protocol planned study treatment. This SAP now describes the analyses for the final CSR which 
will be generated when all patients discontinued study treatment.  
The originally planned efficacy and safety analyses are reduced based on the futility outcome. 
However, some subgroup analyses have been added (e.g. safety and efficacy by anthracyclin 
for AML induction therapy (Daunorubicin vs Idarubicin)) and some analyses are only 
performed now for the final CSR (e.g. QoL, PK, 
).
2
Study design, objectives and endpoints
This is a randomized, double-blind, multi-center, placebo-controlled phase III study using a 
group sequential design with two interim analyses for the primary endpoint event-free survival 
(EFS) and regular safety looks. The study population comprises 502 adult patients with newly 
diagnosed FLT3-MN (SR<0.05) AML.  Patients will be stratified according to age (<60 vs. ≥ 
60 years) and will be randomized in a 1:1 ratio into one of two treatment arms:

Midostaurin + chemotherapy
Or

Placebo + chemotherapy


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Figure 2-1
Study design
bid: twice daily;  1 cycle = 28 days, d: day(s); HSCT: Hematopoietic Stem Cell Transplantation; dauno: daunorubicin; ida: 
idarubicin; aHydroxyurea therapy allowed for ≤ 7 days; bMidostaurin/Placebo treatment from day 8(Induction 1) and from 
day 4 (induction 2 and consolidation) until 48 hours prior to start of next treatment cycle; cAge  ≥60: no daunorubicin / 
idarubicin in IND 2,  cytarabine 1000mg/m2 ; d Patients in CR/CRi may proceed to HSCT at any time and will enter the post-
consolidation after HSCT-recovery; e Patients in CRi must have adequate blood count recovery to move to next treatment 
phase
The study contains three treatment phases:

Induction treatment phase

Consolidation treatment phase

Post-consolidation phase
A patient has to meet the following criteria to continue the next treatment phase:

A patient achieves CR or CRi with adequate blood count recovery defined as the 
following:

Complete Recovery in neutrophil count (1 x 10E9/L)

Minimal recovery in platelet count (50 x 10E9/L)
Of note, a patient not meeting the above criteria up to 93 days after start of induction phase is 
considered as “induction failure”.
The primary objective is to determine if the addition of midostaurin to standard induction and 
consolidation therapy, followed by single agent post-consolidation therapy improves event-free 
survival (EFS) in patients with newly diagnosed FLT3-MN (SR<0.05) AML.
The primary endpoint is EFS and is determined according to the IWG criteria for AML 
[Cheson et al 2003, ELN 2017 / Döhner et al 2017] as per investigator assessment. The final 
analysis was planned to be when a total of 285 EFS events are observed. The first and second 
interim analyses were planned after observing 40% and 75% of 285 EFS events, respectively. 


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The key secondary objective is to determine if the addition of midostaurin to standard 
induction and consolidation therapy, followed by single agent post-consolidation therapy 
improves overall survival (OS) in patients with newly diagnosed FLT3-MN (SR<0.05) AML.
The key secondary endpoint is OS. OS was to be initially hierarchically tested if EFS is 
significant in any of the interim and final analyses following a separate group-sequential plan 
using Haybittle-Peto stopping boundaries. Since the study was futile at the first interim analysis 
and therefore stopped due to futility, OS was not tested but will be analyzed and reported in the 
final clinical study report (CSR).
Other secondary 
 objectives are:
Objective
Endpoint
To compare CR + CRi with adequate blood count 
recovery rate in the two treatment groups.
CR and CRi with adequate blood count recovery rate 
according to the International Working Group (IWG) for 
AML [Cheson et al 2003, ELN 2017 / Döhner et al 2017]
as per investigator assessment.
To compare the percentage of patients who 
reached CR or CRi with adequate blood count 
recovery with MRD negative bone marrow in the 
two treatment groups.
Percentage of patients with CR or CRi with adequate 
blood count recovery with MRD negative bone marrow.
To compare the time to MRD- between the two 
treatment arms in the two treatment groups.
Number of days from date of randomization to first 
documented MRD-
To compare the percentage of patients with MRD 
negative status in the post-consolidation phase in 
the two treatment groups.
Percentage of patients with MRD negative status during 
post-consolidation
Phase
To compare DFS, as well as the Cumulative 
Incidence of Relapse (CIR) and Cumulative 
Incidence of Death (CID) in the two treatment 
groups.
DFS, as measured from the date of first CR or CRi with 
adequate blood count recovery to relapse or death from 
any cause, whichever occurs first. 
CIR is defined for patients with CR or CRi with adequate 
blood count recovery: time from achieving CR or CRi with 
adequate blood count recovery until onset of relapse. 
Patients without relapse are censored at the last 
adequate response assessment. Patients who died 
without relapse are counted as a competing cause of 
failure. 
CID is defined for patients with CR or CRi with adequate 
blood count recovery: time from achieving CR or CRi with 
adequate blood count recovery until death. Patients who 
did not die are censored at the last contact date. Patients 
who relapsed are counted as a competing cause of 
failure. 
To compare the time to CR or CRi with adequate 
blood count recovery in the two treatment groups.
Number of days from date of randomization to first 
documented CR or CRi with adequate blood count 
recovery. 
To compare the time to neutrophil recovery in the two 
treatment groups.
Number of days from the first day of a chemotherapy 
cycle to first day neutrophils ≥0.5 x 109/L.
Number of days from day 1 of commencing induction 
therapy to first day neutrophils ≥1.0 x 109/L.




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Data analysis general information
The statistical analysis of this study will be performed by Novartis. SAS® version 9.4 or later 
(SAS Institute Inc., Cary, NC, USA) will be used for all analyses. All data are part of the Clinical 
Database and will be exported to SAS® files for analysis. EAST version 6.4 or later (Cytel Inc.®) 
will be used to determine stopping boundaries in the group sequential plan.
The final EFS analysis was supposed to be performed by Novartis. However, since the study 
was stopped at first interim analysis only an updated EFS analysis will be provided in the final 
CSR. The first interim analysis of EFS was performed by an independent external statistician 
and an independent external programmer (CRO not involved with the conduct of the study). 
The study was stopped at this first interim and no further analyses are to be performed (i.e. study 
stopped).
The study will end when the last ongoing patient will have completed or discontinued treatment. 
All events with start date before or on the cut-off date and end date after the cut-off date will be 
reported as ‘ongoing’. The same rule will be applied to events starting before or on the cut-off 
date and not having documented end date. This approach applies, in particular, to adverse event 
and concomitant medication reports. For these events, the end date will not be imputed and 
therefore will not appear in the listings.
General analysis conventions
General analysis conventions
Pooling of centers:  Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small number of patients enrolled at centers, no center effect will 
be assessed.
Qualitative data (e.g., gender, race) will be summarized by means of contingency tables by 
treatment group; a missing category will be included as applicable. 
Quantitative data (e.g., age, weight) will be summarized by means of summary statistics 
(mean, standard deviation, median,  25th – 75th percentiles, minimum, maximum) by treatment 
group.
3
General definitions 
3.1
Cut-off date used for the analysis
The data base lock date will be the cut-off date used for the final clinical study report (CSR).
3.2
Study drug and study treatment
Study drug refers to Midostaurin (PKC412) or Placebo (PBO). 
Study treatment refers to 

Midostaurin + Chemotherapy (idarubicin/daunorubicin, cytarabine) or 

Placebo + Chemotherapy (idarubicin/daunorubicin, cytarabine) (control group).


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Study treatment components refer to

Midostaurin/Placebo or

Idarubicin/Daunorubicin or

Cytarabine
Study drug combination partner refers to Idarubicin/Daunorubicin or Cytarabine
3.3
Date of first administration of study drug
The date of first administration of study drug is derived as the first date when a non-zero dose 
of study drug was administered and recorded on the exposure electronic case report form 
(eCRF). The date of first administration of study drug will also be referred as start of study 
drug.
3.4
Date of last administration of study drug
The date of last administration of study drug is defined as the last date when a non-zero dose of 
study drug was administered and recorded on the exposure electronic case report form (eCRF). 
3.5
Date of first administration of study treatment
The date of first administration of study treatment is derived as the first date when a non-zero 
dose of any component of study treatment was administered and recorded on the exposure eCRF. 
For example, if the 1st dose of study drug A is administered on 04Jan2019, and the 1st dose of 
its combination partner, drug B, is administered on 03Jan2019, the date of the first 
administration of study treatment is on 03Jan2019). The date of the first administration of study 
treatment will also be referred as the start of study treatment.
3.6
Date of last administration of study treatment
The date of last administration of study treatment is derived as the last date when a non-zero 
dose of any component of study treatment was administered and recorded on exposure eCRF 
of any study treatment component. For example, if the last dose of Midostaurin is administered 
on 15Apr2019, and the last dose of a combination partner, e.g., Cytarabine, is administered on 
17May2019, the date of last administration of study treatment is then on 17May2019.
3.6.1
Baseline
Baseline is the result of an investigation describing the “true” uninfluenced state of the subject.
For efficacy evaluations, the last assessment before or at the date of randomization is taken as 
the “baseline” value or assessment, if available. 
In the context of a baseline definition, ECOG PS assessment as well as all PRO variables will 
follow the efficacy rule, irrespective of addressing quality of life or disease symptoms.
For PRO completion summary and PROs, baseline is defined by instrument and scale for QOL 
and by instrument for QUE.  For QUE, the last “partially” completed (or better) answer will be 
used for baseline in case of more than 1 baseline assessment. In case of >1 non-completed 
answers (whatever reason), the last answer will be used. For QOL, the last assessment with non-
missing score within eligible baseline visit per scale/category will be used as baseline for that 


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scale. For Global Severity questionnaire the baseline is defined by instrument; the last available 
assessment per baseline will be used.
For safety evaluations (e.g. laboratory and ECG), the last available assessment before or at the 
date the study treatment administration will be used as the “baseline” assessment. 
If patients have no value as defined above, the baseline result will be considered to be missing.
3.6.2
On-treatment assessment/event
All on-treatment assessments/events are any assessments/events obtained in the time interval:
[Date of first administration of study treatment; date of last administration of study 
treatment +30 days], i.e., inclusive lower and upper limit. 
The calculation of study treatment duration may use different rules as specified in Section 6.1.
3.6.3
Study day
For the study day calculation, if the event or assessment date is after the randomization date or 
after the treatment start date, the following calculations listed below apply:
The study day for safety assessments (e.g. adverse event [AE] onset, laboratory abnormality 
occurrence, vital sign measurement, dose interruption etc.) will be calculated as:
The date of the assessment / event - start date of study treatment + 1 day.
If an AE starts before the start of study treatment the study day displayed on the listing will be 
negative. In this case the study day will be calculated as:
The date of onset of the event - start date of study treatment.
The study day for efficacy assessments (e.g., efficacy endpoints EFS and OS, response 
assessment, quality of life [QoL] etc.) will be calculated as:
The date of the assessment / event - randomization date + 1 day.
For any assessment or events that happened prior to the start of the study drug or 
randomization, e.g., time since diagnosis of disease, the study days will be calculated for safety 
assessments as:
Study Day = Event date - Date of first study treatment.
Note that the day of first dose of study treatment is Day 1 and the day before the date of first 
study treatment is Day – 1, not Day 0.
In this study, ‘death’ is an efficacy endpoint. However, it will also be included in safety analysis. 
For safety, the ‘study day’ will be calculated following the rules for safety assessments as 
described above. For efficacy ‘time-to-event’ variables, the study day will be derived following 
the rules for non-safety assessments as described above. The study day will be displayed in the 
data listings.
3.6.4
Screening failure
Screening failures are patients who have been screened and have failed the inclusion and 
exclusion criteria; these patients are never randomized.  Patients who are randomized but never 


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receive study treatment are not considered as screening failures but will be included in the full 
analysis set.
3.7
Last contact date
The last contact date will be used for censoring of subjects in the analysis of overall survival.
The last contact date is defined as the latest complete date from the below list on or before the 
data cut-off date (Table 3-1). The cut-off date will not be used for last contact date, unless the
subject was seen or contacted on that date. No date post cut-off date will be used.
Completely imputed dates (e.g. the analysis cut-off date programmatically imputed to replace
the missing end date of a dose record) will not be used to derive the last contact date. Partial 
date imputation is allowed for event (death)/censoring only if coming from the ‘Survival’ eCRF.
The last contact date will be derived for subjects not known to have died at the analysis cut-off 
using the last complete date among the following:
Table 3-1
Last contact date data sources
Source data
Conditions
Date of Randomization 
No condition
Last date subject was known to be alive from Survival 
Follow-up page 
Subject status is reported to be alive or 
unknown
Start/End dates from further antineoplastic therapy
Non-missing medication/procedure term
Start/End* dates from drug administration record 
Non-missing dose 
Response assessment date
Response marked as ‘done’
Laboratory/PK collection dates
Sample collection marked as ‘done’
Vital signs date
At least one non-missing parameter value
ECOG performance status date
Non-missing performance status
Start/End dates of AE
Non-missing verbatim term
3.8
Analysis sets
3.8.1
Full Analysis Set (FAS)
The Full Analysis Set (FAS) comprises all patients to whom study drug has been assigned by 
randomization. According to the intent to treat principle, patients will be analyzed according to 
the treatment and stratum they have been assigned to during the randomization procedure.
3.8.2
Safety set (SS)
The Safety Set (SS) includes all patients who received at least one dose of study treatment 
starting at day 1 and being randomized with at least one dose of Midostaurin or placebo. Patients 


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will be analyzed according to the study treatment received, where treatment received is defined 
as the randomized treatment if the patient took at least one dose of that treatment. Patients who 
started therapy at day 1 but discontinued prior to randomization at day 8 will be listed separately.
3.8.3
Pharmacokinetic analysis set
Pharmacokinetic Analysis Set for all (PAS-all)
The Pharmacokinetic analysis set for all (PAS-all) includes all subjects in the safety set, and 
provide at least one evaluable PK concentration.
For a concentration to be evaluable: 

Dosing information must be properly documented (data and time of administration)

The planned dose of midostaurin must be taken prior to sampling.

For pre-dose samples: no vomiting within 4 hours after the midostaurin dose prior to 
sampling, the sample is collected before the next dose administration.

For post-dose samples: no vomiting within 4 hours after midostaurin dosing 
The PAS-all will be the primary population used for all pharmacokinetic analyses using trough 
concentration data.
Pharmacokinetic Analysis Set for full PK profile (PAS-full) 
The Pharmacokinetic analysis set for full PK profiles (PAS-full) includes all subjects in the 
PAS-all, who provide an evaluable PK profile. A profile is considered evaluable if all of the 
following conditions are satisfied:

Subject receives the planned first dose of midostaurin on C1D8 of Induction therapy

Subject did not vomit within 4 hours of the first dose of midostaurin on C1D8 of Induction 
therapy

Subject provides at least one primary PK parameter (Cmax, AUC0-t)
The PAS-full will be the primary population used for all pharmacokinetic analyses based on 
full PK profile data.
3.8.4
Stratum information used for analyses
For all stratified analyses based on the FAS, stratification information will be used as provided 
by the IRT. 
Subgroup analyses by age will use the actual stratum information as derived from baseline 
characteristics which might be different from that used for randomization as provided by the 
IRT. In case no baseline characteristics for stratification factors are available, the information 
as provided by IRT will be used. 
3.8.5
Subgroup of interest
The main efficacy endpoints EFS, OS, DFS, CIR, CID, CR/CRi and MRD as well as other key 
safety endpoints will be summarized by the following subgroups not only to examine the 


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treatment effect across demographic, baseline disease characteristics variables and anthracyclin
for AML induction therapy but also to evaluate midostaurin in these different subgroups:

Age (< 60 years / ≥ 60 years)

Sex (male / female)

European Leukemia Network (ELN) 2017 risk classification (favorable / Intermediate / 
Adverse).

ITD or TKD signal ratios (<0.015, 0.015 - < 0.03, >= 0.03-0.05)

Anthracyclin for AML induction therapy (Idarubicin vs. Daunorubicin).

Following geographic regions as defined by the World Health Organization (WHO) 
(http://apps.who.int/ghodata/). Hong Kong and Taiwan are not members of the WHO and 
will be assigned to the region Western Pacific.

Region 1: Europe

Region 2: Western Pacific

Region 3: Americas
Other endpoints and subgroups may be added if deemed necessary. For each of subgroups, The 
HR and their 95% CIs be presented by means of forest plots for EFS, OS, DFS, CIR and CID.
4
Patient disposition, demographics and other baseline 
characteristics
The Full Analysis Set (FAS) will be used for all baseline and demographic summaries. 
Summaries will be reported by treatment group and for all patients.  No inferential statistics 
will be provided.
4.1
Baseline demographics
All demographic data will be summarized by treatment group. 
4.2
Disease characteristics of acute myeloid leukemia (AML) 
Summary statistics and frequency counts with percentages will be tabulated for diagnosis
and characteristics of AML. This analysis will include the following:

Time since initial diagnosis to start of treatment.

AML diagnosis, WHO classification 2016.

Classification of AML

Bone marrow blast count.

Presence of Auer rods.

Platelets, neutrophils, blasts and hemoglobin values in peripheral blood.

Extramedullary disease assessment.

European Leukemia Network (ELN) 2017 risk classification will be assigned based on 
cytogenetic abnormalities and mutations for these patients who are all FLT3 negative. 
In order to be assigned as intermediate or adverse risk group, patients must have 


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cytogenetic abnormalities and mutations assessed, however, they can be assigned as 
favorable when only the respective cytogenetic abnormality or mutation was assessed:

favorable risk group includes any patient with any of the following cytogenetic 
abnormalities or mutations: 

t(8;21)(q22;q22.1); RUNX1-RUNX1T1

inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11

Biallelic mutated CEBPA

Mutated NPM1

if patients are not in the favorable risk group as defined above, then they are 
assigned to adverse risk group if they have any of the following cytogenetic 
abnormalities or mutations: 

t(6;9)(p23;q34.1);DEK-NUP214

t(v;11q23.3); KMT2A rearranged

t(9;22)(q34.1;q11.2); BCR-ABL1

inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1)

-5 or del(5q); -7 ; -17/abn(17p)

Complex karyotype

Mutated RUNX1 (unless t(9;11) (p21.3;q23.3))

Mutated ASXL1 (unless t(9;11) (p21.3;q23.3))

Mutated TP53

if patients are neither in the favorable nor adverse risk group as defined above, 
they are in the intermediate risk group if there is presence of either of the 
following: 

Wild type NPM1

t(9;11)(p21.3;q23.3); MLLT3-KMT2A

Any cytogenetic abnormalities not classified  as favorable or adverse
4.3
Medical history
Medical history and ongoing conditions, including cancer-related conditions and symptoms 
entered on (e)CRF will be summarized by treatment group. Separate summaries will be 
presented for ongoing and historical medical conditions.  The summaries will be presented by 
primary system organ class (SOC), preferred term (PT) and treatment group. Medical history 
and current medical conditions will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) terminology. The MedDRA version used for reporting will be specified 
as a footnote in the applicable tables/listings.
4.4
Concomitant medications with specific impact on the analysis
Patients who take additional anti-neoplastic therapy before discontinuing study treatment (i.e., 
anti-neoplastic therapy other than study treatment) will be identified as protocol deviations.
4.5
Patient disposition
Enrollment by country and center will be summarized by treatment group using the FAS. The 
number of screened patients and the reason for screening failure will be displayed. 


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The following summaries will be provided:

Number (%) of patients who were randomized (based on data from IRT system)

Number (%) of patients who were randomized but not treated with Midostaurin/Placebo

Primary reason for not being treated (based on ‘End of Treatment Phase Completion’ 
eCRF page)

Treatment phase: Induction, consolidation and post-consolidation

Number (%) of patients who were treated (based on exposure eCRF pages of each 
study treatment component completed with non-zero dose administered).

Number (%) of patients who are still on-treatment

Number (%) of patients who discontinued the study treatment

Number (%) of patients who entered consolidation, post-consolidation phase

Number (%) of patients who completed each treatment phase: induction, consolidation 
and post-consolidation treatment phases as per protocol.

Primary reason for study treatment discontinuation for each treatment phase 
(induction, consolidation, post-consolidation)

Post-treatment follow-up phase

Number (%) of patients who have entered the post-treatment follow-up 

Number (%) of patients who have discontinued from the post-treatment follow-up

Reasons for discontinuation from the post-treatment follow-up 

Survival follow-up phase

Number (%) of patients who have entered the survival follow-up 

Number (%) of patients who have discontinued from the post-treatment follow-up

Reasons for discontinuation from the post-treatment follow-up 
5
Protocol deviations
The number (%) of patients in the FAS with any protocol deviation will be tabulated by 
deviation category. All protocol deviations will be listed.
6
Treatments (study treatment, rescue medication, 
concomitant therapies, compliance)
6.1
Study treatment / compliance
Duration of exposure, actual cumulative dose, dose intensity (DI) and relative dose intensity 
(RDI) will be summarized by treatment group, separately for each component of study treatment. 
The duration of exposure will also be presented for the study treatment. Duration of exposure 
will be categorized into time intervals; frequency counts and percentages will be presented for 
the number of patients in each interval (0 to ≤4 weeks, 4 to ≤8 weeks, 8 to ≤ 12 weeks, 12 to 
≤ 24 weeks, 24 to ≤ 48 weeks, > 48 weeks). The number (%) of patients, who have dose 
reductions or interruptions, and the reasons, will be summarized by treatment group. 


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Patient level listings of all doses administered on treatment along with dose change reasons will 
be produced. The safety set will be used for all summaries and listings of study treatment. 
6.2
Cycle definition
Cycle length will be calculated from the cycles recorded in the visit panel. Each cycle ends the 
day before the next cycle starts.
Cycle length= (date of Day 1 of the next cycle – date of Day 1 of the current cycle).
The length of last cycle (last date of last intake to the study component) – (date of Day 1 of the 
last cycle.
6.3
Duration of exposure to Midostaurin/placebo
Duration of exposure to a study component (days) = (last date of last intake to the study 
component) – (date of first administration of the study component) + 1; 
6.4
Duration of exposure to cytarabine, daunorubicin or Idarubicin in 
induction and consolidation treatment phases
For each treatment cycle, duration of exposure to the study treatment components (days) = (last 
date of last intake to the study component) – (date of first administration of the study 
component) + 1; 
Therefore, the total duration of exposure will be the sum of exposures for each treatment cycles 
in induction and consolidation.
6.5
Duration of exposure to study treatment
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to Midostaurin/Placebo, Daunorubicin (or Idarubicin) and Cytarabine:
Duration of exposure to study treatment (days) = (last date of exposure to study treatment) –
(date of first administration of study treatment) + 1; 
The last date of exposure to study treatment is the latest of the last dates of exposure to 
Midostaurin/Placebo, Daunorubicin (or Idarubicin) and Cytarabine. 
6.6
Cumulative dose
Cumulative dose of a study treatment component is defined as the total dose given during the 
study treatment exposure and will be summarized for each of the study treatment components. 
The actual cumulative dose refers to the total actual dose administered, over the duration for 
which the patient is on the study treatment as documented in the Dose Administration eCRF. 
Cumulative dose for Midostaurin/Placebo is presented in mg. Daunorubicin or (Idarubicin) and 
Cytarabine is subcutaneously administered and dose administered is collected in mg/m2. 
For patients who did not take any drug the actual cumulative dose is by definition equal to zero.
The planned cumulative dose for a study treatment component refers to the total planned dose 
as per the protocol in the duration of exposure to study treatment. 


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6.7
Planned dose intensity (PDI), Dose intensity (DI) and relative 
dose intensity (RDI) by cycle
6.7.1
Planned cycles lengths
A cycle length is planned to be 28 days for all patients who reached CR, CRi with adequate 
blood count recovery, PR or No response at end of each cycle. If the patient has CRi without 
adequate blood count recovery, the planned cycle length might be prolonged to:

Up 42 days for induction cycle 1

Up 49 days for induction cycle 2

Up 49 days for all consolidation and post-consolidation treatment cycles.
6.7.2
Dose Intensity (DI) by cycle analysis
6.7.2.1
Midostaurin/Placebo
For cycles except last cycle or last cycle with length as scheduled or longer

DI _c [mg/day] = (Total actual dose in an actual cycle [mg]) / actual cycle length [days]
For all cycles

RDI_c [%] = DI_c [mg/day] / Planned Dose Intensity [mg/day] * 100
6.7.2.2
Cytarabine, daunorubicin or Idarubicin
The same rules will be applicable as above with the unit of mg/m2.
6.7.3
Dose Intensity (DI) over study period
6.7.3.1
Midostaurin / Placebo
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows:
DI (mg/day) =
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!
 "#
and i =1,2,3,…, k are the indices for the cycle.
For patients who did not take any drug the DI is by definition equal to zero.
Relative dose intensity (RDI) is defined as follows:
RDI [%] = DI [mg/day] / Planned Dose Intensity [mg/day] * 100
6.7.3.2
Cytarabine, daunorubicin or Idarubicin
The same rules will be applicable as above with the unit of mg/m2.
Frequencies for RDI will be produced by treatment group, study treatment component and 
treatment phase for the following categories:

0 to < 50%

50 to < 70%


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
70 to < 90%

90 to < 110%

≥ 110%
6.8
Dose reductions, interruptions or permanent discontinuations 
‘Dose changed’, ‘Dose interrupted’, and ‘Dose permanently discontinued’ fields from the 
exposure eCRF pages will be used to determine the dose reductions, dose interruptions, and 
permanent discontinuations, respectively.
The corresponding fields ‘Reason for dose change/dose interrupted’ and ‘Reason for permanent 
discontinuation’ will be used to summarize the reasons.
A dose change is either ‘change in prescribed dose level’ or ‘dosing error’ where actual dose 
administered is different from the prescribed dose.
For the purpose of summarizing interruptions and reasons, in case multiple entries for 
interruption that are entered on consecutive days with different reasons will be counted as 
separate interruptions. However, if the reason is the same in this block of entries, then it will be 
counted as one interruption. 
Reduction: A dose reduction is, where the prescribed dose level is lower than the previous 
prescribed dose level or where the actual dose administered is lower than the calculated dose 
amount based on the prescribed dose. Therefore any dose change to correct a dosing error will 
not be considered a dose reduction.  Only dose change is collected in the CRF, number of 
reductions will be derived programmatically based on the change and the direction of the change. 
In addition, if a patient moves to a less frequent regimen, such changes will then be counted as 
dose reductions.  
7
Analysis of the primary objective
The primary objective of this study was to determine if the addition of midostaurin to standard 
induction and consolidation therapy, followed by single agent post-consolidation therapy 
improves event-free survival (EFS) in patients with newly diagnosed FLT3-WT AML.
As the study concluded at the first efficacy interim analysis due to futility, the endpoints will 
be derived and summarized based on the final data, but no testing (p-values) will be provided 
in the final CSR.
7.1
Primary endpoint - EFS
The primary endpoint is EFS as per the International Working Group (IWG) for AML [Cheson 
et al., 2003, ELN 2017] criteria per investigator assessment.  EFS is defined as the time from 
the date of randomization to failure to obtain a CR or CRi with adequate blood count recovery 
in induction (i.e. induction failure), relapse from CR or CRi with adequate blood count recovery, 
or death due to any cause, whichever occurs first. 


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7.2
Statistical hypothesis, model, and method of analysis
The study is designed to test the following statistical hypothesis for EFS using a stratified log-
rank test (stratified according to randomization stratification factor of age (<60 vs. ≥ 60 years)) 
at the one-sided 2.5% level of significance: 
H01: θ1 ≥ 1 vs. Ha1: θ1 < 1
Where θ1 is the hazard ratio (Midostaurin treatment arm vs. placebo arm) of EFS.
In accordance with the stratified randomization scheme used in the study, a stratified two-sided 
3-look group sequential log-rank test with a cumulative type I error rate of α=0.025, one-sided, 
will be used to test the null hypothesis (H01). The stratification factor is:

Age : <60 vs. ≥ 60 years
For EFS, the hazard ratio for treatment effect will be estimated and its two-sided 95% 
confidence intervals will be reported. The estimation will be based on a cox proportional 
hazards model with treatment and the stratification factor in it.
In addition, survivorship functions will be estimated by using the Kaplan-Meier product-limit 
method and displayed as graphs. The estimations are performed by treatment group. Median 
EFS time and its two-sided 95% confidence intervals will be reported for both treatments. 
The primary analysis will be based on the FAS. Response status will be based on investigator’s 
assessments as per the International Working Group (IWG) criteria for AML [Cheson et al 2003, 
ELN 2017].
7.2.1
Handling of missing values/censoring/discontinuations
In the primary analysis, a patient who had not an EFS event at the date of the analysis cut-off 
will have his/her EFS censored at the time of the last adequate response assessment before the 
cut-off date.
Induction failure is defined as failure to achieve CR or CRi with adequate blood count recovery
up to 93 days after start of induction phase.
A patient who failed to achieve CR or CRi without adequate blood count recovery in induction 
phase based on available response assessments, would have his/her EFS event documented at 
randomization date.
A patient who discontinued induction treatment phase without an efficacy assessment will also 
be considered to have failed to achieve CR or CRi with adequate blood count recovery and 
would have his/her EFS event at randomization date as well.
However, a patient who discontinued due to lack of efficacy in the consolidation and post-
consolidation treatment phase without any supportive response assessment will be censored at 
the last adequate response assessment date.
EFS events documented after the initiation of HSCT or new anti-neoplastic therapy will be 
considered as EFS event for the primary EFS analysis.
If an EFS event is observed after two or more missing or non-adequate response assessments, 
then EFS will be censored at the last adequate response assessment before the EFS event. If an 


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EFS event is observed after a single missing or non-adequate response assessment, the actual 
date of event will be used. An adequate response assessment is considered any disease 
assessment indicating response status apart from ‘unknown’ or ‘not done’. The event and 
censoring times for EFS are summarized as follow:
Table 7-1
Primary EFS analysis (event date / outcome)
Situation
Options for event date
Outcome
A
No baseline assessment 
Randomization date
Censored
B1
Relapse at / or before next scheduled 
assessment date or death
Date of relapse/death
Event
B2
Relapse/death after exactly one missing 
assessment
Date of relapse/death
Event
B3
Relapse/death after two or more missing 
assessments
Date of last adequate assessment
Censored
B4
Relapse/death after HSCT or anti-neoplastic 
therapy 
Date of relapse/death
Event
C
Induction failure (incl. lack of post-baseline 
efficacy assessment) 
Randomization date 
Event
D
No relapse/ no induction failure / no death
Date of last adequate response 
assessment 
Censored
E
Treatment discontinuation due to lack of efficacy 
without documented relapse in the consolidation 
and post-consolidation treatment phases.
Date of last adequate response 
assessment
Censored
Of note, a response assessment (especially relapse) can also be done based on one component 
of response, e.g. peripheral blood.
Missing adequate response assessment is defined as an assessment not done or classified as 
‘unknown’. For simplicity, the ‘missing adequate response assessment’ will also be referred as 
‘missing assessment’.
As detailed in Table 7-1, the EFS censoring and event date options depend on the presence and 
the number of missing assessments.  
An exact rule to determine whether there are any missing assessments is needed after end of the 
induction phase. This rule will be based on the distance between the last adequate response 
assessment date and the event date.
The threshold D1 is defined as the interval between the response assessments plus the protocol-
allowed window around the assessments. Similarly, the threshold D2 is defined as 2 times the 
protocol-specified interval between the response assessments plus the protocol allowed window 
around the assessments. 
During consolidation and post-consolidation treatment phases:
Response assessment are performed between day 21 and day 28 of each cycle:

Therefore, for patients with a previous CR or CRi with adequate blood count recovery, 
the next assessment will be done on the next cycle between day 21 and day 28. The 
threshold D1 is defined as 28 days (maximum cycle length for patient with CR or CRi 


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with adequate blood count recovery) + 7 (in case the last assessment was done on day 
21) = 35 days and the threshold D2 as 70 days.

For patients with a previous CRi without adequate blood count recovery, the cycle will 
be prolonged up to 21 days. Therefore, the threshold D1 is defined as 7 (in case the last 
assessment was done on day 21) + 21 = 28 days and the threshold D2 is 56 days. 
During follow-up phase: 

The threshold D1 is defined as 90 days and the threshold D2 as 2 * 90 days = 180 days 
The analysis will assume one missing assessments if the distance between the last adequate 
response assessment and the event date is within (D1, D2] and 2 or more missing assessment if 
the distance is larger than D2.
EFS will be summarized between the 2 treatment groups within each of the following subgroups
as defined in section 3.8.5.by forest plots
HRs and 2-sided 95% CIs will be provided based on the stratified Cox proportional hazards 
model. This model will use the BY statement to derive estimates by subgroup. Point estimates 
of HR and 2-sided 95% CI will be provided by subgroup in a forest plot.
8
Analysis of the key secondary objective: overall survival 
(OS)
The key secondary objective is to determine if the addition of midostaurin to standard induction 
and consolidation therapy, followed by single agent post-consolidation therapy improves 
overall survival (OS) in patients with newly diagnosed FLT3-MN AML.
8.1
Key secondary endpoint - overall survival (OS) 
OS is defined as the time from date of randomization to date of death due to any cause. If a 
patient is not known to have died, survival will be censored at the date of last contact.
Table 8-1
Primary OS analysis (event date / outcome)
Situation
Options for event date
Outcome
A
Death
Death date
Event
B
Death after New anticancer therapy / HSCT Death date
Event
C
Withdrawal of consent 
Last contact date prior to withdrawal of consent
Censored
D
No death
Last contact date
Censored
8.2
Statistical hypothesis, model, and method of analysis
Assuming proportional hazards model for OS, the following statistical hypothesis for OS will 
be tested using a stratified log-rank test (stratified according to randomization stratification 
factor of age) at the one-sided 2.5% level of significance: 
H02: θ2 ≥ 1 vs. Ha2: θ2 < 1
Where θ2 is the hazard ratio (Midostaurin treatment arm vs. placebo arm) of OS.


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The analyses for OS will be based on the FAS population according to the treatment group 
patients were randomized and the strata they were assigned at randomization. For the final CSR, 
OS will be summarized only descriptively. No testing will be performed. For the original testing 
plan, please refer to study protocol. OS will be estimated using the Kaplan-Meier method. The 
median OS along with 95% confidence intervals will be presented by treatment group. The 
stratified Cox regression will be used to estimate the HR of OS, along with 95% confidence 
interval. All OS analyses will be based on the FAS.
OS will be summarized between the 2 treatment groups within each of the subgroups as defined 
in Section 3.8.5.
HRs and 2-sided 95% CIs will be provided based on the stratified Cox proportional hazards 
model. This model will use the BY statement to derive estimates by subgroup. Point estimates 
of HR and 2-sided 95% CI will be provided by subgroup in a forest plot.
8.3
Analysis of secondary endpoints
The secondary efficacy variables include CR or CRi with adequate blood count recovery rate, 
MRD, DFS, CIR and CID. The assessment of these endpoints, except MRD, will be based on 
the IWG criteria for AML [Cheson et al 2003, ELN 2017 / Döhner et al 2017] as per investigator 
assessment. All these endpoints will only be descriptively summarized with 95% CIs but 
without any p-values.
The rate of CR/CRi with adequate blood count recovery will be analyzed based on the FAS. 
However, DFS, Cumulative Incidence of Relapse (CIR) and Cumulative Incidence of Death 
(CID) will be analyzed based on data from responders (CR or CRi with adequate blood count 
recovery within 93 days after start of treatment) in the FAS. Assessment of relapse from CR or 
CRi with adequate blood count recovery, DFS, CIR and CID will not consider whether a patient 
received HSCT. All secondary analyses will include all data observed up-to the cut-off date, 
unless otherwise specified.
8.3.1
CR/CRi rate
Number and percentage of patients achieving CR or CRi with adequate blood count recovery 
rate will be reported by cycle of induction therapy (i.e. cycle 1 or cycle 2) and by treatment 
phases. Patients with CR /CRi with adequate blood count recovery after 93 days after start of 
chemotherapy are considered as induction failure and thus will not be reported as responders. 
Those patients will be listed separately.
Response assessment as per investigator evaluation will be listed for all patients by treatment 
group. Bone marrow, platelet, neutrophils, auer rods, extramedullary disease and transfusion
assessment will be listed as well.
8.3.2
Time to CR or CRi with adequate blood count recovery
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 within 93 days after start of 
chemotherapy whichever occurs first. Patients without experiencing CR, CRi with adequate 
blood count recovery will be censored according to the following events:


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
Patients experiencing induction failure will be censored at maximum follow-up (i.e. date 
of FPFV to date of LPLV used for the analysis).
The date of last adequate response assessment is the date of the last response assessment 
other than unknown before an event or a censoring reason occurred. In this case the last response 
evaluation date at that assessment will be used. 
Table 8-2
Censoring rules for time to CR or CRi with adequate blood count 
recovery
Situation
Start-date
End-date
Outcome
A
CR or CRi with 
adequate blood 
count recovery
within 93 days 
after start of 
chemotherapy
Date of randomization
Date of first onset of CR or CRi with adequate 
blood count recovery within 93 after start of 
treatment (before cut-off date)
Event
B
Induction failure
Date of randomization
At maximum follow-up (i.e. FPFV to LPLV used 
for the analysis) (before cut-off date)
Censor
8.3.3
Disease Free survival (DFS)
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 died will be censored at the last adequate 
response assessment before cut-off date. DFS will be analyzed for patients who achieved CR 
or CRi with adequate blood count recovery within 93 days after start of chemotherapy.
Discontinuation due to lack of efficacy or failure to meet continuation criteria (collected on the 
‘End of treatment’ and ‘End of post treatment follow up’ disposition pages without supporting
documentation of relapse as per IWG criteria for AML [Cheson et al 2003, ELN 2017 / Döhner 
et al 2017] will not be considered relapse for DFS derivation.
DFS will be estimated using the Kaplan-Meier method. The median DFS along with 95%
confidence intervals will be presented by treatment group. The stratified Cox regression will be 
used to estimate the HR of DFS, along with 95% confidence interval.
Table 8-3
Censoring rules for DFS analysis
Situation
Start date
End Date
Outcome
A
Relapse from CR or CRi with 
adequate blood count 
recovery or death due to any 
reason
Date of first occurrence of 
CR or CRi with adequate 
blood count recovery
Date of Relapse from 
CR or CRi with 
adequate blood count 
recovery or death due 
to any reason
Event
B
No Relapse from CR or CRi 
with adequate blood count 
recovery nor death due to any 
reason
Date of first occurrence of 
CR or CRi with adequate 
blood count recovery
within 93 days after start 
of treatment
Date of last adequate 
assessment 
Censored


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Situation
Start date
End Date
Outcome
C
New anticancer therapy 
given/HSCT prior to relapse 
from CR or CRi with 
adequate blood count 
recovery or death
Date of first occurrence of 
CR or CRi with adequate 
blood count recovery
Date of Relapse from 
CR or CRi with 
adequate blood count 
recovery or death due 
to any reason
Event
8.3.4
Cumulative Incidence of Relapse (CIR) 
Cumulative Incidence of Relapse (CIR) is defined for patients with CR or CRi with adequate 
blood count recovery within 93 days after start of chemotherapy and is time from achieving the 
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. 
Table 8-4
Censoring rules for CIR analysis
Situation
Start date
End Date
Outcome
A
Relapse from CR or CRi with 
adequate blood count 
recovery 
Date of first occurrence of 
CR or CRi with adequate 
blood count recovery
within 93 days after start 
of treatment
Date of Relapse from 
CR or CRi with 
adequate blood count 
recovery 
Event of 
interest
B
Death without relapse
Date of first occurrence of 
CR or CRi with adequate 
blood count recovery
within 93 days after start 
of treatment
Death date
Competing 
event, 
censored
C
No Relapse from CR or CRi 
with adequate blood count 
recovery 
Date of first occurrence of 
CR or CRi with adequate 
blood count recovery
within 93 days after start 
of treatment
Date of last adequate 
assessment 
Censored
D
Treatment discontinuation 
due to ‘Lack of efficacy’ or 
‘failure to meet continuation 
criteria’ without documented 
relapse, i.e. clinical relapse 
based on investigator claim
Date of first occurrence of 
CR or CRi with adequate 
blood count recovery
within 93 days after start 
of treatment
Date of last adequate 
assessment 
Censored
E
New anticancer therapy 
given/HSCT prior to relapse 
from CR or CRi with 
adequate blood count 
recovery 
Date of first occurrence of 
CR or CRi with adequate 
blood count recovery
within 93 days after start 
of treatment
Date of Relapse from 
CR or CRi with 
adequate blood count 
recovery or death due 
to any reason
Event of 
interest
Cumulative Incidence of Relapse (CIR) will be estimated using the Kaplan-Meier method. The 
median CIR along with 95% confidence intervals will be presented by treatment group. The 
stratified Cox regression will be used to estimate the HR of CIR, along with 95% confidence 
interval.
8.3.5
Cumulative Incidence of Death (CID)
Cumulative Incidence of Death (CID) is defined for all patients achieving CR or CRi with 
adequate blood count recovery within 93 days after start of chemotherapy and is measured from 


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the date of achievement of CR or CRi with adequate blood count recovery 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 without death are counted as a competing cause of failure.
Table 8-5
Censoring rules for CID analysis
Situation
Start date
End Date
Outcome
A
Death due to any reason 
Date of first occurrence of 
CR or CRi with adequate 
blood count recovery within 
93 days after start of 
treatment
Death date 
Event of 
interest
B
Relapse without death
Date of first occurrence of 
CR or CRi with adequate 
blood count recovery within 
93 days after start of 
treatment
Relapse date
Competing 
event, 
censored
C
No death 
Date of first occurrence of 
CR or CRi with adequate 
blood count recovery within 
93 days after start of 
treatment
Date of last 
contact date 
Censored
D
New anticancer therapy 
given/HSCT prior to deaths
Date of first occurrence of 
CR or CRi with adequate 
blood count recovery within 
93 days after start of 
treatment
death due to any 
reason
Event of 
interest
CID will be estimated using the Kaplan-Meier method. The median CID along with 95%
confidence intervals will be presented by treatment group. The stratified Cox regression will be 
used to estimate the HR of CID, along with 95% confidence interval.
8.3.6
Measurable Residual Disease (MRD) by flowcytometry (LAIP 
approach)
8.3.6.1
MRD status
MRD status will be reported for all patients as best response of MRD assessment outcome. Thus, 
patients who reached at least once MRD- will have their MRD status as negative. If all MRD 
assessment are positive or undetermined then MRD status will be reported as such.
It is acknowledged that for patients who failed induction therapy, no MRD assessment should 
be available. MRD status of these patients will be reported as ‘not done due to induction failure’. 
If patient failed induction therapy but have MRD assessment evaluated, MRD status will be 
reported as is in the analysis. Of note, some patients reached CR or CRi with adequate blood 
count recovery after 93 days after start of treatment and are considered to have failed induction 
therapy. 
Patients completing successfully induction therapy (i.e. CR or CRi with adequate blood count 
recovery within 93 days after start of treatment) without MRD assessment will be reported as 
‘missing’ for their status of MRD. This will be the case also for consolidation and post-
consolidation until CR or CRi with adequate blood count recovery is not maintained.


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The percentage of patients with MRD negative/positive/undetermined/missing (irrespective of 
investigator response assessment as per ELN criteria) be summarized along with exact 95% CI 
by treatment group and by treatment phase (i.e. Induction (I and II), consolidation and post-
consolidation). If sufficient number of patients entering post consolidation, comparisons of the 
MRD levels between the end of the consolidation phase during the post-consolidation phase 
will be performed by treatment groups. Status of MRD for patients moving to HSCT and re-
entering post-consolidation will be summarized prior and post HSCT.
In addition, the percentage of patients with CR and MRD-, CR with MRD+, CR and 
undetermined status of MRD and CR with missing MRD data will be reported by treatment 
groups. Similarly for CRi with adequate blood count recovery and other response categories 
(CRi without adequate blood count recovery, PR, etc.). Only CR and CRi with adequate blood 
count recovery will be counted within 93 days after start of chemotherapy will be considered.
Moreover, the kinetics of MRD levels (quantitative) will be displayed in terms of boxplot by 
over time for each treatment phase.
8.3.6.2
Time to MRD negative
The time to MRD negative status is defined as the time from randomization to first occurrence 
of MRD negativity. Patients without reaching MRD negative status level will be censored 
according to the following events:

Patients experiencing induction failure will be censored at maximum follow-up (i.e. date 
of FPFV to date of LPLV used for the analysis).

Patients not experiencing induction failure will be censored at their last adequate MRD 
assessment. If a patient does not have any adequate MRD assessment, patients will be 
censored at randomization date.
An adequate MRD assessment is considered any assessment indicating MRD status apart from 
‘unknown’ or ‘not done’ or ‘undetermined’. ‘Undetermined’. 
8.3.6.3
Duration of MRD negative
The duration of MRD- will be derived only for patients who reached MRD- and is defined from 
first occurrence of MRD – to MRD +, relapse or death whichever occurs first.
Patients without MRD+, relapse from CR nor death will be censored at last adequate MRD 
assessment.
8.3.6.4
Landmark analysis
A landmark analysis of OS at specific timepoints (e.g. at 3 months) will be performed to assess 
any potential impact of MRD status on OS by treatment group and overall. For that, patients 
who completed induction therapy will be classified as per their MRD status at end of induction: 
MRD+, MRD-, MRD undetermined, MRD missing. 
8.3.7
Time to neutrophil/platelet recovery
The time to neutrophil will be assessed for the following criteria: 

Number of days from start of treatment to the first day neutrophils ≥0.5 x 109/L. 


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
Number of days from start of treatment to the first day neutrophils ≥1.0 x 109/L.
Similarly, the time to platelet transfusion independent recovery will be assessed for the 
following criteria:

Number of days from start of treatment to the first day platelets ≥50 x 109/L. This partial 
recovery will be considered only if no transfusion was provided within the last 48h
preceding the partial platelet recovery (i.e. ≥50 x 109/L).

Number of days from start of treatment to the first day platelets ≥100 x 109/L. Moreover, 
the time to adequate blood count recovery will be assessed as:

Number of days from start of treatment to the first day platelets ≥50 x 109/L and the first 
day neutrophils ≥1.0 x 109/L. Patients with platelet values >=100 x 109/L and neutrophils 
>=1.0 x 109/L prior to start of treatment will be excluded for this analysis.
Patient not meeting the recovery criteria mentioned above will be censored at last laboratory 
assessment. In case of no laboratory assessment, patient will be censored at start of Midostaurin. 
Patients who died, failed induction will be censored at maximum follow-up (i.e. LPLV). If 
patients reached recovery after HSCT, this will be taken into account and not censored at time 
of HSCT.
The analyses above will be repeated for induction and consolidation treatment phases. 
Time to platelet and to neutrophil recovery will be plotted by treatment group along with their 
corresponding number of events, HR and 95% confidence intervals.
8.3.8
Transfusions
All transfusions will be listed and summarized using the FAS. The number of transfusion per 
patients will be summarized by treatment phase and for each cycle.
8.3.9
Hematopotic stem cell transplantation (HSCT)
Patient moving to HSCT will be reported by treatment phase. HSCT in CR or CRi with adequate
blood count recovery and relapse/induction failure will be distinguished in the analysis. HSCT 
analyses will be based on the FAS.
9
Safety analyses
All safety analyses will be based on the safety set. Safety summaries (tables, figures) include
data from the on-treatment period see (Section 3.5.2). Safety data will be presented in listing 
for patients who started treatment but were not randomized.
9.1
Deaths
Death summaries for on-treatment, and all (including both on-treatment and post-treatment) 
fatal cases will be produced by treatment group, SOC and PT. All deaths on safety set will be 
listed, post treatment deaths will be flagged. Separate listings of deaths prior to randomization 
will be provided for all screened subjects. Death summaries at day 30 and day 60 after start of 
treatment will also be summarized by treatment group, age and anthracyclin.


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9.2
Adverse events (AEs)
Reporting of AEs
All AEs recorded during the study will be listed and summarized. AEs will be summarized via 
treatment group by presenting the number and percentage of patients having at least one AE 
(regardless of study drug treatment in each primary system organ class) and for each preferred 
term using MedDRA coding (MedDRA version 22.0 or later will be used). A patient with 
multiple occurrences of an AE will be counted only once in the respective AE category. 
AE summaries will be presented by primary system organ class, preferred term, and maximum 
CTC grade (CTCAE version 5.0 will be used). A patient with multiple CTC grades for an AE 
category will be summarized under the maximum CTC grade recorded for the event. 
AE summaries will include all treatment-emergent AEs starting on or after Study Day 1 (i.e. on 
or after the day of the first intake of study treatment) and starting no later than 30 days after 
study treatment discontinuation. 
AE summaries
The following incidences of AE summaries will be produced by treatment group:

AEs regardless of study drug relationship by primary system organ class and preferred 
term.

AEs regardless of study drug relationship by primary system organ class and preferred 
term by age (< 60 vs. => 60 years).

AEs regardless of study drug relationship by primary system organ class, preferred term
and anthracyclin.

AEs regardless of study drug relationship by primary system organ class, preferred term, 
anthracyclin and age(<60 vs. >= 60 years)

AEs with suspected relationship to study drug by primary system organ class and
preferred term.

Deaths by primary system organ class and preferred term.

Deaths by primary system organ class and preferred term and age  (<60 vs. >= 60 years)

Deaths by primary system organ class and preferred term with Idarubicin /Daunorubicin 
during Induction

Deaths by primary system organ class and preferred term and age with Idarubicin 
/Daunorubicin during Induction (<60 vs. >= 60 years)Deaths by primary system organ 
class and preferred term after Hematopoietic stem cell transplantation (HSCT)

SAEs regardless of study drug relationship by primary system organ class and preferred 
term 

SAEs with suspected relationship to study drug by primary system organ class and 
preferred term 

Non-SAEs by primary system organ class and preferred term 

SAEs with fatal outcome by primary system organ class and preferred term


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
AEs leading to study drug discontinuation, regardless of study drug relationship by 
primary system organ class and preferred term 

AEs requiring dose adjustment or temporarily study-drug interruption regardless of study 
drug relationship by primary system organ class and preferred term 

AEs requiring additional therapy regardless of study drug relationship by primary system 
organ class and preferred term.

AEs requiring hospitalization regardless of study drug relationship by primary system 
organ class and preferred term.
9.2.1
Adverse events of special interest (AESI) 
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to compound midostaurin. These groupings are defined using 
MedDRA terms, SMQs (standardized MedDRA queries), HGLTs (high level group terms), 
HLT (high level terms) and PTs (preferred terms) in the Case Retrieval Sheet. For each specified 
AESI, number and percentage of patients with at least one event of the AESI occurring will be 
summarized. A listing of all grouping levels down to the MedDRA preferred terms used to 
define each AESI will be generated. 
9.3
Laboratory data
On analyzing laboratory assessments, data from all sources (central and local laboratories) will 
be combined. The summaries will include on-treatment laboratory assessments.
The following summaries will be produced for the laboratory data (by laboratory parameter):

Shift tables using CTC grades to compare baseline to the worst post-baseline value will be 
produced for hematology and biochemistry laboratory parameters with CTC grades.
For laboratory parameters where CTC grades are not defined.

Shift tables to the worst post-baseline value will be produced using the low/normal/high 
classifications based on laboratory reference ranges. 
Liver function parameters
Liver function parameters of interest are total bilirubin (TBIL), Alanine transaminase (ALT) 
and enzymes aspartate transaminase (AST). The number (%) of patients with worst post-
baseline values as per Novartis Liver Toxicity guidelines will be summarized:

ALT or AST > 3xULN 

ALT or AST > 5xULN

ALT or AST > 8xULN 

ALT or AST > 10xULN

ALT or AST > 20xULN

TBIL > 2xULN

TBIL > 3xULN

ALT or AST > 3xULN & TBIL > 2xULN


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9.4
ECG and cardiac imaging data
Analyses of QT prolongation will be based on QTcF measurement. In general, QTcF would be 
referred to as QTc throughout the document. 
Baseline definition
Baseline is defined from pre-dose ECGs performed on Cycle 1 Day 1 if available. Otherwise, 
the pre-dose ECG measurements taken on most recent day prior to the start of any study 
treatment within 14 days is considered as baseline. Unscheduled visits are included.
Population for analysis
Notable ECG assessments:
Patients will be considered evaluable (included in “Total”) for outlier analysis if they are at risk 
at baseline and have at least one post-baseline ECG measurement. For change from baseline 
analyses they have to have at least one baseline ECG measurement and one post-baseline 
measurement.
A patient is considered at risk at baseline, if the baseline of this patient is missing or:

≤ 450 ms for abnormality “value of > 450 ms and ≤ 480 ms”

≤ 480 ms for abnormality “value of > 480 ms and ≤ 500 ms”

≤ 500 ms for abnormality “value of > 500 ms”
QTc analysis
QTc analysis will be mainly based on QTcF and QTcB. Notable abnormalities will be 
summarized for the following:

An increase of 30 to 60 ms in QTcF (and QTcB)

An increase of > 60 ms in QTcF (and QTcB)

Patients with any QTcF/QTcB value of > 450 and ≤ 480 ms

Patients with any QTcF/QTcB value of > 480 and ≤ 500 ms

Patients with any QTcF/QTcB value of > 500 ms
9.5
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The variables 
collected in studies: height [cm], body temperature [°C], heart rate [beats per minute (bpm)], 
systolic and diastolic blood pressure [mmHg], and respiratory rate [breaths per minute].
Patients with clinically notable vital sign abnormalities will be summarized and listed and 
assessments collected later than 30 days after study treatment discontinuation will be flagged 
in the listings. The criteria for clinically notable abnormalities are depicted in Table 9-1 and 
Table 9-2.
Table 9-1
Clinically notable elevated vital sign values
Variable
Criteria
Systolic BP
180 mmHg and an increase 20 mmHg from baseline


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Variable
Criteria
Diastolic BP
105 mmHg and an increase 15 mmHg from baseline.
Body temperature
39.1°C (102.3°F)
Heart rate
120 bpm with increase from baseline of 15 bpm
Respiratory rate
≥ 30 bpm
Table 9-2
Clinically notable below normal vital sign values
Variable
Criteria
Systolic BP
90 mmHg and a decrease 20 mmHg from baseline
Diastolic BP
50 mmHg and a decrease 15 mmHg from baseline
Body temperature
35°C (95°F)
Heart rate
50 bpm with decrease from baseline of 15 bpm
Respiratory rate
≤ 10 breaths per minute
9.6
Pharmacokinetic endpoints  
9.6.1
Exposure to the sum of active moities
The exposure variable will be derived for all PK exposure endpoints (see Table 9-3; not 
applicable to Tmax) to consider the contribution of the active metabolites to the total exposure 
of the compound.
The exposure to the sum of active moieties combines the concentration of the parent-  
(Midostaurin) and the two active metabolites (CGP52421 and CGP62221) scaled based on their 
relative potencies, and parent to metabolite molecular weight ratio for AML indication as shown 
below:
$% + '()52421 ∗(0.06) ∗Midostaurin mwt
CGP52421mwt + '()62221 ∗(1.40) ∗Midostaurin mwt
CGP62221mwt
Where mwt is the molecular weight of each analyte: 

Midostaurin =570.65

CGP52421=587.23

CGP62221=556.63
9.6.2
PK parameters
PK parameters for midostaurin and the active metabolites (CGP52421, CGP62221) and sum of 
active moieties will be determined using non-compartmental method(s) using Phoenix 
WinNonlin (Version 6.4 or later- Certara L.P.) for the patients who had full PK sampling on 
Cycle 1 Day 8 of the induction therapy. 
PK parameters listed in Table 9-3 will be estimated and reported, when feasible (dependent on 
sampling scheme, and validity of samples). 
Concentration data from patients collected after C1D8 (during induction, consolidation, post-
consolidation phases at trough (predose) and C3h according to the PK sampling schedule [see 


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Study protocol CPKC412E2301 Table 7-8] will be analyzed where possible, and relevant NCA 
parameters determined (Cmin, C3h).
AUC0-t (AUC0-12h at C1D8) and Cmax are defined as primary parameters (contributing to 
PAS-full definition). 
NCA PK parameters and all concentrations will be summarized and reported. Summary 
statistics will include n (number of values to be reported), arithmetic and geometric mean, 
median, SD, CV, geometric CV, minimum and maximum. 
Table 9-3
Non-compartmental PK parameters
AUC0-t
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
The AUC from time zero to the last measurable concentration sampling time after the 
first dose (tlast) (mass x time x volume-1)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after the first dose administration (mass x volume-1)
Cmin
Minimal observed pre-dose concentration (when feasible)
C3h
Concentration at 3 hours post-dose (when feasible)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time)
1 For parent drug only
2 AUC%Extrap and Rsqadj will be used in the interpretation of the primary PK parameters and 
therefore will be included in the listings only.
Descriptive statistics (n, arithmetic mean, CV% mean, standard deviation (SD), median, 
geometric mean, CV% geo-mean, minimum and maximum) will be presented by treatment for 
PAS-full for all PK parameters defined in Table 9-3 except Tmax, where only n, median, 
minimum and maximum will be presented. All individual PK parameters will be listed using 
the PAS-all.
9.7
Patient-reported outcomes
The Functional Assessment of Cancer Therapy – Leukemia (FACT-Leu) and the 5-level EQ-
5D version (EQ-5D-5L) will be collected and assessed. 
In order to summarize patient-reported outcome (PRO) variables, assessments will be time 
slotted using time-windows as defined in study protocol. The baseline assessment is defined 
according to the rule for efficacy variables (Section 3.5.1).
The FAS will be used for all PRO summaries. 
Frequency tables for compliance to completing all patient-reported questionnaires will be 
provided by treatment group and time point for FACT-Leu and EQ-5D-5L (Yes, fully 
completed/ Yes, partially completed/ No, patient missed scheduled assessment visit/ No, patient 
refused due to poor health/ No, patient refused (unrelated to health)/ No, study staff felt patient 
was too ill/ No, questionnaire not available in the appropriate language/ No, institutional error/ 


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No, other). The number of patients with at least one post-baseline value of the respective 
questionnaire will be used as the denominator for frequency tables.
Descriptive statistics (mean, standard deviation, median, minimum, and maximum) will be used 
to summarize the scored scales at each scheduled assessment time point for the FACTLeu and 
EQ5D-5L (VAS) by treatment arm. Additionally, change from baseline in the scores at the time
of each assessment will be summarized. Patients with an evaluable baseline score and at least 
one evaluable post baseline score during the treatment period will be included in the change 
from baseline analyses.
9.7.1
FACT-Leu
Assessment schedule
The questionnaire was to be completed at:

Screening

Induction phase : Cycle 1 Day 1 (C1D1), Cycle 2 Day 1 (C2D1) and end of induction 
phase

Consolidation phase: prior to each consolidation cycle.

Post-consolidation phase: Day 1 of each cycle and at end of post-consolidation phase

Follow-up phase. Every 6 months.
Data derivation
For each subscales in Table 9-4 Scoring will be done according to the instructions of the authors 
(Cella 1997). Higher score values for Physical well-being (PWB), Emotional well-being (EWB) 
and Additional Concerns (AC) indicate greater symptomatology or problems whereas higher 
scores for Social/family well-being (SWB) and Functional well-being (FWB) indicate lower 
symptomatology or problems.
Table 9-4
Fact-Leu scales
(Sub)Scale
Item numbers
Score range
Physical well-being (PWB)
GP1 to GP7
0 – 28
Social/family well-being (SWB)
GS1 to GS7
0 – 28
Emotional well-being (EWB)
GE1 to GE6
0 – 24
Functional well-being (FWB)
GF1 to GF7
0 – 28
Additional Concerns (AC)
BRM3, P2, BRM2, ES3,  LEU1, TH1, 
TH2, HI12, BMT6,  C2, C6,  An7, N3, 
LEU5, LEU6, BRM9 and LEU7 
0 – 68
Analyses

For each treatment group, calculated scores and changes from baseline will be 
summarized by time window. 

The change from baseline will be evaluated in the calculated subscale scores using a 
mixed models for repeated measures (MMRM) up to end of post-consolidation phase. The 
following factors and covariates are included in the repeated measurement model: time, 
treatment, treatment by time interaction, age (<60/≥60 years) and baseline score. 






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13
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