Clinical trial NCT03280030
Conditions: Acute Myeloid Leukemia
Keywords: midostaurin PKC412 cytarabine daunorubicin acute myeloid leukemia combination treatment FLT3 acute myeloid leukemia (AML) acute myelogenous leukemia (AML)
Sponsor: Novartis Pharmaceuticals
Start date: 2018-04-06; Completion date: 2022-11-14
Enrollment: 67 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluated the efficacy and safety of midostaurin in combination with daunorubicin/cytarabine induction, high dose cytarabine consolidation and midostaurin single agent continuation therapy in newly diagnosed patients with FLT3-mutated acute myeloid leukemia (AML).

Detailed description:
This was a Phase II, multi-center trial consisting of two parts; Part 1: an open label, safety evaluation part in Japan only (minimum of three evaluable subjects) and Part 2: a double-blind, randomized, placebo-controlled part (60 subjects). Part 1 in Japan and Part 2 outside Japan were initiated simultaneously. Part 1 was conducted to evaluate the safety and tolerability of midostaurin in combination with daunorubicin/cytarabine induction and high-dose cytarabine consolidation in Japanese subjects and was a pre-requisite before allowing participation of Japan in Part 2. Data from Part 1 was reviewed by an Independent safety Committee (ISC) designated by the Sponsor. The ISC reviewed all available safety data in subjects from Japan up to the time of the safety review data cut-off date (6-Sep-2018). A meeting with the ISC was held on 25-Sep-2018: based on safety evaluation in three evaluable subjects, the ISC members recommended to start Part 2 in Japan.

Part 2 of the study included screening phase, treatment phase composed of up to 18 cycles of midostaurin/placebo treatment in combination with chemotherapy (daunorubicin and cytarabine) during induction and consolidation and alone during continuation and 30 days safety follow up from last dose of study treatment (daunorubicin or cytarabine or midostaurin/placebo); and follow up phase for continued remission and survival follow-up (until 36 months after Day 1 of the last subject). Subjects who provided written informed consent were screened for eligibility during the period up to 7 days immediately prior to starting chemotherapy (Day 1). The subject was randomized at Day 8 to receive either midostaurin or placebo only if FLT3 status was mutated. Treatment phase included induction, consolidation and continuation therapies.

Induction therapy: All screened subjects started induction therapy with chemotherapy from Day 1 to Day 7, while the FLT3 mutation status was being determined. Subjects who achieved CR already with induction Cycle 1 went directly to consolidation therapy without a second cycle of induction therapy. Subjects who did not achieve CR with one cycle of induction received a second induction cycle with same treatment as in Cycle 1. Subjects who did not achieve CR after induction 2 discontinued the study treatment and were followed in safety follow up and survival follow-up.

Consolidation therapy: Subjects who achieved a CR after 1 or 2 cycles of induction received consolidation therapy with 3 cycles of high-dose cytarabine for the Japan Adult Leukemia Study Group (JALSG) regimen and 4 cycles of high-dose cytarabine as tolerated for the Randomized AML Trial In FLT3+ subjects \<60 Years old (RATIFY) regimen. Subjects received midostaurin/placebo, orally twice a day, on Days 8 to 21 of each cycle. Each consolidation cycle began within two weeks following hematopoietic recovery (ANC ≥ 1.0 x 109/L, platelet count ≥ 100 x 109/L) but no sooner than four weeks from the beginning of the previous cycle.

Continuation therapy: After hematopoietic recovery (ANC ≥ 1.0 x 109/L, platelet count ≥ 100 x 109/L) following the final cycle of consolidation but no sooner than 14 days after the last dose of midostaurin/placebo during the last consolidation cycle, subjects who maintained a CR received up to 12 cycles (28 days/cycle) of continuous therapy with midostaurin or placebo twice a day. Safety was assessed in this treatment phase for each subject until 30 days after the end of treatment (EOT) and included routine safety monitoring.

The follow-up phases included post treatment follow-up and survival follow-up. During post-treatment follow-up, all subjects continued to be assessed for relapse i.e. every 2 months during years 1 and 2, every 3 months on year 3 and 4 and then yearly and at time of relapse until relapse, withdrawal of consent, death, loss to follow up, or end of study, whichever was earlier following the end of study treatment for any reason other than persistent AML. Subjects who discontinued study treatment due to persistent AML or relapse and the post treatment follow-up phase due to relapse entered a survival follow-up period during which survival was recorded every 3 months. Survival information was obtained by clinical visits or telephone calls or other means until death, withdrawal of consent, lost to follow-up or end of study, whichever was earlier.

Arms: arm 1: Patients took study drug on day 8-21 during induction and consolidation phase; then on days 1-28 for 12 cycles in the continuation (post consolidation) phase. arm 2: Patients took placebo on day 8-21 during induction and consolidation phase; then on days 1-28 for 12 cycles in the continuation (post consolidation) phase.
Interventions: intervention 1: Midostaurin intervention 2: Placebo
Intervention descriptions: intervention 1: Midostaurin 50 mg \[two 25 mg capsules\] were administered twice per day by mouth on day 8-21 during induction and consolidation phase; then on days 1-28 for 12 cycles in the continuation (post consolidation) phase. intervention 2: Placebo, two capsules, were administered twice per day by mouth on day 8-21 during induction and consolidation phase; then on days 1-28 for 12 cycles in the continuation (post consolidation) phase.

Protocol documents:
Prot_000.pdf: 
Clinical Development 
Midostaurin/PKC412 
Oncology Clinical Protocol CPKC412A2220/NCT03280030
A phase II, randomized, double-blind, multi-center, 
placebo-controlled study to evaluate the efficacy and 
safety of twice daily oral midostaurin in combination with 
daunorubicin/cytarabine induction, high-dose cytarabine 
consolidation, and midostaurin single agent continuation 
therapy in newly diagnosed patients with FLT3-mutated 
acute myeloid leukemia (AML) 
Document type 
Amended Protocol Version 
EUDRACT number 
Not applicable 
Version number 
03 (Clean) 
Development phase 
II 
Document status 
Final 
Release date 
10-Sep-2020
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template version 15-Jan-2017 


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Table of contents 
Table of contents .................................................................................................................. 2 
List of tables ......................................................................................................................... 7 
List of figures ....................................................................................................................... 7 
List of abbreviations ............................................................................................................ 8 
Glossary of terms ............................................................................................................... 11 
Amendment 3 (10-Sep-2020) ............................................................................................ 12 
Amendment 02 (25-Mar-2019) .......................................................................................... 14 
Amendment 01 (13-Aug-2018) ......................................................................................... 17 
Protocol summary .............................................................................................................. 20 
1 
Background ........................................................................................................................ 26 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 26 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) ............. 27 
1.2.1 
Overview of Midostaurin ....................................................................... 27 
2 
Rationale ............................................................................................................................ 33 
2.1 
Study rationale and purpose ................................................................................... 33 
2.2 
Rationale for the study design ................................................................................ 34 
2.3 
Rationale for dose and regimen selection ............................................................... 35 
2.4 
Rationale for choice of combination drugs ............................................................ 35 
2.5 
Rationale for age range of enrolled patients ........................................................... 36 
2.6 
Rationale for choice of comparator drugs .............................................................. 36 
 37 
2.8 
Risks and benefits .................................................................................................. 37 
3 
Objectives and endpoints ................................................................................................... 38 
4 
Study design ....................................................................................................................... 41 
4.1 
Description of study design .................................................................................... 41 
4.1.1 
Part 1: Safety evaluation part ................................................................ 41 
4.1.2 
Part 2: Randomized Part ........................................................................ 43 
4.2 
Timing of interim analyses and design adaptations ............................................... 46 
4.3 
Definition of end of study ...................................................................................... 47 
4.4 
Early study termination .......................................................................................... 47 
5 
Population .......................................................................................................................... 47 
5.1 
Patient population ................................................................................................... 47 
5.2 
Inclusion criteria .................................................................................................... 47 
5.3 
Exclusion criteria ................................................................................................... 48 
6 
Treatment ........................................................................................................................... 50 


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6.1 
Study treatment ...................................................................................................... 50 
6.1.1 
Dosing regimen ..................................................................................... 50 
6.1.2 
Ancillary treatments .............................................................................. 55 
6.1.3 
Rescue medication ................................................................................. 55 
6.1.4 
Guidelines for continuation of treatment ............................................... 56 
6.1.5 
Treatment duration ................................................................................ 56 
6.2 
Dose Escalation Guidelines .................................................................................... 56 
6.3 
Dose modifications ................................................................................................. 56 
6.3.1 
Dose modification and dose delay......................................................... 56 
6.3.2 
Dose adjustments for QTcF prolongation .............................................. 61 
6.3.3 
Follow-up for toxicities ......................................................................... 61 
6.4 
Concomitant medications ....................................................................................... 62 
6.4.1 
Permitted concomitant therapy .............................................................. 62 
6.4.2 
Permitted concomitant therapy requiring caution and/or action ............ 62 
6.4.3 
Prohibited concomitant therapy ............................................................. 63 
6.5 
Patient numbering, treatment assignment or randomization .................................. 63 
6.5.1 
Patient numbering .................................................................................. 63 
6.5.2 
Treatment assignment or randomization ............................................... 64 
6.5.3 
Treatment blinding ................................................................................ 64 
6.6 
Study drug preparation and dispensation ............................................................... 65 
6.6.1 
Study treatment packaging and labeling ................................................ 65 
6.6.2 
Drug supply and storage ........................................................................ 66 
6.6.3 
Study drug compliance and accountability ............................................ 67 
6.6.4 
Disposal and destruction ........................................................................ 67 
7 
Visit schedule and assessments .......................................................................................... 67 
7.1 
Study flow and visit schedule ................................................................................ 67 
7.1.1 
Molecular pre-screening ........................................................................ 80 
7.1.2 
Screening ............................................................................................... 80 
7.1.3 
Run-in period ......................................................................................... 82 
7.1.4 
Treatment period ................................................................................... 82 
7.1.5 
Discontinuation of study treatment ........................................................ 83 
7.1.6 
Withdrawal of consent ........................................................................... 84 
7.1.7 
Follow up for safety evaluations ............................................................ 84 
7.1.8 
Follow up for efficacy evaluations ........................................................ 84 
7.1.9 
Survival follow up ................................................................................. 85 
7.1.10 
Lost to follow-up ................................................................................... 85 


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7.2 
Assessment types ................................................................................................... 85 
7.2.1 
Efficacy assessments ............................................................................. 85 
7.2.2 
Safety and tolerability assessments ....................................................... 88 
7.2.3 
Pharmacokinetics ................................................................................... 92 
7.2.4 
Biomarkers ............................................................................................ 94 
 97 
7.2.6 
Patient reported outcomes...................................................................... 97 
8 
Safety monitoring and reporting ........................................................................................ 98 
8.1 
Adverse events ....................................................................................................... 98 
8.1.1 
Definitions and reporting ....................................................................... 98 
8.1.2 
Laboratory test abnormalities .............................................................. 100 
8.1.3 
Adverse events of special interest ....................................................... 100 
8.2 
Serious adverse events ......................................................................................... 100 
8.2.1 
Definitions ........................................................................................... 100 
8.2.2 
Reporting ............................................................................................. 101 
8.3 
Emergency unblinding of treatment assignment .................................................. 102 
8.4 
Pregnancies .......................................................................................................... 102 
8.5 
Warnings and precautions .................................................................................... 103 
8.6 
Independent Safety Committee ............................................................................ 103 
8.7 
Study Steering Committee ................................................................................... 104 
8.8 
Data Monitoring Committee ................................................................................ 104 
9 
Data collection and management ..................................................................................... 104 
9.1 
Data confidentiality .............................................................................................. 104 
9.2 
Site monitoring ..................................................................................................... 105 
9.3 
Data collection ..................................................................................................... 105 
9.4 
Database management and quality control .......................................................... 105 
10 Statistical methods and data analysis ............................................................................... 106 
10.1 
Analysis sets ......................................................................................................... 107 
10.1.1 
Full Analysis Set .................................................................................. 107 
10.1.2 
Safety set ............................................................................................. 107 
10.1.3 
Per-Protocol set .................................................................................... 107 
10.1.4 
Dose-determining analysis set ............................................................. 107 
10.1.5 
Pharmacokinetic analysis set ............................................................... 108 
10.1.6 
Other analysis sets ............................................................................... 108 
10.2 
Patient demographics/other baseline characteristics ............................................. 108 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ...................... 108 


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10.4 
Primary objective ................................................................................................. 109 
10.4.1 
Variable ............................................................................................... 109 
10.4.2 
Statistical hypothesis, model, and method of analysis ........................ 110 
10.4.3 
Handling of missing values/censoring/discontinuations ...................... 110 
10.4.4 
Supportive and Sensitivity analyses .................................................... 111 
10.5 
Secondary objectives ............................................................................................ 111 
10.5.1 
Key secondary objective(s) .................................................................. 111 
10.5.2 
Other secondary efficacy objectives .................................................... 111 
10.5.3 
Safety objectives .................................................................................. 113 
10.5.4 
Pharmacokinetics ................................................................................. 114 
10.5.5 
Patient-reported outcomes ................................................................... 115 
116 
 116 
 117 
10.7 
Interim analysis .................................................................................................... 117 
10.8 
Sample size calculation ........................................................................................ 118 
10.9 
Power for analysis of key secondary variables .................................................... 120 
11 Ethical considerations and administrative procedures ..................................................... 120 
11.1 
Regulatory and ethical compliance ...................................................................... 120 
11.2 
Responsibilities of the investigator and IRB/IEC/REB........................................ 120 
11.3 
Informed consent procedures ............................................................................... 120 
11.4 
Additional consent form ....................................................................................... 121 
11.5 
Discontinuation of the study ................................................................................ 121 
11.6 
Publication of study protocol and results ............................................................. 121 
11.7 
Study documentation, record keeping and retention of documents ..................... 121 
11.8 
Confidentiality of study documents and patient records ...................................... 122 
11.9 
Audits and inspections ......................................................................................... 122 
11.10 Financial disclosures ............................................................................................ 122 
12 Protocol adherence ........................................................................................................... 122 
12.1 
Amendments to the protocol ................................................................................ 123 
13 References (available upon request) ................................................................................ 124 
14 Appendices ....................................................................................................................... 128 
14.1 
Appendix 1 - The Bayesian model, prior, and operating characteristics ............. 128 
14.1.1 
Introduction ......................................................................................... 128 
14.1.2 
Motivation ........................................................................................... 128 
14.1.3 
Statistical model .................................................................................. 128 


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14.1.4 
Prior specifications .............................................................................. 128 
14.1.5 
Operating characteristics for interim analysis ..................................... 130 
14.1.6 
Operating characteristics for supportive analysis ................................ 132 
14.2 
Appendix 2 – Concomitant medications .............................................................. 133 
14.2.1 
List of prohibited medications ............................................................. 133 
14.2.2 
Permitted medications to be used with caution ................................... 133 
14.3 
Appendix 3 – PGIC questionnaire ....................................................................... 135 
14.4 
Appendix 4 – EORTC QLQ-C30 (version 3) ...................................................... 136 
14.5 
Appendix 5 - EORTC QLQ-C30 Scoring Manual ............................................... 138 


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List of tables 
Table 3-1 
Objectives and related endpoints ........................................................... 39 
Table 6-1 
Dose and treatment schedule ................................................................. 55 
Table 6-2 
Criteria for dose reduction / interruption and re-initiation of 
midostaurin/placebo, daunorubicin and cytarabine treatment for 
adverse events ........................................................................................ 58 
Table 6-3 
Dispensing and preparation ................................................................... 65 
Table 6-4 
Supply and storage of study treatments ................................................. 66 
Table 7-1 
Visit evaluation schedule ....................................................................... 69 
Table 7-2 
ECOG performance status scale ............................................................ 89 
Table 7-3 
Clinical laboratory parameters collection plan ...................................... 89 
Table 7-4 
Central ECG assessment monitoring schedule ...................................... 91 
Table 7-5 
Pharmacokinetic blood collection log for midostaurin, CGP52421 
and CGP62221 ...................................................................................... 93 
Table 7-6 
Biomarker sample collection plan ......................................................... 94 
Table 10-1 
Outcome and event/censor dates for EFS analysis .............................. 110 
Table 10-2 
Noncompartmental pharmacokinetic parameters ................................. 115 
Table 14-1 
Data from CPKC412A2301 study ....................................................... 130 
Table 14-2 
Hypothetical scenarios ......................................................................... 130 
Table 14-3 
Simulation results ................................................................................ 131 
Table 14-4 
Posterior probability to show median HR < 1 under several 
hypothetical true scenarios .................................................................. 132 
 
 
List of figures 
Figure 4-1 
Independent Safety Committee review in Part 1 safety evaluation 
part (Japan only) .................................................................................... 43 
Figure 4-2 
Overview of Randomized Part (Part 2) .................................................. 44 


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List of abbreviations 
 
Advanced SM 
Advanced systemic mastocytosis 
AE 
Adverse Event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
ANC 
Absolute Neutrophil Count 
APL 
acute promyelocytic leukemia 
ASM 
Aggressive systemic mastocytosis 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the curve 
AUCinf 
Area under the curve from time 0 to infinite 
AUClast 
Area under the curve from time zero to the last measurable concentration sampling time 
after the first dose (tlast) 
AUC0-t 
Area under the curve from time zero to a measurable concentration sampling time (t) 
BCRP 
breast cancer resistant protein 
BCS 
Biopharmaceutics classification system 
bid 
bis in diem/twice a day 
BMA 
bone marrow aspirate 
BR 
Blast reduction 
BSA 
Body Surface Area 
CABG 
Coronary artery bypass graft 
CALGB 
Cancer and Leukemia Group B 
CIR 
Cumulative incidence of relapse 
CIVI 
Continuous intravenous infusion 
CL/F 
mean apparent plasma clearance 
Cmax 
maximum plasma concentration 
CMO&PS 
Chief Medical Office and Patient Safety 
CMV 
Cytomegalovirus 
CNS 
Central Nervous System 
CR 
Complete remission 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRp 
Morphologic complete remission with incomplete platelet count recovery 
CSF 
Cerebrospinal fluid 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
CYP3A4 
Cytochrome P450 3A4 enzyme 
DFS 
Disease-free survival 
DILI 
Drug-induced liver injury 
DMC 
Data Monitoring Committee 
EBV 
Epstein-Barr Virus 
ECG 
Electrocardiogram 


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ECHO 
ECOG PS 
Echocardiogram 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
Electronic Case Report/Record Form; the term CRF can be applied to either EDC or Paper 
EDD 
Expected Delivery Date 
EFS 
Event-free survival 
ELN 
European LeukemiaNet 
EORTC 
European Organisation for the Research and Treatment of Cancer 
EOT 
End of Treatment 
FAS 
Full analysis set 
FDA 
FGFR 
Food and Drug Administration 
Fibroblast Growth Factor Receptor 
FLT3 
FMS-like tyrosine kinase receptor-3 
GGT 
Gamma-glutamyltransferase 
GI 
Gastrointestinal 
HiDAC 
High-dose cytarabine 
HIV 
Human Immunodeficiency Virus 
HR 
Hazard Ratio 
HSV 
Herpes simplex virus 
I.V 
Intravenous(ly) 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
ILD 
Interstitial Lung disease 
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 
ITT 
Intent-to-treat 
JALSG 
Japan Adult Leukemia Study Group 
LFT 
Liver function tests 
LVEF 
Left Ventricular Ejection Fraction 
MCL 
Mast cell leukemia 
MDS 
Myelodysplastic Syndrome 
MI 
Myocardial infarction 
MR 
Minor Response 
 
 
MUGA 
Multigated Acquisition Scan 
NCA 
Non-compartmental Analysis 
NCCN 
National Comprehensive Cancer Network 
NGS 
Next generation sequencing 
NOEL 
no observable effect level 
OATP1B1 
Organic Anion Transporting Polypeptide 1B1 
OS 
Overall Survival 
p.o. 
per os/by mouth/orally 
PAS 
Pharmacokinetic Analysis Set 


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PD 
Pharmacodynamic 
PGIC 
Patient Global Impression of Change 
P-gp 
P-glycoprotein 
PHI 
Protected Health Information 
 
 
PK 
Pharmacokinetic(s) 
popPK 
Population pharmacokinetics 
PPS 
Per-Protocol Set 
PR 
Partial remission 
PRO 
Patient reported outcome 
PT 
Prothrombin time 
QLQ 
Quality of Life Questionnaire 
QT/QTcF 
QT interval/QT interval corrected with Fridericia’s formula 
RATIFY 
Randomized AML Trial In FLT3+ patients <60 Years old 
REB 
Research Ethics Board 
RoW 
Rest of World 
RT 
Radiotherapy 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCT 
Hematopoietic Stem Cell Transplantation 
SM 
Systemic Mastocytosis 
TBIL 
Total bilirubin 
TdP 
Torsades de Pointes 
TKD 
Tyrosine Kinase Domain 
ULN 
Upper limit of normal 
US 
United States 
VEGFR 
Vascular endothelial growth factor receptor 
WBC 
white blood cell(s) 
WHO 
World Health Organization 
WT 
Wild Type 


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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, bone marrow, blood, plasma, 
serum, 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.q28 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) 
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 arms of a study 
Other study treatment 
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment 
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. 
Phase 
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, treatment phase, follow up 
Randomization number 
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment 
Subject Number 
A unique identifying number assigned to each patient/subject/healthy 
volunteer who enrolls in the study 
Stage related to study timeline 
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc. 
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 
Includes any drug or combination of drugs in any study arm administered to 
the patient (subject) as part of the required study procedures, including 
placebo and active drug run-ins. 
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and non-investigational 
treatments in combination 
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 or the combination 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints 
Withdrawal of study consent 
Withdrawal of consent occurs only when a patient does not want to 
participate in the study any longer, does not want any further visits or 
assessments, and does not allow any further collection of personal data 


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Amendment 3 (10-Sep-2020) 
Amendment rationale 
This is a global protocol amendment. 
As of 21 November 2019, the study fully completed enrollment and 62 patients have been 
randomized in part 2 of the study. As of 9 September 2020, 28 EFS events have been 
documented, and 20 patients are still in follow-up for EFS. 
The primary analysis of the study was planned to be conducted when at least 36 EFS events 
were observed which was assumed to take place 21 months after the first patient was 
randomized in November 2018. Considering the actual enrollment curve, the EFS accumulation 
curve until the time of this protocol amendment, and the rate of discontinuations without EFS 
event, a delayed occurrence of additional EFS events is expected and therefore a substantial 
longer follow-up than originally planned is needed to document at least 36 EFS events (expected 
cut-off is end of 2021 instead of August 2020 as originally anticipated). 
Therefore, the present protocol amendment indicates now that the primary analysis will be 
performed using the pre-defined cut-off date of 30 November 2020 with the number of EFS 
events documented by this date. Based on current situation and assumption which has been used 
in protocol section 10.8, 33 EFS events in total are anticipated (5 additional EFS events 
expected) until 30 November 2020. Of note, we have observed only 2 EFS events (in 5 months) 
after 9 April 2020. The minimum follow-up period for all patients who are in follow-up for EFS 
will be at least 12 months (from last patient randomized from November 2019 to November 
2020). The end of study will occur at the latest 36 months after the start of the study treatment 
for the last patient (anticipated as November 2022). At this time, the final analysis will be 
performed and the final CSR be written. 
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 underline for insertions. 
 
Changes to protocol: 
• Protocol summary, section 10, section 10.7 and section 10.8: revised the primary 
analysis to “The primary analysis will be performed using the pre-defined cut-off date 
of 30 November 2020 with the number of EFS events documented by this date”. 
• Section 4.3: removed the timing of the primary analysis. 
• Section 4.3, section 10, and section 10.7: revised the timing of the end of study/final 
analysis to “The end of study will occur at the latest 36 months after the start of the 
study treatment for the last patient.” 
• Protocol summary, section 4.2, section 10.4.2 and section 10.7: clarified that “the 
study will be continuing blinded to patients, investigators and monitors until the 
primary analysis and thereafter the study will be unblinded. At the final analysis more 
mature data can be evaluated”. 
• Section 6.5.3: “at the time of the interim analysis (see Section 10.7)” and “at the time 
of the conclusion of the study” replaced by “at the time of the primary analysis (see 
Section 10.7)”. “prior to the study conclusion” removed. 


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• Section 10.8: removed “as well as Hong Kong, Korea, Russia and Taiwan”. “As per 
the initial protocol design (i.e. pre-Amendment 3)” added. 
• Section 10.8: added the rationale to revise the timing of the primary analysis, expected 
additional EFS observed until the cut-off for the primary analysis and the study power 
under the original assumptions. 
 
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. 


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Amendment 02 (25-Mar-2019) 
Amendment rationale 
Status of the study: At the time of this protocol amendment, part 1 conducted only in Japan is 
completed and 15 patients are randomized in part 2. 
In order to detect earlier if the efficacy success criterion for EFS is met, an interim analysis is 
now introduced. Therefore additional text is added in the statistical section to indicate that an 
interim analysis for efficacy is to be conducted when 60 patients are randomized and at least 24 
EFS events are documented. This interim analysis will be assessed by a DMC, however, even 
if interim success criteria are met, the study will be continuing until the final (primary) analysis 
at which more mature data can be evaluated and more precise estimates obtained. In case that 
36 EFS events are documented before randomization completion, the interim analysis can be 
skipped and Novartis will conduct primary analysis as initially planned. Integrity of the study 
will not be compromised. Blinding of the study personnel, investigators and patients will be 
unequivocally maintained and a DMC is established for performing this interim analysis. At 
interim analysis, unblinding of study drug assignment will only occur when success criteria for 
interim analysis are met. 
BMA is required to establish AML diagnosis in this protocol. However, in rare cases it is not 
possible to obtain bone marrow (dry tap). In case of failure to get bone marrow on attempted 
BMA, it is recommended to perform a bone marrow biopsy (Döhner 2017). Furthermore, the 
presence of ≥20% blasts in the bone marrow or peripheral blood is sufficient for confirming 
AML diagnosis (Arber et al 2016, Döhner 2017). These are the reason why the protocol is 
modified to indicate that in case of documented dry tap at study entry, a bone marrow biopsy 
has to be performed for confirming AML diagnosis. Moreover, as the results of a biopsy may 
take several days and may delay initiation of AML treatment, AML diagnosis based on 
peripheral blood showing ≥ 20% blasts will be accepted. 
Exclusion criterion relating to chest X-ray at screening has been modified to specify that 
patients with a treated lung infection which is controlled by treatment are eligible. Lung 
infection is frequent in AML patients during the course of the disease; this intercurrent condition 
is usually controlled by adequate treatment and is compatible with AML treatment. 
Concomitant therapy section has been updated to clarify management of permitted therapies 
requiring caution and/or action. 
The management of patients who are confirmed as FLT3<0 or undeterminate before D8 of 
Induction Cycle 1 was clarified (End of Treatment (EoT) and Safety Follow-up visit). 
Other minor changes and corrections were made throughout the protocol for consistency and/or 
clarifications. 
 
Changes to the protocol 
• Protocol summary: Exclusion criteria 7 and 11 updated. Data analysis updated for 
adding description of interim analysis 


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• Section 4.1.2: clarification for timepoint of 30 days safety follow-up visit: 
midostaurin/placebo replaced with study treatment; their regimen may not be switched 
during the course of the study: “may” replaced with “must” 
• Figure 4-2 updated: clarification for patients not randomized due to FLT3<0 or 
unknown who should have EoT and Safety follow-up visit. 
• Section 4.1.2.1: clarification added for patients who can’t have BMA (dry tap) for 
diagnosis. 
• Section 4.1.2.2: Induction therapy: Patients not achieving CR after induction 2 will 
discontinue study treatment and will be followed in survival follow-up: addition of 
“and in safety follow up”. 
• Section 4.2: ‘No interim efficacy analysis will be conducted’ removed and description 
of interim analysis added to comply with program 
• Section 5.3: exclusion criteria #7 was updated to align with PKC412E2301 study 
• Section 5.3: exclusion criteria #11 was modified; addition of “or a lung infection 
which is controlled by treatment” 
• Section 6.1: management of patient not shown to have a qualifying FLT3 activating 
mutation clarified: discontinuation of study updated to discontinuation of treatment 
• Section 6.1.1.1. JALSG Remission Induction. Addition of “More details are enclosed 
within the Investigator Brochure please refer to it” 
• Table 6-2: updated for clarity 
• Section 6.3.3: clarification for timepoint of 30 days safety follow-up visit: 
midostaurin/placebo replaced with study treatment 
• Sections 6.4.2: addition of section related to “concomitant administration of drugs 
with a “known”, “possible” or “conditional” risk of Torsades de Pointes “ 
• 
 Section 6.4.3: removal of section related to “concomitant administration of drugs 
with a “known”, “possible” or “conditional” risk of Torsades de Pointes “” 
• Section 6.5.1: The IRT must be notified within 2 days that the patient was not 
randomized. Addition of “ by using appropriate form”. 
• Section 6.5.3: description of independent statistician/programmer and unblinding 
condition added 
• Table 7-1: addition of EOT assessments for FLT3<0 patients 
• Table 7-1: Investigator assessment of Disease Response: “induction 1” removed for 
alignment with section 7.2.1 
• Section 7.1.2: Addition of instructions for patients who have biopsy for diagnosis (if 
dry tap for BMA). Clarification added regarding repetition of laboratories assessments 
during screening period. 
• Section 7.1.2.2: clarification added for patients who failed to be randomized. Addition 
of EOT and safety follow-up visits and information for patients who will move to 
PKC412E2301 study. 


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• Section 7.1.9: clarification on when should be done the safety follow-up visit: 30 days 
after the last dose of ... “midosaturin/placebo” replaced with “study treatment” 
 
• Section 8.8: section related to DMC added 
• Section 10: description of interim analysis added 
• Section 10.4.1: clarified what analysis set used for all (interim, primary and final) 
efficacy analyses for part 2 
• Section 10.4.2: description of interim analysis added 
• Section 10.4.2: change wording ‘sensitivity’ to ‘supportive’ 
• Section 10.7: ‘No interim efficacy analysis is planned in this study.’ removed and 
description of interim analysis added 
• Section 10.8: description of interim analysis added and the simulation results with 
interim analysis added 
 
 
• Section 14.1: description of operating characteristics for interim analysis added 
• Section 14.2: updated to reflect changes in sections 6.4.2 and 6.4.3 
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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Amendment 01 (13-Aug-2018) 
Amendment rationale 
Status of the study: At the time of this protocol amendment, 6 patients are enrolled in the 
protocol, part 1 (1 screen failure, 1 discontinuation due to CR not achieved and 4 on treatment 
and 1 patient enrolled in part 2 (screen failure due to FLT3 negative). 
Increase of age limit in inclusion criteria is implemented because international treatment 
guidelines for AML increasingly recommend that standard induction and consolidation 
chemotherapy be considered on the basis of patient tolerability as assessed by the treating 
physician and not chronological age. Additionally, clinical experience with midostaurin is 
increasingly established in older patients. Safety and tolerability is further assured on the basis 
of an interim clinical study report (CSR) for study ADE02T, an investigator initiated study in 
which FLT3-mutated patients ≤70 were treated with midostaurin combined with standard 
induction and consolidation chemotherapy followed by midostaurin monotherapy.Suitability to 
intensive chemotherapy is to be confirmed by the investigator, and a specific inclusion criterion 
has been added. 
Addition of low-dose cytarabine as treatment allowed for cytoreduction prior to induction 
treatment is implemented to comply with Asian standard medical practice. 
Procedures in relation to diagnosis confirmed by BMA, FLT3 testing,
 during 
screening period is clarified and updated. 
Timeframe for BMA is extended at the end of induction cycle (s) to comply with local standard 
medical practice and avoid additional BMA, which represents an invasive procedure for patients. 
CR determination is an examination routinely done and there are a limited number of 
investigational sites in this Phase II study. This is why CR central review will not be performed 
for the study and all the related sections are modified accordingly. However, for CR 
documented, the sites are requested to store the relevant slides. 
Changes in dose modifications guidelines are implemented for more clarity. 
Other minor changes and corrections were made throughout the protocol for consistency and/or 
clarifications. 
 
Changes to the protocol 
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 underline for insertions. 
Minor typos and grammatical errors were updated throughout the protocol. 
• Title and throughout the document: removed location specific information 
• Throughout the document: updated wording related to data collection, Case Report Form 
(CRF) to align with evolving CRF standards, updated Common Terminology Criteria for 
Adverse Events (CTCAE) version (Version 4.03 replaced with Version 5.0) 
• List of abbreviations: updated for completeness 
• Glossary of terms: Updated ‘Personal data’ and ‘withdrawal of consent’ to coincide with 
new template. 


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• Section 1.2.1.1: Pharmacokinetics and drug metabolism: “in animals” removed in the title 
and section updated 
• Section 1.2.1.1: pre-clinical toxicity: fertility section updated 
• Section 1.2.1.2: Pharmacokinetics and drug metabolism in humans section updated 
• Section 2.5: rationale for age of enrolled patients changed 
• Section 4.1.2: Figure 4-2 updated to reflect clarification on diagnosis confirmed during 
screening period and age 
• Section 4.1.2.1: screening phase updated for clarity 
• Section 4.1.2.2: induction therapy: post-treatment follow up replaced with survival follow 
up to align with Figure 4-2 
• Section 4.1.2.2: continuation therapy: guidance related to acute toxicity removed for 
clarity since all dose modifications are detailed in table 6-2 
• Section 5.2: inclusion criterion #1 : addition of reference 
• Section 5.2: inclusion criterion #3 modified 
• Section 5.2: inclusion criterion #5 aligned with study E2301 
• Section 5.2: inclusion criterion #7 added, suitability for intensive chemotherapy 
• Section 5.3: exclusion criterion #8: low-dose cytarabine and other supportive therapy 
added to align with study E2301 
• Section 5.3: exclusion criterion #17: barrier method of contraception language aligned 
with Investigator’s Brochure (IB) 
• Section 6.1.1: dosing regimen: supply of chemotherapy updated 
• Sections 6.1.1.1 and 6.1.1.2: Remission induction and second Remission induction: 
response assessment removed from those sections to avoid redundancy 
• Section 6.1.1.3: continuation therapy: number of cycles requested during consolidation for 
RATIFY regimen clarified 
• Section 6.3.1: table 6-2: dose modifications clarified when recommended or mandatory 
• Section 6.4 and Appendix 2: permitted concomitant therapy, permitted requiring caution 
and prohibited concomitant therapy sections updated to align with program 
• Section 6.5.3: treatment blinding: information related to central review removed 
• Section 6.6.1: supply of chemotherapy updated 
• Section 6.6.2 and Table 6-4: supply of chemotherapy updated 
• Section 7.1: table 7-1: total bilirubin clarified, “D” removed and replaced with “S” for 
pregnancy test and for other hepatic tests, timeframe for BMA during induction changed 
(from D21 to D28), biopsy added for disease assessment, 
 
 cytogenetic data removed after screening and 
concomitant medication capture removed for patients in follow-up. 


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• Section 7.1.2.2: FLT3 data collection added for screen failures and addition of “until Day 
8 of 1st cycle of induction” for information collected for patients who failed to be 
randomized 
 
 
 
• Section 7.1.6: withdrawal of consent updated to align with new template 
• Section 7. 2.1: addition of biopsy requested if dry tap, information related to CR review 
changed (slides kept at site), addition of description of response assessment for induction 
cycles 1 and 2,
• Section 7.2.2.1: Physical exam definition clarified 
• Section 7.2.2.5, table 7-3: sediment analysis replaced with microscopic analysis for 
consistency with table 7-1 
• Section 7.2.2.5.4 urinalysis: “specific gravity, blood, bilirubin, ketones and WBC” 
removed 
• Section 7.2.2.5.5 Fertility information updated 
• Section 7.2.3: PK analysis updated for clarity 
• Table 7-5: window/period added for PK sample collection Day 8 and total volume added 
• Table 7-6: clarification on the collection of BMA or (not and) blood for FLT3 and 
timepoint for BMA at Day21 extended until Day 28. 
• Section 8.1.1: Updated AE outcome categories and relationship to study treatment updated 
to reflect CRF 
• Section 10.5.3.5: subgroup analysis by country is removed and addition of “details of 
analysis described in the SAP if appropriate” 
• Sections 10.4.4 and 10.5.2.3: analysis related to CR review removed 
• Section 10.5.4 and Table 10-2: pharmacokinetics updated 
• Section 13: references changed to reflect updates in rational sections 
• Section 14.5 appendix 5: replacement of page 6 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC/REB 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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Protocol summary 
Title 
A phase II, randomized, double-blind, multi-center, placebo-controlled study to 
evaluate the efficacy and safety of twice daily oral midostaurin in combination 
with daunorubicin/cytarabine induction, high-dose cytarabine consolidation, and 
midostaurin single agent continuation therapy in newly diagnosed patients with 
FLT3-mutated acute myeloid leukemia (AML) 
Brief title 
A study of midostaurin efficacy and safety in newly diagnosed patients with FMS- 
like tyrosine kinase receptor-3 (FLT3)-mutated AML 
Sponsor and 
Clinical Phase 
Novartis, 
Phase II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
● The purpose of this study is to obtain clinical data, comparable to those 
obtained in study [CPKC412A2301], from patients of variable ethnicity located in 
regions that did not participate in [CPKC412A2301]. This study will evaluate the 
efficacy and safety of midostaurin in combination with daunorubicin/cytarabine 
induction, high-dose cytarabine consolidation, and midostaurin single agent 
continuation therapy in newly diagnosed patients with FLT3-mutated acute 
myeloid leukemia (AML). 
● In Japan, an open-label safety evaluation part (Part 1) will be conducted in 
this population to evaluate the safety and tolerability of midostaurin in 
combination with standard chemotherapy in Japanese patients. This part will be 
conducted prior to participation of Japanese patients in the randomized part 
(below). 
● A randomized part (Part 2) will be conducted to evaluate the efficacy and 
safety of midostaurin versus placebo in combination with standard chemotherapy 
in this patient population. 
Primary Objective(s) and 
Key Secondary Objective 
Primary Objective: 
● Safety evaluation part (Part 1): To evaluate the safety and tolerability of 
midostaurin in combination with daunorubicin/cytarabine induction and high-dose 
cytarabine consolidation in Japanese patients with newly diagnosed AML. 
● Randomized part (Part 2): To evaluate the efficacy based on event-free 
survival (EFS) of midostaurin versus placebo in combination with 
daunorubicin/cytarabine induction, with high-dose cytarabine consolidation, and 
with midostaurin single agent continuation therapy in newly diagnosed patients 
with FLT3-mutated AML. 
Key Secondary Objective: not applicable 
Secondary Objectives 
Randomized part (Part 2): 
Objective 1: Determine the overall survival (OS) in the two treatment groups 
Objective 2: Determine the rate of complete remission (CR) in the two treatment 
groups 
Objective 3: Determine the cumulative incidence of relapse (CIR) in the two 
treatment groups 
Objective 4: Evaluate the safety of midostaurin compared to placebo in 
combination with chemotherapy and as single agent continuation therapy 
Objective 5: Evaluate the pharmacokinetics (PK) of midostaurin and its two major 
metabolites CGP62221 and CGP52421 
Objective 6: Determine the effect of study treatment on quality of life 


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Study design 
This study is a phase II, multi-center trial consisting of 2 parts: 
● Part 1: open label, safety evaluation part in Japan only (minimum of three 
evaluable patients) 
● Part 2: double-blind, randomized, placebo-controlled part (60 patients) 
Part 1 in Japan and Part 2 outside Japan will begin in parallel. At the completion 
of Part 1, and depending on the findings of the safety evaluation, the trial in 
Japan will advance to Part 2. 
In Part 1, patients will be enrolled into the study irrespective of leukemia FLT3 
genotype (i.e., patients with either FLT3-WT or FLT3-mutated AML will be 
eligible). In part 2, patients will be enrolled only if they are confirmed in a 
Novartis-designated central laboratory to have FLT3-mutated AML. 
In Part 1, the safety evaluation period will begin on Day 1 of the first Induction 
cycle (Cycle 1 Day 1) and will continue until Day 21 of the first consolidation 
cycle. This interval will allow for an assessment of the safety of midostaurin with 
chemotherapy throughout induction and will provide also an assessment of 
safety events after consolidation therapy with high-dose cytarabine. 
Part 2 will comprise three phases: 
● Screening phase: written informed consent will be collected, and all eligibility 
criteria including diagnosis will be verified (up to 7 days) 
● Treatment phase: patients will begin induction chemotherapy (daunorubicin 
and cytarabine) from Day 1 to Day 7. If the FLT3 mutation status is confirmed, 
then patients will be randomized on Day 8 to receive either midostaurin 50 mg 
bid or placebo 50 mg bid until Day 21. If a patient is shown to have achieved a 
CR after the first cycle of induction therapy, the patient will begin consolidation 
therapy; if the patient does not achieve a CR, a second cycle of induction therapy 
identical to that of the first cycle will be administered. Patients who do not 
achieve a CR after one or two cycles of induction therapy will be removed from 
study treatment. Patients who achieve a CR after induction therapy will proceed 
to consolidation therapy with high-dose cytarabine (3 or 4 cycles) with sequential 
midostaurin or placebo (Days 8 through 21 of each cycle) as assigned. Patients 
with a continued remission after consolidation therapy will receive midostaurin or 
placebo as a single agent continuation therapy for 12 cycles (D1 through D28 of 
each cycle). 60 patients will be randomized into Part 2. Randomization will be 
stratified according to FLT3 mutation status (FLT3- Internal Tandem duplication 
(ITD) low, FLT3-ITD high, FLT3-TKD) and according to the chemotherapy 
regimen (RATIFY or JALSG). Patients will continue study treatment until disease 
persistence or relapse (designated as Progressive Disease in the electronic 
Case Report Form (eCRF)) as assessed by Cheson criteria, intolerable toxicity, 
and withdrawal of consent, death, or discontinuation from the study treatment for 
any other reason, whichever is earlier. Regardless of the reason for treatment 
discontinuation (except death), all patients will be followed for safety for 30 days 
after the last dose of study treatment. 
● Follow-up phase: following treatment discontinuation, patients who are alive 
will be followed for relapse (if not already demonstrated) and survival. 
Population 
Part 1: Safety evaluation part in Japan (minimum of three patients) 
● Adult patients ≤ 70 years with newly diagnosed FLT3-mutated or FLT3-WT 
AML. 
Part 2: Double blind, randomized, placebo controlled (60 patients) 
● Adult patients ≤ 70 years with newly diagnosed FLT3-mutated AML 


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Inclusion criteria 
Patients eligible for inclusion in this study must meet all of the following eligibility 
criteria: 
1. Diagnosis of AML (≥ 20% blasts in the bone marrow based on WHO 2016 
classification). Patients with APL (acute promyelocytic leukemia) with PML- 
RARA are not eligible 
2. Documented presence of an ITD and/or TKD activating mutation in the FLT3 
gene, as determined by analysis in a Novartis designated laboratory 
An exception will be patients who are enrolled into the part 1 in Japan, who may 
be treated with midostaurin irrespective of AML FLT3 genotype 
3. Age ≥ 18 years, ≤ 70 years of age 
4. AML patients with a history of antecedent myelodysplasia (MDS) remain 
eligible for treatment on this trial but must not have received prior cytotoxic 
therapy (e.g., azacytidine or decitabine) 
5. 
Patients must meet the following laboratory value criteria that indicate 
adequate organ function at the screening visit: 
• 
Estimated (by Cockcroft-Gault) creatinine clearance ≥ 30 ml/min 
● 
Total bilirubin ≤ 1.5 x ULN, except in the setting of isolated Gilbert 
syndrome 
● 
Aspartate transaminase (AST) ≤ 3.0 x ULN 
● 
Alanine transaminase (ALT) ≤ 3.0 x ULN 
6. Written informed consent must be obtained prior to any screening 
procedures. 
For patients in Japan less than 20 years of age, written consent is required from 
the patient as well as from their legal representative. 
7. Suitability for intensive chemotherapy in the judgment of the investigator 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Neurologic symptoms suggestive of CNS leukemia unless CNS leukemia has 
been excluded by a lumbar puncture. Patients with CSF fluid positive for AML 
blasts are not eligible 
2. Developed therapy-related AML after prior radiotherapy (RT) or 
chemotherapy for another cancer or disorder 
3. Isolated extramedullary leukemia (please refer to Section 7.2.2.1) 
4. Known hypersensitivity to midostaurin, cytarabine or daunorubicin or to any 
of the excipients of midostaurin/placebo, cytarabine or daunorubicin 
5. 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 
6. Prior treatment with a FLT3 inhibitor (e.g., midostaurin, quizartinib, sorafenib) 
7. Patients who take strong CYP3A4/5 enzyme inducing drugs or strong 
CYP3A4/5 enzyme inducing herbal supplements (see Appendix 2) unless they 
can be discontinued or replaced prior to enrollment. 
8. Prior chemotherapy for leukemia or myelodysplasia. However, the following 
prior therapies are allowed: 
a. 
Emergency leukapheresis 
b. 
Emergency treatment for hyperleukocytosis with hydroxyurea or low- 
dose cytarabine for ≤ 7 days 
c. 
Cranial radiotherapy (RT) for central nervous system (CNS) leukostasis 
(one dose only) 
d. 
Hematopoietic growth factor/cytokine support; other supportive therapy 
including antibiotics at the discretion of the investigator 
9. Any surgical procedure, excluding central venous catheter placement or other 
minor procedures (e.g., skin or bone marrow biopsy) within 14 days prior to Day 
1 


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10. 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 
11. Abnormal chest X-ray unless the abnormality represents a non-active, or 
non-clinically significant finding, such as scarring or a lung infection which is 
controlled by treatment. 
12. Known impairment of gastrointestinal (GI) function or GI disease that might 
alter significantly the absorption of midostaurin13. 
Known confirmed 
diagnosis of human immunodeficiency virus (HIV) 
14. Evidence of active HBV or HCV viral infection (confirmed by peripheral blood 
viral load). Patients with positive serology results indicative of high risk for viral 
reactivation must have negative viral load results within 28 days prior to Day 1 
15. Cardiac or cardiac repolarization abnormality, including any of the following: 
● 
History of myocardial infarction (MI), angina pectoris, coronary artery 
bypass graft (CABG) within 6 months prior to Day 1 
● 
Clinically significant 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 
● 
QT interval corrected with Fridericia’s formula (QTcF) at screening > 
470 ms 
● 
Long QT syndrome, family history of idiopathic sudden death or 
congenital long QT syndrome, or any of the following: 
• 
Risk factors for torsades de pointe (TdP) including uncorrected 
hypokalemia or hypomagnesemia, history of cardiac failure, or 
history of clinically significant/symptomatic bradycardia 
• 
Concomitant medication(s) with a known risk of Torsades de 
Pointes that cannot be discontinued or replaced safely with an 
alternative medication 
• 
Inability to determine the QTcF interval 
16. Pregnant or nursing (lactating) women 
17. Women of child-bearing potential, unless they are using highly effective 
methods of contraception during dosing and for 4 months after stopping 
medication 
18. Sexually active males unless they use a condom during intercourse while 
taking the drug during treatment and for 4 months after stopping treatment and 
should not father a child in this period 
Investigational and 
reference therapy 
Part 1: Midostaurin in sequential combination with daunorubicin and cytarabine 
induction, in sequential combination with high dose cytarabine consolidation, and 
as single agent continuation therapy 
Part 2: Midostaurin or placebo in sequential combination with daunorubicin and 
cytarabine induction, in sequential combination with high dose cytarabine 
consolidation, and as single agent continuation therapy 
Efficacy assessments 
Bone marrow aspirate (BMA) and peripheral blood specimens will be evaluated 
for remission versus persistent or relapsed disease (Progressive Disease) 
according to Cheson criteria. 
The following responses will be collected: 
● Complete remission (CR) 
● Morphologic complete remission with incomplete platelet count recovery 
(CRp) 
● Partial Remission (PR) 
● Treatment Failure 
● Relapse after CR 


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Safety assessments 
● Physical examination 
● ECOG PS (Eastern Cooperative Oncology Group Performance Status) 
● Weight and vital signs 
● 12-lead electrocardiogram (ECG) 
● MUGA, ECHO 
● Laboratory assessments including hematology, chemistry, coagulation and 
urinalysis 
● Adverse events (AEs) with severity, relationship to study treatment and 
seriousness 
Other assessments 
● PK parameters 
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. 
● Patient reported outcomes assessment by the European Organization for 
Research and Treatment of Cancer quality of life (EORTC QLQ-C30) 
 
Data analysis 
Part 1: Safety evaluation part in Japan 
The safety and tolerability of midostaurin in combination with chemotherapy in 
Japan will be assessed based on the incidence of Safety Events among 
evaluable patients. A Safety Event is defined as death or serious adverse event 
leading to treatment discontinuation that occurs on or before Day 21 of the first 
consolidation cycle (safety evaluation period) and that is determined by the 
Independent Safety Committee to be definitely or probably related to 
midostaurin. Evaluable patient is defined as patients who have completed the 
safety evaluation period without a potential Safety Event or have experienced a 
potential Safety Event within this period. 
All patients enrolled in part 1 will be listed and reviewed irrespective of the 
combination treatment (JALSG or RATIFY regimen). 
Part 2: Double Blind, randomized, placebo-controlled part 
The primary endpoint is event-free survival (EFS), defined as the time from the 
date of randomization until an EFS event is observed. An EFS event is defined 
as a failure to obtain a complete remission (CR) in induction, relapse after CR, or 
death due to any cause, whichever occurs first. 
The interim and primary efficacy analyses will be the comparison of the 
distribution of EFS between the two treatment arms. The estimated hazard ratio 
(HR) of EFS not censored at stem cell transplantation (SCT) will be calculated 
using Cox regression model stratified according to the 2 stratification factors 
(FLT3 mutation status: ITD allelic ratio <0.7, ITD allelic ratio ≥ 0.7, TKD; and 
regimen: RATIFY regimen, JALSG regimen). In addition, associated 95% Wald 
confidence interval (CI) will be calculated. The success of the study will be 
claimed when estimated HR is less than 1. In addition, for interim analysis, the 
Bayesian predictive probability of (HR for EFS when 36 EFS events are 
documented < 1) given data up to the data cut off for interim analysis > 0.9 also 
need to be satisfied to declare the success of the study. 


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The survival distribution of EFS will be estimated using the Kaplan-Meier 
method. The results will be plotted graphically by treatment arm. The median of 
EFS along with 95% confidence intervals will be presented by treatment arm. 
The interim analysis will be performed when 60 patients are randomized and at 
least 24 EFS events are documented (expected around 14 months from the date 
of first patient to be randomized). This interim analysis will be assessed by a 
Data Monitoring Committee (DMC), however, even if interim success criteria are 
met, the study will be continuing blinded to patients, investigators and monitors 
until the primary analysis and thereafter the study will be unblinded. At the final 
analysis more mature data can be evaluated. In case that 36 EFS events are 
documented before randomization completion, the interim analysis can be 
skipped and Novartis will conduct primary analysis.The primary analysis will be 
performed using the pre-defined cut-off date of 30 November 2020 with the 
number of EFS events documented by this date. The final analysis will be 
performed with a cut-off at 36 months after the start of the study treatment of the 
last patient. After treatment phase, all patients will be followed in the follow up 
phases (for continued remission and survival) until the cut-off at 36 months after 
the start of study treatment of the last patient. 
For all of interim, primary and final analyses, the type I error alpha will not be 
considered because this study will pursue an estimation approach rather than 
formal hypothesis testing in which the criteria for success is based on the 
probability of HR< 1 in favor of midostaurin. 
Refer to Section 10.4.3 and Section 10.4.4 for details on censoring, as well as 
supportive and sensitivity analyses that will be performed for the primary 
endpoint. 
Key words 
PKC412, midostaurin, cytarabine, daunorubicin, acute myeloid leukemia, 
combination treatment, FLT3 


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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
AML, one of the most common types of acute leukemia in adults, is a heterogeneous group of 
neoplasms that is characterized by the presence of acquired mutations as well as cytogenetic 
and epigenetic alterations that mediate disease pathogenesis and determine prognosis. Risk 
stratification in AML is based principally on characterization of cytogenetic abnormalities and 
mutational profiling, and the latter is especially important in patients lacking karyotypic 
abnormalities (Döhner 2017, Arber et al 2016). 
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. 
Approximately 30% of patients with newly diagnosed AML have an activating mutation in the 
FLT3 gene, usually either an internal tandem duplication mutation (ITD, in approximately 20% 
of AML patients), or a point mutation in the activating loop of the tyrosine kinase domain (TKD, 
approximately 6-8% of AML patients); rarely, both occur in the same leukemia (Kayser and 
Levis 2014). 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. FLT3-ITD mutations, particularly when they are present at a high allelic ratio 
relative to wild-type FLT3, are associated with poor prognosis; such leukemias are associated 
with an inferior disease-free survival (DFS) and overall survival (OS) and with a higher risk of 
relapse (Kottaridis et al 2001, Whitman et al 2001, Thiede et al 2002, Pratcorona et al 2013). 
The reported prognostic significance of the FLT3-TKD mutation has been inconsistent. 
Initial therapy for AML in younger patients (generally less than 60 years of age) has a goal of 
inducing a durable complete remission and has changed little in the past three decades. For 
patients with an adequate performance status, initial therapy 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 this approach is 30 to 40% in patients 
under the age of 60 years, and the rate is less than 15% in older patients (Stone et al 2005). 
Patients with AML characterized by poor prognostic features are recommended to enroll into 
clinical trials and/or to undergo stem cell transplantation (SCT) 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- 
SCT compared to chemotherapy alone or autologous SCT (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 following SCT 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) (Brunet et al 2012). Not all patients are eligible 
for transplantation, particularly those of advanced age. SCT is associated with a substantial risk 
of treatment-related complications and post-transplant relapses, particularly in leukemias with 
high risk features such as the FLT3-ITD mutation with a high allelic ratio. Thus, despite the 
availability of SCT therapy for some patients, there remains a high unmet medical need in 
FLT3-mutated AML. 


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The ability to delay or prevent relapses in these patients would be a significant advance beyond 
current treatment. A prolonged duration of remission would provide potentially a major clinical 
benefit by allowing more eligible patients to undergo a SCT. This benefit 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, improving the response rate could also result 
in long-term clinical benefit. Currently there are no approved FLT3-targeted therapies. Because 
of the adverse prognostic impact of FLT3 gene mutations and the lack of effective therapy for 
many patients with this disease, an unmet medical need exists in patients with FLT3-mutated 
AML. 
The CALGB10603 ([CPKC412A2301], RATIFY) trial, which enrolled patients principally in 
North America and Europe < 60 years of age with newly diagnosed FLT3-mutated acute 
myeloid leukemia (AML), showed that midostaurin combined with standard induction and 
consolidation therapy following by single agent midostaurin continuation treatment conferred 
a survival advantage compared to placebo plus chemotherapy. 
The purpose of this present study is to extend these findings in additional patients from countries 
not involved in RATIFY trial and to obtain bridging clinical data in other regions. 
 
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
1.2.1 
Overview of Midostaurin 
1.2.1.1 
Non-clinical experience 
Preclinical pharmacology 
Midostaurin (PKC412, CGP41251) is an orally bioavailable staurosporine analog with potent 
activity against both the FLT3-ITD and FLT3 mutant kinases as well as against wild-type FLT3. 
In addition, it inhibits other molecular targets including several isoforms of protein kinase C, 
KIT, Vascular endothelial growth factor receptor (VEGFR)-2, 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. 
The anti-proliferative effects of midostaurin were demonstrated in cell-based models with 
expression of the FLT3-ITD or FLT3-TKD mutant kinases (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, 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). 


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Pharmacokinetics and drug metabolism 
The oral absorption of [14C]midostaurin in all species was shown to be 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 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 subjects, 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, and the highest radioactivity 
was observed in the liver after an oral dose and in the brown fat, adrenal glands, and liver after 
an intravenous dose. Radioactivity was taken up by the pituitary gland and crossed the blood 
brain barrier. After multiple doses, the radioactivity in tissues was 2-10-fold higher than that 
after a single dose. No melanin binding was observed. [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%). 
Midostaurin undergoes extensive hepatic metabolism through CYP3A4 enzymes which are 
either induced or inhibited by a number of concomitant drugs. Based on in vitro data, 
midostaurin and/or its metabolites have the potential to inhibit and to induce cytochrome P450 
(CYP) enzymes. Therefore, midostaurin may be a victim or a perpetrator of drug-drug 
interactions in vivo. 
 
Pre-clinical toxicology 
Midostaurin has been extensively evaluated in various in vitro systems and in vivo models. 
In the repeat-dose studies, target organs for toxicity were the gastrointestinal (GI) tract (emesis 
in dogs and monkeys, diarrhoea and mucosal alteration), testes (decreased spermatogenesis), 
bone marrow (hypocellularity) and lymphoid organs (depletion/atrophy). The effect on the bone 
marrow and lymphoid organs was accompanied by hematological changes of decreased white 
blood cells, lymphocytes and erythrocytic parameters. An increase in liver enzymes (ALT and 
AST) was seen consistently, without histopathological correlates in rats, and in dogs and 
monkeys in long-term studies of ≥3 months duration. In dogs, a decrease in heart rate, 
prolongation of the P-Q interval, and sporadically occurring atrioventricular blocks was seen in 


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individual animals. All findings were fully reversible or showed a trend towards reversibility. 
In vitro and in vivo mutagenicity tests revealed no genotoxicity. The no observable effect level 
(NOEL) in the 12-month toxicity studies was 3 mg/kg in rat and 1 mg/kg in dog. No 
carcinogenicity studies have been performed. 
In animal studies, midostaurin caused embryo-fetal toxicities, including late embryo-fetal death 
and reduced fetal birth weight, with delays in fetal growth at doses lower that the recommended 
human dose. Effects on fertility and general reproductive toxicity were also found. In some, but 
not all, pre-clinical animal studies, midostaurin induced effects on testes that could potentially 
affect male fertility: degeneration of the seminiferous tubules to atrophy of the testes in rat and 
hypospermatogenesis with oligospermia/aspermia in dog. When recovery was evaluated, these 
effects were at least partially recoverable after 4 weeks out of treatment. This is to be expected 
since spermatogenesis in the dog requires about 40-60 days and full reversibility could not have 
occurred in the 1-month recovery period. In females from rat only, in two studies some adverse 
effects on the reproductive organs were observed: uterine atrophy and follicular effects 
(decrease number of corpora lutea or ovarian follicular distension). These effects could 
potentially affect female fertility. When evaluated, there was recovery in one out of the two 
studies. Of note these findings were observed at exposure multiples below one (i.e. compared 
with exposure in human at therapeutically efficacious dose, 50/100 mg bid). 
In conclusion, non-clinical safety data obtained from various toxicology studies performed with 
midostaurin support its clinical development. For all study participants, the potential adverse 
effects on fertility as they have a likelihood of recovery will be managed via the Informed 
Consent Form (ICF). 
Please refer to the Investigator’s Brochure for additional information. 
 
1.2.1.2 
Clinical experience 
 
Pharmacokinetics and drug metabolism in humans 
Midostaurin is a compound with good absorption and poor solubility. Three of its metabolites 
demonstrated pharmacological activities (the constituent epimers of 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 in concentration 
until reaching a steady-state on Day 28. CGP52421 concentrations do not appear to decline 
significantly such as observed for midostaurin and CGP62221. Midostaurin is rapidly absorbed 
after oral administration, with peak plasma concentrations observed at 1-3 hours post dose. The 
mean apparent volume of distribution of midostaurin (99 L) is higher than that of total body 
water (42 L), indicating a high tissue distribution. Midostaurin is predominantly metabolized 
by CYP3A4 into 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 AUC0-168h, respectively. The compound related materials 
are mainly distributed to plasma and minimally to red blood cells. The median terminal half- 
lives of midostaurin, CGP62221 and CGP52421 in plasma are approximately 20.5, 32.3 and 
471 hours, respectively. The mean apparent plasma clearance (CL/F) was 2.4-3.1 l/h in healthy 
patients. In AML and advanced systemic mastocytosis (advanced SM) patients, population 


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pharmacokinetics (popPK) estimates for clearance of midostaurin- at steady-state were 5.9 l/h 
and 4.4 l/h, respectively. 
The Human Mass Balance study results indicated that fecal 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 approximately 4% of the dose is recovered in 
urine. 
The exposure of midostaurin and its metabolites after single doses was generally similar among 
Caucasians, Asians and Black healthy subjects. 
Although there was a slight decrease or increase of exposure in Blacks and Asians, respectively, 
compared to Caucasians, it is not deemed to be clinically relevant given the overall exposure- 
efficacy and exposure-safety profile of midostaurin. Similar conclusions were drawn from 
population PK analysis, where race (Caucasian vs non-Caucasian) showed no significant impact 
on PK of midostaurin and its active metabolites. 
Additional information can be found in the midostaurin [Investigator’s Brochure]. 
 
Summary of efficacy in clinical studies: midostaurin single agent therapy 
Study [CPKC412A2104] was an open-label Phase II study conducted in 20 patients of 18 years 
and older with FLT3 mutated AML or high risk MDS, and it was designed to evaluate the 
preliminary anti-tumor activity of single agent midostaurin (75 mg tid). The primary endpoint 
of this study was best clinical response (CR and PR). No patient achieved a CR or PR based on 
the investigator assessment. However, the majority (15/20; 75%) of patients had a greater than 
50% reduction in the peripheral blood blast count, and 6/15 (40%) achieved a greater than 50% 
reduction in bone marrow blast count. 
Study [CPKC412A2104E1] was an open-label, randomized Phase II study conducted in 95 
patients of 18 years and older with AML or high risk MDS (FLT3-mutated or FLT3-WT) to 
evaluate the clinical activity of single agent midostaurin. Patients were assigned to receive twice 
daily doses of either 50 or 100 mg until disease progression or the occurrence of unacceptable 
treatment-related toxicity. The primary endpoint of this study was best clinical response 
(CR/PR/MR/MR+BR/BR) (CR=complete response, PR=partial response, MR=minor response, 
BR=blast reduction). Ninety-five patients were enrolled and were included in the intent-to-treat 
(ITT) analyses: 35 in the FLT3-mutated group, and 60 in the FLT3-WT group. The overall 
clinical response rate (proportion of patients with CR, PR, MR+BR, MR or BR) was 71.4% in 
patients with FLT3-mutated AML and 56.1% in patients with FLT3-WT AML. Most of these 
patients had a best response of blast reduction +/- minor response. Overall, similar biological 
activity of midostaurin was observed in patients with mutated FLT3 and in those with wild-type 
FLT3 at either the 50 mg bid or 100 mg bid doses (Fischer et al 2010). 
Study [CPKC412A2104E2] was an open-label Phase I/II study conducted in 29 patients of age 
18 years and older with AML or high risk MDS (FLT3-mutated or FLT3-WT) to evaluate the 
clinical activity of intra-patient dose-escalation of midostaurin up to a maximum of 600 mg/day, 
or concomitant administration of midostaurin 50 mg bid with itraconazole 100 mg bid. Twenty- 
nine patients were enrolled and were included in the ITT analyses: 13 patients in the 
midostaurin+itraconazole arm, and 16 patients in the midostaurin dose escalation arm. All 
patients were diagnosed with AML. The primary efficacy endpoint of this study was best 


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clinical response (CR/PR/MR/MR+BR/BR). In patients with FLT3-mutated AML, five (55.6%) 
patients achieved a clinical response (BR +/- MR) in the midostaurin dose escalation arm, and 
no patient obtained a clinical response in the midostaurin+itraconazole arm. In patients with 
FLT3-WT AML, two (28.6%) patients in the midostaurin dose escalation arm and four (66.7%) 
patients in the midostaurin+itraconazole arm obtained a clinical response; among these, one 
patient in the midostaurin+itraconazole arm obtained a CR. Based on these results, no additional 
benefit was observed by increasing the dosing of midostaurin beyond 100 mg bid or by 
combining midostaurin with itraconazole. 
The collective findings from these studies supported further evaluation of midostaurin in 
combination with chemotherapy in patients with AML. 
 
Summary of efficacy in clinical studies: midostaurin combination therapy 
Study [CPKC412A2106] was a multi-center, open-label Phase Ib study conducted in 69 patients 
aged 18-60 years (19 with FLT3-mutated and 50 FLT3-WT) with newly diagnosed AML to 
evaluate the safety and PK of midostaurin administered in combination sequentially and 
concomitantly with standard induction and consolidation chemotherapy. A higher CR rate was 
reported in AML with a FLT3 mutation compared to FLT3-WT AML (15/19 patients, 78.9% 
vs 24/50 patients, 48.0%, respectively). Among 19 patients with FLT3-mutated AML, 4/6 
(66.7%) in the 100 mg bid arm and 11/13 (84.6%) in the 50 mg bid arm obtained a CR. Single 
agent midostaurin (100 mg bid) was administered either sequentially or concomitantly with 
standard daunorubicin/cytarabine induction therapy followed by consolidation therapy with 
high dose cytarabine. During the study, a high proportion of patients experienced 
gastrointestinal AEs at a dose of 100 mg bid and discontinued the study. Subsequently, the 
midostaurin dose was reduced from 100 mg bid to 50 mg bid to optimize the tolerability of 
midostaurin through protocol amendment. The sequential regimen was also associated with 
improved tolerability. Based on the safety profile from this study, midostaurin 50 mg bid 
administered sequentially with standard induction/consolidation chemotherapy was established 
as the recommended regimen for subsequent studies in patients with AML (Stone et al 2012). 
Study [CPKC412A2301], hereafter referred to as Study [A2301] and as the “RATIFY regimen”, 
is a randomized, double-blind, multi-center, placebo-controlled Phase III study conducted in 
717 patients with newly diagnosed FLT3 mutation positive (ITD or TKD) AML. Patients were 
randomized in a 1:1 ratio (360 patients to the midostaurin arm and 357 to the placebo arm) with 
stratification by FLT3 mutation status (ITD allelic ratio <0.7, ITD allelic ratio ≥ 0.7, or TKD). 
The primary efficacy endpoint was OS non-censored at the time of SCT, and the key secondary 
endpoint was EFS non-censored at the time of SCT. The study met its primary objective: a 
significant improvement in OS was demonstrated with a hazard ratio (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. 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. The efficacy results for midostaurin 
plus chemotherapy were consistently superior to that for placebo plus chemotherapy with 
respect to the CR rate, OS (censored for SCT), DFS, and cumulative incidence of relapse (CIR). 


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Summary of safety in clinical studies 
Midostaurin has been extensively studied in both oncologic and non-oncologic indications as 
well as in a large number of healthy volunteers over the past two decades. 
The largest clinical safety experience for midostaurin has been in two indications: 
• In combination with standard chemotherapy in patients with newly diagnosed FLT3- 
mutated AML 
• As a single agent in patients with advanced systemic mastocytosis (Advanced SM) 
[formerly aggressive systemic mastocytosis (ASM) or mast cell leukemia (MCL) with or 
without an associated hematologic non-mast cell lineage disorder (AHNMD)] 
In the pivotal phase III [A2301] trial of patients with AML, midostaurin or placebo was 
administered in combination with standard induction and consolidation therapy following by 
single agent continuation. 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. 
In this study, the safety profile for both the midostaurin and placebo groups was relatively 
consistent. Most AEs, AEs suspected to be related to study drug, 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 were predominantly 
cytopenias (thrombocytopenia, anemia, neutropenia) and gastrointestinal events (nausea, 
vomiting) compared to those for patients receiving midostaurin monotherapy, as expected from 
the known toxicities of the RATIFY regimen. 
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. Midostaurin did not increase the incidence or 
severity of cytopenias (leukopenia, neutropenia, thrombocytopenia) febrile neutropenia, 
infections or bleeding events and did not negatively impact time to recovery, suggesting that 
adding midostaurin to chemotherapy does not increase the risk for such events. Cytopenias are 
common findings in patients with AML who are treated with chemotherapy (Atallah et al 2007). 
The most frequent non-hematologic grade 3/4 AEs in the midostaurin group were infections 
(device-related), diarrhea, and exfoliative dermatitis; for the placebo group, the most common 
were hypokalemia, diarrhea, and pneumonia. AEs were generally balanced between the two 
treatment arms, with the exception of exfoliative dermatitis and transaminase elevations, which 
occurred more frequently in midostaurin-treated patients. 
Non-fatal cases of cardiac dysfunction, including congestive heart failure, occurred in a small 
proportion of patients (1.3% in both treatment groups). In the advanced SM population, 7.0% 
had cardiac dysfunction, and a few patients had notably decreased LVEF (<45%). 
Pulmonary toxicity/ILD events (primarily pneumonitis) occurred in approximately 14% of 
patients in Study [A2301], with a similar frequency in the midostaurin (including one fatal case) 
and placebo groups. In the advanced SM population, ILD AEs were reported in 3.5% of patients, 
none of which had a fatal outcome. 
Clinical data indicate that strong CYP3A4 inhibitors increase midostaurin steady-state exposure 
2.7 fold, with limited impact on the two major metabolites. In Study [A2301], concomitant 


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moderate or strong CYP3A4 inhibitors were administered to 45% of all patients, primarily in 
the induction and consolidation phases as part of routine antifungal prophylaxis, the midostaurin 
exposure was increased by 1.44 when co-administered with CYP3A4 inhibitors in this study. 
However, a review of the grade 3/4 AE in Study [A2301] showed no clinical difference in the 
incidence or pattern of grade 3-4 AEs between patients receiving CYP3A4 inhibitors and those 
who had not. 
The impact of strong CYP3A4 inducers was investigated in healthy volunteers. The co- 
administration of rifampin (strong CYP3A4 inducer) with midostaurin led to a decrease of 94% 
of midostaurin exposure after a single dose. Prediction of exposures was made based on PBPK 
modeling suggesting a lesser impact at steady-state with a predicted decrease in exposure 
between 34% and 37%. However in absence of clinical evidence in patients at steady-state 
CYP3A4 inducers should be avoided. 
Nonclinical studies demonstrated embryo-fetal toxicity of midostaurin in rats and rabbits, and 
the possibility that midostaurin can cause fetal harm when administered to a pregnant woman 
cannot be excluded. There are no adequate data of midostaurin in pregnant women. Midostaurin 
must not be taken during pregnancy or in women of childbearing potential not using 
contraception. Pregnant women must be advised of the potential risk to the foetus. Women of 
childbearing potential must be advised to use a highly effective method of contraception while 
receiving midostaurin and for four months post study for women because of the long half-life 
(T1/2) of the metabolite, CGP52421 (482 hours). Women using hormonal contraceptives should 
add a barrier method of contraception. 
Sexually active males must use a condom during intercourse while taking drug and for 4 months 
after stopping midostaurin. 
Animal studies showed adverse effects of midostaurin on fertility indices. Advise females and 
males of reproductive potential that midostaurin may impair fertility. 
It is not known whether midostaurin is excreted in breast milk. Transfer of midostaurin and its 
active metabolites was observed in lactating rats. Women taking midostaurin should therefore 
not breast-feed, and such patients are ineligible for this trial. 
Please refer to the [Investigator’s Brochure] for additional information. 
 
2 
Rationale 
2.1 
Study rationale and purpose 
Study [A2301] was conducted predominantly in Europe and North America and showed that 
midostaurin added to standard chemotherapy yielded a statistical improvement in overall 
survival compared to placebo plus chemotherapy (see Section 1 above). The present trial will 
provide additional information regarding midostaurin plus standard-of-care chemotherapy to 
supplement the limited data collected in Study [A2301] from patients in other regions. 
In Japan, a dose-escalation, single-dose, phase I study (study [CPKC412A1101]; hereafter 
referred to as study [A1101]) was conducted to investigate the PK and tolerability of 
midostaurin administered alone in Japanese healthy adults. Overall the PK profiles of 
midostaurin and its metabolites (CGP62221 and CGP52421) in Japanese subjects were in 


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agreement with the results seen in non-Japanese subjects. No deaths or serious adverse events 
were observed in Study [A1101]; AEs that occurred in the study were similar to those in 
previous studies outside Japan, and many of them were mild. Therefore, there appear to be no 
major differences in the tolerability of midostaurin administered alone between Japanese and 
non-Japanese population. 
The safety and efficacy of midostaurin combined with chemotherapy in newly diagnosed FLT3- 
mutated AML has not yet been studied in Japanese patients. In contrast to the regimen used in 
Study [A2301], a standard of care for adult patients up to age 64 years with newly diagnosed 
AML was independently established by the Japan Adult Leukemia Study Group (JALSG) in 
the AML201 study period. It was shown to produce CRs in 70-80% of newly diagnosed AML 
patients (Ohtake 2011, Miyawaki 2011). Approximately 40% of patients in remission survived 
for greater than 5 years without relapse. There is no large clinical experience of midostaurin 
with this chemotherapy regimen (hereafter termed the “JALSG regimen”), and this present 
study will provide needed information regarding this combination in Japanese patients. 
The RATIFY and JALSG regimens both include daunorubicin and cytarabine chemotherapies. 
The doses and administration schedules for these chemotherapies are similar in the two 
regimens, but the JALSG regimen uses a lower dose of cytarabine during induction, a higher 
cumulative dose of daunorubicin during induction, and a higher cumulative dose of cytarabine 
during consolidation (see Table 6-1). 
In summary, this trial will provide needed clinical information about midostaurin in 
combination with standard-of-care chemotherapy in newly diagnosed FLT3-mutated AML in 
populations that were underrepresented in Study [A2301], and it will provide additional 
information in particular within Japan where an alternative regimen is typically the treatment 
standard. Outside Japan, where the RATIFY regimen is one standard of care for adults with 
newly diagnosed AML, midostaurin will be combined with this chemotherapy standard. 
 
2.2 
Rationale for the study design 
By assessing the safety and efficacy of midostaurin versus placebo in patients from countries 
not involved in study [A2301] with newly diagnosed FLT3 mutated AML (treated with 
intensive induction chemotherapy and consolidation therapy), this study will allow a side-by- 
side comparison to patients from Study [A2301]. The justification for randomization is that the 
primary endpoint, event free survival, can be affected by patient related factors in this 
previously underrepresented (in Study [A2301]) patient population, and will be best assessed 
through a randomized comparison to placebo. 
Patients who have AML with a FLT3 mutation will be randomly assigned in a 1:1 ratio to one 
of two study treatments within six strata, which are defined by: 
1. RATIFY or JALSG regimen, and 
2. FLT3 genotype: FLT3-TKD, FLT3-ITD with a mutant signal ratio < 0.7, or FLT3-ITD 
with a mutant signal ratio ≥ 0.7. 
Stratified randomization will be performed as follows: each patient will be classified into the 
corresponding stratum according to the FLT3 genotype and according to the treatment regimen 
that is selected, and then either midostaurin or placebo will be assigned to the patient randomly 


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using a block randomization scheme within each stratum, thereby ensuring balance of the 
treatment groups with respect to the FLT3 genotype and to the treatment regimen. 
Patients will be treated with one or two cycles of remission induction with daunorubicin and 
cytarabine, followed by sequential midostaurin or placebo. Patients who demonstrate a CR 
during either induction cycle will receive three or four cycles as tolerated of high-dose 
cytarabine consolidation chemotherapy with sequential midostaurin/placebo as assigned (in 
Japan, only patients will receive 3 cycles of consolidation as per their standard of care). If a 
patient continues to be in remission, continuation therapy for up to twelve 28-day cycles will 
be administered with midostaurin/placebo as assigned. Patients who receive SCT therapy will 
be removed from study treatment but will be followed for continued remission and for survival. 
In countries other than Japan, the study will begin with the randomized part. However, in Japan 
a safety evaluation part will precede advancement to the randomized part of the study. The 
purpose of this safety evaluation part will be to provide an assessment of the safety of 
midostaurin combined with chemotherapy in Japanese patients. Either the RATIFY regimen or 
the JALSG regimen may be used in Japan in combination with midostaurin. Given the 
prevailing practice pattern in Japan, it is anticipated that the majority of patients will receive 
midostaurin with the JALSG regimen. A committee of independent medical experts (hereafter 
termed the “Independent Safety Committee”) will assess the safety experience of the 
midostaurin plus chemotherapy in Japanese patients before additional patients are enrolled into 
the randomized part in Japan. If the Independent Safety Committee determines that midostaurin 
plus chemotherapy is safe and adequately tolerated in Japanese patients, then in this country the 
trial will advance to the randomized part. 
 
2.3 
Rationale for dose and regimen selection 
The recommended dose of midostaurin in combination with standard chemotherapy for newly 
diagnosed AML was established in the [CPKC412A2106] trial described in Section 1.2.1.2, 
which indicated that midostaurin 50 mg administered twice daily in sequential combination 
with chemotherapy was the best tolerated regimen. Study [A2301] confirmed the safety and 
efficacy of the midostaurin combination in patients with newly diagnosed FLT3 mutated AML. 
In addition, preliminary analyses suggest that midostaurin exposure is similar between Asian 
and Caucasian populations. 
 
2.4 
Rationale for choice of combination drugs 
For all regions participating in this bridging study, midostaurin/placebo will be evaluated in 
combination with the chemotherapy used in Study [A2301], the “RATIFY regimen”. 
In addition, in Japan, physicians will have the option of treating patients using midostaurin 
(midostaurin or placebo in the randomized part) in combination with the JALSG regimen, which 
is the most common therapy used in Japan for adults with newly diagnosed AML (see Section 
2.2). Physicians in Japan may also select the RATIFY regimen as the chemotherapy 
combination. Patients will be enrolled first in a safety evaluation part to evaluate the safety of 
midostaurin plus chemotherapy in Japanese patients. 
In Japan, either the RATIFY or JALSG regimens will be used. In other countries, only the 
RATIFY regimen will be used. 


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2.5 
Rationale for age range of enrolled patients 
Study [A2301] enrolled patients from age 18 to less than 60 years and showed that midostaurin 
combined with chemotherapy was adequately tolerated (Stone 2015). 
Since the time that Study [A2301] was developed, there has been an emerging awareness that 
older patients (age ≥ 60 years) with newly diagnosed AML can benefit from intensive remission 
induction chemotherapy (Juliusson et al 2009, Juliusson et al 2011). AML occurs mainly in 
patients aged 65 years or older, median age at diagnosis is between 65 and 72 years and this 
median age is increasing (Juliusson et al 2009). 
The current standard of care is not to limit intensive induction chemotherapy to patients <60 
years of age, taking into account other important clinical parameters including disease factors, 
comorbidities, fitness or performance status. The United States National Comprehensive 
Cancer Network (US NCCN) Guidelines (O’Donnell et al. 2017) recommends for older patients 
(age>60 years) with AML, using patient performance status, in addition to adverse features and 
comorbid conditions, to select treatment options rather than to rely on a patient’s chronologic 
age alone. Similar treatment recommendations are offered by the European Leukemia Network 
(Döhner et al 2017). As the basis for the European LeukemiaNet (ELN) recommendations, a 
model is referenced (Sorror et al 2017) concluding that intensive therapy leads to better long 
term survival than does non-intensive therapy even in older patients with significant co- 
morbidities. Hence, age alone should not be the decisive and sole determinant to guide therapy 
(Döhner et al 2017). In Japan, a similar trend in terms of treatment approach is reported 
(Miyawaki 2017), suitability to chemotherapy is judged by the treating physician and intensive 
treatment including transplantation is now sometimes performed up to the age 70 years. 
The presence of FLT3 mutations is associated with very poor survival in both younger and older 
patients. [ADE02T] study was conducted to investigate the efficacy and safety of midostaurin 
combined with chemotherapy in FLT3 mutated AML patients up to 70 years. The analysis of 
interim ADE02T results from the first 245 patients enrolled (median age: 53.6 years old, range 
20 – 69) showed that overall the safety and tolerability of the treatment in ADE02T was very 
similar compared to [A2301] both in patients >60 and ≤60 years. A similar pattern of superior 
OS and EFS was observed both in patients >60 and ≤60 years of age in Study ADE02T. In order 
to better define efficacy of midostaurin for patients ≥60 years of age from the ADE02T trial, a 
propensity score has been prepared in order to compare ADE02T to a large cohort of historical 
controls with FLT3-ITD mutations. This analysis shows an OS and EFS midostaurin treatment 
benefit in patients regardless of age (≥60 or <60 years). In conclusion, the available evidence 
indicates that midostaurin, added to chemotherapy, is well tolerated both in younger and older 
patients with FLT3-mutated AML, and may provide additional benefit in patients who are 
eligible for intensive chemotherapy regardless of age. 
The efficacy, safety and tolerability of intensive induction chemotherapy in patients ≥60 years 
is better understood and clinical experience with midostaurin is more established in the older 
patients; this the reason why this study will enroll patients up to ≤70 years. 
 
2.6 
Rationale for choice of comparator drugs 
As discussed in Section 2.2 above, patients treated in the midostaurin plus chemotherapy group 
will be compared to those treated in the placebo plus chemotherapy group. This comparator will 


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provide the best means of determining the safety and incremental clinical activity of 
midostaurin in the setting of standard chemotherapy with the RATIFY or JALSG regimens. 
 
 
2.8 
Risks and benefits 
The safety of midostaurin has been evaluated in an extensive clinical program including more 
than 1800 patients, including the large, placebo-controlled Study [A2301] of midostaurin in 
combination with chemotherapy, two Phase II studies in advanced SM, 9 other Phase I-II studies 
conducted in patients with AML and other indications, and clinical pharmacology trials. 
The potential benefit of midostaurin combined with chemotherapy in this setting is suggested 
by Study [A2301], which showed that in comparison with placebo plus chemotherapy there was 
a statistically significant improvement in OS and EFS (see Section 1.2.1.2), and other endpoints 
were consistent in showing the treatment benefit of midostaurin. 
All patients developed one or more grade 3-4 cytopenias during chemotherapy, which are 
common findings in patients with AML who are treated with chemotherapy (Atallah et al 2007). 
The main non-hematologic adverse effects of midostaurin were GI disturbances, primarily 
nausea, vomiting and diarrhea, and these were observed consistently in clinical trials with 
midostaurin. This is consistent with the toxicity profiles of the backbone chemotherapy drugs: 
reported in >50% of AML patients having intensive chemotherapy despite the use of anti-emetic 
therapy (Lopez-Jimenez et al 2006). 


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Midostaurin undergoes extensive hepatic metabolism through CYP3A4, and midostaurin and/or 
its metabolites have been shown to inhibit and to induce CYPP450 enzymes in vitro. 
Nonclinical studies demonstrated embryo-fetal toxicity of midostaurin in rats and rabbits, and 
the possibility that midostaurin can cause fetal harm when administered to a pregnant woman 
cannot be excluded. There are no adequate data of midostaurin in pregnant women. 
It is not known whether midostaurin is excreted in breast milk. Transfer of midostaurin and its 
active metabolites was observed in lactating rats. Women taking midostaurin should therefore 
not breast-feed, and such patients are ineligible for this trial. 
 
3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below. 


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Table 3-1 
Objectives and related endpoints 
 
Objective 
Endpoint 
Analysis 
Primary 
Safety Evaluation part (Part 1, Japan only) 
Section 10.4 
To Evaluate the safety and tolerability of midostaurin 
in combination with daunorubicin/cytarabine induction 
and high-dose cytarabine consolidation in Japanese 
patients with newly diagnosed AML. 
Incidence and severity of Safety Events, defined as death or serious adverse 
event leading to treatment discontinuation that occurs on or before Day 21 of the 
first Consolidation cycle and that is determined by the Independent Safety 
Committee to be definitely or probably related to midostaurin. 
Double-blind, randomized, placebo-controlled (Part 2) 
To Evaluate the efficacy based on event-free survival 
(EFS) of midostaurin versus placebo in combination 
with daunorubicin/cytarabine induction, with high-dose 
cytarabine consolidation, and with midostaurin single 
agent continuation therapy in newly diagnosed 
patients with FLT3-mutated AML. 
Event-free survival (EFS) defined as the time from the date of randomization until 
an EFS event is observed. An EFS event is defined as a failure to obtain a CR 
within induction 2, relapse after CR, or death due to any cause, whichever occurs 
first. 
Secondary 
Randomized part (Part 2) 
Determine overall survival (OS) in the two treatment 
groups 
Overall survival (OS), defined as the time from the date of randomization to date 
of death due to any cause. 
Section 10.5.2 
Determine rate of complete remission (CR) in the two 
treatment groups 
CR rate, defined as the proportion of patients with a CR according to Cheson 
criteria, at various timepoints. 
Determine cumulative incidence of relapse (CIR) in 
the two treatment groups 
CIR (only for patients who have achieved CR after study treatment initiation), as 
measured from the date of first CR to relapse or death due to AML, whichever 
occurs first. 
Evaluate safety of midostaurin compared to placebo 
in combination with chemotherapy and as single 
agent continuation therapy 
Frequency/severity of AEs, ECG and laboratory abnormalities. 
Section 10.5.3 
Evaluate the pharmacokinetics of midostaurin and its 
two major metabolites CGP52421 and CGP62221 
Pharmacokinetic parameters for midostaurin and two major metabolites 
CGP52421 and CGP62221. 
Section 10.5.4 


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Objective 
Endpoint 
Analysis 
Determine the effect of study treatment on quality of 
life 
European Organization for Research and Treatment of Cancer (EORTC) QLQ- 
C30 total score and functional scales scores (scores and absolute change from 
baseline at each scheduled assessment). 
PGIC score as frequencies and percentages by scheduled timepoint. 
Section 10.5.5 


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4 
Study design 
4.1 
Description of study design 
This study is a phase II, multi-center trial consisting of 2 parts. 
• Part 1: open label, safety evaluation part in Japan only (minimum of three evaluable 
patients) 
• Part 2: double-blind, randomized, placebo-controlled part (60 patients) 
Part 1 in Japan and Part 2 outside Japan will be conducted in parallel. At the completion of Part 
1, and depending on the findings of the safety evaluation, the trial in Japan will advance to Part 
2. 
 
4.1.1 
Part 1: Safety evaluation part 
The part 1 will be conducted to evaluate the safety and tolerability of midostaurin in 
combination with daunorubicin/cytarabine induction and high-dose cytarabine consolidation in 
Japanese patients. Data from the part 1 will be reviewed by an Independent Safety Committee 
designated by the Sponsor (Figure 4-1) 
Patients will be enrolled into the study irrespective of leukemia FLT3 genotype (i.e., patients 
with either FLT3-WT or FLT3-mutated AML will be eligible). 
The safety evaluation period will begin on Day 1 of the first induction cycle (Cycle 1 Day 1) 
and will continue until Day 21 of the first consolidation cycle. The period will allow for an 
assessment of the safety of midostaurin with chemotherapy throughout induction and will 
provide also an assessment of Safety Events (for example, CNS neurotoxicity and ocular 
toxicity) specific to consolidation with high dose cytarabine. The first safety review by the 
Independent Safety Committee will take place when at least three evaluable patients have 
completed the safety evaluation period without a potential Safety Event or have experienced a 
potential Safety Event within this period. A Safety Event is defined as death or serious adverse 
event leading to treatment discontinuation during the safety evaluation period and that is 
determined by the Independent Safety Committee to be definitely or probably related to 
midostaurin. All potential deaths and treatment discontinuations due to serious adverse events 
will be adjudicated by the Independent Safety Committee; it will take into consideration the 
attribution of the event by the investigator, but in its decision-making for trial conduct the 
attribution of event by the Independent Safety Committee will prevail. 
The Independent Safety Committee will review all available safety data in patients from Japan 
up to the time of the safety review data cut-off date. After determining whether each death or 
serious adverse event leading to treatment discontinuation during the safety evaluation period 
meets criteria for a Safety Event, it will consider this tabulation in combination with the entire 
safety experience in Japanese patients to determine the ongoing conduct of the trial. 
The Independent Safety Committee will be provided through its charter with guidelines for 
determining the conduct of the trial: 


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• If one Safety Event occurs among the first three patients enrolled during the safety 
evaluation period, then the Independent Safety Committee will determine whether an 
additional cohort of three patients should be enrolled into the part 1. 
• If there is no Safety Event among the first three evaluable patients or no more than one 
Safety Event among the first six evaluable patients during the safety evaluation period, 
then the Independent Safety Committee will determine whether the trial may advance to 
the part 2 in Japan. 
• If two or more Safety Events are observed in the first three or six evaluable patients, the 
Independent Safety Committee will determine whether conduct of the trial in Japan should 
be terminated without advancement to the part 2. The Independent Safety Committee may 
determine that additional information is needed through continued recruitment of patients 
into the part 1 before making a final determination regarding advancement to the part 2 or 
termination of the study in Japan. 
Although the Independent Safety Committee will consider these guidelines in its determination 
of continuing study conduct in Japan, it will also take into consideration the individual 
circumstances of the Safety Events and will make use of the clinical judgement of the 
Independent Safety Committee members. 
Patients in the part 1 in Japan may be treated with midostaurin in combination with the JALSG 
or RATIFY regimen. Although it is anticipated that most patients would be treated in Japan 
with the JALSG regimen, there is no required minimum number of patients to be treated with 
either chemotherapy regimen. Both regimens may contribute to the overall safety evaluation, 
or the Independent Safety Committee may consider during its deliberation potential differences 
in the two combination regimens. 
Prior to the decision of the Independent Safety Committee to initiate the part 2 of the trial (if 
applicable), patients in the part 1 who remain in remission will continue to be treated according 
to the study protocol. If a decision is made by the Independent Safety Committee to defer 
initiation of the part 2 in Japan or to suspend treatment of patients in Japan, then the continued 
treatment with midostaurin of patients already enrolled in the part 1 will be determined by the 
Study Steering Committee, the individual investigators, and the Sponsor, and the decision will 
take into consideration the findings of the Independent Safety Committee. 


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Figure 4-1 
Independent Safety Committee review in Part 1 safety evaluation part 
(Japan only) 
 
 
4.1.2 
Part 2: Randomized Part 
For the part 2 of the study, the start of patient enrollment in countries outside Japan will be 
concurrent with the start of the part 1 in Japan. The part 2 in Japan will begin only after the 
Independent Safety Committee agrees that midostaurin in combination with chemotherapy is 
adequately tolerated in Japanese patients. Novartis will report the decision to the full Study 
Steering Committee (Section 8.7). 
Patients meeting all eligibility criteria (except FLT3 mutation) may begin the study treatment 
with chemotherapy. The FLT3 mutation status will be evaluated in a Novartis designated 
laboratory. 
• Patients who are determined to have AML with a FLT3 mutation (ITD and/or TKD) will 
be randomized on Cycle 1 Day 8 (first cycle of induction therapy) and will be assigned to 
midostaurin or placebo by using a stratified randomization according to FLT3 mutation 
and treatment regimen (see Section 2.2). 
• Patients who are determined to have AML without a FLT3 mutation or with an unknown 
FLT3 mutation status by Cycle 1 Day 8 will be discontinued from the treatment. 
Outside Japan, only the RATIFY regimen will be used. 
During Part 1 (implemented in Japan only), safety and tolerability of midostaurin with the 
JALSG or with the RATIFY regimen will be assessed. There is no requirement for a minimum 
number of patients treated with each regimen. It is therefore possible, for example, that Part 1 
will be completed only with patients treated with JALSG or only with patients treated with 
RATIFY. If the ISC endorses proceeding to Part 2, then investigators in Japan may choose 


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either RATIFY or JALSG for future patients. Once patients are enrolled in the study, their 
regimen must not be switched during the course of the study. 
The study will include: 
• Screening phase (7 days); 
• Treatment phase composed of up to 18 cycles of midostaurin/placebo treatment in 
combination with chemotherapy (daunorubicin and cytarabine) during induction and 
consolidation and alone during continuation and 30 days safety follow up from last dose 
of study treatment (daunorubicin or cytarabine or midostaurin/placebo); 
• Follow up phase for continued remission and survival 
Refer to Figure 4-2 for study design. 
Figure 4-2 
Overview of Randomized Part (Part 2) 
 
 
4.1.2.1 
Screening phase 
Patients who provided written informed consent will be screened for eligibility during the 
period up to 7 days immediately prior to starting chemotherapy (daunorubicin and cytarabine). 
The patient will be randomized at Day 8 and will receive either midostaurin or placebo only if 
FLT3 status is mutated. 
During the screening phase the investigator must: 
• Obtain signed informed consent from the patient prior to any study procedures 
• Assess the inclusion and exclusion criteria as detailed in Section 5 
• Perform all screening procedures as detailed in Table 7-1 
Results of all screening/baseline evaluations must be reviewed by the investigator or his/her 
designee prior to enrollment of each patient into the study to ensure that all inclusion and 
exclusion criteria are satisfied. 


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The diagnosis of AML by BMA may be confirmed before or during the screening period. In 
case of dry tap (failure to obtain bone marrow after BMA attempts), bone marrow biopsy can 
be used for confirming AML diagnosis; alternatively peripheral blood (showing ≥20% blasts) 
may be used at investigator’s discretion if bone marrow biopsy may delay treatment initiation. 
4.1.2.2 
Treatment phase 
Induction therapy 
All screened patients will start induction therapy with chemotherapy (daunorubicin and 
cytarabine) from Day 1 to Day 7, while the FLT3 mutation status is being determined. 
An Interactive Response Technology (IRT) system will be used to randomize patients to the 
study treatment groups and the patient eligibility checklist will be embedded into the IRT 
randomization process. 
Only randomized patients (with FLT3 mutation) will receive midostaurin/placebo, orally twice 
a day, on days 8 to 21. 
Patients who achieve CR already with induction cycle 1 will go directly to consolidation therapy 
without a second cycle of induction therapy. Patients who do not achieve CR with one cycle of 
induction will receive a second induction cycle with same treatment than in cycle 1. 
Patients not achieving CR after induction 2 will discontinue study treatment and will be 
followed in safety follow up and survival follow-up. 
 
Consolidation therapy 
Patients who achieved a CR after 1 or 2 cycles of induction will receive consolidation therapy 
with 3 cycles of high-dose cytarabine for JALSG regimen and 4 cycles of high-dose cytarabine 
as tolerated for RATIFY regimen. 
Patients will receive midostaurin/placebo, orally twice a day, on days 8 to 21 of each cycle. 
Each consolidation cycle will begin within two weeks following hematopoietic recovery (ANC 
≥ 1.0 x 109/L, platelet count ≥ 100 x 109/L) but no sooner than four weeks from the beginning 
of the previous cycle. 
For patients of age 60 years or older at the time of study entry, the dose of cytarabine may be 
reduced at the discretion of the investigator to 1500 mg/m2/dose for JALSG regimen and to 
1000-1500 mg/m2/dose for RATIFY regimen. 
Continuation therapy 
After hematopoietic recovery (ANC ≥ 1.0 x 109/L, platelet count ≥ 100 x 109/L) following the 
final cycle of consolidation but no sooner than 14 days after the last dose of midostaurin/placebo 
during the last consolidation cycle, patients who maintain a CR will receive up to 12 cycles (28 
days/cycle) of continuous therapy with midostaurin or placebo twice a day. 
Study treatment will continue until completion of 12 cycles of continuation therapy, persistent 
AML, relapse, intolerable toxicity, withdrawal of consent by the patient, lost to follow up, death, 
or the sponsor terminates the study, whichever is earlier. 


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Safety will be assessed in this treatment phase for each patient until 30 days after the end of 
treatment (EOT) and will include routine safety monitoring except in case of death, loss to 
follow up or withdrawal of consent. 
 
4.1.2.3 
Follow up phases 
The follow-up period will comprise the following: 
 
Post treatment follow-up 
During the post treatment follow-up, use of subsequent anti-neoplastic cancer therapies (i.e. 
surgery, SCT, radiotherapy, local and systemic anti-neoplastic medications) initiated after study 
treatment discontinuation will be recorded. 
Following the end of study treatment for any reason other than persistent AML, relapse, 
withdrawal of consent, death, or loss to follow up, all patients will continue to be assessed for 
relapse i.e. every 2 months during years 1 and 2, every 3 months on year 3 and 4 and then yearly 
and at time of relapse until relapse, withdrawal of consent, death, loss to follow up, or end of 
study, whichever is earlier. For further details see Section 7. 
 
Survival follow up 
Patients who discontinued study treatment due to persistent AML or relapse and the post 
treatment follow-up phase due to relapse will enter a follow-up period during which survival 
will be recorded every 3 months (see Section 4.3). Survival information can be obtained by 
clinical visits or telephone calls or other means until death, withdrawal of consent, loss to 
follow-up or end of study, whichever is earlier. 
During the survival follow-up, subsequent anti-neoplastic therapies initiated after 
discontinuation of study treatment will be reported until death, withdrawal of consent, loss to 
follow-up or end of study, whichever is earlier. 
 
4.2 
Timing of interim analyses and design adaptations 
During the part 1, the Independent Safety Committee will evaluate all available safety data from 
patients treated in Japan to determine if the midostaurin combination with chemotherapy is safe 
and is adequately tolerated in Japanese patients. All patients enrolled in part 1 will be listed and 
reviewed irrespective of the combination treatment (JALSG or RATIFY regimen). For 
additional information, see Section 4.1 and Section 10.7. 
During the part 2, an interim analysis for efficacy will be conducted when 60 patients are 
randomized and at least 24 EFS events are documented (expected around 14 months from the 
date of first patient randomized assuming the recruitment period as 14 months). This interim 
analysis will be assessed by a DMC, however, even if interim success criteria are met, the study 
will be continuing blinded to patients, investigators and monitors until the primary analysis and 
thereafter the study will be unblinded. At the final analysis more mature data can be evaluated. 
In case that 36 EFS events are documented before randomization completion, the interim 
analysis can be skipped and Novartis will conduct primary analysis. For detailed information, 
please refer to Section 10.7. 


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4.3 
Definition of end of study 
The end of study will occur at the latest 36 months after the start of the study treatment for the 
last patient. All patients will remain in post-treatment or survival follow-up until the data cut- 
off date of the final analysis, and all available data will be analyzed. 
 
4.4 
Early study termination 
The study may be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient 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 a discontinued or 
withdrawn patient. 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 IRBs and/or ECs of the early termination of 
the trial. 
 
5 
Population 
5.1 
Patient population 
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study. 
 
5.2 
Inclusion criteria 
Patients eligible for inclusion in this study must meet all of the following eligibility criteria: 
1. Diagnosis of AML (≥ 20% blasts in the bone marrow based on WHO 2016 classification 
(Arber et al 2016). Patients with APL (acute promyelocytic leukemia) with PML-RARA 
are not eligible 
2. Documented presence of an ITD and/or TKD activating mutation in the FLT3 gene, as 
determined by analysis in a Novartis designated laboratory 
 
An exception will be patients who are enrolled into the part 1 in Japan, who may be 
treated with midostaurin irrespective of AML FLT3 genotype 
3. Age ≥ 18 years, ≤ 70 years of age 
4. AML patients with a history of antecedent myelodysplasia (MDS) remain eligible for 
treatment on this trial but must not have received prior cytotoxic therapy (e.g., azacytidine 
or decitabine) 
5. Patients must meet the following laboratory value criteria that indicate adequate organ 
function at the screening visit: 
• Estimated (by Cockcroft-Gault) creatinine clearance ≥ 30 ml/min 
• Total bilirubin ≤ 1.5 x ULN, except in the setting of isolated Gilbert syndrome 
• Aspartate transaminase (AST) ≤ 3.0 x ULN 
• Alanine transaminase (ALT) ≤ 3.0 x ULN 
6. Written informed consent must be obtained prior to any screening procedures. 


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For patients in Japan less than 20 years of age, written consent is required from the patient 
as well as from their legal representative. 
7. Suitability for intensive chemotherapy in the judgment of the investigator (Miyawaki 
2017, O’Donnell et al 2017, Döhner et al 2017) 
 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Neurologic symptoms suggestive of CNS leukemia unless CNS leukemia has been 
excluded by a lumbar puncture. Patients with CSF fluid positive for AML blasts are not 
eligible. 
2. Developed therapy-related AML after prior radiotherapy (RT) or chemotherapy for 
another cancer or disorder 
3. Isolated extramedullary leukemia (please refer to Section 7.2.2.1) 
4. Known hypersensitivity to midostaurin, cytarabine or daunorubicin or to any of the 
excipients of midostaurin/placebo, cytarabine or daunorubicin 
5. 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 
6. Prior treatment with a FLT3 inhibitor (e.g., midostaurin, quizarbinib, sorafenib) 
7. Patients who take strong CYP3A4/5 enzyme inducing drugs or strong CYP3A4/5 enzyme 
inducing herbal supplements (see Appendix 2) unless they can be discontinued or replaced 
prior to enrollment 
8. Chemotherapy for leukemia or myelodysplasia. However, the following prior therapies are 
allowed: 
a. Emergency leukapheresis 
b. Emergency treatment for hyperleukocytosis with hydroxyurea or low-dose cytarabine 
for ≤ 7 days 
c. Cranial radiotherapy (RT) for central nervous system (CNS) leukostasis (one dose 
only) 
d. Hematopoietic growth factor/cytokine support; other supportive therapy including 
antibiotics at the discretion of the investigator 
9. Any surgical procedure, excluding central venous catheter placement or other minor 
procedures (e.g., skin or bone marrow biopsy) within 14 days prior to Day 1 
10. 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 
11. Abnormal chest X-ray unless the abnormality represents a non-active, or non-clinically 
significant finding, such as scarring or a lung infection which is controlled by treatment 
12. Known impairment of gastrointestinal (GI) function or GI disease that might alter 
significantly the absorption of midostaurin 
13. Known confirmed diagnosis of human immunodeficiency virus (HIV) 


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14. Evidence of active HBV or HCV viral infection (confirmed by peripheral blood viral 
load). Patients with positive serology results indicative of high risk for viral reactivation 
must have negative viral load results within 28 days prior to Day 1. 
15. Cardiac or cardiac repolarization abnormality, including any of the following: 
• History of myocardial infarction (MI), angina pectoris, coronary artery bypass graft 
(CABG) within 6 months prior to Day 1 
• Clinically significant 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 
• QTcF at screening > 470 ms 
• Long QT syndrome, family history of idiopathic sudden death or congenital long QT 
syndrome, or any of the following: 
• Risk factors for torsades de pointe (TdP) including uncorrected hypokalemia or 
hypomagnesemia, history of cardiac failure, or history of clinically 
significant/symptomatic bradycardia 
• Concomitant medication(s) with a ''Known risk of Torsades de Pointes'' per 
wwwqtdrugs.org that cannot be discontinued or replaced safely with an 
alternative medication 
• Inability to determine the QTcF interval 
16. Pregnant or nursing (lactating) women 
17. 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 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 
• 
In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment 


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It is currently unknown whether midostaurin may reduce the effectiveness of hormonal 
contraceptives; therefore, females using systemically acting 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 
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 
18. Sexually active males unless they use a condom during intercourse while taking the drug 
during treatment and for 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 
19. Patients/parents unwilling or unable to comply with the protocol 
 
6 
Treatment 
6.1 
Study treatment 
In this study, the term “Study drug” indicates midostaurin or placebo. 
The term “Study treatment” 
indicates treatment with daunorubicin, cytarabine, or 
midostaurin/placebo. 
In the part 1, patients may be enrolled irrespective of their FLT3 mutation status. 
In the part 2, induction therapy may begin while the FLT3 mutation status is being determined. 
A patient may not receive midostaurin or placebo unless eligibility has been confirmed based 
on the presence of a FLT3 mutation as determined by the Novartis designated laboratory. If the 
patient is not shown to have a qualifying FLT3 activating mutation, then the patient will be 
discontinued from treatment by Cycle 1 Day 8 of the first cycle of induction and will not receive 
study drug. 
 
6.1.1 
Dosing regimen 
On Day 1 of study treatment, the first dose of induction chemotherapy will be administered, 
and each day is 24 hours in length. 
Daunorubicin and cytarabine are approved drugs. 
Daunorubicin and cytarabine will be supplied globally by Novartis or supplied locally as per 
local practice if agreed and approved by the global clinical team. Please refer to the Package 
Insert for complete guidelines for administration and for safety monitoring guidelines. 
The dosage of daunorubicin 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, and sites will use a formula for BSA 
calculation according to the local standard. 


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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. Failure to use actual body weight in the calculation of drug 
dosages will be considered as a protocol deviation. Physicians who are uncomfortable with 
administering chemotherapy dose based on actual body weight should not enroll obese patients. 
 
6.1.1.1 
Induction and Consolidation therapies for JALSG Regimen (Japan 
only) 
 
JALSG Remission Induction: 
• Cytarabine 100 mg/m2/day will be administered by continuous intravenous infusion 
(CIVI) on Days 1-7 (168 hour infusion). 
• Daunorubicin 50 mg/m2/day will be administered intravenously by IV push (IVP) or 
short (30 minutes) infusion on Days 1-5. 
• Study drug (midostaurin 50 mg [two 25 mg capsules] or placebo [2 capsules]) will be 
administered twice per day by mouth on Days 8-21. 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 sample and prior to 
post-dose PK samples, when instructed by the study staff. Each 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 gelatin capsules should be removed from the blister pack only 
shortly prior to administration. The patient may notice a strong odor when he/she opens the 
blister card. No worry, this is normal. The odor is due to a chemical in the capsules 
interacting with a chemical in the blister card foil. The capsules are not affected by this and 
the odor will go away shortly after opening the blister card. More details are enclosed within 
the Investigator Brochure please refer to it. 
 
Response assessment: see Section 7.2.1 
 
JALSG Second Remission Induction: 
For patients who do not achieve a CR in their first remission induction treatment, a second 
remission induction will begin no earlier than Day 24 and ≥ 3 days after completing 
midostaurin/placebo (whichever is latest). 
• Cytarabine 100 mg/m2/day will be administered by continuous intravenous infusion 
(CIVI) on Days 1-7 (168 hour infusion). 
• Daunorubicin 50 mg/m2/day will be administered intravenously by IV push (IVP) or 
short (30 minutes) infusion on Days 1-5. 


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• Study drug (midostaurin 50 mg [two 25 mg capsules] or placebo [2 capsules]) will be 
administered twice per day by mouth on Days 8-21 as described above for JALSG 
remission induction midostaurin/placebo. 
 
• Response assessment: see Section 7.2.1 
JALSG Remission Consolidation (3 Cycles): 
Patients who achieve a CR after remission induction will receive consolidation therapy with 
midostaurin/placebo + chemotherapy according to their initial treatment assignment. 
Patients will receive three cycles of consolidation therapy. 
Each cycle of consolidation therapy will comprise: 
• High-dose cytarabine (HiDAC) 2000 mg/m2 will be administered by intravenous 
infusion over 3 hours every 12 hours on Days 1-5. Serial neurologic evaluations will be 
performed before and following the infusion of high-dose cytarabine. For patients of age 
60 years or older at the time of study entry, the dose may be reduced as an option to 1500 
mg/m2/dose at the discretion of the investigator. 
• Ocular or systemic administration of corticosteroid therapy for prophylaxis against 
corneal toxicity due to high-dose cytarabine is required. Dosing and administration should 
adhere to local standard of care. 
• Study drug (midostaurin 50 mg [two 25 mg capsules] or placebo [2 capsules]) will be 
administered twice a day by mouth on Days 8-21 as described above for JALSG remission 
induction midostaurin/placebo. 
Each consolidation cycle will begin within two weeks following hematopoietic recovery (ANC 
≥ 1.0 x 109/L, platelet count ≥ 100 x 109/L) but no sooner than four weeks from the beginning 
of the previous cycle. At the end of the final consolidation cycle, a bone marrow examination 
will be performed to evaluate for continued remission. 
 
6.1.1.2 
Induction and Consolidation therapies for RATIFY regimen (for all 
countries): 
 
RATIFY Remission 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 will be administered intravenously by IV push (IVP) or 
short (30 minutes) infusion on Days 1-3. 


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• Study drug (midostaurin 50 mg [two 25 mg capsules] or placebo [2 capsules]) will be 
administered twice per day by mouth on Days 8-21. 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 sample and prior to 
post-dose PK samples, when instructed by the study staff. Each 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 gelatin capsules should be removed from the blister pack only 
shortly prior to administration. The patient may notice a strong odor when he/she opens 
the blister card. No worry, this is normal. The odor is due to a chemical in the capsules 
interacting with a chemical in the blister card foil. The capsules are not affected by this 
and the odor will go away shortly after opening the blister card. 
 
Response assessment: see Section 7.2.1. 
 
RATIFY Second Remission Induction: 
For patients who do not achieve a CR in their first remission induction treatment, a second 
remission induction will begin no earlier than Day 24 and ≥ 3 days after completing 
midostaurin/placebo (whichever is latest). 
• 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 will be administered intravenously by IV push (IVP) or 
short (30 minutes) infusion on Days 1-3. 
• Study drug (midostaurin 50 mg [two 25 mg capsules] or placebo [2 capsules]) will be 
administered twice per day by mouth on Days 8-21 as described above for RATIFY 
remission induction midostaurin/placebo. 
Response assessment: see Section 7.2.1 
 
RATIFY Remission Consolidation (4 Cycles as tolerated): 
Patients who achieve a CR after remission induction will receive consolidation therapy with 
midostaurin/placebo + chemotherapy according to their initial treatment assignment. 
Patients will receive four cycles as tolerated of consolidation therapy.Each cycle of 
consolidation therapy will comprise: 
• High-dose cytarabine (HiDAC) 3000 mg/m2 will be administered by intravenous 
infusion over 3 hours every 12 hours on Days 1, 3 and 5. Serial neurologic evaluations 
will be performed before and following the infusion of high-dose cytarabine. For patients 
of age 60 years or older at the time of study entry, the dose may be reduced to 1000-1500 
mg/m2/dose at the discretion of the investigator. 
• Ocular or systemic administration of corticosteroid therapy for prophylaxis against 
corneal toxicity due to high-dose cytarabine is required. Dosing and administration should 
adhere to local standard of care. 


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• Study drug (midostaurin 50 mg [two 25 mg capsules] or placebo [2 capsules]) will be 
administered twice a day by mouth on Days 8-21 as described above for RATIFY 
remission induction midostaurin/placebo. 
Each consolidation cycle will begin within two weeks following hematopoietic recovery (ANC 
≥ 1.0 x 109/L, platelet count ≥ 100 x 109/L) but no sooner than four weeks from the beginning 
of the previous cycle. At the end of the final consolidation cycle, a bone marrow examination 
will be performed to evaluate for continued remission. 
 
6.1.1.3 
Continuation therapy (up to 12 cycles) for either JALSG or RATIFY 
regimen: 
Patients treated either with the JALSG or RATIFY regimen and who maintain a CR (by bone 
marrow aspirate and peripheral blood evaluation) after completing 3 (JALSG) or 4 cycles as 
tolerated (RATIFY) of consolidation therapy will receive midostaurin/placebo continuation 
therapy according to the initial treatment assignment. 
Prior to initiation of midostaurin/placebo Continuation therapy, all significant acute toxicity 
from consolidation therapy must have resolved to a severity of less than Grade 2. 
Midostaurin/placebo continuation therapy will begin after hematopoietic recovery (ANC ≥ 1.0 
x 109/L, platelet count ≥ 100 x 109/L) following the final cycle of consolidation but no sooner 
than 14 days after the last dose of midostaurin/placebo during the last consolidation cycle. 
Patients who are unable to complete 4 cycles of HiDAC consolidation because of toxicity may 
still be eligible for continuation therapy after 3 cycles of consolidations. 
Each cycle of continuation therapy will comprise: 
• 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. 
Each 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 gelatin capsules should be 
removed from the blister pack only shortly prior to administration. The patient may notice 
a strong odor when he/she opens the blister card. No worry, this is normal. The odor is 
due to a chemical in the capsules interacting with a chemical in the blister card foil. The 
capsules are not affected by this and the odor will go away shortly after opening the 
blister card. 


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Table 6-1 
Dose and treatment schedule 
 
Study phase 
Regimen 
Study 
treatment 
Pharmaceutical 
form and route of 
administration 
Dose 
Frequency 
and/or Regimen 
Induction phase 
JALSG 
Cytarabine 
Continuous 
intravenous 
infusion (CIVI) 
100 mg/m2/day 
Days 1-7 (168 
hour infusion) 
Daunorubicin 
Intravenously by IV 
push or short (30 
minutes) infusion 
50 mg/m2/day 
Days 1-5 
Midostaurin / 
Placebo 
Capsules for oral 
use 
50 mg/dose 
Twice daily on 
Days 8-21 
RATIFY 
Cytarabine 
Continuous 
intravenous 
infusion (CIVI) 
200 mg/m2/day 
Days 1-7 (168 
hour infusion) 
Daunorubicin 
Intravenously by IV 
push or short (30 
minutes) infusion 
60 mg/m2/day 
Days 1-3 
Midostaurin / 
Placebo 
Capsules for oral 
use 
50 mg/dose 
Twice daily on 
Days 8-21 
Consolidation 
phase 
JALSG 
High-dose 
cytarabine 
Intravenous over 3 
hours 
2000 
mg/m2/dose* 
12-hour intervals 
on Days 1-5 
Midostaurin / 
Placebo 
Capsules for oral 
use 
50mg/dose 
Twice daily on 
Days 8-21 
RATIFY 
High-dose 
Cytarabine 
Intravenous over 3 
hours 
3000 
mg/m2/dose** 
12-hour intervals 
on Days 1, 3 and 
5 
Midostaurin/ 
Placebo 
Capsules for oral 
use 
50 mg/dose 
Twice daily on 
Days 8-21 
Continuation 
phase 
JALSG or 
RATIFY 
Midostaurin/ 
Placebo 
Capsules for oral 
use 
50 mg/dose 
Twice daily for 28 
consecutive days 
of each 28-day 
treatment cycle 
For patients of age 60 years or older at the time of study entry, the dose may be reduced as an option to: 
* 1500 mg/m2/dose at the discretion of the investigator 
** 1000-1500 mg/m2/dose at the discretion of the investigator 
 
6.1.1.4 
Hematopoietic stem cell transplantation 
A patient who is treated with hematopoietic stem cell transplantation (SCT) according to 
investigator judgement will discontinue study treatment prior to the start of the SCT 
conditioning regimen. The study treatment will not be resumed at any time thereafter. The 
patient will continue to be followed for remission in post treatment follow up. 
 
6.1.2 
Ancillary treatments 
High dose cytarabine during Consolidation cycles: Ocular or systemic administration of 
corticosteroid therapy with high-dose cytarabine will be local standard of care. 
 
6.1.3 
Rescue medication 
Not applicable 


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6.1.4 
Guidelines for continuation of treatment 
Patients who meet criteria for CR by the end of the second cycle of induction will proceed to 
consolidation therapy cycles. A patient who meets criteria for persistent disease will be removed 
from study treatment. Thereafter, a patient who continues to be in remission according to 
Cheson criteria (Cheson 2003) will continue each cycle of study treatment. 
Criteria for dose interruption are described in Section 6.3. Study drug interruptions of greater 
than 28 consecutive days will require discontinuation from study treatment. 
 
6.1.5 
Treatment duration 
The treatment phases, and the total maximum planned duration of treatment is 18 cycles. 
Planned durations of each therapy are: 
• Induction therapy: 1 or 2 cycles (daunorubicin, cytarabine and midostaurin/placebo). One 
cycle is defined as the time from the start of study treatment to the time of hematopoietic 
recovery or determination of persistent disease, whichever is first. 
• Consolidation therapy: 3 cycles for JALSG regimen and 4 cycles as tolerated for RATIFY 
regimen (high-dose cytarabine and midostaurin/placebo). One cycle is defined as the time 
from the start of study treatment to the time of hematopoietic recovery or determination of 
disease relapse, whichever is first. 
• Continuation therapy: up to 12 cycles (midostaurin/placebo). Each cycle is 28 days in 
duration. 
Patients may be discontinued from study treatment prior to treatment completion for reasons of 
unacceptable toxicity, disease persistence or relapse (designated as Progressive Disease in 
eCRF), withdrawal of consent by the patient, failure to adhere 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 maximize patient safety and 
to allow patients to continue the study treatment. The schedule of dose modifications applies 
both to patients in the part 1 and in the part 2. 
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 or listed in Section 7.1.5. 
Dose changes will be recorded on the appropriate CRF. 


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Study drug (midostaurin/placebo) 
Table 6-2 describes adverse events, laboratory values, or other assessments that require 
interruption or dose modification of study drug. 
During induction and consolidation therapies, modifications should be done in case of non- 
hematologic toxicities (pulmonary, cardiac or other non-hematologic toxicities) related or 
unrelated to midostaurin/placebo. 
During continuation therapy, modifications should be done in case of hematologic and non- 
hematologic toxicities (pulmonary, cardiac or other non-hematologic toxicities) related or 
unrelated to midostaurin/placebo. 
If interruptions occur, missed doses of study drug will not be made up. 
Study drug interruptions of greater than 28 consecutive days will require discontinuation from 
study treatment. 
 
Cytarabine 
Doses will be modified only during the consolidation phase with high-dose cytarabine and in 
case of neurotoxicity for RATIFY regimen and in case of hematology and non-hematology 
toxicity for JALSG regimen. Please follow Table 6-2 for each regimen. 
 
Daunorubicin 
Doses will be modified during induction phase in case of hepatotoxicity. Please follow Table 
6-2 for each regimen (RATIFY or JALSG). 


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Table 6-2 
Criteria for dose reduction / interruption and re-initiation of midostaurin/placebo, daunorubicin and cytarabine 
treatment for adverse events 
 
Dose modifications for midostaurin/placebo 
Hematologic toxicities 
During induction and consolidation 
cycles 
During continuation cycles 
No dose modifications are required for hematologic toxicity due to midostaurin/placebo during induction and consolidation 
therapy. 
In the presence of grade 4 neutropenia during continuation therapy, midostaurin/placebo must be held until 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, midostaurin/placebo study treatment must be discontinued. 
Non-Hematologic toxicities: 
● Pulmonary toxicities 
During induction, consolidation and 
continuation cycles 
For ≥ grade 3 pneumonitis or interstitial lung disease without an infectious etiology, 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 the toxicity does not resolve to ≤ grade 1 within 28 days after midostaurin/placebo interruption, the 
patient must be discontinued from the study treatment. 
● Cardiac Toxicity 
During induction, consolidation and 
continuation 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. Midostaurin/placebo dose must be decreased 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. Midostaurin/placebo must be held or interrupted 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 in time to start the next cycle, 
midostaurin/placebo may be held up to 28 days. If there is no improvement of QTcF to ≤ 470 ms within 28 days after 
midostaurin/placebo interruption, the patient must be discontinued from study treatment. 
● Other Non-Hematologic toxicity 
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 toxicities that are considered related to 
midostaurin/placebo, midostaurin/placebo must be interrupted until toxicity resolves to ≤ grade 2. 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 


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up. If the toxicity does not resolve to ≤ grade 2 within 28 days after midostaurin/placebo interruption, the patient must be 
discontinued from the study treatment. 
During continuation cycles 
● Grade 1/2: Persistent grade 1 or 2 toxicity during continuation therapy that patients deem to be unacceptable may 
prompt a study drug interruption for as long as 28 days. If the study drug is interrupted for more than 28 days, the patient 
must be discontinued from the 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 the 
toxicity does not resolve to ≤ grade 2 within 28 days after midostaurin/placebo interruption, the patient must be discontinued 
from the study treatment. 
Dose modifications for high-dose cytarabine (HiDAC) consolidation therapy 
RATIFY regimen 
JALSG regimen 
During consolidation cycles 
Contributions of concomitant medications to neurotoxicity 
should be assessed and other medications discontinued if 
possible. 
For neurotoxicity ≥ grade 2 due to high-dose cytarabine 
during consolidation therapy, discontinue high-dose 
cytarabine for the remainder of the cycle. 
High-dose cytarabine may be considered at the next 
consolidation therapy cycle with a dose modification from 
3000 mg/m2 to 2000 mg/m2 if the toxicity has resolved to ≤ 
grade 1. 
For any grade 2 or higher central nervous system AE 
(neurotoxicity) that is attributed by the investigator to HiDAC, 
this drug should not be used for further treatment. 
If there are any following AEs in a given cycle that are attributed 
by the investigator to be related to HiDAC, the number of days 
of administration of HiDAC should be decreased as described 
below. Once the dose is reduced, the dose may not be re- 
escalated at any time even if there are no additional AEs 
occuring after the dose reduction. 
Non-hematologic toxicity: 
● Grade 3 (not including grade 3 anorexia, nausea, vomiting), 
decrease 1 day administration (4 days instead of 5 days) 
● Grade 4, decrease 2 days administration (3 days instead of 
5 days) 
For a second occurrence of neurotoxicity ≥ grade 2, high- 
dose cytarabine should be permanently discontinued. 
Hematologic toxicity: 
● Grade 4 febrile neutropenia with life threatening sepsis, 
decrease 1 day administration (4 days instead of 5 days) 
● Delayed recovery of ANC and platelet (failure to reach ANC 
≥ 1.0 x 109/L, platelet count ≥ 100 x 109/L by Day 35 of 
treatment cycle), then decrease 1 day administration (4 days 
instead of 5 days) 


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● If ANC < 2.0 x 109/L or platelet count < 150 x 109/L just 
before administration, decrease cytarabine administration by 1 
day (4 days instead of 5 days) 
Dose modifications for daunorubicin due to hepatotoxicity (except in the setting of isolated Gilbert syndrome) 
RATIFY regimen 
JALSG regimen 
During induction cycles 
Total Bilirubin (mg/dL) 
% daunorubicin dose to administer 
% daunorubicin dose to administer 
≤ 2 
100% 
100% 
> 2 – ≤ 3.0 
75% (25% dose reduction) 
75% (25% dose reduction) 
> 3.0 
50% (50% dose reduction) 
50% (50% dose reduction) 
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 
Guidelines on dose modification instructions are provided in Table 6-2 above. Dose reductions 
will be based on local assessment of the ECG and corrected if discrepancy occurred on the 
central review report. 
 
6.3.3 
Follow-up for toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event or 
clinically significant laboratory value will be followed at least weekly (or more frequently if 
required by institutional practices, or if clinically indicated) for 4 weeks, and subsequently at 
approximately 4-week intervals, until resolution or stabilization of the event, whichever comes 
first. Appropriate clinical experts should be consulted as deemed necessary. All patients must 
be followed up for adverse events and serious adverse events for 30 days following the last dose 
of study treatment (midostaurin/placebo or daunorubicin or cytarabine). 
 
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: 
1. 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 
2. 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 is needed to ensure that liver test elevations are not caused by cholestasis, 
defined as alkaline phosphatase (ALP) elevation > 2.0 x ULN with an 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 
treatment, and repeat LFT testing 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. 
• Laboratory tests should include ALT, AST, albumin, creatinine kinase, TBIL, direct and 
indirect bilirubin, GGT, prothrombin time (PT) or INR and ALP. 
• 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. 


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• Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted. 
• Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is 
performed in the study. 
• Additional testing for other hepatotropic viral infection (CMV, EBV or 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”; such an event therefore will meet the definition of an SAE and is reported as an 
SAE using the term “potential drug-induced liver injury”. All such 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. Discussions regarding discontinuation of patients requiring concomitant 
medication should be discussed with Novartis 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. It is required that all patients receive maximal prophylaxis for the prevention 
of nausea and vomiting, using antiemetics according to local practice. 
The patient must be told to notify the investigational site about any new medications that 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 appropriate eCRF. 
 
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), breast cancer resistant protein (BCRP), and Organic Anion Transporting 
Polypeptide 1B1 (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 


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are substrates of CYP1A2, CYP2B6, CYP2C8, CYP2C9, 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, CYP2E1, CYP3A, P-gp and substrates of BCRP and 
OATP1B1 is available in Appendix 2 (Section 14.2.2). 
As far as possible avoid co-administering drugs with a “Known”, “Possible”, or “Conditional” 
risk of Torsades de Pointes (TdP) during the course of the study. 
• If concomitant administration of drugs with a “known risk of TdP” is required and cannot 
be avoided, then the study drug must be interrupted. If, based on the investigator 
assessment and clinical need, study drug is resumed, close ECG monitoring is advised. In 
such scenarios, the study drug should be resumed only after the discontinuation 
(preferably after five half-lifes after discontinuation) of the drugs with a known risk of 
TdP. 
• 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 
https://crediblemeds.org/and in Appendix 2. 
 
6.4.3 
Prohibited concomitant therapy 
Strong CYP3A4 inducers: Concomitant use of midostaurin 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, co-administration of 
the strong CYP3A4 inducer rifampicin (rifampin; 600 mg daily) to steady state with a single 
dose of midostaurin decreased maximum plasma midostaurin concentration (Cmax) by 73% 
and area under the curve from time 0 to infinite (AUCinf) by 96% in average, respectively. 
CGP62221 exhibited a similar pattern. The mean area under the curve from time zero to the last 
measurable concentration sampling time after the first dose (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 2. 
 
6.5 
Patient numbering, treatment assignment or randomization 
6.5.1 
Patient numbering 
Each patient is identified in the study by a Subject Number, 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 Number consists of the Center Number 
(Center No.) (as assigned by Novartis to the investigative site) with a sequential patient number 
suffixed to it, so that each patient is numbered uniquely across the entire database. Upon signing 


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the informed consent form, the patient is assigned to the next sequential Subject Number 
available to the investigator through the Clinical Data Management System interface. 
The investigator or designated staff will contact the Interactive Response Technology (IRT) and 
provide the requested identifying information for the patient to register them into the IRT. Once 
assigned, the Subject Number must not be reused for any other patient and the Subject Number 
for that individual must not be changed. If the patient is not randomized or does not start study 
treatment, the reason will be entered into the Disposition CRF. 
The IRT must be notified within 2 days that the patient was not randomized by using appropriate 
form. 
 
6.5.2 
Treatment assignment or randomization 
In double blind part 2, 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. 
Randomization will be stratified by chemotherapy regimen (JALSG or RATIFY) and by AML 
FLT3 genotype: tyrosine kinase domain (TKD) mutation, FLT3 internal tandem duplication 
(ITD) mutation with allelic ratio < 0.7, or FLT3-ITD mutation with allelic ratio ≥ 0.7. 
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, who have AML with a 
demonstrated FLT3 mutation through the Novartis-designated central 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, 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 primary 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 an independent 
statistician and an independent programmer who will perform the interim analysis and the 
bioanalyst to avoid the unnecessary analysis of placebo samples. The identity of the study drug 


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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) and at the time of the primary analysis (see Section 10.7). Although not anticipated, for any 
health authority that requests such information, every effort will be made to have an 
independent team respond to the request while keeping the study team blinded. In rare cases 
when unblinding occurs because of emergency patient management, the actual treatment arm 
will not be communicated to any Novartis employee involved 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. 
Study drug provided is midostaurin 25 mg and matching placebo control. 
Study drug will be supplied by Novartis as soft gelatine 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. 
 
Table 6-3 
Dispensing and preparation 
 
Study treatment 
Dispensing 
Preparation 
Midostaurin or placebo 
Capsules including instructions for 
administration are dispensed by study 
personnel on an outpatient basis. 
Not applicable 
 
Patients will be provided with adequate 
supply of study drug for self-administration 
at home until at least their next scheduled 
study visit. 
Daunorubicin 
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: 
In part 1 of the study, midostaurin will be provided as global clinical open label supply and will 
be packed and labeled under the responsibility of Novartis Drug Supply Management. In part 
2, 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 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 


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medication number(s) assigned by IRT to the patient. Site personnel will add the patient 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 and cytarabine: 
Daunorubicin and cytarabine will be commercial open label and will be supplied globally by 
Novartis or supplied locally as per local practice if agreed and approved by the global clinical 
team. 
When supplied globally, daunorubicin will be supplied as a vial of 20 mg powder for 
preparation of a solution for injection and cytarabine as vials of 100 mg and 1000 mg solution 
for injection. 
For chemotherapy supplied globally, the labels will comply with the legal requirements of each 
country and will include storage conditions, a unique medication number (corresponding to 
study treatment and strength).The label has 2-parts; 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. 
 
6.6.2 
Drug supply and storage 
Study treatment 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 and cytarabine. 
These instructions should be made clear to the patient for storage and self-administration of 
midostaurin/placebo at home. 
Site staff will be responsible for managing re-supplies for the chemotherapy (daunorubicin or 
idarubicin and cytarabine) and for midostaurin/placebo. 
Midostaurin/placebo as well as chemotherapy supplied globallywill be managed by IRT system. 
Site staff should enter dispensed drugs into the IRT system immediately so that the IRT can 
provide drug re-supplies in a timely manner. 
Chemotherapy supplied locally according to local practice and regulation as agreed by the 
global clinical team will not 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 and product 
information 
Daunorubicin 
Supplied globally by Novartis or 
Refer to drug label and product 
Cytarabine 
supplied locally as per local 
practice if agreed and approved 
by the global clinical team. 
information 
 


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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 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. 
 
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 7 days prior to Day 1 as per Table 
7-1. 


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• During each induction and consolidation cycle, PK and ECG assessments must be 
performed on the specified day. Other assessments will be performed within a strict +/- 
three days window. 
• Then during continuation cycles, all other assessments will be performed within a strict 
+/- three days window to take into account scheduling over public holidays if not 
explicitly specified otherwise. 
Reasonable 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 
Induction Phase 
Cycle 1 -2 
EOT (FLT3<0) 
End of Induction 
Phase / EOT 
Prior to each 
Consolidation 
cycle 
Consolidation Phase 
Cycle 1-4 
End of 
Consolid 
ation 
Phase / 
EOT 
Visit name 
D 
Screening IND C1-IND C2 
CON C1-CON C4 
CON 
DISPOSI 
TION 
Day of cycle 
-7 to -1 
1 
2 
3 
4 
5 
7 
8 
11 
15 
18 
21 24 28 
1 
3 
5 
8 
11 15 21 28 
Visit Number (For incremental cycle, follow the convention of +10 from previous visit) 
Visit Number 
1 
11 
0 
12 
0 
13 
0 
14 
0 
15 
0 
16 
0 
170 180 190 200 210 22 
0 
23 
0 
1979 
370 
38 
0 
39 
0 
40 
0 
41 
0 
42 
0 
43 
0 
44 
0 
45 
0 
1989 
Informed consent 
Obtain study 
Informed Consent D 
x 
IRT (not apply for part1) 
Registration 
D 
x 
Eligibility checklist D 
x 
Induction 1: when 
FLT3 mutation status is 
confirmed 
Randomization 
D 
x 
Patient history 
Diagnosis/ Disease 
history 
D 
x 
Demography 
D 
x 
Inclusion/ exclusion 
criteria 
D 5.2 / 
5.3 
x 


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Category 
Protocol 
Section 
Screening 
Induction Phase 
Cycle 1 -2 
EOT (FLT3<0) 
End of Induction 
Phase / EOT 
Prior to each 
Consolidation 
cycle 
Consolidation Phase 
Cycle 1-4 
End of 
Consolid 
ation 
Phase / 
EOT 
Visit name 
D 
Screening IND C1-IND C2 
CON C1-CON C4 
CON 
DISPOSI 
TION 
Day of cycle 
-7 to -1 
1 
2 
3 
4 
5 
7 
8 
11 
15 
18 
21 24 28 
1 
3 
5 
8 
11 15 21 28 
Visit Number (For incremental cycle, follow the convention of +10 from previous visit) 
Visit Number 
1 
11 
0 
12 
0 
13 
0 
14 
0 
15 
0 
16 
0 
170 180 190 200 210 22 
0 
23 
0 
1979 
370 
38 
0 
39 
0 
40 
0 
41 
0 
42 
0 
43 
0 
44 
0 
45 
0 
1989 
FLT3 mutation 
status on BMA 
(Table 7-6) 
D 
x 
FLT3 mutation 
status on PB (see 
Table 7-6) 
D 
x 
Cytogenetics 
D 
x 
Medical History 
D 
x 
Prior antineo 
plastic medications D 
x 
Prior / concomitant 
medications and 
procedures 
D 
x 
Continuous 
X X 
Continuous 


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Category 
Protocol 
Section 
Screening 
Induction Phase 
Cycle 1 -2 
EOT (FLT3<0) 
End of Induction 
Phase / EOT 
Prior to each 
Consolidation 
cycle 
Consolidation Phase 
Cycle 1-4 
End of 
Consolid 
ation 
Phase / 
EOT 
Visit name 
D 
Screening IND C1-IND C2 
CON C1-CON C4 
CON 
DISPOSI 
TION 
Day of cycle 
-7 to -1 
1 
2 
3 
4 
5 
7 
8 
11 
15 
18 
21 24 28 
1 
3 
5 
8 
11 15 21 28 
Visit Number (For incremental cycle, follow the convention of +10 from previous visit) 
Visit Number 
1 
11 
0 
12 
0 
13 
0 
14 
0 
15 
0 
16 
0 
170 180 190 200 210 22 
0 
23 
0 
1979 
370 
38 
0 
39 
0 
40 
0 
41 
0 
42 
0 
43 
0 
44 
0 
45 
0 
1989 
Physical examination 
Performance status D 7.2.2.4 
x 
x 
x (at EOT) 
x 
x 
x 
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 
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) 
Extamedullary 
involvement 
D 
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 7-3) 
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: total bili only) 
D 7.2.2.5.2 x 
x 
x 
B 
x 
B 
x 
B 
x 
B 
x 
x 
x 
x (at EOT) 
x 
x 
x 
x 
x 
x (at EOT) 
Coagulation 
D 7.2.2.5.3 x 
x 
x 
x 
x 
x 
Other hepatic tests 
for suspected DILI S 6.3.3.1 
If clinically indicated 
Urinalysis dipstick 
and microscopic 
analysis 
D 
7.2.2.5.4 x 
If clinically 
indicated 


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Category 
Protocol 
Section 
Screening 
Induction Phase 
Cycle 1 -2 
EOT (FLT3<0) 
End of Induction 
Phase / EOT 
Prior to each 
Consolidation 
cycle 
Consolidation Phase 
Cycle 1-4 
End of 
Consolid 
ation 
Phase / 
EOT 
Visit name 
D 
Screening IND C1-IND C2 
CON C1-CON C4 
CON 
DISPOSI 
TION 
Day of cycle 
-7 to -1 
1 
2 
3 
4 
5 
7 
8 
11 
15 
18 
21 24 28 
1 
3 
5 
8 
11 15 21 28 
Visit Number (For incremental cycle, follow the convention of +10 from previous visit) 
Visit Number 
1 
11 
0 
12 
0 
13 
0 
14 
0 
15 
0 
16 
0 
170 180 190 200 210 22 
0 
23 
0 
1979 
370 
38 
0 
39 
0 
40 
0 
41 
0 
42 
0 
43 
0 
44 
0 
45 
0 
1989 
Serum (S) or Urine 
(U) Pregnancy test S 7.2.2.5.5 X (S) 
x 
(U) 
x 
U 
x (U at EOT) 
x 
(U) 
x (U at 
EOT) 
Imaging/other assessments 
Chest X-ray 
7.2.2.6 
x 
If clinically 
indicated 
ECG (Table 7-4) 
D 7.2.2.7.1 x 
x 
x 
x 
x 
x 
x 
Cardiac 
MUGA/ECHO 
D 7.2.2.7.2 x 
If clinically 
indicated 
x 
If clinically indicated 
x 
Safety 
Adverse events 
D 8.1 
x 
Continuous 
x 
x 
Continuous 
Pharmacokinetics 
PK sampling (see 
Table 7-5) 
D 
7.2.3 
X 
(I1 
only 
) 
X 
(I1 
only 
) 
X 
(I1 
only 
) 
X 
(I1 
only 
) 
X 
(I1 
only 
) 
X 
(C 
1 
an 
d 
C3 
) 
X 
(C 
1 
an 
d 
C3 
) 


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Category 
Protocol 
Section 
Screening 
Induction Phase 
Cycle 1 -2 
EOT (FLT3<0) 
End of Induction 
Phase / EOT 
Prior to each 
Consolidation 
cycle 
Consolidation Phase 
Cycle 1-4 
End of 
Consolid 
ation 
Phase / 
EOT 
Visit name 
D 
Screening IND C1-IND C2 
CON C1-CON C4 
CON 
DISPOSI 
TION 
Day of cycle 
-7 to -1 
1 
2 
3 
4 
5 
7 
8 
11 
15 
18 
21 24 28 
1 
3 
5 
8 
11 15 21 28 
Visit Number (For incremental cycle, follow the convention of +10 from previous visit) 
Visit Number 
1 
11 
0 
12 
0 
13 
0 
14 
0 
15 
0 
16 
0 
170 180 190 200 210 22 
0 
23 
0 
1979 
370 
38 
0 
39 
0 
40 
0 
41 
0 
42 
0 
43 
0 
44 
0 
45 
0 
1989 


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Category 
Protocol 
Section 
Screening 
Induction Phase 
Cycle 1 -2 
EOT (FLT3<0) 
End of Induction 
Phase / EOT 
Prior to each 
Consolidation 
cycle 
Consolidation Phase 
Cycle 1-4 
End of 
Consolid 
ation 
Phase / 
EOT 
Visit name 
D 
Screening IND C1-IND C2 
CON C1-CON C4 
CON 
DISPOSI 
TION 
Day of cycle 
-7 to -1 
1 
2 
3 
4 
5 
7 
8 
11 
15 
18 
21 24 28 
1 
3 
5 
8 
11 15 21 28 
Visit Number (For incremental cycle, follow the convention of +10 from previous visit) 
Visit Number 
1 
11 
0 
12 
0 
13 
0 
14 
0 
15 
0 
16 
0 
170 180 190 200 210 22 
0 
23 
0 
1979 
370 
38 
0 
39 
0 
40 
0 
41 
0 
42 
0 
43 
0 
44 
0 
45 
0 
1989 
Assessment of disease 
Investigator 
assessment of 
Disease Response 
(BMA or biopsy 
and PB) 
D 
7.2.1 
x 
x 
X (if 
previous 
BMA not 
sufficient to 
confirm CR) 
if clinically appropriate and at 
time of relapse 
x 
Patient reported outcomes 
EORTC QLQ-C30 D 7.2.6.1 
x 
x 
x (at EOT) 
x 
x (at EOT) 
PGIC 
D 7.2.6.2 
x 
x (at EOT) 
x 
x (at EOT) 
Disposition 
D 
x 
x 
x 
x 
IRT 
Dispensation 
Midostaurin/Placeb 
o 
D 
x 
x 
Treatment 
Discontinuation 
D 
X x (at EOT) 
x (at EOT) 


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Category 
Protocol 
Section 
Screening 
Induction Phase 
Cycle 1 -2 
EOT (FLT3<0) 
End of Induction 
Phase / EOT 
Prior to each 
Consolidation 
cycle 
Consolidation Phase 
Cycle 1-4 
End of 
Consolid 
ation 
Phase / 
EOT 
Visit name 
D 
Screening IND C1-IND C2 
CON C1-CON C4 
CON 
DISPOSI 
TION 
Day of cycle 
-7 to -1 
1 
2 
3 
4 
5 
7 
8 
11 
15 
18 
21 24 28 
1 
3 
5 
8 
11 15 21 28 
Visit Number (For incremental cycle, follow the convention of +10 from previous visit) 
Visit Number 
1 
11 
0 
12 
0 
13 
0 
14 
0 
15 
0 
16 
0 
170 180 190 200 210 22 
0 
23 
0 
1979 
370 
38 
0 
39 
0 
40 
0 
41 
0 
42 
0 
43 
0 
44 
0 
45 
0 
1989 
Study treatment administration 
Midostaurin / 
Placebo 
D 
Continuous twice daily 
Continuous 
twice daily 
Daunorubicin 
JALSG (J) / 
RATIFY (R) 
D 
J/R J/R J/R J 
J 
Cytarabine 
JALSG (J) / 
RATIFY (R) 
D 
continuous IVCI (J/R) 
J: 
continuous 
Day 1 to 5 
R: Days 1, 
3 and 5 


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B.: End of consolidation phase until end of study 
 
Category 
Protocol Section 
Prior to 
1st cycle 
of 
Continu 
ation 
phase 
Continuation Phase Cycle 1- 
12 
End of 
Continu 
ation 
Phase 
/EoT 
30 day 
safety 
follow 
up 
Post treatment follow up 
(until 36 months after Day 1 of 
the last patient) 
Survival 
follow up 
(until 36 
months 
after Day 1 
of the last 
the patient 
Visit name 
D 
CONT C1- CONT C12 
Day of cycle 
1 
15 
Visit Number (For incremental cycle, follow 
the convention of +10 from previous visit) 
730 
740 
750 
1999 
Patient history 
Prior/concomitant medications 
and procedures 
D 
continuous 
Antineoplastic therapies after 
discontinuation of study 
treatment 
D 
x 
Every 2 months for years 1 and 2 
and every 3 months for years 3 and 
4 and then yearly 
x 
Transplant after 
discontinuation of study 
treatment 
D 
x 
Every 2 months for years 1 and 2 
and every 3 months for years 3 and 
4 and then yearly 
x 
Physical examination 
Performance status 
D 
7.2.2.4 
X 
x 
x 
Weight 
D 
7.2.2.3 
x 
x 
x 
Vital signs 
D 
7.2.2.2 
x 
x 
x 
Every 2 months for years 1 and 2 
and every 3 months for years 3 and 
4 and then yearly 
Physical examination 
S 
7.2.2.1 
x 
x 
x 
Extramedullary involvement 
D 
x 
x 
x 
Lab assessments (see Table 7-3) 
Hematology 
D 
7.2.2.5. 
1 
x 
x 
X (C1 and C2 
continuation only if 
no grade 2 or higher 
x 
Every 2 months for years 1 and 2 
and every 3 months for years 3 and 
4 and then yearly 


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Category 
Protocol Section 
Prior to 
1st cycle 
of 
Continu 
ation 
phase 
Continuation Phase Cycle 1- 
12 
End of 
Continu 
ation 
Phase 
/EoT 
30 day 
safety 
follow 
up 
Post treatment follow up 
(until 36 months after Day 1 of 
the last patient) 
Survival 
follow up 
(until 36 
months 
after Day 1 
of the last 
the patient 
Visit name 
D 
CONT C1- CONT C12 
Day of cycle 
1 
15 
Visit Number (For incremental cycle, follow 
the convention of +10 from previous visit) 
730 
740 
750 
1999 
anemia, 
thrombocytopenia, or 
neutropenia 
Chemistry 
D 
7.2.2.5. 
2 
x 
x 
x 
Other hepatic tests for 
suspected DILI 
S 
6.3.3.1 
If clinically indicated 
Urinalysis dipstick and 
microscopic analysis 
D 
7.2.2.5. 
4 
If clinically indicated 
Serum (S) or Urine (U) 
Pregnancy test 
S 
7.2.2.5. 
5 
x (U) 
x (U) 
x (S) 
Imaging/other assessments 
Chest X-ray 
D 
7.2.2.6 
If clinically indicated 
ECG (Table 7-4) 
D 
7.2.2.7. 
1 
x 
X 
(cycle 
2 to 
cycle 
12) 
Completi 
on of 
C12 or at 
EOT 
Cardiac MUGA/ECHO 
D 
7.2.2.7.2 If clinically indicated 
x 
Safety 
Adverse events 
D 
8.1 
Continuous 
Pharmacokinetics 


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Category 
Protocol Section 
Prior to 
1st cycle 
of 
Continu 
ation 
phase 
Continuation Phase Cycle 1- 
12 
End of 
Continu 
ation 
Phase 
/EoT 
30 day 
safety 
follow 
up 
Post treatment follow up 
(until 36 months after Day 1 of 
the last patient) 
Survival 
follow up 
(until 36 
months 
after Day 1 
of the last 
the patient 
Visit name 
D 
CONT C1- CONT C12 
Day of cycle 
1 
15 
Visit Number (For incremental cycle, follow 
the convention of +10 from previous visit) 
730 
740 
750 
1999 
PK sampling (see Table 7-5) 
D 
7.2.3 
x 
C5, 
C9 
Completi 
on of 
C12 
Assessment of disease 
Investigator assessment of 
Disease Response (BMA or 
biopsy and Peripheral blood) 
D 
C5, 
C9 
Completi 
on of 
C12/At 
relapse 
Every 4 months after completion of 
continuation therapy up until 1 year. 
OR, If discontinuation of study 
treatment for any other reason than 


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Category 
Protocol Section 
Prior to 
1st cycle 
of 
Continu 
ation 
phase 
Continuation Phase Cycle 1- 
12 
End of 
Continu 
ation 
Phase 
/EoT 
30 day 
safety 
follow 
up 
Post treatment follow up 
(until 36 months after Day 1 of 
the last patient) 
Survival 
follow up 
(until 36 
months 
after Day 1 
of the last 
the patient 
Visit name 
D 
CONT C1- CONT C12 
Day of cycle 
1 
15 
Visit Number (For incremental cycle, follow 
the convention of +10 from previous visit) 
730 
740 
750 
1999 
relapse, every 4 months until relapse 
or until 30 months after the start of 
treatment, whichever comes first 
AND at time of relapse for all 
patients 
Patient reported outcomes 
EORTC QLQ-C30 / PGIC 
D 
7.2.6.1 
/ 
7.2.6.2 
x 
x 
Every 4 months during the first year 
Disposition 
D 
x 
X 
IRT 
Dispensation 
Midostaurin/Placebo 
D 
x 
Treatment Discontinuation 
D 
x 
Study treatment administration 
Midostaurin/Placebo 
D 
continuous twice daily (from 
D1 to D28) 
Follow-up 
Survival Follow-up 
D 
x every 3 
months 


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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-7 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. 
Assessments done according to the timelines above as per local practice or under a local 
protocol, prior to signing the study specific informed consent form will not have to be repeated 
during the screening phase and results can be used for the study. At the discretion of the 
investigator, the final diagnosis of AML by BMA can be confirmed after the informed consent 
form has been signed for the study. In case of dry tap (failure to obtain bone marrow after BMA 
attempt): confirmation of AML diagnosis can be based on a bone marrow biopsy or on 
peripheral blood (documenting presence ≥ 20% blasts) at investigator’s discretion if bone 
marrow biopsy may delay initiation of the treatment. 
For patients with diagnosis already confirmed at a referral site, the relevant samples must be 
available and must be used by the investigational site to confirm the diagnosis and cytogenetics. 
If the relevant samples are not available, BMA or any relevant samples will be collected to 
confirm the diagnosis and cytogenetics at screening. 
 
 
As part of screening procedures, a BMA or a whole blood sample will be collected and shipped 
immediately to the Novartis designated central 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 and diagnostic assay development. 
Re-screening is not allowed, and a patient who does not meet all inclusion/exclusion criteria 
will be considered to be a screen failure. However, hematology and biochemistry laboratories 
assessments could be repeated during the screening period if needed. 
 
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 for the patient to be 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. 


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FLT3 status will be entered in the IRT by the Novartis-designated central laboratory that 
analyzed the samples. An email with the results will be sent to the site by IRT. 
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 
Demographics, 
Informed 
Consent, 
and 
Inclusion/Exclusion Criteria 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). 
 
Information to be collected on patients who failed to be randomized 
Patients who are determined to have negative or unknown FLT3 mutation at Day 8 of 1st cycle 
of induction will be not randomized at Day 8 and then will be discontinued from the treatment. 
In addition to data collected at screening until Day 8 of 1st cycle of induction, the reason for 
end of treatment will be entered on the Disposition CRF, data from EOT (FLT3<0) and any 
AEs/SAEs if applicable, will be collected until safety follow up visit. However, if a patient 
with FLT3 mutation negative is enrolled in Novartis sponsored study (PKC412E2301) the 
AE/SAE collection will be performed in study PKC412E2301 as per protocol and the same 
information will not be collected again in study A2220. 
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 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 (ECOG), height, weight, vital signs) 
• Extramedullary involvement 
• 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) 


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7.1.3 
Run-in period 
Not applicable 
 
7.1.4 
Treatment period 
Patients will be assigned on Cycle 1 Day 8 of induction therapy to midostaurin or placebo using 
a stratified randomization according to FLT3 mutation and treatment regimen. 
• Study treatment will begin on Day 1 of Cycle 1 with chemotherapy: daunorubicin from Day 
1 to Day 3 or Day 5 and cytarabine from Day 1 to Day 7. Study treatment will continue on 
Day 8 with midostaurin/placebo until Day 21. 
• 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: assessments will be scheduled 2 times per week until hematology 
recovery. This cycle may be longer than 28 days (until hematology recovery occurs), and 
the assessments will be performed accordingly. If the patient has evidence of persistent 
leukemia on a bone marrow evaluation from Day 21 to Day 28 or 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 
 
. For details of assessments in induction Cycles 1 and 2, refer 
to Table 7-1. 
• Patients who achieve a CR will continue with consolidation therapy for up to 4 cycles. In 
case of toxicities with RATIFY regimen, patients are allowed to have 3 cycles only at the 
discretion of the investigator. For JALSG regimen, patients will have 3 cycles during 
consolidation therapy. 
• Patients who remain in remission after consolidation therapy will begin continuation 
therapy for up to 12 cycles of 28 days each. Continuation therapy will begin no sooner than 
14 days after the last dose of midostaurin/placebo during the last cycle of consolidation 
therapy. Patients who remain in remission after 12 cycles of continuation therapy will 
continue in post-treatment follow-up. 
 
Time windows for scheduling assessments 
• Reasonable 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 strict ± 3 days window, unless otherwise indicated. 


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• Patients who discontinue study treatment must have an End of Treatment (EOT) visit 
performed ≤ 7 days after stopping study treatment. 
 
7.1.5 
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. 
• Disease Progression (disease persistence or relapse after CR) 
• 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 treatment 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 and Section 7.1.10. 
For patients who discontinue treatment for reasons other than documented disease persistence 
or relapse (designated as Progressive Disease in eCRF), death, loss to follow-up, or withdrawal 
of consent, a bone marrow aspirate must continue to be performed every 4 months until relapse 
or until 30 months after the start of treatment, whichever comes first. 
The investigator (or designee) must also contact the IRT to register the patient’s 
discontinuation from study treatment within 2 days. 
 
7.1.5.1 
Replacement policy 
 
Part 1: Safety evaluation part in Japan 
If a subject is considered to be non-evaluable for the safety evaluation, a new subject will be 
enrolled until the minimum number of 3 evaluable patients is obtained prior to the next schedule 
Independent Safety Committee evaluation. 
 
Part 2: Randomized part 
Patients will not be replaced during the part 2. 


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7.1.6 
Withdrawal of consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a patient: 
• 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 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 Rest of Word (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. 
 
7.1.7 
Follow up for safety evaluations 
All patients must have safety evaluations for 30 days, after the last dose of study treatment 
(including cytarabine, daunorubicin or midostaurin/placebo). 
Data collected should be added to the Adverse Events CRF and the Concomitant Medications 
CRF. 
 
7.1.8 
Follow up for efficacy evaluations 
Patients who discontinue study treatment for reasons other than death, disease persistence or 
relapse (designated as Progressive Disease in the eCRF) should continue to have bone marrow 
assessments as scheduled in the protocol until relapse, as outlined in Section 7.1. 
After the Safety Follow-up visit, patients will enter the post-treatment follow-up phase. 
During this phase, the following data will be collected: 
• Antineoplastic therapy/transplantation after discontinuation of treatment: every 2 months 
during first 2 years then every 3 months for years 3 and 4, and then yearly. 


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The following assessments will be performed: 
• Vital signs, blood samples for hematology 
 every 2 months for years 1 and 
2, every 3 months for years 3 and 4 and then yearly 
 
• Questionnaires (EORTC QLQ-C30 / PGIC): Every 4 months during the first year. 
Patients will be followed in post-treatment follow up until relapse or end of study, whichever 
occurs first. 
 
7.1.9 
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 study treatment) or have relapse during post-treatment follow-up 
(see Figure 4-2). 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. 
 
7.1.10 
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 Disposition 
CRF. 
 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
Disease assessments will be performed locally through evaluation of bone marrow specimens, 
peripheral blood samples, and other relevant data that will be collected as described in Table 7- 
1. The response assessment will be according to Cheson criteria (Cheson 2003). Response 
assessments will require a bone marrow aspirate to be performed. In the event of a dry tap or 
an aspiration that is inadequate for interpretation, a bone marrow biopsy is required for response 
assessment. 
Complete remission (CR): Complete remission is defined as all of the following: 
• Peripheral Blood Counts 
• Absolute neutrophil count ≥ 1.0 x 109/L. 
• Platelet count ≥ 100 x 109/L. 
• No leukemic blasts in the peripheral blood. 


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• Adequate erythroid recovery so that RBC transfusions are not necessary. 
• No Auer rods. 
• Bone Marrow 
• Adequate cellularity. 
• No Auer rods. 
• < 5% blast cells. 
• No extramedullary leukemia (such as CNS or soft tissue involvement). 
Morphologic complete remission with incomplete platelet count recovery (CRp) 
• CRp satisfies all CR criteria except platelets < 100 x 109/L, but platelet transfusions are 
not necessary. 
Partial Remission (PR) 
• Must meet all criteria of a CR except that the bone marrow may contain 5%-24% blasts. 
Treatment Failure 
• Resistance disease: 
• Patient survives ≥ 7 days post chemotherapy; persistent AML in blood and bone 
marrow. 
• Aplasia: 
• Patient survives ≥ 7 days post chemotherapy; death while cytopenic, with aplastic 
bone marrow 
• Indeterminate cause: 
• Patient who die < 7 days post therapy 
• Patient who die > 7 days post therapy with no peripheral blood blasts, but no bone 
marrow examination 
• Patient who do not complete the first course of therapy 
Relapse 
Any of the following, occurring after CR: 
• The reappearance of circulating blast cells not attributable to “overshoot” following 
recovery from myelosuppressive therapy. 
• >5% blasts in the marrow, not attributable to another cause (e.g., CSF, bone marrow 
regeneration). 
• Development of extramedullary leukemia. 
Remission Induction cycle 1 
For the first induction cycle, a bone marrow aspirate will be obtained from Day 21 to Day 28 
to determine the presence of residual leukemia (≥ 5% blasts) according to Cheson criteria 
(Cheson 2003) and the need for a second induction cycle or CR. 
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. 


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Protocol No. CPKC412A2220 
 
• If the Day 21 or subsequent bone marrow aspirations show ≥5% leukemic blasts in a 
cellular marrow (>20%) or otherwise meet criteria for persistent leukemia, then the patient 
will receive a second cycle of induction therapy. 
• Patients for whom a CR is documented on Day 21-Day 28 BMA, will advance to 
consolidation therapy. 
• In absence of “hematology recovery” (defined as ANC ≥ 1.0 x 109/L and platelets ≥ 100 x 
109/L) at the time of the Day 21-Day 28 bone marrow aspiration showing <5% leukemic 
blasts in a cellular marrow (>20%), the patient will be observed until hematology recovery 
and another bone marrow aspiration will be performed within about one week after 
recovery of ANC and platelets to document continued presence of CR. Physicians should 
consider earlier bone marrow exams in patients, as clinically indicated. 
If a CR (as described in Section 10.5.2.2) is documented, then the relevant slides must be kept 
at the site. 
 
Remission Induction cycle 2 
For the second induction cycle, a bone marrow aspirate will be obtained from Day 21 to Day 
28 to determine the presence of residual leukemia (≥ 5% blasts) or CR according to Cheson 
criteria (Cheson 2003). 
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. 
• Patients for whom a CR is documented, will advance to consolidation therapy. 
• In absence of “hematology recovery” (defined as ANC ≥ 1.0 x 109/L and platelets ≥ 
100 x 109/L) at the time of the Day 21-Day 28 bone marrow aspiration showing <5% 
leukemic blasts, the patient will be observed until hemotology recovery and another 
bone marrow aspiration will be performed within about one week after recovery of 
ANC and platelets to document continued presence of CR. Physicians should consider 
earlier bone marrow exams in patients, as clinically indicated. 
• Patients failing to achieve CR will be discontinued from study treatment but will 
continue to be followed for survival. 
If a CR (as described in Section 10.5.2.2) is documented, then the relevant slides must be kept 
at the site. 
 
Consolidation therapy: 
A bone marrow examination will be performed to evaluate for continued remission at the end 
of the final cycle of consolidation and within one week of hematopoietic recovery (ANC ≥ 1.0 
x 109/L and platelets ≥ 100 x 109/L). 
Continuation therapy: 
A bone marrow examination will be performed to evaluate for continued remission at the start 
of Cycle 5, at the start of Cycle 9, and at the end of Cycle 12 of continuation therapy or at any 
time at relapse. 


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Protocol No. CPKC412A2220 
 
Post-treatment follow-up: 
A bone marrow examination will be performed to evaluate for continued remission every four 
months after completion of continuation therapy, up until 1 year. For patients who discontinue 
study treatment for other reasons than relapse prior to completion of continuation therapy, every 
4 months until relapse or until 30 months after the start of treatment, whichever comes first. A 
bone marrow examination will also be performed at any time of relapse. 
 
7.2.2 
Safety and tolerability assessments 
Safety will be monitored by assessing physical examination, performance status, laboratory 
examinations, ECGs, MUGA as well as collecting of the adverse events at every visit. 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 
A 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, 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. 
Extramedullary involvement will be assessed at the time of physical examination. 
7.2.2.2 
Vital signs 
Vital signs include blood pressure (supine position preferred when ECG is collected), pulse 
measurement, and body temperature and will be measured at screening and at subsequent time 
points as specified in Table 7-1. 
7.2.2.3 
Height and weight 
Height will be measured at screening. 
Body weight (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 used 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 7-2. 


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Table 7-2 
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 
 
7.2.2.5 
Laboratory evaluations 
 
Table 7-3 
Clinical laboratory parameters collection plan 
 
Test Category 
Test Name 
Hematology (Local) 
Hgb, WBC with differential (including basophils, eosinophils, lymphocytes, 
monocytes, neutrophils, bands, blasts), platelets 
Biochemistry (Local) 
Albumin, alkaline phosphatase, ALT, AST, LDH, calcium, magnesium, phosphorous, 
sodium, potassium, creatinine, creatine kinase, total bilirubin, direct bilirubin, total 
cholesterol, BUN/urea, uric acid, amylase, lipase, fasting glucose 
Coagulation (Local) 
International normalized ratio (INR), activated partial thromboplastin time (aPTT) 
Urinalysis (Local) 
Dipstick examination includes protein, glucose, pH; microscopic analysis 
Other hepatic tests in 
case of suspected 
DILI (Local) 
GGT, creatinine kinase, 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 of serum/urine 
Clinical laboratory analyses are to be performed by the local laboratory (in 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 eCRF. 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 eCRF. Laboratory data will be summarized using the Common Terminology 
Criteria for Adverse events (CTCAE) version 5.0. Additional laboratory evaluations are left to 
the discretion of the investigator. 


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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 7-3. 
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 eCRF. 
 
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 7-3. 
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 eCRF. 
It should be noted in the patient’s eCRF if the patient was fasting as the time of blood sampling. 
 
7.2.2.5.3 Coagulation 
Coagulation analyses (International normalized ratio (INR) and activated partial thromboplastin 
time (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 7-3. 
 
7.2.2.5.4 Urinalysis 
Dipstick analysis (including pH, glucose and protein) is to be performed by the local laboratory 
at screening and during treatment phase if clinically indicated. 
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 and at 30-day 
Safety follow up visit. 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 8 during induction and 
consolidation cycles and Day 1 during continuation cycles). 
Urine pregnancy tests will be required to be performed as well as at the End of Treatment 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. 


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Male patients treated with 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 patients. 
 
7.2.2.6 
Radiological examinations 
Radiological examinations should be performed as clinically indicated. 
 
7.2.2.7 
Cardiac assessments 
 
7.2.2.7.1 Electrocardiogram (ECG) 
A standard triplicate 12 lead ECG will be performed according to the relevant Visit Evaluation 
Schedule (Table 7-1 and Table 7-4). 
 
Table 7-4 
Central ECG assessment monitoring schedule 
 
Cycle 
Day 
Time 
ECG Type 
Screening 
-3 to -1 
Pre-dose (baseline ECG) 
12 Lead, 
triplicate 
Induction Phase, 
cycles 1 and 2 
Day 8, Day 11, 
Day 21 
Pre-dose (before PK) 
Post-dose at 3 hours ± 0.5 hour (before pK) 
12 Lead, 
triplicate 
Consolidation 
Phase, each cycle 
Day 8, Day 11, 
Day 21 
Pre-dose (before PK) 
Post-dose at 3 hours ± 0.5 hour (before pK) 
12 Lead, 
triplicate 
Prior to 1st cycle of 
Continuation 
Pre-dose (before PK) 
12 Lead, 
triplicate 
Continuation, cycle 2 
to cycle 12 
Day 1 
Pre-dose (before PK) 
12 Lead, 
triplicate 
Continuation, cycle 
12 
D28 
Pre-dose (before PK) 
12 Lead, 
triplicate 
Continuation 
Treatment 
discontinuation 
12 Lead, 
triplicate 
Unscheduled sample 
Anytime 
12 Lead, 
triplicate 
Interpretation of the tracing must be made by a qualified physician. Each ECG tracing should 
be labeled with the study number, patient initials (where regulations permit), patient 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 triplicate 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 7-1 and 
prior to PK samples. 
The individual ECGs should be recorded approximately 2 minutes apart. The mean QTcF value 
for each visit will be calculated from the triplicate ECGs for each patient. 
Dose adjustments in case of QT prolongation should be performed per Section 6.3. 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. Unscheduled ECGs with clinically significant 
findings should be collected in triplicate. Local cardiologist ECG assessment may also be 
performed at any time during the study at the discretion of the investigator. 


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All ECGs, including unscheduled triplicate safety ECGs with clinically relevant findings, 
collected during the study should be transmitted to the central core ECG laboratory for review. 
The results of the centrally assessed ECGs are automatically transferred into the clinical 
database. 
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, EOT and whenever clinically indicated. 
 
7.2.2.7.3 Cardiac enzymes 
Not applicable 
 
7.2.2.8 
Tolerability 
Not applicable 
 
7.2.3 
Pharmacokinetics 
Serial blood samples will be collected from all patients to assess single dose and steady-state 
plasma PK midostaurin and its two active metabolites. Non-compartmental Analysis (NCA) PK 
parameters will be estimated from each individual plasma concentration-time profile using 
appropriate methods and software. Refer to Section 10.5.4 for a table of PK parameters that will 
be estimated. 
 
7.2.3.1 
Pharmacokinetic blood collection and handling 
Blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in 
a forearm vein. At specified time points described in Table 7-5, 3 mL blood draws will be 
collected into tubes containing sodium heparin and gently inverted several times to thoroughly 
mix the anticoagulant. Tubes will be centrifuged to separate plasma and plasma will 
immediately be transferred into labeled 1.8 mL polypropylene screw-cap tubes. Plasma samples 
will be placed in a freezer in an upright position until shipment to the bioanalytical laboratory 
for analysis. 
The exact collection date and time of all samples must be documented on the PK blood 
collection CRF. The date and exact time of dosing, as well as the date and actual time of blood 
sampling must be recorded on the CRF. 
Refer to the [CPKC412A2220 Laboratory Manual] for detailed instructions for the collection, 
handling, and shipment of PK samples. 


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Table 7-5 
Pharmacokinetic blood collection log for midostaurin, CGP52421 and 
CGP62221 
 
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 (+/- 5min) 
3 
1 
103 
Induction 1 Cycle 1* 
8 
3h (+/- 15min) 
3 
1 
104 
Induction 1 Cycle 1* 
8 
6h (+/- 30min) 
3 
1 
105 
Induction 1 Cycle 1* 
8 
12h (+/- 30min) 
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 
8 
Pre-dose 
3 
6 
113 
Consolidation Cycle 1 
8 
Post-dose 3hrs +/- 0.5 
hrs 
3 
7/701 
114 
Consolidation, cycle 1 
21 
Pre-dose 
3 
7 
115 
Consolidation, cycle 1 
21 
Post-dose 3hrs +/- 0.5 
hrs 
3 
8/801 
116 
Consolidation, cycle 3 
8 
Pre-dose 
3 
8 
117 
Consolidation, cycle 3 
8 
Post-dose 3hrs +/- 0.5 
hrs 
3 
9/901 
118 
Consolidation, cycle 3 
21 
Pre-dose 
3 
9 
119 
Consolidation, cycle 3 
21 
Post-dose 3hrs +/- 0.5 
hrs 
3 
11/1101 
121 
Continuation , cycle 5 
1 
Pre-dose 
3 
12/1201 
122 
Continuation, cycle 9 
1 
Pre-dose 
3 
13/1301 
123 
Completion of C12 
28 
Pre-dose 
3 
Total volume 
69 
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 refer to the 
administration the day before (The information has to be collected) 
Unscheduled blood samples will be uniquely, sequentially numbered 1001, 1002, … 


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7.2.3.2 
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. 
 
7.2.4 
Biomarkers 
In addition to establishing FLT3 mutation status in order to determine patient eligibility for the 
study, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 7-6 
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 


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7.2.4.2 
Additional biomarker assessments 
Not applicable 
 
 
 
 
 
 
 
 
Other assessments 
No additional tests will be performed on patients entered into this study. 


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7.2.6 
Patient reported outcomes 
The European Organization for Research and Treatment of Cancer’s core quality of life 
questionnaire (EORTC-QLQ-C30, version 3.0) will be used to evaluate patient-reported 
outcome measures of health-related quality-of-life, functioning, disease symptoms, treatment- 
related side effects, and global health status. The EORTC QLQ-C30 is recognized as reliable 
and valid measures (Aaronson 1993, Rabin 2001, Cormier 2008) frequently used in clinical 
trials of patients with newly diagnosed acute myeloid leukemia. In addition, the patient global 
impression of change (PGIC) will also be administered at the same time. This one item 
questionnaire will be used to anchor the results of the EORTC QLQ-C30. 
All patient-reported outcome (PRO) measures will be administered at screening, at Day21 of 
each cycle until the end of consolidation phase, then Day1 of each cycle during the continuation 
phase, at End of study treatment and during the post treatment follow-up every 4 months during 
the first year, according to the Visit Evaluation in Table 7-1. However, the PGIC will not be 
administered at screening. 
PRO data will be collected using an electronic tablet device and should be administered in the 
patient’s local language at the beginning of the study visit prior to any interaction with the study 
investigator including any tests, treatments or receipt of results from any tests to avoid biasing 
the patient’s perspective. Patients should be given sufficient space and time to complete all 
study questionnaires and all administered questionnaires should be reviewed for completeness. 
If missing responses are noted, patients should be encouraged to complete them. Attempts 
should be made to collect responses to the questionnaire for all patients, including from those 
who discontinue prior to the study evaluation completion visit, however, if patients refuse to 
complete questionnaire, this should be documented in study source records. Patient’s refusal to 
complete study questionnaire is not protocol deviation. 
Completed questionnaires, including both responses to the questions and any unsolicited 
comments written by the patient, must be reviewed and assessed by the investigator before the 
clinical examination for responses which may indicate potential AEs or SAEs. This review 
should be documented in study source records. 
If an AE or SAE is confirmed then the physician should record the event as instructed in Section 
8 of this protocol. Investigators should not encourage the patients to change responses reported 
in questionnaires. 


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7.2.6.1 
EORTC QLQ-C30 
The EORTC QLQ-C30 contains 30 items and is composed of both multi-item scales and single- 
item measures. These include five functional scales (physical, role, emotional, cognitive and 
social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), six single items 
(dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global 
health status/QoL scale (Aaronson 1993). All of the scales and single-item measures range in 
score from 0 to 100. A high scale score represents a higher response level. Thus, a high score 
for a functional scale represents a high / healthy level of functioning; a high score for the global 
health status / QoL represents a high QoL, but a high score for a symptom scale / item represents 
a high level of symptomatology / problems. All scoring will follow the scoring procedures 
defined by the EORTC Scoring Manual (Fayers 2001). 
 
7.2.6.2 
Patient Global Impression of Change (PGI-C) 
The PGI-C is a single self-reported item that asks about change in status of a patient’s overall 
satisfaction with medication since starting the standalone study. The specific wording of the 
PGI-C is “Directions: Circle the one number that best describes how your overall satisfaction 
with your medication has changed since starting the study”: “Very much improved” =1; “Much 
improved” =2; “Minimally improved” =3; “No change” =4; “Minimally worse” =5; “Much 
worse” =6; “Very much worse” =7. PGI-C questions have been widely used to assess the patient 
perspective of improvement in clinical trials and have shown clinical validity in a variety of 
indications, including depression (Mallinckrodt et al 2005), urinary incontinence (Kinchen et al 
2005) and adult asthma (Guy 1976, Hahn 1995). 
 
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. 
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. 


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Adverse events will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (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 
though a Death form. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) 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 
(subject) 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 (Reasonable possibility that AE is related: No, 
Yes) 
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, 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 serious adverse event (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 
sequalae, 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 necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per Cheson's guidelines for hematological malignancies), should not 
be reported as a serious adverse event. 
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of progressive disease) will be 
reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug. 


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8.1.2 
Laboratory test abnormalities 
 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an Adverse event 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 Adverse Events 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 the sponsor’s product or program, 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. 
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. AESIs 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 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 


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• 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 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. 


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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, patient number, and instructions for contacting the local Novartis 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. 
Study treatment must be discontinued once emergency unblinding has occurred. 
 
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 Chief Medical Office and Patient Safety (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. 
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: 


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• 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 
Independent Safety Committee 
The data from the part 1 in Japan will be evaluated by the Independent Safety Committee, which 
will comprise three external Japanese medical experts who will comprehensively determine the 
safety and tolerability of midostaurin in combination with the JALSG or RATIFY regimen in 
Japanese patients. The Independent Safety Committee will evaluate data from the part 1 only. 
The Independent Safety Committee will take into consideration all available safety data up to 
the time of the safety review data cut-off date, which comprises data during induction therapy 
through to the end of the safety evaluation period (Day 21 of first consolidation cycle). 
The first safety review by the Independent Safety Committee will take place when at least three 
evaluable patients have completed the safety evaluation period without a potential Safety Event 
or have experienced a potential Safety Event within this period. However, the Independent 
Safety Committee may review the safety of patients before this time if deemed necessary based 
on the ongoing safety experience. 


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8.7 
Study Steering Committee 
The Study Steering Committee will be established comprising investigators participating in the 
trial. 
The Study Steering Committee will ensure transparent management of the study according to 
the protocol through recommending and approving modifications as circumstances require. The 
Study Steering Committee will review protocol amendments as appropriate. Together with the 
clinical trial team, the Study Steering Committee will also develop recommendations for 
publications of study results including authorship rules. The details of the role of the Study 
Steering Committee will be defined in a Steering Committee charter. 
The Study Steering Committee will not have access to un-blinded trial data prior to the primary 
analyses. 
 
8.8 
Data Monitoring Committee 
This study will include a data monitoring committee (DMC) that will be used only for the 
interim analysis, 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 review efficacy and safety data, and inform the sponsor whether the success criteria will 
be met at the interim analysis (for more detailed information for the interim analysis, see Section 
10.7). 
Specific details regarding composition, responsibilities, data monitoring and meeting frequency, 
documentation of DMC reports, minutes, and recommendations will be described in a separate 
charter that is established between the sponsor and the DMC. 
 
9 
Data collection and management 
9.1 
Data confidentiality 
Information about study patients 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 patients 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 
information. Access to the system will be controlled by a sequence of individually assigned 


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user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training. 
 
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 Electronic Case Report Forms (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 the electronic Case Report Forms are 
complete and accurate and that entry and updates are performed in a timely manner. Data 
collected by site by analyzed centrally such as 
 PK, ECG will be sent electronically 
to Novartis. 
 
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 is 
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 


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system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
Samples and/or data will be processed centrally, and the results will be sent electronically to 
Novartis (or a designated CRO) or entered into the eCRFs by the designated laboratory staff. 
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 (or designated CRO). 
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 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 
Safety evaluation part (Part 1, Japan only) 
The safety and tolerability of midostaurin in combination with chemotherapy in Japan will be 
assessed based on the incidence of Safety Events during the safety evaluation period. A Safety 
Event is defined as death or serious adverse event leading to treatment discontinuation that 
occurs on or before Day 21 of the first consolidation cycle and that is determined by the 
Independent Safety Committee to be definitely or probably related to midostaurin. 
All patients enrolled part 1 will be listed and reviewed irrespective of the combination treatment 
(JALSG or RATIFY regimen). 
The analyses for the safety review will be performed when the available data is adequate to 
perform a data analysis. Details will be described in a separate SAP for the safety review (see 
Section 10.7). 
 
Randomized part (Part 2) 
In the part 2, interim, primary and final analyses will be conducted. 
The interim analysis will be performed when 60 patients are randomized and at least 24 EFS 
events are documented. The interim analysis will be performed by an independent statistician 
and an independent programmer. Please refer to Section 10.7 for more details. 
The primary analysis will be performed using the pre-defined cut-off date of 30 November 2020 
with the number of EFS events documented by this date. 


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The end of study will occur at the latest 36 months after the start of the study treatment for the 
last patient. At this time, the final analysis will be performed. 
All patients will remain in post-treatment or survival follow-up until the cut-off date of the final 
analysis and all available data from all patients up to this cut-off date will be analyzed. 
For screen failure, patients who signed the informed consent but never started the study 
treatment for any reason, and non-randomized patients, the eCRF data collected will not be 
included in analyses, but will be reported in CSR as separate listings as appropriate. 
 
10.1 
Analysis sets 
10.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients to whom study drug (midostaurin /placebo) 
has been assigned by randomization. Therefore, all Japanese patients treated during the part 1 
will not be eligible for the FAS. According to the intent to treat principle, patients will be 
analyzed according to the treatment and strata they have been assigned to during the 
randomization procedure. 
 
10.1.2 
Safety set 
The Safety Set includes all randomized patients who received at least one dose of study drug. 
Patients will be analyzed according to the part in which they are enrolled and the study treatment 
received, where treatment received is defined as the randomized treatment if the patient took at 
least one dose of that treatment or the first treatment received if the randomized treatment was 
never received. 
 
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 the requirements of the study protocol. 
Oncology standards for protocol deviations potentially leading to exclusion from the PPS are: 
• Type of indication different from those required by the CSP (e.g., incorrect 
histology/cytology, not refractory, not metastatic, different grade of cancer, etc.) 
• if prior therapy does not match with CSP requirements in terms of number and types of 
previous therapy regimens 
• missing or incomplete documentation of classification of disease (as required in the CSP) 
• another anti-neoplastic therapy administered after start of study treatment and prior to first 
efficacyassessment 
• study treatment received different from treatment assigned by randomization 
10.1.4 
Dose-determining analysis set 
Not applicable. 


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10.1.5 
Pharmacokinetic analysis set 
 
10.1.5.1 Pharmacokinetic analysis set for all (PAS-all) 
The Pharmacokinetic analysis set for all (PAS-all) includes all patients who took at least one 
dose of midostaurin and provide at least one evaluable PK concentration. 
For a concentration to be evaluable, patients are required to: 
• Take the planned dose of midostaurin prior to sampling 
• For pre-dose samples: do not vomit within 4 hours after the dosing of midostaurin prior to 
sampling, have the sample collected before the next dose administration 
• For post-dose samples: do not vomit within 4 hours after the dosing of midostaurin 
The PAS-all will be the primary population used for all pharmacokinetic analyses using trough 
concentration data. 
 
10.1.5.2 Pharmacokinetic analysis set for full PK (PAS-full) 
The Pharmacokinetic analysis set for full PK (PAS-full) includes all patients in the PAS-all, 
who provide an evaluable PK profile. A profile is considered evaluable if all of the following 
conditions are satisfied: 
• Patient receives the planned dose of midostaurin on C1D8 of induction therapy 
• Patient did not vomit within 4 hours of the dosing of midostaurin on C1D8 of induction 
therapy 
• Patient provides at least one primary PK parameter 
The PAS-full will be the primary population used for all pharmacokinetic analyses using full 
PK data. 
 
10.1.6 
Other analysis sets 
Not applicable. 
 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment arm for the FAS and the Safety Set. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. 
Relevant medical histories and current medical at baseline will be summarized by system organ 
class and preferred term, by treatment arm. 
 
10.3 
Treatments (study treatment, concomitant therapies, 
compliance) 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, minimum, 
and maximum will be presented. 


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The duration of exposure in day to study drug (midostaurin/placebo), daunorubicin and 
cytarabine as well as the dose intensity (computed as the ratio of actual cumulative dose 
received and actual duration of exposure) and the relative dose intensity (computed as the ratio 
of dose intensity and planned dose intensity) will be summarized by means of descriptive 
statistics using the safety set. 
The duration of exposure for the study treatment will also be presented by chemotherapy 
regimen and treatment arm. 
The number of patients with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized by chemotherapy regimen and treatment 
arm and all dosing data will be listed. 
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 arm. 
The number of regimens of the new anti-neoplastic therapy initiated after discontinuation of 
study treatment regardleess of end of study treatment reason will be summarized for the FAS. 
In addition, the regimen of the next line of therapy, defined as the first new anti-neoplastic 
therapy initiated after discontinuation of study treatment regardless of end of study treatment 
reason, and its duration and best response will be summarized for the FAS. 
 
10.4 
Primary objective 
The primary objective for the part 1 is to evaluate the safety and tolerability of midostaurin in 
combination with chemotherapy in Japanese patients with newly diagnosed AML. 
The primary objective for the part 2 is to evaluate the efficacy based on event-free survival 
(EFS) of midostaurin versus placebo in combination with daunorubicin/cytarabine induction, 
with high-dose cytarabine consolidation, and with midostaurin single agent continuation 
therapy in newly diagnosed patients with FLT3-mutated AML. 
 
10.4.1 
Variable 
The primary variable for the part 1 in Japan is the incidence of Safety Events, defined as death 
or serious adverse event leading to treatment discontinuation that occurs on or before Day 21 
of the first consolidation cycle and that is determined by the Independent Safety Committee to 
be definitely or probably related to midostaurin, among evaluable patients. 
The primary efficacy variable for the part 2 is event-free survival (EFS), defined as the time 
from the date of randomization until an EFS event is observed. An EFS event is defined as a 
failure to obtain a CR within induction 2, relapse after CR, or death due to any cause, whichever 
occurs first. Clinical response (CR, CRp, PR and treatment failure after CR) will be assessed 
via local review according to criteria defined in Section 10.5.2.2. For patients with treatment 
failure, the EFS will be replaced to 1. 
All efficacy analyses for the part 2 will be based on FAS and will include all data observed up- 
to the cut-off date. If a patient has not observed EFS event at the analysis cut-off date, EFS will 
be censored at the date of the last adequate clinical assessment before the cut-off date. 


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10.4.2 
Statistical hypothesis, model, and method of analysis 
As the primary analysis for the part 1, all adverse events of all patients enrolled in the part 1 
will be listed. 
The interim and primary efficacy analyses for the part 2 will be the comparison of the 
distribution of EFS between the two treatment arms. The estimated hazard ratio (HR) of EFS 
not censored at SCT will be calculated using Cox regression model stratified according to the 
2 stratification factors (FLT3 mutation status: ITD allelic ratio <0.7, ITD allelic ratio ≥ 0.7, 
TKD; and regimen: RATIFY regimen, JALSG regimen). In addition, associated 95% Wald 
confidence interval (CI) will be calculated. The success of the study will be claimed when 
estimated HR is less than 1. In addition, for the interim analysis, the Bayesian predictive 
probability of (HR for EFS when 36 EFS events are documented < 1) given data up to the data 
cut off for interim analysis > 0.9 also need to be satisfied to declare the success of the study 
(described in Section 10.7). This interim analysis will be assessed by a DMC, however, even if 
interim success criteria are met, the study will be continuing blinded to patients, investigators 
and monitors until the primary analysis and thereafter the study will be unblinded. At the final 
analysis more mature data can be evaluated . 
The survival distribution of EFS will be estimated using the Kaplan-Meier method. The results 
will be plotted graphically by treatment arm. The median of EFS along with 95% confidence 
intervals will be presented by treatment arm. 
 
10.4.3 
Handling of missing values/censoring/discontinuations 
In the primary analysis for the part 2, EFS will be censored at the date of the last adequate 
clinical assessment if no EFS event is observed prior to the analysis cut-off date. 
The date of last adequate clinical assessment will be the final timepoint for the evaluation of 
efficacy before an event or a censoring reason occurred. In this case the last clinical assessment 
date at that assessment will be used. If no post-baseline assessments are available (before an 
event or a censoring reason occurred) then the date of randomization will be used. 
Refer to Table 10-1 for censoring and event date options and outcomes for EFS. 
 
Table 10-1  Outcome and event/censor dates for EFS analysis 
Situation 
Date 
Outcome 
No baseline assessment 
Date of randomization 
Censored 
No post-baseline assessment 
Date of randomization 
Censored 
Treatment failure 
Date of randomization + 1 
EFS event 
Relapse or death at or before next 
scheduled assessment 
Relapse or death after exactly one 
missing assessment 
Date of relapse or death 
EFS event 
 
Date of relapse or death 
EFS event 
Relapse or death after two or more 
missing assessments 
Date of last adequate assessment 
prior to missed assessment 
Censored 
No relapse or death 
Date of last adequate assessment 
Censored 
Strong CYP3A4 inducer given prior 
to protocol defined progression 
Date of last adequate assessment 
Censored 
 


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Situation 
Date 
Outcome 
New anticancer therapy given prior 
to protocol defined progression 
Ignore the new anticancer therapy 
and follow situations above 
As per above situations 
 
 
10.4.4 
Supportive and Sensitivity analyses 
In part 2, sensitivity analyses in the FAS will be performed for EFS per local review where: 
• A sensitivity analysis by using EFS defined as the time from the start of the study 
treatment until an EFS event is observed. 
• A sensitivity analysis considering SCT: patients are considered as censored at the time of 
the transplant if they received SCT. 
In addition, the Bayesian posterior probability of (HR for EFS per local review < 1) will be 
calculated as a supportive analysis. Assuming a weakly informative prior distribution derived 
from Study [A2301] data, the distribution of the HR will be updated with all available data 
from the patients included in the FAS (for more detail, refer to Section 14.1). 
If the primary analysis shows successful, subgroup analyses to assess the homogeneity of the 
treatment effect across demographic and baseline disease characteristics will be performed. The 
subgroups are as follows: 
• FLT3 mutation status (stratification factor; ITD allelic ratio <0.7, ITD allelic ratio ≥ 0.7, 
TKD) 
• chemotherapy regimen (stratification factor; RATIFY regimen, JALSG regimen) 
• gender 
• age category: < 60 years, ≥ 60 years 
For each of the subgroups, the treatment effect will be assessed separately within each category. 
The HR and their 95% CIs will be presented by means of forest plots. 
 
10.5 
Secondary objectives 
10.5.1 
Key secondary objective(s) 
Not applicable. 
 
10.5.2 
Other secondary efficacy objectives 
The secondary objectives in this study are: 
• To determine overall survival (OS) in the two treatment groups 
• To determine the rate of complete remission (CR) in the two treatment groups 
• To determine the cumulative incidence of relapse (CIR) in the two treatment groups 
• To evaluate the safety of midostaurin compared to placebo in combination with 
chemotherapy and as single agent continuation therapy 
• To evaluate the pharmacokinetics of midostaurin and its two major metabolites CGP52421 
and CGP62221 
• To determine the effect of the study treatment on quality of life 


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10.5.2.1 Overall survival (OS) 
OS is defined as the time from the date of randomization to date of death due to any cause. All 
deaths occurring on or before the cut-off date in the FAS will be used in the OS analysis. If a 
patient is not known to have died at the time of analysis cut-off, OS will be censored at the date 
of last contact. 
The OS distribution will be estimated using the Kaplan-Meier method, and the Kaplan-Meier 
curves, medians and 95% CIs of the medians will be presented for each treatment arm. The HR 
along with its 95% CI will be calculated, using a stratified Cox model using the randomization 
stratification factors. 
As sensitivity analyses performed in the FAS, the hazard ratio and 95% CI for OS will be 
obtained from: 
• A sensitivity analysis by using OS defined as the time from the start of the study treatment 
until an OS event is observed. 
• A sensitivity analysis considering SCT: patients are considered as censored at the time of 
the transplant if they received SCT. 
If the estimated HR by a stratified Cox model using the randomization stratification factors is 
less than 1, subgroup analyses to assess the homogeneity of the treatment effect across 
demographic and baseline disease characteristics will be performed. The subgroups are as 
follows: 
• FLT3 mutation status (stratification factor; ITD allelic ratio <0.7, ITD allelic ratio ≥ 0.7, 
TKD) 
• chemotherapy regimen (stratification factor; RATIFY regimen, JALSG regimen) 
• gender 
• age category: < 60 years, ≥ 60 years 
For each of the subgroups, the treatment effect will be assessed separately within each category. 
The HR and their 95% CIs will be presented by means of forest plots. 
 
10.5.2.2 Complete remission (CR) rate 
CR rate is defined as the proportion of patients with a CR according to Cheson criteria (Cheson 
2003). CR rate will be calculated using the FAS. 
CR rate will be summarized for end of induction cycle 1, end of induction cycle 2, end of 
consolidation and after treatment discontinuation. The difference in CR rates along with two- 
sided exact 95% CIs (Clopper and Pearson 1934). 
 
10.5.2.3 Cumulative incidence of relapse 
Cumulative incidence of relapse (CIR) is defined for patients who have achieved CR only. CIR 
will be calculated from the date of first CR to relapse or death due to AML, whichever occurs 
first. If a patient is not known to have relapse at the time of analysis cut-off, CIR will be 
censored at the date of last adequate assessment. If a patient has died due to other reason than 
AML without relapse prior to death, CIR will be censored at the date of the death. 


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The survival distribution of CIR distributions will be estimated using the Kaplan-Meier method, 
and Kaplan-Meier curves, medians and 95% CIs (Brookmeyer and Crowley 1982) of the 
medians will be presented for each treatment arm. The HR for CIR will be calculated, along 
with its 95% CI, using a stratified Cox model using the randomization stratification factors. 
As a sensitivity analysis, the same analyses when patients are considered as censored at the time 
of the transplant if they received SCT will be performed. 
 
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 arm. 
The overall observation period will be divided into three mutually exclusive segments: 
• pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study treatment 
• on-treatment period: from day of first dose of study treatment to 30 days after last dose of 
study treatment 
• post-treatment period: starting on day 31 after last dose of study treatment. 
10.5.3.2 Adverse events (AEs) 
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs. 
The incidence of treatment-emergent AEs (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment. 
Serious AEs, non-serious AEs and AEs of special interest (AESI) during the on-treatment 
period will be tabulated. 
All deaths (on-treatment and post-treatment) will be summarized. 
All AEs, deaths and serious AEs (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. 
 
10.5.3.3 Laboratory abnormalities 
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (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. Grade 5 
will not be used. 
For laboratory tests where grades are not defined by CTCAE version 5.0, results will be 
categorized as low/normal/high based on laboratory normal ranges. 


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The following listings/summaries will be generated separately for hematology, and 
biochemistry tests: 
• Listing of all laboratory data with values flagged to show the corresponding CTCAE 
version 5.0 grades if applicable and the classifications relative to the laboratory normal 
ranges 
• For laboratory tests where grades are defined by CTCAE version 5.0, shift tables using 
CTCAE version 5.0 grades to compare baseline to the worst on-treatment value 
• For laboratory tests where grades are not defined by CTCAE version 5.0, shift tables using 
the low/normal/high/ (low and high) classification to compare baseline to the worst on- 
treatment value. 
10.5.3.4 Other safety data 
ECG 
12-lead ECGs including PR, QRS, QT, QTcF, and HR will be obtained for each subject during 
the study. ECG data will be read and interpreted centrally. 
Categorical Analysis of QT/QTcF interval data based on the number of patients meeting or 
exceeding predefined limits in terms of absolute QT/QTcF intervals or changes from baseline 
will be presented. In addition, a listing of these patients will be produced by treatment arm. 
 
Vital signs 
Data on vital signs will be tabulated and listed, notable values will be flagged. 
 
Other assessments 
Cardiac MUGA/ECHO will be collected at baseline, EOT visit and during the study if clinically 
needed. 
Chest X ray will be collected at baseline and during the study if clinically needed. 
 
10.5.3.5 Supportive analyses for secondary objectives 
To assess the homogeneity of the treatment safety profile of study drug across demographic and 
baseline disease characteristics, subgroup analyses may be performed. Details of such analyses 
will be described in the SAP if appropriate. 
 
10.5.3.6 Tolerability 
Tolerability of study drug will be assessed by summarizing the number of dose interruptions 
and dose reductions. Reasons for dose interruption and dose reductions will be listed by patient 
and summarized. 
 
10.5.4 
Pharmacokinetics 
PK parameters for midostaurin and its two major metabolites CGP52421 and CGP62221 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 


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therapy. PK parameters listed in Table 10-2 will be estimated and reported, when feasible. 
AUClast, AUC0-t and Cmax are defined as primary parameters (contributing to PAS definition). 
All others are secondary and will be determined if feasible (including CL/F). 
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. 
Trough 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. 
More details on the PK analysis will be given in the SAP. 
Exposure-response analyses for relevant efficacy and safety endpoints will be further discussed 
as appropriate in the SAP. 
 
Table 10-2    Noncompartmental pharmacokinetic parameters 
 
AUC0-t 
The area under the curve (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 
The total score of the QLQ-C30 and PGIC score are identified as the primary PRO variables of 
interest. Physical functioning, emotional functioning and social functioning scale scores of the 
QLQ-C30 are identified as secondary PRO variables of interest. The FAS will be used for 
analyzing PRO data. Scoring of PRO data and methods for handling of missing items or missing 
assessments will be handled according to the scoring manual (see Appendix 5). No imputation 
procedures will be applied for missing items or missing assessments. 
The QLQ-C30 scores will be analyzed using a repeated measures model for longitudinal data 
to assess the treatment effect over time including terms for treatment, stratification factors, time 
of visit (in weeks counting from the time of randomization to the time of a particular post 
baseline measurement in time windows), treatment by time of visit interaction, and baseline 
score. The differences in least square means between treatment and control group, and the 
corresponding 95% CI at selected timepoints will be presented. All available data until the end 
of treatment will be used in the repeated measures models for longitudinal data which assume 


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that the missing scores at any time point are missing-at-random. Additional sensitivity analysis 
may be performed to assess the possible violation of missing-at-random assumption for the 
missing data mechanism if deemed appropriate. Details will be specified in the SAP. 
Descriptive statistics will be used to summarize the QLQ-C30 scores and absolute change from 
baseline scored scales at each scheduled assessment. 
Also, the PGIC score will be presented as frequencies and percentages by scheduled timepoint 
and treatment arm. 
Patient reported Outcomes will be administered electronically (ePROs), questionnaires will be 
loaded on a tablet. The site will need to register the patient’s arrival prior to handing the site 
based tablet. The site coordinator has to make sure that the tablets are charged and the site sets 
up their log in information (user ID and passwords) prior to handing the device to patients. Note 
that if one site has multiple ePRO devices, and if they plan to have the same patient use different 
devices to fill out their PRO data at different points of time, they must ask the patients to create 
their log in ID’s in each of the devices. Please ask site staff to train patients, provide them with 
helpdesk information and reference guides for ePROs. In exceptional cases only, e.g., in the 
event of technical problems with the ePRO device(s), the patient should be asked to complet a 
paper version of the questionnaire(s). 
 
 


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10.7 
Interim analysis 
For part 2, an interim analysis for efficacy will be conducted when 60 patients are randomized 
and at least 24 EFS events are documented (expected around 14 months from the date of first 
patient randomized in the study assuming the recruitment period as 14 months). In case that 36 
EFS events are documented before randomization completion, the interim analysis can be 
skipped and Novartis will conduct primary analysis. 


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At the interim analysis, the study will be considered as a positive result when the following both 
success criteria are met: 
• Criterion 1: estimated HR at interim analysis < 1. 
• Criterion 2: the Bayesian predictive probability of (HR for EFS when 36 EFS events are 
documented < 1) given data up to the data cut off for interim analysis > 0.9. To calculate 
the predictive probability, assuming a weakly informative prior distribution derived from 
Study [A2301] data and the prior distribution will be updated using the available data 
from patients in the FAS at interim analysis (for more detail of weakly informative prior, 
refer to Section 14.1). 
This interim analysis will be assessed by a DMC, however, even if interim success criteria are 
met, the study will be continuing blinded to patients, investigators and monitors until the 
primary analysis and thereafter the study will be unblinded. At the final analysis more mature 
data can be evaluated. 
The interim analysis will be performed by an independent statistician and an independent 
programmer who provides the results to the DMC. The DMC will then be assessing the success 
criteria. Further details will be described in the DMC charter. 
If Health Authorities require to submit the study results after interim analysis but before primary 
analysis, additional analysis may be performed. 
The primary analysis will be performed using the pre-defined cut-off date of 30 November 2020 
with the number of EFS events documented by this date. The end of study will occur at the 
latest 36 months after the start of the study treatment for the last patient. At this time, the final 
analysis will be performed. 
For all of interim, primary and final analyses, the type I error alpha will not be considered 
because this study will pursue an estimation approach rather than formal hypothesis testing in 
which the criteria for success is based on the probability of HR< 1 in favor of midostaurin. 
ISC will review all available safety data in the part 1 to evaluate whether the trial may advance 
to the part 2 in Japan. The analyses may be performed by a trial statistician internal to Novartis 
and their results will be provided to the Independent Safety Committee, when the available data 
is adequate to perform a data analysis. Details will be described in a separate SAP for the safety 
review. 
 
10.8 
Sample size calculation 
Safety evaluation part (in Japan only) 
A minimum of 3 (if no Safety Events) or 6 eligible Japanese patients will be required to confirm 
the tolerability of midostaurin in combination with standard chemotherapy in the safety 
evaluation period. No formal statistical power calculations to determine sample size were 
performed for this study. 


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Randomized part 
This is a bridging study that will support the registration in Japan. This study will pursue an 
estimation approach rather than formal hypothesis testing in which the criterion for success is 
based on the probability of HR< 1 in favor of midostaurin. 
As per the initial protocol design (i.e. pre-Amendment 3), the required sample size for the part 
2 of the study was determined based on the empirical probability to meet the success criterion. 
It was assumed that EFS for midostaurin and placebo in A2220 would follow the same survival 
distributions as observed in study [A2301]. Consequently all factors which might affect the EFS 
prolongation e.g. SCT rate in CR1 were also assumed to be the same as in Study [A2301]. It 
was also assumed that there was no difference between the two chemotherapy regimens 
(RATIFY regimen and JALSG regimen). 
In order to calculate the probability to meet the success criterion, a simulation study was 
performed using actual EFS data from Study [A2301]. To simulate a study, 30 patient 
observations were randomly selected from each treatment arm of Study [A2301] and 30000 
studies were simulated. The median EFS and HR for EFS were calculated for each study. The 
median EFS in the control arm averaged 5.4 months and in the midostaurin arm 10.3 months. 
The average hazard ratio was 0.77 (corresponding to a 23% reduction in the hazard rate for 
EFS), which was similar to estimated HR in Study [A2301] of 0.728. 
In addition to the above assumptions, assuming that enrollment will continue for approximately 
15 months at a uniform rate of 4 patients a month and the primary analysis will occur when 36 
EFS events are documented (expected 21 (95%CI: [14.4, 34.2]) months from date of first patient 
to be randomized), 60 patients will need to be randomized to the two treatment arms in 1:1 ratio 
to meet the success criterion with a probability of 84.1%. 
In addition to the above simulation, another simulation was performed to calculate the 
probability of success at interim analysis. When the enrollment period will be 14 months 
considering the currently expected enrollment rate, the probability to meet success criteria at 
interim analysis (described in Section 10.7) is 78.1% and the time from first patient to be 
randomized to the interim analysis is expected to be 14.1 (2.5 - 97.5 percentile: [14.0 – 15.4]) 
months based on same survival distribution as in Study [A2301]. In addition, the conditional 
probability to meet the success criterion of primary analysis under showing positive result at 
interim analysis is 96.8%. For more details, please refer to Section 14.1. 
Based on the overall observed EFS events over time, the rate of discontinuations without EFS 
event and the predictions of future events, there is a risk that the targeted 36 EFS events will 
not be observed within a reasonable timeframe. Therefore the primary analysis will be 
performed using the pre-defined cut-off date of 30 November 2020 with the number of EFS 
events documented by this date. 
As per the current number of patients who are still on follow-up for EFS and the survival 
distributions of EFS post-induction observed in study [A2301], additional 5 EFS events are 
expected to be observed until 30 November 2020. The study power would be approximately 
82.7% when total 33 EFS events are observed under the original assumptions shown above (that 
is, EFS for midostaurin and placebo in A2220 would follow the same survival distributions as 
observed in study [A2301], consequently all factors which might affect the EFS prolongation 


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e.g. SCT rate in CR1 were the same as in Study [A2301], and there was no difference between 
the two chemotherapy regimens). 
 
10.9 
Power for analysis of key secondary variables 
Not applicable. 
 
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 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, 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. 
 
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 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 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. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 


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11.4 
Additional consent form 
Not applicable 
 
11.5 
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. 
 
11.6 
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., LPLV), those for interventional clinical trials involving 
pediatric patients within 6 months of study completion. 
Novartis follows the 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. 
 
11.7 
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 


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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. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (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. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs. 
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. 
 
11.8 
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. 
 
11.9 
Audits and inspections 
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities. 
 
11.10 
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 


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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. 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 (e.g. UK requires the notification of urgent safety measures 
within 3 days) but not later than 10 working days. 


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13 
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14 
Appendices 
14.1 
Appendix 1 - The Bayesian model, prior, and operating 
characteristics 
14.1.1 
Introduction 
In this study, the Bayesian predictive probability of (HR for EFS when 36 EFS events are 
documented < 1) will be calculated at the interim analysis and the Bayesian posterior probability 
of (HR for EFS per local review < 1) will be calculated as a supportive analysis at the primary 
analysis. This section provides details of the statistical model, the derivation of prior 
distributions for the model parameters, and the operating characteristics of the study design. 
 
14.1.2 
Motivation 
Because this is the bridging study and its target population is very rare, the sample size of this 
study is very small. Therefore, the available information should be very limited. At the interim 
analysis, the available information should be more limited. 
In such a case, borrowing available information from the original study is very useful to 
strengthen the result of this study. Bayesian approach is one of effective way to borrow the 
available information from the original study. 
 
14.1.3 
Statistical model 
Let 𝑌𝑌 denote the natural logarithm of the observed hazard ratio (HR). We assume that the 
asymptotic normality of the log-rank statistic for 𝑌𝑌 holds [see D. Schoenfeld, Biometrika, Vol. 
68, No. 1 (Apr., 1981), pp. 316-319] such that under a 1:1 randomization we have that: 
Y|𝜃𝜃 ~ 𝑁𝑁(𝜃𝜃, √4/𝑘𝑘0
2), where 𝜃𝜃 is the unknown true log(HR) and 𝑘𝑘0 is the number of events. 
The prior for the true log(HR) parameter 𝜃𝜃 is defined as a mixture between an informative and 
a non-informative prior. For the informative part of the prior we use the meta-analytic- 
predictive (MAP) approach which facilitates the Study [A2301] data and accounts for between- 
study heterogeneity. Its derivation is detailed below. The non-informative mixture component 
is used in order to account for the possibility that the data in the new study is strongly deviating 
from the previously observed Study [A2301] result. We place equal weight of 50% on each 
prior component. The definition of the non-informative prior and the overall operating 
characteristics are detailed below. 
 
14.1.4 
Prior specifications 
 
Description of the meta-analytic-predictive (MAP) approach 
The aim of the MAP approach is to derive an informative prior for the log(HR) parameter in 
the new study which we denote with 𝜃𝜃∗. The MAP approach accounts for possible between- 
trial heterogeneity using an exchangeability model for the study specific mean of the log(HR) 
values of the historical studies (i.e., Study [A2301]). 


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Let 𝑌𝑌ℎ and 𝑘𝑘ℎ be the log(HR) and the total number of events in the historical study ℎ (h= 
1, … , 𝐻𝐻). Under the normal approximation of the log(HR) the MAP prior is defined by: 
𝑌𝑌ℎ | 𝜃𝜃ℎ ~ 𝑁𝑁 (𝜃𝜃ℎ, √4/𝑘𝑘ℎ
2) 
𝜃𝜃ℎ | 𝜇𝜇, 𝜏𝜏 ~ N(𝜇𝜇, 𝜏𝜏2), 
h = 1, … , H 
𝜃𝜃∗ | 𝜇𝜇, 𝜏𝜏 ~ N(𝜇𝜇, 𝜏𝜏2), 
μ~𝑃𝑃𝜇𝜇 
τ ~ 𝑃𝑃𝜏𝜏 
𝜃𝜃∗| (𝑦𝑦ℎ, 𝑘𝑘ℎ ∶ ℎ = 1, … , 𝐻𝐻 ) 
The model is a standard hierarchical normal-normal model with the population mean parameter 
μ and the between-trial heterogeneity parameter 𝜏𝜏 . The priors 𝑃𝑃𝜇𝜇 and 𝑃𝑃𝜏𝜏 for the population 
parameters will be defined below. The MAP prior for the model parameter 𝜃𝜃∗ is the predictive 
distribution. 
Since the predictive distribution is not available analytically, MCMC is used to simulate values 
from this distribution. This is implemented using Stan version 2.7.0. The sample from this 
distribution, which is obtained as numerical MCMC sample, is then approximated by a mixture 
of normal distributions. Normal mixtures with increasing numbers of mixture components are 
fitted to the sample using the expectation-maximization (EM) algorithm (Dempster 1977). The 
optimal number of components of the mixture is then identified using the Akaike information 
criterion (AIC) (Akaike 1974). 
 
Weakly informative prior derived by MAP approach 
Available log(HR) from the Study [A2301] study are used to derive the MAP prior for the 
model parameter 𝜃𝜃. The MAP prior for the model parameter is derived as follows: 
• H = 1. 
• We set the prior 𝑃𝑃𝜇𝜇 for μ to be non-informative by assigning it a normal distribution with 
mean 0 and standard deviation of 2. This corresponds to a single observation of no effect 
such that μ~N(0, 22). 
• In order to incorporate the moderate heterogeneity between the Study [A2301] data and 
the current data, the prior 𝑃𝑃𝜏𝜏 for the between-trial standard deviation 𝜏𝜏 is assumed to 
follow a half-normal distribution with the standard deviation set to 1/2. This represents the 
assumption of heterogeneous trails as the sampling standard deviation is 2, see [DOI: 
10.1002/bimj.201500236]. 
• From the historical data of Study [A2301] (Table 14-1), 𝑌𝑌1=log(0.728) = -0.317 and 𝑘𝑘1= 
521. 


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Table 14-1 
Data from CPKC412A2301 study 
 
MIDOSTAURIN 
PLACEBO 
HR [95% CI] 
Event Free Survival 
N=360 
N=357 
MIDOSTAURIN / PLACEBO (1) 
Number of events (%) 
244 ( 67.8) 
277 ( 77.6) 
0.728 (0.613, 0.866) 
Treatment failure 
125 ( 34.7) 
150 ( 42.0) 
Relapse 
98 ( 27.2) 
102 ( 28.6) 
Death 
21 ( 5.8) 
25 ( 7.0) 
(1) Hazard ratio (HR) estimated using Cox regression model stratified according to the randomization FLT3 
mutation factor. CI: Wald Confidence Interval. 
An EFS event is defined as a failure to obtain a CR in Induction, relapse from CR, or death due to any cause, 
whichever occurs first. 
 
Prior mixture 
In order to account for the possibility that the data of the new study A2220 is potentially very 
different (non-exchangeable), the mixture for the MAP prior is complemented with a non- 
informative prior corresponding to a single event of no effect. 
To obtain the mixture prior, 50% weight will be assigned to the MAP prior 𝜃𝜃∗ and 50% weight 
will be assigned to the non-informative component. These weights are a priori fixed and will 
be updated by the trail data for the observed log(HR). 
 
14.1.5 
Operating characteristics for interim analysis 
In order to show how the Bayesian interim study design performs, a simulation study is used. 
Several example scenarios were investigated (Section 14.1.5.1), and in each case 15,000 trials 
were simulated, with results summarized in Section 14.1.5.3. 
 
14.1.5.1 Scenarios 
In order to show how the design performs, 4 hypothetical scenarios shown in Table 14-2 were 
investigated. Scenarios 1 to 3 follows our expected assumption that both survival distributions 
are as observed in Study [A2301] with different enrollment periods (14 months as assumed, 
shorter period of 10 months and longer period of 18 months). Scenario 4 considers that there is 
no difference of survival distributions for EFS in midostaurin and placebo. 
 
Table 14-2 
Hypothetical scenarios 
Scenario 
Survival distribution for EFS 
in midostaurin in A2220 
1 
 
 
Survival distribution for EFS in 
placebo in A2220 
 
 
Enrollment 
period 
14 months 
2 
Same distribution as observed 
in midostaurin in study A2301 
Same distribution as observed in 
placebo in study A2301 
10 months 
3 
18 months 
4 
Same distribution as observed 
in placebo in study A2301 
Same distribution as observed in 
placebo in study A2301 
14 months 
 
 
14.1.5.2 Simulation details 
In order to calculate the probability to meet the success criterion, a simulation study was 
performed using actual EFS data from Study [A2301]. To simulate a study, 30 patient 


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observations in each arm were randomly selected from Study [A2301] according to scenarios 
shown in Table 14-2. 
In this simulation, the interim analysis occurs when 60 patients are randomized and 24 EFS 
events are documented. When both the Bayesian predictive probability of (HR when 36 EFS 
events are documented < 1) exceeds 90% and the estimated HR at interim analysis < 1, then the 
study is assessed as positive at the interim analysis. 
The primary analysis occurs when 36 EFS events are documented. When estimated HR < 1, 
then the study is assessed as positive at the primary analysis. 
 
Metrics 
Operating characteristics were reviewed for the simulations to compare the relative 
performance under each scenario. The metrics reviewed were: 
1. Probability to show study is positive at the interim analysis (I) 
2. Probability to show study is negative at the interim analysis but positive at the primary 
analysis (II) 
3. Conditional probability to show study is negative at primary analysis after showing it to be 
positive at interim analysis (risk to declare study positive at interim analysis) (III) 
4. Mean number of EFS events documented at interim analysis (IV) 
5. Estimated study duration at interim analysis from date of first patient randomized (V) 
6. Estimated study duration at primary analysis from date of first patient randomized (VI) 
 
14.1.5.3 Simulation results 
Table 14-3 below summarizes the simulated operating characteristics of the model for the 4 
different scenarios studied. 
 
Table 14-3 
Simulation results 
 
 
V 
(Months) 
Mean [2.5% 
quantile, 
97.5% 
quantile] 
VI 
(months) 
Mean [2.5% 
quantile, 97.5 
quantile] 
Probability to 
show study is 
positive when 
only primary 
analysis is 
conducted 
(%) 
14.1 [14.0, 
20.7 [13.9, 
84.3 
15.4] 
33.7] 
10.4 [10.0, 
18.3 [11.1, 
84.7 
13.0] 
31.1] 
18.0 [18.0, 
23.2 [17.0, 
83.8 
18.0] 
36.6] 
14.0 [14.0, 
16.9 [13.0, 
49.9 
14.0] 
24.6] 
 
Scenario 
Metric 
I 
(%) 
II 
(%) 
I+II 
(%) 
III 
(%) 
IV 
1 
78.1 
8.8 
86.9 
3.2 
28.3 
2 
74.3 
12.7 
87.0 
3.0 
26.2 
3 
80.5 
6.5 
87.0 
3.2 
30.0 
4 
48.7 
6.7 
55.4 
11.6 
30.6 


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Simulation results suggested the following: 
1. The probability to show positive study (metric I+II) is almost 87% irrespective of enrollment 
speed under our expected assumption that both survival distributions are as observed in [A2301] 
2. The risk to show positive but there is no effect on midostaurin is increased by about 5% (i.e. 
55.4 – 49.9) compared to the study design without interim analysis 
3. The time to declare positive study might be shortened by about 6 months by conducting an 
interim analysis 
 
14.1.6 
Operating characteristics for supportive analysis 
In order to show how the Bayesian model performs, different scenarios were investigated. Table 
14-4 shows the probability for a successful trial result of a median HR < 1 (median log(HR) < 
0) under some hypothetically assumed true HR values and number of EFS events. 
 
Table 14-4 
Posterior probability to show median HR < 1 under several 
hypothetical true scenarios 
 
#EFS events/assumed true HR 
0.37 
0.60 
0.76 
1.00 
1.20 
1.35 
30 
0.999 
0.974 
0.904 
0.709 
0.520 
0.393 
35 
1.000 
0.980 
0.911 
0.704 
0.499 
0.363 
39 
1.000 
0.983 
0.917 
0.700 
0.482 
0.340 
45 
1.000 
0.987 
0.924 
0.695 
0.460 
0.310 


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carbamazepine, enzalutamide, lumacaftor, phenobarbital, phenytoin, 
rifabutin, rifampicin (rifampin), mitotane, St. John’s wort (Hypericum 
perforatum)1 
Strong inducers of CYP3A4 
14.2 
Appendix 2 – 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 Food and 
Drug Administration (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 (UW) Drug Interaction Database 
(http//wwwdruginteractioninfo.org/). 
 
14.2.1 
List of prohibited medications 
 
1 Herbal product 
 
14.2.2 
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) 
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 


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Medications with a known risk for QT prolongation 
Medications with a known risk 
for QT prolongation4 
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 Combination ritonavir-boosted regimens are listed here in the Drug-Drug Interaction (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. 
4 For current lists of medications that may cause QT prolongation and/or Torsades de Pointes (TdP), 
refer to the CredibleMeds® website (https://crediblemeds.org). Please contact the medical monitor 
with any questions. 


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14.3 
Appendix 3 – PGIC questionnaire 
 
 
 


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14.4 
Appendix 4 – EORTC QLQ-C30 (version 3) 
 


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14.5 
Appendix 5 - EORTC QLQ-C30 Scoring Manual 
 
 


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SAP_001.pdf: 
Clinical Development
Midostaurin/PKC412
CPKC412A2220/NCT03280030
A phase II, randomized, double-blind, multi-center, placebo-controlled 
study to evaluate the efficacy and safety of twice daily oral midostaurin in 
combination with daunorubicin/cytarabine induction, high-dose 
cytarabine consolidation, and midostaurin single agent continuation 
therapy in newly diagnosed patients with FLT3-mutated acute myeloid 
leukemia (AML)
Statistical Analysis Plan (SAP) for final analysis
Document type:
SAP Documentation
Document status:
Final
Release date:
06-Dec-2022
Number of pages:
53
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted (Current)
06-
Dec-
2022
Before 
final 
DBL
Original version for final analysis


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Table of contents
Table of contents .................................................................................................................3
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
1.1.1
Part 1: Safety evaluation part ..................................................................6
1.1.2
Part 2: Randomized Part..........................................................................8
1.1.3
Timing of interim analyses and design adaptations..............................11
1.1.4
Definition of end of study .....................................................................12
1.1.5
Early study termination.........................................................................12
1.2
Study objectives and endpoints .............................................................................12
2
Statistical methods.............................................................................................................14
2.1
Data analysis general information .........................................................................14
2.1.1
General definitions................................................................................15
2.2
Analysis sets ..........................................................................................................18
2.2.1
Subgroup of interest ..............................................................................20
2.3
Patient disposition, demographics and other baseline characteristics ...................21
2.3.1
Safety evaluation part (Part 1, Japan only) ...........................................21
2.3.2
Randomized part (Part 2) ......................................................................21
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................23
2.4.1
Safety evaluation part (Part 1, Japan only) ...........................................23
2.4.2
Randomized part (Part 2) ......................................................................23
2.5
Analysis of the primary objective..........................................................................28
2.5.1
Primary endpoint...................................................................................29
2.5.2
Statistical hypothesis, model, and method of analysis..........................29
2.5.3
Handling of missing values/censoring/discontinuations.......................30
2.5.4
Supportive analyses...............................................................................30
2.6
Analysis of the key secondary objective ...............................................................32
2.7
Analysis of secondary efficacy objective(s)..........................................................32
2.7.1
Secondary endpoints .............................................................................32
2.7.2
Statistical hypothesis, model, and method of analysis..........................33
2.8
Safety analyses.......................................................................................................33
2.8.1
Adverse events (AEs)............................................................................34
2.8.2
Deaths....................................................................................................36
2.8.3
Laboratory data .....................................................................................36
2.8.4
Other safety data ...................................................................................38


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2.9
Pharmacokinetic endpoints....................................................................................39
2.10
PD and PK/PD analyses.........................................................................................41
2.11
Patient-reported outcomes .....................................................................................42
2.12
Biomarkers.............................................................................................................43
45
2.14
Interim analysis......................................................................................................46
3
Sample size calculation .....................................................................................................47
3.1
Primary analysis.....................................................................................................47
3.2
Power for analysis of key secondary variables......................................................48
4
Change to protocol specified analyses ..............................................................................48
5
Appendix ...........................................................................................................................48
5.1
Imputation rules.....................................................................................................48
5.1.1
Study drug.............................................................................................48
5.2
AEs coding/grading ...............................................................................................50
5.3
Laboratory parameters derivations ........................................................................51
5.4
Statistical models...................................................................................................51
5.4.1
Analysis of time-to-event data ..............................................................51
5.4.2
Analysis of Binary Data........................................................................52
6
Reference...........................................................................................................................53


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List of abbreviations
AE
Adverse Event
AESI
Adverse Event of Special Interest
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
CI
Confidence Interval
CIR
Cumulative Incidence of Relapse
CR
Complete Remission
CRp
Morphologic Complete Remission with incomplete platelet count recovery
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CV
Coefficient of Variation
DAR
Dosage Administration Record
DI 
Dose Intensity
EFS
Event-Free Survival
EOT
End of Treatment
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
HR
Hazard Ratio
ISC
Independent Safety Committee
IRT
Interactive Response Technology
LLOQ
Lower Limit of Quantitation 
LPLV
Last patient last visit
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
OS
Overall Survival
PDI
Planned Dose Intensity
PK
Pharmacokinetics
PPS
Per-Protocol Set
PR
Partial Remission
PRO
Patient-reported Outcomes
PT
Preferred Term
RAP
Report and Analysis Process
RDI
Relative Dose Intensity
SAP
Statistical Analysis Plan
SCT
Stem Cell Transplantation
SD
Standard Deviation
SMQ
Standardized MedDRA Queries
SOC
System Organ Class
WBC
White Blood Cell
WHO
World Health Organization


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1
Introduction
This statistical analysis plan (SAP) describes all planned analyses for the clinical study report(s) 
(CSR) of study CPKC412A2220, a phase II, randomized, double-blind, multi-center, placebo-
controlled study to evaluate the efficacy and safety of twice daily oral midostaurin in 
combination with daunorubicin/cytarabine induction therapy, high-dose cytarabine 
consolidation and midostaurin single agent continuation therapy in newly diagnosed patients 
with FLT3-mutated acute myeloid leukemia (AML).
The content of this SAP is based on protocol CPKC412A2220 version 03 (released on 10-Sep-
2020). All decisions regarding final analysis, as defined in the SAP document, have been made 
prior to database lock.
1.1
Study design
This study is a phase II, multi-center trial consisting of 2 parts.

Part 1: open label, safety evaluation part in Japan only (minimum of three evaluable 
patients)

Part 2: double-blind, randomized, placebo-controlled part (60 patients)
Part 1 in Japan and Part 2 outside Japan will be conducted in parallel. At the completion of Part
1, and depending on the findings of the safety evaluation, the trial in Japan will advance to Part 
2.
1.1.1
Part 1: Safety evaluation part
The part 1 will be conducted to evaluate the safety and tolerability of midostaurin in 
combination with daunorubicin/cytarabine induction and high-dose cytarabine consolidation in 
Japanese patients. Data from the part 1 will be reviewed by an Independent Safety Committee 
designated by the Sponsor (Figure 1-1).
Patients will be enrolled into the study irrespective of leukemia FLT3 genotype (i.e., patients 
with either FLT3-WT or FLT3-mutated AML will be eligible).
The safety evaluation period will begin on Day 1 of the first induction cycle (Cycle 1 Day 1) 
and will continue until Day 21 of the first consolidation cycle. The period will allow for an 
assessment of the safety of midostaurin with chemotherapy throughout induction and will 
provide also an assessment of Safety Events (for example, CNS neurotoxicity and ocular 
toxicity) specific to consolidation with high dose cytarabine. The first safety review by the 
Independent Safety Committee will take place when at least three evaluable patients have 
completed the safety evaluation period without a potential Safety Event or have experienced a 
potential Safety Event within this period. A Safety Event is defined as death or serious adverse 
event leading to treatment discontinuation during the safety evaluation period and that is 
determined by the Independent Safety Committee to be definitely or probably related to 
midostaurin. All potential deaths and treatment discontinuations due to serious adverse events 
will be adjudicated by the Independent Safety Committee; it will take into consideration the 
attribution of the event by the investigator, but in its decision-making for trial conduct the 
attribution of event by the Independent Safety Committee will prevail.


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The Independent Safety Committee will review all available safety data in patients from Japan 
up to the time of the safety review data cut-off date. After determining whether each death or 
serious adverse event leading to treatment discontinuation during the safety evaluation period 
meets criteria for a Safety Event, it will consider this tabulation in combination with the entire 
safety experience in Japanese patients to determine the ongoing conduct of the trial.
The Independent Safety Committee will be provided through its charter with guidelines for 
determining the conduct of the trial:

If one Safety Event occurs among the first three patients enrolled during the safety 
evaluation period, then the Independent Safety Committee will determine whether an 
additional cohort of three patients should be enrolled into the part 1.

If there is no Safety Event among the first three evaluable patients or no more than one 
Safety Event among the first six evaluable patients during the safety evaluation period, 
then the Independent Safety Committee will determine whether the trial may advance to 
the part 2 in Japan.

If two or more Safety Events are observed in the first three or six evaluable patients, the 
Independent Safety Committee will determine whether conduct of the trial in Japan should 
be terminated without advancement to the part 2. The Independent Safety Committee may 
determine that additional information is needed through continued recruitment of patients 
into the part 1 before making a final determination regarding advancement to the part 2 or 
termination of the study in Japan.
Although the Independent Safety Committee will consider these guidelines in its determination 
of continuing study conduct in Japan, it will also take into consideration the individual 
circumstances of the Safety Events and will make use of the clinical judgement of the 
Independent Safety Committee members.
Patients in the part 1 in Japan may be treated with midostaurin in combination with the JALSG 
or RATIFY regimen. Although it is anticipated that most patients would be treated in Japan 
with the JALSG regimen, there is no required minimum number of patients to be treated with 
either chemotherapy regimen. Both regimens may contribute to the overall safety evaluation, 
or the Independent Safety Committee may consider during its deliberation potential differences 
in the two combination regimens.
Prior to the decision of the Independent Safety Committee to initiate the part 2 of the trial (if 
applicable), patients in the part 1 who remain in remission will continue to be treated according 
to the study protocol. If a decision is made by the Independent Safety Committee to defer 
initiation of the part 2 in Japan or to suspend treatment of patients in Japan, then the continued 
treatment with midostaurin of patients already enrolled in the part 1 will be determined by the 
Study Steering Committee, the individual investigators, and the Sponsor, and the decision will 
take into consideration the findings of the Independent Safety Committee (ISC).


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Figure 1-1
Independent Safety Committee review in Part 1 safety evaluation part 
(Japan only)
1.1.2
Part 2: Randomized Part
For the part 2 of the study, the start of patient enrollment in countries outside Japan will be 
concurrent with the start of the part 1 in Japan. The part 2 in Japan will begin only after the 
Independent Safety Committee agrees that midostaurin in combination with chemotherapy is 
adequately tolerated in Japanese patients. Novartis will report the decision to the full Study 
Steering Committee ([study protocol Section 8.7]).
Patients meeting all eligibility criteria (except FLT3 mutation) may begin the study treatment 
with chemotherapy. The FLT3 mutation status will be evaluated in a Novartis designated 
laboratory.
Patients who are determined to have AML with a FLT3 mutation (ITD and/or TKD) will be 
randomized on Cycle 1 Day 8 (first cycle of induction therapy) and will be assigned to 
midostaurin or placebo by using a stratified randomization according to FLT3 mutation and 
treatment regimen (see [study protocol Section 2.2]).

Patients who are determined to have AML without a FLT3 mutation or with an unknown 
FLT3 mutation status by Cycle 1 Day 8 will be discontinued from the treatment.
Outside Japan, only the RATIFY regimen will be used.
During Part 1 (implemented in Japan only), safety and tolerability of midostaurin with the 
JALSG or with the RATIFY regimen will be assessed. There is no requirement for a minimum 
number of patients treated with each regimen. It is therefore possible, for example, that Part 1 
will be completed only with patients treated with JALSG or only with patients treated with 


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RATIFY. If the ISC endorses proceeding to Part 2, then investigators in Japan may choose 
either RATIFY or JALSG for future patients. Once patients are enrolled in the study, their 
regimen must not be switched during the course of the study.
The study will include:

Screening phase (7 days);

Treatment phase composed of up to 18 cycles of midostaurin/placebo treatment in 
combination with chemotherapy (daunorubicin and cytarabine) during induction and
consolidation and alone during continuation and 30 days safety follow up from last dose 
of study treatment (daunorubicin or cytarabine or midostaurin/placebo);

Follow up phase for continued remission and survival.
Refer to Figure 1-2 for study design.
Figure 1-2
Overview of Randomized Part (Part 2)
1.1.2.1
Screening phase
Patients who provided written informed consent will be screened for eligibility during the 
period up to 7 days immediately prior to starting chemotherapy (daunorubicin and cytarabine). 
The patient will be randomized at Day 8 and will receive either midostaurin or placebo only if 
FLT3 status is mutated.
During the screening phase the investigator must:

Obtain signed informed consent from the patient prior to any study procedures

Assess the inclusion and exclusion criteria as detailed in [protocol Section 5]

Perform all screening procedures as detailed in [study protocol Table 7-1]


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Results of all screening/baseline evaluations must be reviewed by the investigator or his/her 
designee prior to enrollment of each patient into the study to ensure that all inclusion and 
exclusion criteria are satisfied.
The diagnosis of AML by BMA may be confirmed before or during the screening period. In 
case of dry tap (failure to obtain bone marrow after BMA attempts), bone marrow biopsy can 
be used for confirming AML diagnosis; alternatively peripheral blood (showing ≥20% blasts) 
may be used at investigator’s discretion if bone marrow biopsy may delay treatment initiation.  
1.1.2.2
Treatment phase
Induction therapy
All screened patients will start induction therapy with chemotherapy (daunorubicin and 
cytarabine) from Day 1 to Day 7, while the FLT3 mutation is being determined.
An Interactive Response Technology (IRT) system will be used to randomize patients to the 
study treatment groups and the patient eligibility checklist will be embedded into the IRT 
randomization process.
Only randomized patients (with FLT3 mutation) will receive midostaurin/placebo, orally twice 
a day, on days 8 to 21.
Patients who achieve CR already with induction cycle 1 will go directly to consolidation therapy 
without a second cycle of induction therapy. Patients who do not achieve CR with one cycle of 
induction will receive a second induction cycle with same treatment than in cycle 1.
Patients not achieving CR after induction 2 will discontinue study treatment and will be 
followed in safety follow-up and survival follow-up.
Consolidation therapy
Patients who achieved a CR after 1 or 2 cycles of induction will receive consolidation therapy 
with 3 cycles of high-dose cytarabine for JALSG regimen and 4 cycles of high-dose cytarabine 
as tolerated for RATIFY regimen.
Patients will receive midostaurin/placebo, orally twice a day, on days 8 to 21 of each cycle.
Each consolidation cycle will begin within two weeks following hematopoietic recovery (ANC 
≥ 1.0 x 109/L, platelet count ≥ 100 x 109/L) but no sooner than four weeks from the beginning 
of the previous cycle.
For patients of age 60 years or older at the time of study entry, the dose of cytarabine may be 
reduced at the discretion of the investigator to 1500 mg/m2/dose for JALSG regimen and to 
1000-1500 mg/m2/dose for RATIFY regimen.
Continuation therapy
After hematopoietic recovery (ANC ≥ 1.0 x 109/L, platelet count ≥ 100 x 109/L) following the 
final cycle of consolidation but no sooner than 14 days after the last dose of midostaurin/placebo 
during the last consolidation cycle, patients who maintain a CR will receive up to 12 cycles (28 
days/cycle) of continuous therapy with midostaurin or placebo twice a day.


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Study treatment will continue until completion of 12 cycles of continuation therapy, persistent 
AML, relapse, intolerable toxicity, withdrawal of consent by the patient, lost to follow up, death, 
or the sponsor terminates the study, whichever is earlier.
Safety will be assessed in this treatment phase for each patient until 30 days after the end of 
treatment (EOT) and will include routine safety monitoring except in case of death, loss to 
follow up or withdrawal of consent.
1.1.2.3
Follow up phases
The follow-up period will comprise the following:
Post treatment follow-up
During the post treatment follow-up, use of subsequent anti-neoplastic cancer therapies (i.e., 
surgery, SCT, radiotherapy, local and systemic anti-neoplastic medications) initiated after study 
treatment discontinuation will be recorded.
Following the end of study treatment for any reason other than persistent AML, relapse, 
withdrawal of consent, death, or loss to follow up, all patients will continue to be assessed for 
relapse i.e., every 2 months during years 1 and 2, every 3 months on year 3 and 4 and then 
yearly and at time of relapse until relapse, withdrawal of consent, death, loss to follow up, or 
end of study, whichever is earlier. For further details see [study protocol Section 7].
Survival follow up
Patients who discontinued study treatment due to persistent AML or relapse and the post 
treatment follow-up phase due to relapse will enter a follow-up period during which survival 
will be recorded every 3 months (see [protocol Section 4.3]). Survival information can be 
obtained by clinical visits or telephone calls or other means until death, withdrawal of consent, 
loss to follow-up or end of study, whichever is earlier.
During the survival follow-up, subsequent anti-neoplastic therapies initiated after 
discontinuation of study treatment will be reported until death, withdrawal of consent, loss to 
follow-up or end of study, whichever is earlier.
1.1.3
Timing of interim analyses and design adaptations
During the part 1, the Independent Safety Committee will evaluate all available safety data from 
patients treated in Japan to determine if the midostaurin combination with chemotherapy is safe 
and is adequately tolerated in Japanese patients. All patients enrolled in part 1 will be listed and 
reviewed irrespective of the combination treatment (JALSG or RATIFY regimen). For 
additional information, see [protocol Section 4.1] and [Section 10.7].
During the part 2, an interim analysis for efficacy will be conducted when 60 patients are 
randomized and at least 24 EFS events are documented (expected around 14 months from the 
date of first patient randomized assuming the recruitment period as 14 months). This interim 
analysis will be assessed by a DMC, however, even if interim success criteria are met, the study 
will be continuing blinded to patients, investigators and monitors until the primary analysis and 
thereafter unblinded. At the final analysis more mature data can be evaluated. In case that 36 


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EFS events are documented before randomization completion, the interim analysis can be 
skipped and Novartis will conduct primary analysis. For detailed information, please refer to 
[protocol Section 10.7].
1.1.4
Definition of end of study
The end of study will occur at the latest 36 months after the start of the study treatment for the 
last patient. All patients will remain in post-treatment or survival follow-up until the data cut-
off date of the final analysis (i.e., last patient last visit (LPLV)), and all available data will be 
analyzed.
1.1.5
Early study termination
The study may be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible for the End of Treatment (EOT) visit, and 
assessments for EOT as described in [study protocol Section 7] should be performed for a 
discontinued or withdrawn patient. 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 IRBs and/or ECs of the 
early termination of the trial.
1.2
Study objectives and endpoints
Objectives and related endpoints are described in Table 1-1 below.
Table 1-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Safety Evaluation part (Part 1, Japan only)
Section 2.5
To Evaluate the safety and 
tolerability of midostaurin in 
combination with 
daunorubicin/cytarabine 
induction and high-dose 
cytarabine consolidation in 
Japanese patients with newly 
diagnosed AML.
Incidence and severity of Safety Events, defined 
as death or serious adverse event leading to 
treatment discontinuation that occurs on or 
before Day 21 of the first Consolidation cycle 
and that is determined by the Independent 
Safety Committee to be definitely or probably 
related to midostaurin.
Double-blind, randomized, placebo-controlled (Part 2)
To Evaluate the efficacy based 
on event-free survival (EFS) of 
midostaurin versus placebo in 
combination with 
daunorubicin/cytarabine 
induction, with high-dose 
cytarabine consolidation, and 
with midostaurin single agent 
continuation therapy in newly 
diagnosed patients with FLT3-
mutated AML.
Event-free survival (EFS) defined as the time 
from the date of randomization until an EFS 
event is observed. An EFS event is defined as a 
failure to obtain a CR within induction 2, relapse 
after CR, or death due to any cause, whichever 
occurs first.
Secondary


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Objective
Endpoint
Analysis
Randomized part (Part 2)
Determine overall survival (OS) 
in the two treatment groups
Overall survival (OS), defined as the time from 
the date of randomization to date of death due 
to any cause.
Section 2.7
Determine rate of complete 
remission (CR) in the two 
treatment groups
CR rate, defined as the proportion of patients 
with a CR according to Cheson criteria, at 
various timepoints.
Determine cumulative 
incidence of relapse (CIR) in 
the two treatment groups
CIR (only for patients who have achieved CR 
after study treatment initiation), as measured 
from the date of first CR to relapse or death due 
to AML, whichever occurs first.
Evaluate safety of midostaurin 
compared to placebo in 
combination with chemotherapy 
and as single agent 
continuation therapy
Frequency/severity of AEs, ECG and laboratory 
abnormalities.
Section 2.8
Evaluate the pharmacokinetics 
of midostaurin and its two 
major metabolites CGP52421 
and CGP62221
Pharmacokinetic parameters for midostaurin 
and two major metabolites CGP52421 and 
CGP62221.
Section 2.10
Determine the effect of study 
treatment on quality of life
European Organization for Research and 
Treatment of Cancer (EORTC) QLQ-C30 total 
score and functional scales scores (scores and 
absolute change from baseline at each 
scheduled assessment).
PGIC score as frequencies and percentages by 
scheduled timepoint.
Section 2.11


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2
Statistical methods
2.1
Data analysis general information
The final analyses will be performed by Novartis and/or a designated CRO. SAS version 9.4 or 
later will be used to perform all data analyses and to generate tables, figures and listings.
Safety evaluation part (Part 1, Japan only)
The safety and tolerability of midostaurin in combination with chemotherapy in Japan will be 
assessed based on the incidence of Safety Events during the safety evaluation period. A Safety 
Event is defined as death or serious adverse event leading to treatment discontinuation that 
occurs on or before Day 21 of the first consolidation cycle and that is determined by the 
Independent Safety Committee to be definitely or probably related to midostaurin.
All Japanese patients who signed ICF by 25Sep2018, the date when Independent Safety 
Committee review was held, will be assessed as patients enrolled in part 1. All patients enrolled 
part 1 will be listed and reviewed irrespective of the combination treatment (JALSG or RATIFY 
regimen). Separate SAP for Indenpendent Safety Committee (ISC) was created.
Randomized part (Part 2)
In the part 2, interim, primary analyses were conducted and final analyses will be conducted.
For screening failure, patients who signed the informed consent but never started the study 
treatment for any reason, and non-randomized patients, the eCRF data collected will not be 
included in analyses, but will be reported in CSR as separate listings as appropriate.
Data included in the analysis
The interim analysis for efficacy were conducted when 60 patients were to be randomized 
(actual 62 patients) and at least 24 EFS events were documented. In case that 36 EFS events 
were documented before randomization completion, the interim analysis could be skipped and 
Novartis would plan to conduct primary analysis. 
The primary analysis was performed using a pre-defined cut-off date of 30 November 2020
with the number of EFS events were documented as per amended protocol version 03 (released 
date 10-Sep-2020) by this date.
The end of study will occur at the latest 36 months after the start of the study treatment for the 
last patient. At this time, the final analysis will be performed.
All statistical analyses will be performed using all data collected in the database up to the data
cutoff date. All data with an assessment date or event start date (e.g., vital sign assessment date
or start date of an adverse event) prior to or on the cut-off date will be included in the analysis.
Any data collected beyond the cut-off date will not be included in the analysis and will not be 
used for any derivations.
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 


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and concomitant medication reports. For these events, the end date will not be imputed and 
therefore will not appear in the listings.
At final analysis the cut-off date means LPLV.
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, etc.) will be summarized by means of contingency tables
by treatment group; a missing category will be included as applicable. Percentages will be 
calculated using the number of patients in the relevant population or subgroup as the 
denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (i.e., mean, standard deviation, median, minimum, and maximum) by treatment group.
2.1.1
General definitions 
Investigational drug and study treatment
Investigational drug will refer to the midostaurin. Control drug will refer to the placebo. The 
study drug will refer to investigational and control drugs. Whereas, study treatment will refer 
to treatment with daunorubicin, cytarabine, or midostaurin/placebo.
Date of first administration of investigational drug
The date of first administration of investigational drug is defined as the first date when a non-
zero dose of investigational drug is administered and recorded on the Dosage Administration 
Record (DAR) eCRF. The date of first administration of study drug will also be referred as start 
of investigational drug.
Date of last administration of investigational drug
The date of last administration of investigational drug is defined asthe last date when a nonzero 
dose of investigational drug is administered and recorded on DAR eCRF. The date of last 
administration of investigational drug will also be referred as end of investigational drug.
Date of first administration of study treatment 
The date of first administration of study treatment is derived as the first date when a nonzero 
dose of any component of study treatment was administered as per the Dosage Administration
Record (DAR) eCRF (Example: if 1st dose of midostaurin/placebo is administered on 05-Jan-
2015, and 1st dose of a combination partner is administered on 03-Jan-2015, then the date of 
first administration of study treatment is on 03-Jan-2015). The date of first administration of 
study treatment will also be referred as start of study treatment.


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Date of last administration of study treatment 
The date of last administration of study treatment is derived as the last date when a nonzero 
dose of any component of study treatment was administered as per the DAR eCRF. (Example: 
if the last midostaurin/placebo is administered on 15-Apr-2014, and the last dose of a 
combination partner is administered on 17-Apr-2014, then the date of last administration of 
study treatment is on 17-Apr-2014).
Study day
The study day describes the day of the event or assessment date, relative to the reference start 
date. 
The study day is defined as:

The date of the event (visit date, onset date of an event, assessment date etc.) −reference 
start date + 1 if event is on or after the reference start date;

The date of the event (visit date, onset date of an event, assessment date etc.) − reference 
start date if event precedes the reference start date.
The reference start date for all efficacy assessments, including PRO and performance status, is 
the date of randomization.The reference start date for all other assessments is the start of the 
study treatment.
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative.
Time unit
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375. If duration is reported in 
years, duration in days will be divided by 365.25.
Baseline
For efficacy evaluations, the last non-missing assessment, including unscheduled assessments 
on or before the randomization date is taken as “baseline” value or “baseline” assessment. In 
the context of baseline definition, the efficacy evaluations also include PRO and performance 
status.
For safety evaluations, the last non-missing assessment, including unscheduled assessments on 
or before the date of start of study treatment is taken as “baseline” value or “baseline” 
assessment.
If patients have no value as defined above, the baseline result will be missing.
On-treatment assessment/event and observation periods 
For all safety analyses, 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


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2. on-treatment period: from day of first dose of study treatment to 30 days after last dose 
of study treatment
3. post-treatment period: starting at day 31 after last dose of study treatment.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g., change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).
However, all safety data (including those from the post-treatment period) will be listed and 
those collected during the pre-treatment and post-treatment period will be flagged.
Last contact date 
The last contact date will be derived for patients not known to have died at the LPLV using the 
last complete date among the following:
Table 2-1
Last contact date data sources
Source data
Conditions
Date of start of study treatment
No Condition
Date of Randomization
No Condition
Last contact date/last date patient was known to 
be alive from Survival Follow-up page
Patient status is reported to be alive, lost to 
follow-up or unknown
Start/End dates from further antineoplastic 
therapy
Non-missing medication/procedure term
Start/End* dates from drug administration record 
Non-missing dose. Doses of 0 are allowed
End of treatment date from end of treatment page
No condition
Any specific efficacy assessment date
Evaluation is marked as ‘done’
Laboratory
PK collection dates
Sample collection marked as ‘done’
Vital signs, ECG date
At least one non-missing parameter value
Performance Status date
Non-missing performance status
Start/End dates of AE 
Non-missing verbatim term
The last contact date is defined as the latest complete date from the above list on or before the 
LPLV. The LPLV will not be used for last contact date, unless the patient was seen or contacted
on that date. No date post LPLV will be used. Completely imputed dates (e.g., the analysis
cut-off date programmatically imputed to replace the missing end date of a dose administration
record) will not be used to derive the last contact date. Partial date imputation is allowed for 
event (death)/censoring is coming from ‘Survival information’ eCRF.
The last contact date will be used for censoring of patients in the analysis of overall survival.


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Hematological toxicities and recovery
Thrombocytopenia is defined as a platelet count below 20.0 x 109/L as reported on the eCRF 
Local Lab Results - Hematology. 
The duration of thrombocytopenia is defined as (first date of increase of platelets over 20.0 x 
109/L – first date of decrease of platelets below 20.0 x 109/L for the considered period + 1). If 
the patient had a platelet transfusion during the period, the patient is considered as not 
assessable.
The time between chemotherapy start and non-transfused recovery from thrombocytopenia is 
defined as (first date of increase of platelets over 20.0 x 109/L – date of first chemotherapy 
(cytarabine or daunorubicin in induction phase, or high dose cytarabine in conslidation phase) 
administration for the considered period + 1). If the patient had a platelet transfusion during the 
period, the patient is considered as not assessable.
Neutropenia is defined as an absolute neutrophil count below 0.5 x 109/L as reported on the 
eCRF Local Lab Results - Hematology.
The duration of neutropenia is defined as (first date of increase of absolute neutrophil count 
over 0.5 x 109/L – first date of decrease of absolute neutrophil count below 0.5 x 109/L for the 
considered period + 1). 
The time between chemotherapy start and recovery from neutropenia is defined as (first date of 
increase of absolute neutrophil count over 0.5 x 109/L – date of first chemotherapy (cytarabine 
or daunorubicin in induction phase, or high dose cytarabine in consolidation phase) 
administration for the considered phase + 1).
Additional analyses might be performed, if need be, in order to better characterize the influence 
of concomedications and blood transfusions on the kinetics of hematologic recovery. 
2.2
Analysis sets
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study drug (midostaurin/placebo) 
has been assigned by randomization. Therefore, all Japanese patients treated during the part 1 
will not be eligible for the FAS. According to the intent to treat principle, patients will be 
analyzed according to the treatment and strata they have been assigned to during the 
randomization procedure.
Per protocol set (PPS) 
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant 
with requirements of the study protocol.
Oncology standards for protocol deviations potentially leading to exclusion from the PPS are: 

type of indication different from those required by the CTP (e.g., incorrect 
histology/cytology, not refractory, not metastatic, different grade of cancer, etc.)

if prior therapy does not match with CTP requirements in terms of number and types of 
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
missing or incomplete documentation of stage of disease (as required in the CTP)

another anti-neoplastic therapy administered after start of study treatment and prior to first 
efficacy assessment

study treatment received different from treatment assigned by randomization
Safety set
The Safety Set includes all randomized patients who received at least one dose of study drug. 
Patients will be analyzed according to the part in which they are enrolled and the study treatment 
received, where treatment received is defined as the randomized treatment if the patient took at 
least one dose of that treatment or the first treatment received if the randomized treatment was 
never received.
Other
Pharmacokinetic analysis set for all (PAS-all) 
The Pharmacokinetic analysis set for all (PAS-all) includes all patients who took at least one 
dose of midostaurin and provide at least one evaluable PK concentration.
For a concentration to be evaluable, patients are required to:

Take the planned dose of midostaurin prior to sampling

For pre-dose samples: do not vomit within 4 hours after the dosing of midostaurin prior to 
sampling, have the sample collected before the next dose administration

For post-dose samples: do not vomit within 4 hours after the dosing of midostaurin
The PAS-all will be the primary population used for all pharmacokinetic analyses using trough 
concentration data.
Pharmacokinetic analysis set for full PK (PAS-full) 
The Pharmacokinetic analysis set for full PK (PAS-full) includes all patients in the PAS-all, 
who provide an evaluable PK profile. A profile is considered evaluable if all of the following 
conditions are satisfied:

Patient receives the planned dose of midostaurin on C1D8 of induction therapy

Patient does not vomit within 4 hours of the dosing of midostaurin on C1D8 of induction 
therapy

Patient provides at least one primary PK parameter
The PAS-full will be the primary population used for all pharmacokinetic analyses using full 
PK data.
Patient Classification: 
Patients may be excluded from the analysis populations defined above based on the protocol 
deviations entered in the database and/or on specific subject classification rules defined in Table 
2-2.


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Table 2-2
Subject classification based on protocol deviations and non-PD 
criteria
Analysis set
PD Identifer leading to exclusion (Edit 
Check Specifications V9.0)
Non protocol deviation leading to 
exclusion
FAS
INCL06
Not applicable
Safety set
INCL06
No dose of study drug 
Per-protocol set
INCL01A, INCL01A01, INCL01A02, 
INCL01B, INCL04, INCL06, EXCL05, 
EXCL06, EXCL07, EXCL08, EXCL09, 
COMD01, TRT03, TRT07, TRT10, 
OTHER02, OTHER04, OTHER11, 
COMD03
Patient randomized with confirming 
FLT3 is wild-type or undeterminate 
PK Analysis Set
INCL06, EXCL07
See definition of PK analysis set
Full PK Analysis 
Set
INCL06, EXCL07
See definition of full PK analysis set
Withdrawal of Informed Consent
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis. The date on which a patient 
withdraws full consent is recorded in the eCRF.
2.2.1
Subgroup of interest
Efficacy
The EFS and OS will be summarized by the following subgroups to examine the homogeneity 
of treatment effect across demographic and baseline disease characteristics will be performed: 

FLT3 mutation status (stratification factor: ITD allelic ratio <0.7, ITD allelic ratio ≥0.7, 
TKD)

chemotherapy regimen (stratification factor: RATIFY regimen, JALSG regimen)

gender

age category: < 60 years, ≥ 60 years
For each of subgroups, the treatment effect will be assessed separately within each category. 
The HR and their 95% CIs will be presented by means of forest plots. Unstratified analysis will 
be performed for each of the subgroups.
The CR rate will also be summarized by the subgroup shown above. The difference of CR rate 
between treatments and their 95% CIs will be presented by means of forest plot.
Safety
AEs, regardless of study treatment relationship, will be summarize by the following subgroups: 

age category: < 60 years, ≥ 60 years

chemotherapy regimen (stratification factor: RATIFY regimen, JALSG regimen)


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
strong CYP3A4 inhibitor intake (Yes/No), for patients who received/did not receive 
strong CYP3A4 inhibitor (listed in protocol appendix 2) concomitant treatments during 
the study. 
For each subgroup, AEs regardless of study treatment relationship will be summarized by SOC, 
PT and maximum CTC grade, and by phase.
2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Safety evaluation part (Part 1, Japan only)
Patient disposition, demographics and other baseline characteristics will be listed for all patients 
enrolled in the safety evaluation part.
2.3.2
Randomized part (Part 2)
The FAS will be used for all baseline and demographic summaries and listings unless otherwise 
specified. Summaries will be reported by treatment arm and for all patients, and listings will be 
reported by treatment arm to assess baseline comparability. No inferential statistics will be 
provided.
2.3.2.1
Basic demographic and background data
All demographic and baseline disease characteristics data will be summarized and listed by 
treatment arm. Categorical data (e.g. gender, age groups: <60, 60-<65 and ≥ 65 years, race, 
ethnicity, WHO performance status) will be summarized by frequency counts and percentages; 
the number and percentage of patients with missing data will be provided. Continuous data (e.g. 
age, weight, height, body surface area (BSA)) will be summarized by descriptive statistics (N,
mean, median, standard deviation, minimum and maximum). BSA will be calculated using 
Gehan and George formula: 
BSA[m2]= 234.94*(height[cm]**0.422)*(weight[kg]**0.515)/10000 using height and weight 
at baseline.
WBC at baseline will be categorized (<20, 20-<50, and ≥50 109/L) and summarized by 
frequency counts and percentages.
Baseline stratification factors
The number (%) of patients in each stratum (constructed by 3 FLT3 mutation status and 2 
regimens) based on data obtained from the IRT system will be summarized overall and by 
treatment arm for the FAS. Discordances between the stratum recorded in IRT at the time of 
randomization and the actual stratum recorded in the clinical database through the data collected 
on eCRF will be cross-tabulated and listed.
Diagnosis and extent of cancer 
Summary statistics will be tabulated for diagnosis and extent of cancer. This analysis will 
include the following: WHO 2016 classification of AML, and sub-classification of AML.


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Medical history
Medical history and ongoing conditions, including cancer-related conditions and symptoms 
entered on eCRF will be summarized and listed by treatment arm. 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 arm. 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 in the CSR 
and as a footnote in the applicable tables/listings.
Cytogenetics
Cytegenetic abnormality(ies) will be summarized.
Extramedullary involvement
Location of extramedually involvement at screening will be summarized.
Other
All data collected at baseline will be listed.
2.3.2.2
Patient disposition
Enrollment by country and center will be summarized for all screened patients and also by 
treatment group using the FAS. The number (%) of screened and the reason for screening failure 
will be displayed. Also, the number (%) of non-randomized patients and its reason will be 
displayed.
The following summaries will be provided overall and by treatment group using the FAS:

Number (%) of patients who were randomized (based on data from IRT system)

Number (%) of patients who were randomized but not treated study drug

Primary reason for not being treated study drug

Number (%) of patients who were treated study drug

Number (%) of patients who are still on-treatment by therapy (induction, consolidation, 
continuation) 

Number (%) of patients who completed therapy (induction, consolidation, continuation) 

Number (%) of patients who discontinued the study treatment by therapy (induction, 
consolication, continuation) 

Primary reason for study treatment discontinuation by therapy (induction, consolidation, 
continuation)

Number (%) of patients who are ongoing 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

Number (%) of patients who are alive on the survival follow-up

Number (%) of patients who dead on the survival follow-up


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
Number (%) of patients who have entered the survival follow-up but whose status is 
unknown 
2.3.2.3
Protocol deviations
The number (%) of patients in the FAS with any protocol deviation will be tabulated by 
deviation category (as specified in the study PD Specification) overall and by treatment group 
for the FAS. Major protocol deviations leading to exclusion from analysis sets will be tabulated 
separately overall and by treatment group. All protocol deviations will be listed.
Protocol deviations related to COVID-19 pandemic will be tabulated separately by deviation 
category, overall and by treatment. PD relationship to COVID-19 pandemic will be displayed 
in the listing for all protocol deviations.
2.3.2.4
Analysis sets
The number (%) of patients in each analysis set (defined in Section 2.2) will be summarized  by 
treatment group and stratum.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Safety evaluation part (Part 1, Japan only)
Study treatment, prior concomitant and post therapies will be listed for all patients enrolled in 
the safety evaluation part.
2.4.2
Randomized part (Part 2)
2.4.2.1
Study treatment / compliance
Duration of exposure, actual cumulative dose, dose intensity (DI) and relative dose intensity 
(RDI) will be summarized by cycle for induction and consolidation, treatment phase (induction, 
consolidation and continuation), overall (for the study drug only) and treatment arm, separately 
for each component of study treatment (Investigational drug, control drug and combination 
partner). The duration of exposure to study treatment will also be presented.
The number (%) of subjects who have dose reductions or interruptions, and the reasons, will be 
summarized by cycle for induction and consolidation, treatment phase (induction, consolidation 
and continuation),and overall, separately for each component of study treatment.
Subject 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 unless otherwise 
specified.


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Duration of exposure to study treatment
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to the investigational drug or control, and any combination partners:
Duration of exposure to study treatment (months) = {(date of last administration of study 
treatment) – (date of first administration of study treatment) + 1}/30.4375. 
Summary of duration of exposure of study treatment will include categorical summaries (<1 
month ; ≥1 month ; ≥3 months ; ≥6 months ; ≥12 months ; ≥18 months , ≥24 months).based 
on clinically meaningful time intervals) and continuous summaries (i.e., mean, standard 
deviation etc.) using appropriate units of time.
Duration of exposure to investigational drug, control drug and combination 
partner
The duration of exposure for the study drug (midostaurin/placebo), cytarabine, high dose 
cytarabine and daunorubicin (labeled as [medication] in the definitions below) will be 
calculated by cycle during induction and consolidation, by therapy (induction, consolidation 
and continuation, when applicable) and overall as below. Each durations will include the non-
planned periods of temporary interruption of the medication for any reason:

Duration of [medication] exposure (days) by cycle = number of days of administration 
during the cycle (including the days temporary interrupted).

Duration of [medication] exposure (days) in induction/consolidation phase = sum of 
durations of [medication] exposure by cycle for all cycles during induction/consolidation 
phase.

Duration of [medication] exposure (days) in continuation phase = [(date of last 
administration of [medication] during continuation phase) – (date of first administration of
[medication] during continuation phase) + 1].

Overall duration of [medication] exposure (days) = sum of durations of [medication] 
exposure by cycle for all cycles in induction, consolidation, and continuation phases.
In a given cycle and for a given medication, the duration of exposure is equal to zero for patients 
who entered the cycle but did not take the medication during this cycle. It is missing for patients 
who did not enter the cycle.
The duration of exposure will be summarized descriptively by cycle, treatment phase 
(induction, consolidation and continuation), overall and treatment group. In addition, the 
duration of exposure will be summarized descriptively by cycle, treatment, overall, regimen 
and treatment group.
Cumulative dose
Cumulative dose of a study treatment is defined as the total dose given during the study 
treatment exposure and will be summarized for each of the study treatment components. 
The planned cumulative dose for a study treatment component refers to the total planned dose 
as per the protocol up to the last date of investigational drug administration.


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The actual cumulative dose refers to the total actual dose administered, over the duration for 
which the subject is on the study treatment as documented in the DAR eCRF.
For patients who did not take any drug the cumulative dose is by definition equal to zero.
For continuous dosing, the actual cumulative dose is the sum of the non-zero doses recorded 
over the dosing period and the planned cumulative dose is the planned starting dose summed 
over the same dosing period.
For intermittent dosing, the actual cumulative dose should be defined based on the days when 
the subject is assumed to have taken a non-zerodose during dosing periods.
Dose intensity and relative dose intensity of study treatment
The Actual Dose Intensity (ADI) for the study drug (midostaurin/placebo) is defined by cycle 
for induction and consolidation, by treatment phase (induction, consolidation and continuation)
and overall as follows:

ADI (mg / day) by cycle = (Cumulative dose during the cycle / duration of study drug 
exposure during the cycle).

ADI (mg / day) by treatment phase = (Cumulative dose during the considered treatment 
phase / duration of study drug exposure during the considered treatment phase), for all 
patients who entered the considered treatment phase.

Overall ADI (mg / day) = (Overall cumulative dose during the study / overall duration of 
exposure).
ADI for cytarabine, high dose cytarabine and daunorubicin (labeled as [medication] in the 
definitions below) is defined by cycle, and by treatment phase (induction and consolidation, 
when applicable) as follows (note: the Body Surface Area (BSA) reported at the beginning of 
each cycle should be taken into account in the calculations of the ADI for the considered cycle):

ADI (mg/m²/cycle) by cycle = ((Cumulative dose during the cycle / BSA at the beginning 
of the cycle)).

ADI (mg/m²/cycle) by treatment phase = (sum of (Cumulative dose during the cycle /
BSA at the beginning of the cycle) for all cycles received during the considered treatment 
phase / number of cycle of which at least one [medication] is administered), for all 
patients who entered the considered treatment phase.
In a given cycle and for a given medication, the ADI is equal to zero for patients who entered 
the cycle but did not take the medication during this cycle. It is missing for patients who did not 
enter the cycle.
The Planned dose intensity (PDI) for the study drug (midostaurin/placebo) is defined, by cycle 
for induction and consolidation, by treatment phase (induction, consolidation and continuation), 
and overall as follows:

PDI (mg/day) = 100 mg/day.
The PDI for cytarabine by cycle in the induction phase is defined as follows: 

PDI (mg/m² / cycle) during JALSG induction = 700 mg/m²/cycle during each cycle.

PDI (mg/m² / cycle) during RATIFY induction = 1400 mg/m²/cycle during each cycle.


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The PDI for high dose cytarabine by cycle in the consolidation phase is defined as follows:

PDI (mg/m² / cycle) during JALSG consolidation = 20000 mg/m²/cycle on each cycle.

PDI (mg/m² / cycle) during RATIFY consolidation = 18000 mg/m²/cycle on each cycle.
The PDI for daunorubicin by cycle in the induction phase is defined as follows:

PDI (mg/m² / cycle) during JALSG induction = 250 mg/m²/cycle on each cycle.

PDI (mg/m² / cycle) during RATIFY induction = 180 mg/m²/cycle on each cycle.
The PDI is not described but is used for the calculation of the Relative dose intensity (RDI).
The Relative dose intensity (RDI) is the percentage of planned dose that was actually received.
The RDI is defined for the study drug (midostaurin/placebo), cytarabine, high dose cytarabine 
and daunorubicin by cycle for induction and consolidation (when applicable), by treatment 
phase (induction, consolidation and continuation, when applicable) and overall as follows:

RDI for the considered period (%) = ADI (mg or mg/m²/day or cycle) for the considered
period / PDI (mg or mg/m²/day or cycle) for the considered period*100.
In a given cycle and for a given medication, the RDI is equal to zero for patients who entered 
th cycle but did not take the medication during this cycle. It is missing for patients who did not 
enter the cycle.
Dose reductions, interruptions or permanent discontinuations
The number of subjects who have dose reductions, permanent discontinuations or interruptions, 
and the reasons, will be summarized by cycle for induction and consolidation, treatment 
(induction, consolidation and continuation), and overall (only for the study drug), separately for 
each component of study treatment. 
‘Dose change’, ‘Dose interrupted’, and ‘Dose permanently discontinued’ fields from the DAR 
eCRF will be used to determine the dose reductions, dose interruptions, and permanent 
discontinuations, respectively. The corresponding fields ‘Reason’ 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 dose reduction, interruptions and their reasons, in case multiple 
entries for dose reduction/interruption that are entered on consecutive days with different 
reasons will be counted as separate reducton/interruptions. However, if the reason is the same 
in this mentioned multiple entries on consecutive days, then it will be counted as one 
reduction/interruption.
Dose reduction is defined as the dose change 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.  Because only dose change is collected in the CRF, 
dose reductions will be clarified programmatically using the definition above.


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2.4.2.2
Prior, concomitant and post therapies
Prior anti-cancer therapy
The number and percentage of patients who received any prior anti-neoplastic medications, will 
be summarized by ATC class, preferred term and treatment. Summaries will include total 
number of regimens, setting, and reason for discontinuation of therapy. Prior anti-neoplastic 
medications will be listed. 
Anti-neoplastic medications will be coded using the WHO Drug Dictionary (WHO-DD). 
Details regarding WHO-DD version will be included in the footnote in the tables/listings. 
The above analyses will be performed using the FAS.
Post treatment anti-cancer therapy
Anti-neoplastic therapies since discontinuation of study treatment will be listed and summarized 
by ATC class, preferred term, and treatment group by means of frequency counts and 
percentages. The number of regimens of the new anti-neoplastic therapy initiated after 
discontinuation of study treatment regardleess of end of study treatment reason will be 
summarized. In addition, the regimen of the next line of therapy, defined as the first new anti-
neoplastic therapy initiated after discontinuation of study treatment regardless of end of study 
treatment reason, and its setting, duration and best response will be summarized.
The above analyses will be performed using the FAS.
Concomitant medications
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a patient coinciding with the study treatment 
period. Concomitant therapy include medications (other than study drugs) starting on or after 
the start date of study treatment or medications starting prior to the start date of study treatment 
and continuing after the start date of study treatment. 
Concomitant medications will be coded using the WHO-DD and summarized by ATC class and 
preferred term using frequency counts and percentages. The same analyses will be performed
for strong CYP3A4 inhibitors. Surgical and medical procedures will be coded using MedDRA 
and summarized by SOC and preferred term. These summaries will include:
1. Medications starting on or after the start of study treatment but no later than 30 days after 
start of last dose of study treatment, and
2. Medications starting prior to start of study treatment and continuing after the start of study 
treatment.
All prior and concomitant therapies will be listed. Any concomitant therapies starting and
ending prior to the start of study treatment or starting more than 30 days after the last date of
study treatment will be flagged in the listing. The safety set will be used for all concomitant 
medication tables and listings.


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Hematopoietic Stem Cell Transplant (HSCT)
The number and percentage of patients who received SCT will be summarized by type of SCT 
(allogeneic related SCT, allogeneic unrelated SCT, autologous SCT, cord blood, and other) and 
treatment arm. According to Table 2-3, type of SCT will be categorized based on source, 
transpalent type, and allogeneic donor type collected in eCRF page. A summary table will be 
produced by:

Overall

Occurred in patients without Complete Remission

Occurred during first CR

Occurred after relapse
The difference in SCT rates with its 95% confidence interval will also be provided.
The time to SCT (defined as the time from randomization to the date of SCT) overall and that 
occurred during first CR will be summarized by treatment arm.
The above analyses will be performed using the FAS.
Table 2-3
Type of SCT
Type
Source
Transplant type
Allogeneic donor type
Allogeneic 
related SCT
1) Other than 
cord blood
Allogeneic-full conditioning
Allogeneic reduced 
conditioning
Sibiling fully matched
Sibiling any mismatch
2) Other than 
cord blood
Other than Autologous
Haploidentical
Allogeneic 
unrelated SCT
Other than cord 
blood
Allogeneic-full conditioning
Allogeneic reduced 
conditioning
Unrelated fully matched
Unrelated any mismatch
Autologous 
SCT
Other than cord 
blood
Autologous
Other than Haploidentical
Cord blood
Cord blood
Other than Autologous
Other than Haploidentical
Others
None of the above
2.5
Analysis of the primary objective
Safety evaluation part (Part 1, Japan only)
The primary objective for the part 1 is to evaluate the safety and tolerability of midostaurin in 
combination with chemotherapy in Japanese patients with newly diagnosed AML.
Randomized part (Part 2)
The primary objective for the part 2 is to evaluate the efficacy based on event-free survival 
(EFS) of midostaurin versus placebo in combination with daunorubicin/cytarabine induction, 
with high-dose cytarabine consolidation, and with midostaurin single agent continuation 
therapy in newly diagnosed patients with FLT3-mutated AML.


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2.5.1
Primary endpoint
Safety evaluation part (Part 1, Japan only)
The primary variable for the part 1 in Japan is the incidence of Safety Events, defined as death 
or serious adverse event leading to treatment discontinuation that occurs on or before Day 21 
of the first consolidation cycle and that is determined by the Independent Safety Committee to 
be definitely or probably related to midostaurin, among evaluable patients.
Randomized part (Part 2)
The primary efficacy variable for the part 2 is event-free survival (EFS), defined as the time 
from the date of randomization until an EFS event is observed. An EFS event is defined as a 
failure to obtain a CR within induction 2, relapse after CR, or death due to any cause, whichever 
occurs first. Patients who do not complete first course of therapy without documented post-
baseline CR should be considered a treatment failure. Clinical response (CR, CRp, PR and 
treatment failure, and relapse after CR) will be assessed via local review according to criteria 
defined in Section 2.7.1. Relevant assessment date collected in the eCRF International Working 
Group (IWG) Response page will be used for the date of clinical response. For patients with 
treatment failure, the EFS will be documented as event at day 1 (refer to Table 2-4).
The final analysis for the part 2 will be based on FAS and will include all data observed up to 
the LPLV. If a patient has not observed EFS event at the LPLV, EFS will be censored at the 
date of the last adequate clinical assessment before the LPLV.
2.5.2
Statistical hypothesis, model, and method of analysis
Safety evaluation part
As the final analysis for the part 1, all adverse events of all patients enrolled in the part 1 will 
be listed.
The Independent Safety Committee will review all available safety data in patients from Japan 
up to the time of the safety review data cut-off date. After determining whether each death or 
serious adverse event leading to treatment discontinuation during the safety evaluation period 
meets criteria for a Safety Event, it will consider this tabulation in combination with the entire 
safety experience in Japanese patients to determine the ongoing conduct of the trial.
Randomized part
The primary efficacy analysis for the part 2 will be the comparison of the distribution of EFS 
between the two treatment arms. The estimated hazard ratio (HR) of EFS not censored at SCT 
will be calculated using Cox regression model stratified according to the 2 stratification factors
(FLT3 mutation status: ITD allelic ratio < 0.7, ITD allelic ratio ≥0.7, TKD; and regimen: 
RATIFY regimen, JALSG regimen) as per IRT (or CRF as this is the same as IRT considering 
a subject with both ITD allelic ratio < 0.7 and TKD as that with ITD allelic ratio < 0.7). In 
addition, associated 95% Wald confidence interval (CI) will be calculated. The success of the 
study will be claimed when estimated HR is less than 1. (Note: The success criteria of the study 
was judged at interim and/or primary analysis and not at this final analysis.)


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The survival distribution of EFS will be estimated using the Kaplan-Meier method. The results 
will be plotted graphically by treatment arm. The median of EFS along with 95% CIs will be 
presented by treatment arm.
2.5.3
Handling of missing values/censoring/discontinuations
In the final analysis for the part 2, EFS will be censored at the date of the last adequate clinical 
assessment if no EFS event is observed prior to the LPLV.
The date of last adequate clinical assessment will be the final timepoint for the evaluation of 
efficacy before an event or a censoring reason occurred. In this case the last clinical assessment 
date at that assessment will be used. If no post-baseline assessment is available and the patient 
is still on treatment at the time of the analysis, then the date of randomization will be used and 
EFS censored.
Refer to Table 2-4 for censoring and event date options and outcomes for EFS.
Table 2-4
Outcome and event/censor dates for EFS analysis
Situation
Date
Outcome
No baseline assessment
Date of randomization
Censored
No post-baseline assessment
Date of randomization
Censored
Treatment failure
Date of randomization + 1
EFS event
Relapse or death at or before 
next scheduled assessment
Date of relapse or death
EFS event
Relapse or death after exactly 
one missing assessment
Date of relapse or death
EFS event
Relapse or death after two or 
more missing assessments
Date of last adequate 
assessment prior to missed 
assessment 
Censored
No relapse or death
Date of last adequate 
assessment 
Censored
Strong CYP3A4 inducer given 
prior to protocol defined 
progression
Date of last adequate 
assessment
Censored
New anticancer therapy given 
prior to protocol defined relapse
Ignore the new anticancer 
therapy and follow situations 
above
As per above situations
2.5.4
Supportive analyses
Sensitivity analyses
The efficacy analysis for EFS will be repeated using the PPS if the number of patients in the 
FAS and PPS differ by more than 10 percent.
Further sensitivity analyses in the FAS will be performed for EFS per local review where:

A sensitivity analysis by using EFS defined as the time from the start of the study 
treatment until an EFS event is observed.


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
A sensitivity analysis considering SCT: patients are considered as censored at the time of 
the transplant if they received SCT.
In addition, the Bayesian posterior probability of (HR for EFS per local review < 1) will be 
calculated as a supportive analysis. Assuming a weakly informative prior distribution derived 
from Study [A2301] data, the distribution of the HR will be updated with all available data from 
the patients included in the FAS (for more detail, refer to [study protocol Section 14.1]).
If 36 EFS events are not documented at the time of final analysis, the Bayesian predictive 
probability of (HR for EFS when 36 EFS events are documented < 1) will be calculated. To 
calculate the predictive probability, assuming a weakly informative prior distribution derived 
from Study [A2301], data and the prior distribution will be updated using the available data 
from patients in the FAS at the time of analysis (for more details of weakly informative prior, 
refer to [study protocol Section 14.1]). 
Subgroup analyses
Subgroup analyses specified in Section 2.2.1 to assess the homogeneity of the treatment effect 
across demographic and baseline disease characteristics will be performed.
For each of the subgroups, the treatment effect will be assessed separately within each category. 
The HR and their 95% CIs will be presented by means of forest plots. Forest plot for EFS will 
be conducted by unstartified analysis for each subgroup because this study is small sample size 
study and it is difficult to conduct stratified analysis for each subgroup.
Censoring pattern of EFS
Number of patients with a EFS event and number of patients censored for the EFS analysis will 
be summarized. In addition, a summary of reasons for EFS censoring will be provided by 
treatment arm based on the following reasons:
1. Ongoing without event
2. Lost to follow-up
3. Withdrew consent
4. Adequate assessment no longer available
5. Event after >= 2 missing efficacy assessments
The EFS censoring reasons are defined in the following way.
If the time interval between the last adequate date of the efficacy assessment and the earliest of 
the following dates is smaller or equal to interval of 2 missing efficacy assessments :
1. Analysis cut-off date  (i.e., LPLV), 
2. Date of consent withdrawal,
3. Visit date of study treatment discontinuation or end of post-treatment follow-up 
discontinuation due to lost to follow-up.
Then the EFS censoring reason will be:
1. ‘Ongoing’, 
2. ‘Withdrew consent’,


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3. ‘Lost to follow-up’.
If the time interval is larger than the interval of 2 missing efficacy assessments with no event 
observed. then the EFS censoring reason will always default to ‘Adequate assessment no longer 
available’. If the time interval between the last adequate efficacy assessment date and the EFS 
event date is larger than the interval of 2 missing efficacy assessments then the patient will be 
censored and the censoring reason will be 'Event documented after two or more missing efficacy 
assessments'.
2.6
Analysis of the key secondary objective
Not applicable.
2.7
Analysis of secondary efficacy objective(s)
The secondary objectives in this study are:

To determine overall survival (OS) in the two treatment groups

To determine the rate of complete remission (CR) in the two treatment groups

To determine the cumulative incidence of relapse (CIR) in the two treatment groups

To evaluate the safety of midostaurin compared to placebo in combination with 
chemotherapy and as single agent continuation therapy

To evaluate the pharmacokinetics of midostaurin and its two major metabolites 
CGP52421 and CGP62221

To determine the effect of the study treatment on quality of life
2.7.1
Secondary endpoints
Overall survival (OS)
OS is defined as the time from the date of randomization to date of death due to any cause. All 
deaths occurring on or before the LPLV in the FAS will be used in the OS analysis. If a patient 
is not known to have died at the time of LPLV, OS will be censored at the date of last contact.
Complete remission (CR) rate
CR rate is defined as the proportion of patients with a CR according to Cheson criteria (Cheson 
2003) as per investigator assessment. CR rate will be calculated using the FAS.
Cumulative incidence of relapse (CIR)
Cumulative incidence of relapse (CIR) is defined for patients who have achieved CR only. CIR 
will be calculated from the date of first CR to relapse or death due to AML, whichever occurs 
first. If a patient is not known to have relapse at the time of LPLV, CIR will be censored at the 


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date of last adequate assessment. If a patient has died due to other reason than AML without 
relapse prior to death, CIR will be censored at the date of the death.
2.7.2
Statistical hypothesis, model, and method of analysis
Overall survival (OS)
The OS distribution not censored at SCT will be estimated using the Kaplan-Meier method, and 
the Kaplan-Meier curves, medians and 95% CIs of the medians will be presented for each 
treatment arm. The HR along with its 95% CI will be calculated, using a stratified Cox model 
using the randomization stratification factors.
As sensitivity analyses performed in the FAS, the hazard ratio and 95% CI for OS will be 
obtained from:

A sensitivity analysis by using OS defined as the time from the start of the study treatment 
until an OS event is observed.

A sensitivity analysis considering SCT: patients are considered as censored at the time of 
the transplant if they received SCT.
Regardless of OS results, subgroup analyses specified in Section 2.2.1 to assess the 
homogeneity of the treatment effect across demographic and baseline disease characteristics 
will be performed. Note: same analysis was conducted for primary CSR with changed from 
planned analysis at the time of primary analysis although original analysis plan was to conduct 
if overall OS HR was less than 1.
For each of the subgroups, the treatment effect will be assessed separately within each category. 
The HR and their 95% CIs will be presented by means of forest plots. Forest plot for OS will 
be conducted by unstartified analysis for each subgroup because this study is small sample size 
study and it is difficult to conduct stratified analysis for each subgroup.
Complete remission (CR) rate
CR rate will be summarized for end of induction cycle 1, end of induction cycle 2, end of 
consolidation, after treatment discontinuation and overall. The difference in CR rates along with 
two-sided 95% CIs.
Cumulative incidence of relapse (CIR)
The survival distribution of CIR distributions will be estimated using the Kaplan-Meier method, 
and Kaplan-Meier curves, medians and 95% CIs (Brookmeyer and Crowley 1982) of the 
medians will be presented for each treatment arm. The HR for CIR will be calculated, along 
with its 95% CI, using a stratified Cox model using the randomization stratification factors.
As a sensitivity analysis, the same analyses when patients are considered as censored at the time 
of the transplant if they received SCT will be performed. 
2.8
Safety analyses
All safety analyses will be based on the safety set.


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2.8.1
Adverse events (AEs)
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs.
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. 
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0. The CTCAE represents a comprehensive grading system for reporting 
the acute and late effects of cancer treatments. CTCAE grading is by definition a 5-point scale 
generally corresponding to mild, moderate, severe, life threatening, and death. This grading 
system inherently places a value on the importance of an event, although there is not necessarily 
proportionality among grades (a grade 2 is not necessarily twice as bad as a grade 1).
AEs will be summarized by number and percentage of subjects having at least one AE in each 
primary system organ class (SOC) and for each preferred term (PT) using MedDRA coding. A 
subject with multiple occurrences of an AE will be counted only once in the respective AE 
category. A subject with multiple CTCAE grades for the same preferred term will be 
summarized under the maximum CTCAE grade recorded for the event. AE with missing 
CTCAE grade will be included in the ‘All grades’ column of the summary tables.
In AE summaries, the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency in the investigational arm
In AE summaries by phase, AEs newly recorded between the start date and the end date of the 
phase will be used, that is, AEs continued from the previous phases and not newly recorded will 
not be included in the summary. If a subject discontinued  study treatment in a specific treatment 
phase, then all AEs observed within 30 days from the study treatment discontinuation in 
addition to those observed during this treatment phase will be considered.
The following AE summaries will be produced by phase and treatment group; 

overview of adverse events and deaths (number and % of subjects with any AE, any AE 
suspected to be related to study treatment, any SAE, any SAE suspected to be related to 
study treatment, any fatal SAE, any fatal SAE suspected to be related to study treatment, 
any AE leading to study drug discontinuation, any AE leading to study drug 
discontinuation suspected to be related to study treatment, any AE leading to dose 
reduction, any AE leading to dose interruption, AEs requiring additional therapy, AEs 
leading to fatal outcome)

AEs, regardless of study treatment relationship, by SOC, PT and maximum CTC grade

AEs, regardless of study treatment relationship, by PT and maximum CTC grade

AEs, regardless of study treatment relationship, by SOC and maximum CTC grade

AEs suspected to be related to study treatment, by SOC, PT and maximum CTC grade

AEs suspected to be related to study treatment, by PT and maximum CTC grade

SAEs, regardless of study treatment relationship, by SOC, PT and maximum CTC grade

SAEs, regardless of study treatment relationship, by PT and maximum CTC grade


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
SAEs suspected to be related to study treatment, by SOC, PT and maximum CTC grade

Non-SAEs, regardless of study treatment relationship, by SOC, PT and maximum CTC 
grade

Non-SAEs suspected to be related to study treatment, by SOC, PT and maximum CTC 
grade
The following AE summaries will be produced by treatment group;

AEs leading to study treatment discontinuation, regardless of study drug relationship, by 
SOC, PT and maximum CTC grade

AEs leading to study treatment discontinuation, regardless of study drug relationship, by 
PT and maximum CTC grade

AEs leading to dose reduction of study treatment, regardless of study drug relationship, by 
SOC, PT and maximum CTC grade

AEs leading to dose interruption of study treatment, regardless of study drug relationship, 
by SOC, PT and maximum CTC grade

AEs requiring additional therapy, regardless of study drug relationship, by SOC, PT and 
maximum CTC grade

AEs leading to fatal outcome, regardless of study drug relationship, by SOC and PT
In addition, a summary of non-SAEs with number of occurrences will be produced (an 
occurrence is defined as >1 day between start and prior end date of record of same preferred 
term) as per EudraCT requirements.
All AEs will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged.
2.8.1.1
Adverse events of special interest / grouping of AEs
Data analysis of AESIs
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. Customized 
SMQs (Novartis MedDRA queries, NMQ) may also be used. A NMQ is a customized group of 
search terms which defines a medical concept for which there is no official SMQ available or 
the available SMQ does not completely fit the need. It may include a combination of single 
terms and/or an existing SMQ, narrow or broad. For each specified AESI, number and 
percentage of patients with at least one event of the AESI occurring during on treatment period 
will be summarized.
Summaries of these AESIs will be provided by treatment arm, (specifying grade, SAE, 
relationship, leading to treatment discontinuation, leading to dose adjustment/interruption, fatal 
outcome, etc.). If sufficient number of events occurred, analysis of time to first occurrence of 
AESI (CTCAE grade ≥3) will be applied. The time to first occurrence of AESI will be censored 
at the date of the last adequate safety assessment if no AESI event (CTCAE grade≥3) is 
observed prior to the LPLV. The date of last adequate safety assessment will be the final 


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timepoint for the safety before a censoring reason is occurred.  If no post-baseline safety 
assessments are available then the date of the start of study treatment will be used.
2.8.2
Deaths
Separate summaries for on-treatment, post-treament and all (including both on-treatment and 
post-treatment) deaths will be produced by treatment arm, SOC and PT.
All deaths will be listed, post treatment deaths will be flagged. A separate listing of deaths prior 
to starting treatment will be provided for all screened subjects.
2.8.3
Laboratory data
CTC grading for Laboratory parameters
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. The calculation of laboratory 
CTC grades will be based on the observed laboratory values only, clinical assessments will not 
be taken into account. The criteria to assign CTC grades are given in Novartis internal criteria 
for CTC grading of laboratory parameters. The latest available version of the document based 
on the underlying CTCAE version 5.0 at the time of analysis will be used.
For laboratory tests where grades are not defined by CTCAE version 5.0, results will be graded 
by the low/normal/high (or other project-specific ranges, if more suitable) classifications based 
on laboratory normal ranges. 
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 is not applicable. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labeled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia. 
Imputation Rules 
CTC grading for blood differentials is based on absolute values. However, this data may not be 
reported as absolute counts but rather as percentage of WBC. 
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X. 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential 

xxx count = (WBC count) * (xxx %value / 100) 
Further derivation of laboratory parameters might be required for CTCAE grading. For instance, 
corrected calcium can be derived using the reported total calcium value and albumin at the same 
assessment using the following formula: 

Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4] 
In order to apply the above formula, albumin values in g/L will be converted to g/dL by 
multiplying by 0.1, calcium values in mmol/L will be converted to mg/dL by dividing by 0.2495. 


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For calculation of laboratory CTC grades 0 and 1, the normal range for derived corrected 
calcium is set to the same limits (in mg/dL) as for calcium. 
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium will be assigned as described above.
Data analysis 
On analyzing laboratory, data from all sources (central and local laboratories (as applicable)) 
will be combined. The summaries will include all assessments available for the lab parameter 
collected no later than 30 days after the last study treatment administration date (see Section 
2.1.1).
All the outputs will be provided overall and by treatment phase (induction, consolidation and 
continuation).
The following summaries will be produced for hematology and biochemistry laboratory data 
(by laboratory parameter and treatment): 

For laboratory tests where grades are defined by CTCAE version 5.0, shift tables using 
CTC grades to compare baseline to the worst on-treatment value 

For laboratory tests where grades are not defined by CTCAE versoin 5.0, shift tables using 
the low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value.
The following listings will be produced for the laboratory data:

Listings of all laboratory data, with CTC grades and classification relative to the 
laboratory normal range. Lab data collected during the post-treatment period will be 
flagged. 

Listing of all CTC grade 3 or 4 laboratory toxicities 
Liver function parameters
Liver function parameters of interest are total bilirubin (TBL), ALT, AST and alkaline 
phosphatase (ALP). 
The number (%) of patients with worst post-baseline values will be summarized:

ALT or AST > 3xULN 

ALT or AST > 10xULN

TBL > 2xULN

TBL > 3xULN

ALT or AST > 3xULN & TBL > 2xULN

ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN (potential Hy’s law)
Hematological toxicities and recovery
The following summary tables will be provided by cycle during induction and consolidation:

Number and percentage of patients having at least one thrombocytopenia, and among 
them the duration of thrombocytopenia and the time between chemotherapy (cytarabine or 
daunorubicin) start and non-transfused recovery from thrombocytopenia (see definitions in 


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Section 2.1.1).

Number and percentage of patients having at least one neutropenia, and among them the 
duration of neutropenia and the time between chemotherapy (cytarabine or daunorubicin) 
start and recovery from neutropenia (see definitions in Section 2.1.1).

Number and percentage of patients requiring platelet transfusion.

Number and percentage of patients requiring red blood cell transfusion.
All blood component transfusion data will be listed.
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
Data handling
The average of the ECG parameters at that assessment should be used in the analyses.
Data analysis
The number and percentage of subjects with notable ECG values collected during the on-
treatment period will be presented by treatment arm. 

QT,  QTcF

New value of > 450 and ≤ 480 ms

New value of > 480 and ≤ 500 ms

New value of > 500 ms

Increase from Baseline of > 30 ms to ≤  60ms

Increase from Baseline of > 60 ms

HR

Increase from baseline >25% and to a value > 100 bpm

Decrease from baseline >25% and to a value < 50 bpm

PR

Increase from baseline >25% and  to a value > 200 ms

New value of > 200 ms

QRS

Increase from baseline >25% and  to a value > 120 ms

New values of QRS > 120 ms
A listing of all ECG assessments will be produced by treatment arm and notable values will be 
flagged. In the listing, the assessments collected during the post-treatment period will be flagged.
Summaries of grouped AEs (‘QT prolongation’) defined in eCRS will be provided by phase 
and treatment separately for all AEs, AEs suspectred to be related to study treatment and SAEs, 
and by treatment for AEs leading to study treatment discontinuation.


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2.8.4.2
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: height (cm), weight (kg), body temperature (°C), pulse 
rate (beats per minute), systolic and diastolic blood pressure (mmHg).
Data handling
Vital signs collected during on-treatment period will be summarized. Values measured outside 
of on treatment period will be flagged in the listings.
Data analysis
For analysis of vital signs the clinically notable vital sign criteria are provided in Table 2-5
below.
Table 2-5
Clinically notable changes in vital signs
Vital sign (unit)
Clinically notable criteria
above normal value 
below normal value
Weight (kg)
increase >= 10% from Baseline
decrease >= 10% from Baseline
Systolic blood 
pressure (mmHg)
>=180 and increase from baseline 
of >=20
<=90 and decrease from baseline 
of >=20
Diastolic blood 
pressure (mmHg)
>=105 and increase from baseline 
of >=15
<=50 and decrease from baseline 
of >=15
Pulse rate (bpm)
>=100 and increase from baseline 
of >25%
<=50 and decrease from baseline of 
> 25%
Body temperature
>= 39.1 
-
The number and percentage of subjects with notable vital sign values (high/low) will be 
presented by treatment arm.
A listing of all vital sign assessments will be produced by treatment arm and notable values will 
be flagged. A separate listing of only the subjects with notable vital sign values will also be 
produced.
2.9
Pharmacokinetic endpoints
Exposure to the sum of active moieties
A further exposure variable will be derived 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 (PKC412) 
and the two active metabolites (CGP52421 and CGP62221) scaled based on their relative 
potencies, and parent to metabolite molecular weight ratio as shown below:
PKC412+ CGP52421* (0.06)*
	

	
+ CGP62221*(1.4)*
	

	
Where mwt is the molecular weight of each analyte is: PKC412=570.65, CGP52421=587.23, 
CGP62221=556.63.


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The potencies of the active metabolites are different across indications. 
PK parameters
PK parameters for midostaurin and its two major metabolites CGP52421, CGP62221 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 2-6 will be estimated and reported, when feasible. 
AUClast, AUC0-t and Cmax are defined as primary parameters (contributing to PAS definition). 
All others are secondary and will be determined if feasible (including CL/F).
Table 2-6
Non-compartmental PK parameters
AUC0-t
The area under the curve (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)
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 2-6 except Tmax, where only n, median, 
minimum and maximum will be presented.
All individual PK parameters will be listed using the PAS-all.
Concentrations for full PK profile
Descriptive statistics (n, m (number of non-zero concentrations), arithmetic mean, CV% mean, 
SD, median, geometric mean, CV% geo-mean, minimum and maximum) for concentrations of 
midostaurin, its active metabolites (CGP52421, CGP62221), and the exposure to the sum of 
active moieties, will be presented at each scheduled time point on C1D8 for the PAS-full. PK 
parameters will also be summarized by analyte.Individual concentration-time profiles for 
midostaurin, its active metabolites, and the exposure to the sum of active moieties,
concentrations on C1D8 with median will be displayed graphically for PAS-all on the semi-log 
view. In addition, the mean (+/- SD) and geometric mean concentration-time profiles for 
midostaurin, its active metabolites, and the exposure to the sum of active moieties, on C1D8 
will be displayed graphically for PAS-full on the linear and semi-log view.
All individual plasma midostaurin, its active metabolites, and the exposure to the sum of active 
moieties  concentration data will be listed for the PAS-all.


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Concentrations after multiple dosing
Descriptive statistics (n, m (number of non-zero concentrations), mean, CV% mean, SD,
median, geometric mean, CV% geo-mean, minimum and maximum) for midostaurin. its active 
metabolites, and the exposure to the sum of active moieties, concentration will be presented at 
each scheduled time point (post-dose or pre-dose) by treatment part for the PAS-all.
The mean (+/- SD) and geometric mean trough concentration-time profiles for midostaurin, its 
active metabolites, and the exposure to the sum of active moieties, over time will be displayed 
graphically by treatment part for PAS-all on the linear view.
All individual plasma midostaurin, its active metabolites, and the exposure to the sum of active 
moieties, concentration data will be listed for the PAS-all.
Handling of PK data below LLOQ or missing
All concentration values below the lower limit of quantitation (LLOQ) (<10.0 ng/mL) are set 
to zero by the Bioanalyst, and will be displayed in the listings as zero and flagged. LLOQ values 
will be treated as zero in any calculations of summary statistics, and treated as missing for the 
calculation of the geometric means and their CV%. The number of non-zero concentrations will 
also be reported in the summary statistics.
Missing values for any PK data will not be imputed and will be treated as missing.
2.10
PD and PK/PD analyses
Special population
The association of trough concentrations of midostaurin, its active metabolites, and the 
exposure to the sum of active moieties on C1D21 of Induction therapy, and FLT3 status will be 
investigated using a Wilcoxon test.
Analysis of relationship between PKC412 exposure and efficacy/safety
endpoints.
All exposure-response analyses will be conducted on parent midostaurin, its active metabolites, 
and the exposure to the sum of active moieties. PAS-all will be used however Part 1 patients 
will be excluded for efficacy related analyses.
EFS will be analysed using a Cox regression model with log-transformed concentration on 
C1D21 as covariate. Hazard ratios will be provided for a 2-fold decrease in exposure, along 
with 95% CI.
OS will be analysed using a Cox regression model with log-transformed concentration on 
C1D21 as covariate.
The occurrence of CR in cycle 1 or 2 of induction therapy will be modelled against log-
transformed Cmin (continuous and categorical) of midostaurin and metabolites on C1D21 
through a logistic regression model. Furthermore, the CR rate for the median observed Cmin 
C1D21 along with 95% CI, will be produced. Further the point estimate of the odds ratio of 
response for a 2-fold decrease in exposure, and corresponding 95% CI will also be produced.


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AESIs suspected to be study drug related will be analysed with the last observed trough 
concentration collected prior to AE onset (log-transformed), with a logistic regression model. 
Probability of an AESI will be estimated along with 95% CI for the median concentration used 
in the analysis. Further point estimates of the difference in probability of response for a 2-fold 
increase in exposure, and corresponding 95% CI will also be produced. Time to onset of AESI 
will also be investigated with a Cox regression model, and HRs related to a 2-fold increase in 
exposure with corresponding 95% CIs will be produced.
AEs leading to discontinuation will also be analysed with log-transformed concentration (last 
observed trough concentration prior to AE onset) as for AESIs. PK/PD analyses related to AESI 
may not be performed if the number of AESI events are limited such as less than 10 events.
A linear mixed effects model will be used to fit the change from baseline in QTcF as a response 
variable, with time-matched concentration (of midostaurin and both metabolites), baseline 
parameter and relevant covariates (identified through backwards selection) fitted as fixed 
effects. 
Time-matched QTcF assessments and concentrations are defined as both non-missing and non-
zero concentrations. Assessments are taken within a 30 minute window of eachother. When 
there are multiple matching concentrations within a 30 minute window of the ECG assessment 
(or vice versa), the closest time match should be selected. When there is more than one closest 
match (before and after), then the PK sample should be after the ECG assessment.
Only observations where the ECG machine was synchronized will be considered. Subject ID 
will be fitted as a random effect. The change from baseline will be estimated (with 95% CI) for 
the median observed Peak Cmin at the therapeutic dose (50mg bid), the median of the observed 
values for each continuous covariate, and the level of the factor with higher observed frequency.  
2.11
Patient-reported outcomes
The global health status/QoL score of the QLQ-C30 and PGIC score are identified as the 
primary PRO variables of interest. Physical functioning, emotional functioning and social 
functioning scale scores of the QLQ-C30 are identified as secondary PRO variables of interest. 
The FAS will be used for analyzing PRO data. Scoring of PRO data and methods for handling 
of missing items or missing assessments will be handled according to the scoring manual (see 
[study protocol Appendix 5]). No imputation procedures will be applied for missing items or 
missing assessments.
Descriptive statistics will be used to summarize the QLQ-C30 scores and absolute change from 
baseline scored scales by each scheduled timepoint and treament arm.
Between-treatment differences for the change in QLQ-C30 scores will be evaluated using a 
mixed effect repeated measures model. Treatment group, stratification factors (FLT3 mutation 
status and chemotherapy regimen), time of visit (in weeks counting from the time of 
randomization to the time of a particular post baseline measurement in time windows), 
treatment by time of visit interaction, and baseline score. An unstructured covariance structure 
will be assumed for the  model. The differences in least square means between treatment and 
control group, and the corresponding 95% CI at selected timepoints will be presented.


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The PGIC score will be presented as frequencies and percentages by scheduled timepoint and 
treatment arm.
2.12
Biomarkers
All 
 analyses other than baseline FLT3 mutational status and ELN 2017
AML risk classification will be reported in separate biomarker report with separate (stand-alone) 
analysis plan. 
As a project standard, Novartis will analyze only biomarkers collected in the clinical database.
 
 
 
There may be circumstances whena decision is made to stop sample collection, or not 
perform or discontinue their analysis due to either practical or strategic reasons (e.g. issued 
related to the quality and/or quantity of the samples or issues related to the assay). Under such 
circumstances, the number of samples may be inadequate to perform a rigorous data analysis 
and the available data will only be listed and potentially summarized.
Additional analyses that may be performed after the completion of the end-of-study CSR will 
be documented in separate reports. These analyses may include but are not limited to the 
analysis of biomarkers generated from samples collected during the study but analyzed after the 
database lock and completion of the CSR. The data analysis will be described in an addendum
of the SAP or in a stand-alone analysis plan document, as appropriate.
2.12.1
Biomarker analysis dataset
The FAS will be used for all biomarker analysis. Unless otherwise specified, all statistical 
analyses of biomarker data will be performed on patients with biomarker data.
The distribution of baseline clinical covariates in treatment arms, the demographic and disease 
characteristics of subjects with available biomarker data may be compared to those of the FAS.  
 
2.12.3
List of biomarkers evaluated and the collection time points
The biomarkers evaluated in the study are listed in Table 2-7 below.


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Table 2-7
Sample biomarker summary table
Biomarker
Time point
Sample
Method
FLT3 mutation
Screening visit 
(eligibility) 
Bone Marrow Aspirate
or 
Peripheral Blood
PCR-CE
2.12.4
General Data Handling and preprocessing
Data preprocessing and transformations are described in detail in the Programming Dataset 
Specification.
The screening assessment (pre-dose) will be used as the baseline value.
When more than one biomarker data value are available for a subject at any time point, the 
mean of the replicate values will be used for all statistical analyses.
Percent change is calculated as ((visit i – baseline) / baseline) * 100. To compute the average 
percent change from baseline is to compute the average expression level at each time point and 
then compute the percent change using the average values. Fold change is calculated as the ratio 
of biomarker value at ((visit i) / (Baseline biomarker value)). The number of subjects for the 
average of percent change from baseline might vary due to potential missing values at 
respective time points. 
2.12.5
Data analysis
2.12.5.1 FLT3 Mutation
FLT3 mutation will be identified by analysizing FLT3 gene for either  an internal tandem 
duplication mutation (ITD) or a point mutation in the activating loop of the tyrosine kinase 
domain (TKD) at baseline. FLT3-ITD mutation will be stratified at ITD allelic ratio <0.7, ITD 
allelic ratio ≥0.7. 


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2.14
Interim analysis
For part 2, an interim analysis for efficacy will be conducted when 60 patients are randomized 
and at least 24 EFS events are documented (expected around 14 months from the date of first 
patient randomized in the study assuming the recruitment period as 14 months). In case that 36 
EFS events are documented before randomization completion, the interim analysis can be 
skipped and Novartis will conduct primary analysis. 
At the interim analysis, the study will be considered as a positive result when the following both 
success criteria are met:

Criterion 1: estimated HR at interim analysis < 1. 

Criterion 2: the Bayesian predictive probability of (HR for EFS when 36 EFS events are 
documented < 1) given data up to the data cut off for interim analysis > 0.9. To calculate 
the predictive probability, assuming a weakly informative prior distribution derived from 
Study [A2301] data and the prior distribution will be updated using the available data 
from patients in the FAS at interim analysis (for more detail of weakly informative prior, 
refer to [study protocol Section 14.1]). 
This interim analysis will be assessed by a DMC, however, even if interim success criteria are 
met, the study will be continuing blinded to patients, investigators and monitors until the 
primary analysis and thereafter unblinded. At the final analysis more mature data can be 
evaluated.
The interim analysis will be performed by an independent statistician and an independent 
programmer who provides the results to the DMC. The DMC will then be assessing the success 
criteria. Further details will be described in the DMC charter.
If Health Authorities require to submit the study results after interim analysis but before primary 
analysis, additional analysis may be performed.
The primary analysis will be performed using the pre-defined cut-off date of 30 November 2020
with the number of EFS events documented by this date. The end of study will occur at the 
latest 36 months after the start of the study treatment for the last patient. At this time, the final 
analysis will be performed.
For all of interim, primary and final analyses, the type I error alpha will not be considered 
because this study will pursue an estimation approach rather than formal hypothesis testing in 
which the criteria for success is based on the probability of HR< 1 in favor of midostaurin.
ISC will review all available safety data in the part 1 to evaluate whether the trial may advance 
to the part 2 in Japan. The analyses may be performed by a trial statistician internal to Novartis
and their results will be provided to the Independent Safety Committee, when the available data 
is adequate to perform a data analysis. Details will be described in a separate SAP for the safety 
review.


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3
Sample size calculation
3.1
Primary analysis
Safety evaluation part (in Japan only)
A minimum of 3 (if no Safety Events) or 6 evaluable Japanese patients will be required to 
confirm the tolerability of midostaurin in combination with standard chemotherapy in the safety 
evaluation period. No formal statistical power calculations to determine sample size were 
performed for this study.
Randomization part
This is a bridging study that will support the registration of midostaurin including in Japan. This 
study will pursue an estimation approach rather than formal hypothesis testing in which the 
criterion for success is based on the probability of HR< 1 in favor of midostaurin.
As per the initial protocol design (i.e. pre-Amendment 3), the required sample size for the part 
2 of the study was determined based on the empirical probability to meet the success criterion. 
It was assumed that EFS for midostaurin and placebo in A2220 would follow the same survival 
distributions as observed in study A2301. Consequently all factors which might affect the EFS 
prolongation e.g., SCT rate in CR1 were also assumed to be the same as in Study A2301. It was 
also assumed that there was no difference between the two chemotherapy regimens (RATIFY 
regimen and JALSG regimen).
In order to calculate the probability to meet the success criterion, a simulation study was 
performed using actual EFS data from Study A2301. To simulate a study, 30 patient 
observations were randomly selected from each treatment arm of Study A2301 and 30000 
studies were simulated. The, median EFS and HR for EFS were calculated for each study. The 
median EFS in the control arm averaged 5.4 months and in the midostaurin arm 10.3 months. 
The average hazard ratio was 0.77 (corresponding to a 23% reduction in the hazard rate for 
EFS), which was similar to estimated HR in Study A2301 of 0.728.
In addition to the above assumptions, assuming that enrollment will continue for approximately 
15 months at a uniform rate of 4 patients a month and the primary analysis will occur when 36 
EFS events are documented (expected 21 (95%CI: [14.4, 34.2]) months from date of first patient 
to be randomized), 60 patients will need to be randomized to the two treatment arms in 1:1 ratio 
to meet the success criterion with a probability of 84.1%.
In addition to the above simulation, another simulation was performed to calculate the 
probability of success at interim analysis. When the enrollment period will be 14 months 
considering the currently expected enrollment rate, the probability to meet success criteria at 
interim analysis (described in [study protocol Section 2.14]) is 78.1% and the time from first 
patient to be randomized to the interim analysis is expected to be 14.1 (2.5 - 97.5 percentile: 
[14.0 – 15.4]) months based on same survival distribution as in Study [A2301]. In addition, the 
conditional probability to meet the success criterion of primary analysis under showing positive 
result at interim analysis is 96.8%.  For more details, please refer to [study protocol Section 
14.1].


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Based on the overall observed EFS events over time, the rate of discontinuations without EFS 
event and the predictions of future events, there is a risk that the targeted 36 EFS events will 
not be observed within a reasonable timeframe. Therefore the primary analysis will be 
performed using the pre-defined cut-off date of 30 November 2020 with the number of EFS 
events documented by this date. 
As per the current number of patients who are still on follow-up for EFS and the survival 
distributions of EFS post-induction observed in study [A2301], additional 5 EFS events are 
expected to be observed until 30 November 2020. The study power would be approximately 
82.7% when total 33 EFS events are observed under the original assumptions shown above (that 
is, EFS for midostaurin and placebo in A2220 would follow the same survival distributions as 
observed in study [A2301], consequently all factors which might affect the EFS prolongation 
e.g. SCT rate in CR1 were the same as in Study [A2301], and there was no difference between 
the two chemotherapy regimens).
3.2
Power for analysis of key secondary variables
Not applicable.
4
Change to protocol specified analyses
In section 2.11 (patient-reported outcomes), the primary PRO variables of interst of QLQ-C30 
was changed from total score to the global health status/QoL score to revise to the correct 
variable.
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
The following rule should be used for the imputation of the dose end date for a given study 
treatment component:
Scenario 1: If the dose end date is completely missing and there is no EOT page and no death 
date, the patient is considered as on-going:
The patient should be treated as on-going and the cut-off date should be used as the dose end 
date. 
Scenario 2: If the dose end date is completely or partially missing and the EOT page is available:
Case 1: The dose end date is completely missing, and the EOT  completion date is complete, 
then this latter date should be used.
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:
Use Dec31yyyy


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Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date:
Use EOT date
Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy  = the year 
of EOT date and mm < the month of EOT date:
Use last day of the Month (mm)
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study.
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment:
Use the treatment start date
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date should 
not be imputed.AE, ConMeds and safety assessment date imputation
Table 5-1
Imputation of start dates (AE, CM) and assessments (LB, EG, VS)
Missing 
Element
Rule
day, month, 
and year
No imputation will be done for completely missing dates
day, month
If available year = year of study treatment start date then 
If stop date contains a full date and stop date is earlier than study treatment start 
date then set start date = 01JanYYYY 
Else set start date = study treatment start date. 
If available year > year of study treatment start date then 01JanYYYY
If available year < year of study treatment start date then 01JulYYYY
Day
If available month and year = month and year of study treatment start date then 
If stop date contains a full date and stop date is earlier than study treatment start 
date then set start date= 01MONYYYY. 
Else set start date = study treatment start date.
If available month and year > month and year of study treatment start date then 
01MONYYYY
If available month and year < month year of study treatment start date then 
15MONYYYY
Table 5-2
Imputation of end dates (AE, CM) 
Missing 
Element
Rule 
(*=last treatment date plus 30 days not > (death date, cut-off date, withdrawl of 
consent date))
day, month, 
and year
Completely missing end dates (incl. ongoing events) will be imputed by the end 
date of the on-treatment period* 
day, month
If partial end date contains year only, set end date = earliest of 31DecYYYY or 
end date of the on-treatment period * 


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Missing 
Element
Rule 
(*=last treatment date plus 30 days not > (death date, cut-off date, withdrawl of 
consent date))
day
If partial end date contains month and year, set end date = earliest of last day of 
the month or end date of the on-treatment period*
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings.
Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘ongoing’ 
rather than the end date provided. 
5.1.1.1
Other imputations
Incomplete date of initial diagnosis of cancer and  date of most recent 
recurrence 
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 01-
Jan.
Incomplete assessment dates for efficacy assessment
If the date of assessment collected in the eCRF IWG Response page is incomplete but other 
relevant investigation dates (e.g., bone marrow aspirate, peripheral blood counts) are available, 
assessment date is calculated as the latest of all investigation dates (e.g., bone marrow aspirate, 
peripheral blood counts) if the overall response at that assessment is CR/CRp/PR (see [study 
protocol Section 7.2.1]). Otherwise – if overall response is treatment failure/relapse – the 
assessment date is calculated as the earliest date of all investigation dates at that evaluation. If 
all measurement dates have no day recorded, the 1st of the month is used. If the month is not 
completed, for any of the investigations, the respective assessment will be considered to be at 
the date which is exactly between previous and following assessment. If a previous and 
following assessment is not available, this assessment will not be used for any calculation.
Applying the cut-off to efficacy assessment
For efficacy related assessments, if an evaluation has some assessments done prior to cut-off 
date and others after the cut-off date, then the evaluation is considered post-cut-off date and 
will be excluded from analysis.
5.2
AEs coding/grading
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0. 
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. This grading system inherently places a 
value on the importance of an event, although there is not necessarily proportionality among 
grades (a grade 2 is not necessarily twice as bad as a grade 1).


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5.3
Laboratory parameters derivations
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (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. The criteria to assign CTCAE grades are given in Novartis internal criteria 
for CTCAE grading of laboratory parameters. The latest available version of the document 
based on the underlying CTCAE version 5.0 at the time of analysis will be used. For laboratory 
tests where grades are not defined by CTCAE version 5.0, results will be graded by the 
low/normal/high (or other project-specific ranges, if more suitable) classifications based on 
laboratory normal ranges.
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 will not be used. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labelled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia.
Imputation Rules
CTC grading for blood differentials is based on absolute values. However, this data may not be 
reported as absolute counts but rather as percentage of WBC.
If laboratory values are provided as ‘<X’ (i.e., below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X.
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential
xxx count = (WBC count) * (xxx %value / 100)
Further derivation of laboratory parameters might be required for CTCAE grading. For 
instance, corrected calcium can be derived using the reported total calcium value and albumin 
at the same assessment using the following formula:
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4]
In order to apply the above formula, albumin values in g/L will be converted to g/dL by  
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium.
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium will be assigned as described above for grading
5.4
Statistical models
5.4.1
Analysis of time-to-event data
Hazard ratio
Hazard ratio will be estimated by fitting the Cox proportional hazards model using SAS 
procedure PHREG (with TIES=EXACT option in the MODEL statement). 


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A stratified unadjusted Cox model will be, i.e. the MODEL statement will include the treatment
group variable as the only covariate and the STRATA statement will include stratification
variable(s).
Hazard ratio with two-sided 95% confidence interval will be based on Wald test.
Kaplan-Meier estimates
An estimate of the survival function in each treatment group will be constructed using Kaplan-
Meier (product-limit) method as implemented in PROC LIFETEST with METHOD=KM
option. The PROC LIFETEST statement will use the option CONFTYPE=LOGLOG.
Median survival for each treatment group will be obtained along with 95% confidence intervals
calculated from PROC LIFETEST output using the method of Brookmeyer and Crowley 
1982. Kaplan-Meier estimates of the survival function with 95% confidence intervals at
specific time points will be summarized. The standard error of the Kaplan-Meier estimate
will be calculated using Greenwood’s formula Collett 1994.
Treatment of ties
The STRATA statement in LIFETEST procedure will be used to analyze time to event data 
with ties. The PHREG procedure in SAS with option TIES=EXACT will be used to fit the Cox 
proportional hazards model.
5.4.2
Analysis of Binary Data
Confidence interval for response rate
Responses will be summarized in terms of percentage rates with 100(1 −α)% confidence 
interval using exact binomial confidence interval (implemented using SAS procedure FREQ
with EXACT statement for one-way table Clopper and Pearson 1934.
5.4.3
ELN 2017 risk stratification categories
Sub-classification of AML subjects will be categorized by using the ELN 2017 risk 
stratification categories Döhner 2017.
Table 5-3
ELN 2017 risk stratification categoriesa
Risk Categoryb
Genetic Abnormality
Favorable
t(8;21)(q22;q22.1); RUNX1-RUNX1T1
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow(c)
Biallelic mutated CEBPA
Intermediate
Mutated NPM1 and FLT3-ITDhigh(c)
Wild type NPM1 without FLT3-ITD or with FLT3-ITDlow(c) (w/o adverse- risk 
genetic lesions)
t(9;11)(p21.3;q23.3); MLLT3-KMT2Ad
Cytogenetic abnormalities not classified as favorable or adverse
Adverse
t(6;9)(p23;q34.1); DEK-NUP214


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Risk Categoryb
Genetic Abnormality
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 karyotypee, monosomal karyotypef
Wild type NPM1 and FLT3-ITDhigh(c)
Mutated RUNX1g
Mutated ASXL1g
Mutated TP53h
a. Frequencies, response rates and outcome measures should be reported by risk category, and, if 
sufficient numbers are available, by specific genetic lesions indicated.
b. Prognostic impact of a marker is treatment-dependent and may change with new therapies.
c. Low, low allelic ratio (<0.5); high, high allelic ratio (>0.5); semi-quantitative assessment of FLT3-
ITD allelic ratio (using DNA fragment analysis) is determined as ratio of the area under the curve 
(AUC) “FLT3-ITD” divided by AUC “FLT3-wild type”; recent studies indicate that acute myeloid 
leukemia with NPM1 mutation and FLT3-ITD low allelic ratio may also have a more favorable 
prognosis and patients should not routinely be assigned to allogeneic hematopoietic-cell 
transplantation.
d. The presence of t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent adverse-risk gene 
mutations.
e. Three or more unrelated chromosome abnormalities in the absence of one of the World Health 
Organization-designated recurring translocations or inversions, i.e., t(8;21), inv(16) or t(16;16), 
t(9;11), t(v;11)(v;q23.3), t(6;9), inv(3) or t(3;3); AML with BCR-ABL1.
f. Defined by the presence of one single monosomy (excluding loss of X or Y) in association with at 
least one additional monosomy or structural chromosome abnormality (excluding core-binding factor 
AML).
g. These markers should not be used as an adverse prognostic marker if they co-occur with 
favorable-risk AML subtypes.
h. TP53 mutations are significantly associated with AML with complex and monosomal karyotype.
6
Reference
1. Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival 
Time. Biometrics, 38, 29 - 41.
2. Cheson BD, Bennett JM, Kopecky KJ, et al (2003). Revised Recommendations of the 
International Working Group for Diagnosis, Standardization of Response Criteria, 
Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid 
Leukemia. J Clin Oncol; 21:4642-9.
3. Clopper CJ and Pearson ES (1934). The use of confidence or fiducial limits illustrated in 
the case of the binomial.  Biometrical, 26, 404-413.
4. Collett D (1994). Modelling survival data in medical research. London, Chapman & Hall.
5. Döhner H, Estey E, Grimwade D, et al (2017) Diagnosis and management of AML in 
adults: 2017 ELN recommendations from an international expert panel. Blood;129(4):424-
447.